HX641 29950 RC648 ,C88 1918 Thyroid and thymus, RECAP T?C64fl O -r- Columbia (Hntoettfitp mtljeCttpofiJlrttigark College of ^fjpstriantf ano burgeons Hibvavp THYROID AND THYMUS BY ANDRE CROTTI, M.D., F.A.C.S., LL.D. FORMERLY PROFESSOR OF CLINICAL SURGERY AND ASSOCIATE PROFESSOR OF ANATOMY AT OHIO STATE UNIVERSITY COLLEGE OF MEDICINE; MEMBER OF THE AMERICAN MEDICAL ASSOCIATION, OHIO STATE MEDICAL ASSOCIATION, COLUMBUS ACADEMY OF MEDICINE, AMERICAN ASSOCIATION OF OBSTETRICIANS AND GYNECOLOGISTS, SOCIETY FOR THE STUDY OF INTERNAL SECRETIONS, HONORARY MEMBER OF THE WEST VIRGINIA STATE MEDICAL SOCIETY, SURGEON TO GRANT AND CHILDREN'S HOSPITALS, COLUMBUS, OHIO WITH 96 ILLUSTRATIONS AND 33 PLATES IN COLORS LEA & FEBIGER I'll I LA DEL I'll I A A.N I) N IW Y<> K K Copyright LEA & FEBIGER 1918 TO THE ONES TO WHOM I OWE THE MOST TO MY MOTHER TO MY WIFE TO MY LATE CHIEF AND FRIEND PROFESSOR HENRY STILLING PROFESSOR OF PATHOLOGY IN THE UNIVERSITY OF LAUSANNE, SWITZERLAND TO MY LATE CHIEF PROFESSOR THEODORE KOCHER BERNE, SWITZERLAND THE FATHER OF GOITER SURGERY Digitized by the Internet Archive in 2010 with funding from Open Knowledge Commons http://www.archive.org/details/thyroidthymusOOcrot PREFACE. The following pages are the results of seventeen years' experience in the field of goiter pathology and surgery in Switzerland and in this country. When first assistant in the pathological laboratory of Prof. Henry Stilling, in Lausanne, Switzerland, I felt a marked attrac- tion toward the goiter problem. Since then that interest has been steadily growing keener. It is not only of the utmost interest medi- cally and surgically, but is also one of the most baffling problems so far as the etiology is concerned, and, furthermore, is of tremendous impor- tance sociologically. The enormous loss to a community, to a state, to a country caused by the goiter pathology, be it hypothyroidism, hyperthyroidism, or cretinism, can scarcely be estimated. Consequently any effort to understand, to explain, or to combat that ailment should be welcome. It was with this end in view that I started to write this book. Some may find my statements somewhat dogmatic at times, and my conclusions perhaps a little sanguine. I feel, however, that in the study of the problems of internal secretion, always tantalizing and interesting, accessibility to ideas is the one prerequisite to success for those who wish to gain achievement in the study, and so long as we have not acquired the whole truth, opinions are of value provided the) are substantiated by facts. In addition to the years of personal experience in the study of the thyroid and thymus glands, I have gathered all that I considered of value from the enormous amount of French, Italian, German, and English literature on the subject, and I have endeavored, in my recital of sources and authorities, to give credit where credit is due. It is my pleasant duty to express my profound gratitude and respect to the memory of my master, Henry Stilling, Professor ol Pathology at the University of Lausanne, Switzerland. I <> him I owe much encouragement and self-confidence. 1 have hoped that my great master. Professor Theodore Kocher, of Berne, Switzerland, would live to see this work in which he was greatly interested. Unfortunately, it was not to be. I owe so much to his inspiration and example that his memory will always be cherished by me. vi PREFACE It is with pleasure and pride that I acknowledge the invaluable assistance of my dear wife in writing the chapter on the Etiology of Simple Goiter. I wish to thank, also, Marcel Guelin, who formerly lived in Moscow, Russia, but is now "somewhere in Siberia.'' His anatomical drawings are the most beautiful and artistic I have ever seen. The difficulty of getting these plates to America (several sets were lost on the way) was a bit of exasperation that was an expected, though unwelcome, outcome of the disturbed conditions due to the Great War. If the work merits success, my friend Guelin must be entitled to a share of the credit. To J. Philip Schneider, Ph.D., Professor of English, Wittenberg College, Springfield, Ohio, and to his wife, Clara Serviss Schneider, go hearty thanks for help in proof-reading, in seeing the work through the press, and for the index. Finally, I wish to acknowledge the assistance I have received from my secretary, Miss Mary Scully, whose untiring efforts have been of great value. To those of my masters who are still alive to receive this contri- bution, I send greetings and offer heartfelt thanks for encouragement and inspiration. May they feel that what of ambition was aroused by their efforts was not aroused in vain. I cannot close the chapter of my debts without mentioning Dr. J. F. Baldwin, surgeon at Grant Hospital, Columbus, Ohio, and without thanking him heartily for his cordial support and encouragement. A. C. Columbus, Ohio. CONTENTS. CHAPTER I. Diseases of the Thyroid and Thymus. Anatomy 17 Blood Supply 19 Lymphatics . 20 Histology 21 Colloid 22 Desquamation 23 Embryology . 23 Postbranchial Bodies 27 1 umors of Mesobranchial Origin 28 Tumors of Branchial Origin 28 CHAPTER II. Physiology of the Thyroid. History 30 Results of Experimental I hyroidectomy ... 31 I hyroid and Parathyroids 32 Postoperative letany in Animals ;: Action of Thyroid Administration and Thyroidectomy on Metabolism ... 36 Action of the Thyroid on the Cardiovascular System }J Action on the Blood 38 Action on the Nutrition 39 Action on the Osseous System 40 Action on the Nervous System 40 Modification of the Urine 40 How Much of the 1 hyroid is it Necessary to Leave in Order to Prevenl Symptoms of Thyroid Insufficiency? 41 CHAPTER III. BlOLOGK \l. Cm MISTRY. Iodm in Thyroid (Hand 44 Conclusions Conc< rning the I hyroid Function and Its Chemistr} =;i Functional Interrelation of the Organs of Internal Secretion 55 viii CONTENTS CHAPTER IV. Pathology. Benign Tumors 60 Parenchymatous Goiters 60 Colloid Goiter 61 Fetal Adenoma 64 Malignant Tumors 65 Epithelial Tumors 67 Malignant Adenoma or Proliferating Goiter 67 Carcinoma 70 Metastatic Colloid Goiter 70 Parastruma or Glycogen-containing Goiter 72 Postbranchial Goiter 73 Papilloma 74 Cancroid 76 Tumors of Connective-tissue Origin 77 Fibrosarcoma 77 Polymorphous-cell Sarcoma 78 Round-cell Sarcoma 78 Myxosarcoma 79 Endothelioma 79 Perithelioma 80 Combination of Various Forms of Malignant Goiter 80 Mixed Tumors 80 Dermoids and Teratoma 81 Accessory Goiters 82 Median Cysts 83 Lingual Goiter 85 Intrathoracic Accessory Goiter .... 86 Ovarian Goiter 87 CHAPTER V. Inflammations of the Thyroid. History 89 Bacterial Thyroiditis 90 Etiology 93 Pathology 95 Symptoms 95 Diagnosis 98 Prognosis 101 Treatment 102 Toxic Thyroiditis 103 Tuberculosis of the Thyroid 106 Follicular 106 Caseous 106 COXTEXTS ix Syphilis of the Thyroid 108 Woody Thyroiditis^ 109 Parasitic Thyroiditis ill Hydatid Cyst of the Thyroid 113 Congestions of the Thyroid .114 Pathological Anatomy 115 Symptoms 115 Treatment 115 1 raumatic Lesions of the Thyroid 115 Contusions 116 Wounds 116 Treatment 117 CHAPTER VI. Anatomopathological Relations of Goiter to the Surrounding Structures. Relation of Goiter to Skin and Muscles 119 Relation of Goiter to the Larynx and Trachea 120 Relation of Goiter to the Pharynx and Esophagus 123 Relation of Nodular Goiter to Bloodvessels 124 Relation of Goiter to Nerves 125 CHAPTER VII. Clinical Symptoms and Diagnosis. Clinical Symptoms 126 Mechanical Symptoms .126 Dyspnea 126 Dysphagia 127 Symptoms Due to Injun' of the Inferior Laryngeal Nerve .... .128 Functional Symptoms 130 Diagnosis of Goiter 130 Is the Tumor Developed in the Thyroid? 150 Laryngoscopic Examination 131 What is its Nature? 132 ( roiter-heart 133 I he Mechanical Goiter-heart 133 The Thyrotoxic Goiter-heart 136 CHAPTER VIII. Intrathoracic ( Ion 1 u. Relation of Intrathoracic Goiter to Neighboring Hssues 14- Symptoms '13 Diagnosis '3- Differential Diagnosis '55 Prognosis '59 x CONTENTS CHAPTER IX. Goiter Death 160 CHAPTER X. Circular Goiter. Symptoms 163 Diagnosis 163 Treatment 164 Retrotracheal or Retro-esophageal Goiter 165 Intratracheal Goiter 165 CHAPTER XI. Congenital Goiter and Goiter in Children. Congenital Goiter 166 Symptoms 167 Treatment 168 Goiter in Children 169 CHAPTER XII. Simple Goiter and Pregnancy. Treatment 171 CHAPTER XIII. Clinical Aspect of Malignant Goiters. Relations to Surrounding Structures 173 Course and Symptoms 175 Diagnosis 178 Treatment 179 Hypothyroidism — Myxedema 182 Synonyms 182 The Kocher-Reverdin Controversy 182 Etiological Relationship between the Various Forms of Hypothyroidism . 187 Nomenclature 189 CONTEXTS XI CHAPTER XIV. Pathology of the Various Forms of Thyroid Insufficiency. Thyroid ioj Skin ig 2 Osseous Svstem 103 Nervous System 104 Vascular System 195 Genital Apparatus ". 195 Surgical Athyroidism and Surgical Cachexia Strumipriva 196 Symptoms 196 Spontaneous Adult Hypothyroidism 198 Etiology 198 Symptoms 200 CHAPTER XV. Congenital Athyroidism, Spontaneous Infantile Hypothyroidism, and Cretinism. Etiology of Congenital Athyroidism and Spontaneous Infantile Hypothyroidism 203 Cretinism. Etiology 204 Symptoms of Congenital Athyroidism, Spontaneous Infantile Hypothyroidism 207 Differential Diagnosis 210 CHAPTER XVI. Small Thyroid Insufficiency 216 CHAPTER XVII. uctuation ( loiter s of ( loiter Etiology of Endemic Goiter and Cretinism Historical Geographical Distribution of Endemic Goiter and Cretinism . Economical, Social and Military Significance of Endemic Goiter and Goiter Epidemics Fluctuations of Endemic Goiter .... Fluctuations of Cretinism Conclusions Drawn from the Study of the F < inner in Animals rheories Regarding the Etiology of Goiter . I he Relation between Water and Endemic I [ydrotelluric Theory Rt pm's or Plutonian I heory . Radio-active Wants and Goiter < Organic Theory .... Contagion 1>\ Contact Theory Infection I heory .... < '•' neral Conclusions Ci (. '1 ei inism 220 221 --7 228 232 234 235 236 241 242 249 250 263 272 275 xii CONTEXTS CHAPTER XVIII. Medical Treatment of Simple Goiter. Prophylaxis 276 Medical Treatment of Goiter 277 Indications for Medical Treatment 277 Contra-indications to Medical Treatment 278 Medicaments 279 Iodin in Treatment of Goiter 279 Crotti's Formula for Treatment of Non-toxic Parenchymatous Goiter . 281 Dangers of Iodin Medication 282 Treatment of Thyroid Insufficiency 283 Thyroid Opotherapy 283 Dangers of Thyroid Opotherapy .... 283 Ingestion Method 285 Polyglandular Treatment 290 CHAPTER XIX. Thyroid Grafting .... ... 291 CHAPTER XX. Indications for Operation in Simple Goiter. Contra-indications to Operation 299 Treatment with Injections 3°° Thyrotoxicosis 3°3 History 3°3 CHAPTER XXI. Cardiovascular Symptoms. Differential Diagnosis of Thyrotoxic Tachycardia 304 Etiological Explanation of Tachycardia 3°6 Palpitation 3°7 Thyrotoxic Heart 3 C 7 Thyrotoxic Pulse 3°9 Test of Functional Capacity of the Heart 3 l ° CHAPTER XXII. Basedow Struma. Vascular Symptoms of the Thyroid 3 J 3 Pathology and Histology of Thyrotoxic Goiter 3 X 5 CONTENTS xiii CHAPTER XXIII. Ocular Symptoms. Exophthalmos 310 Unilateral Not ; 40; Summary of Conclusions Concerning the Etiology of Graves' Disease 403 xvi CONTENTS CHAPTER XXXVIII. Treatment of Graves' Disease. Lipoids . 405 Is There Truly a Medical Treatment for Graves' Disease? 407 Results of Medical Treatment 408 Medical Cases 410 Conclusions 411 When Shall We Consider a Patient Cured? 415 Medical Treatment 417 Rest Cure 417 Medication 419 Diet 420 Hydrotherapy . 421 Electrotherapy 421 General 421 Local 421 Galvanic 421 Electrolysis 422 Radiotherapy 422 Serotherapy 426 Antithyroid Chymotherapy 426 Thyrotoxic Serotherapy 427 Polyglandular Medication 427 Thymus Opotherapy 428 Hypophysis Opotherapy 428 Parathyroid Opotherapy 428 Adrenalin 428 Pancreas Opotherapy 428 Crotti's Treatment for Exophthalmic Goiter 428 CHAPTER XXXIX. Indications and Contra-indications for Surgical Treatment of Exophthalmic Goiter. What Line of Conduct Shall We Follow in Deciding the Course of Treatment in Each Given Case? 434 CHAPTER XL. Surgical Technic of Operations upon the Thyroid Gland. Surgical Technic 439 Anatomical Facts 440 Pathological Planes of Cleavage 442 Blood Supply of the Thyroid 442 Parathyroids 445 Recurrent Laryngeal Nerves 447 COXTEXTS xvii Conclusions Drawn from Anatomical Facts 448 Excision, Resection, or Enucleation ? 448 Excision 449 Resection 449 Enucleation 450 Shall the Operation be Unilateral or Bilateral? 454 How Much Thyroid Tissue Can Safely Be Removed? 457 Shall We Dissect the Parathyroids? 458 Ligations 458 What is the Point of Election for Ligation? 462 Technic of Ligations 463 Isolated Ligation of the Superior Pole 464 Technic for the Isolated Ligation of the Inferior Thyroid Artery .... 464 Isolated Ligation of the Inferior Thyroid on the Inner Border of the Scalenus 465 Hemostasis 466 CHAPTER XLI. Operative Technic for Thyroidectomy - . Incision 469 Operation for Intrathoracic Goiter 475 Technic of Operations for Malignant Goiters 477 CHAPTER XLII. Operative Accidents. Lesions of the Nerves 478 Suffocation and Collapse of the Trachea 479 Injury to the Trachea, Esophagus and Pleura 481 Tracheotomy 481 Air Embolism 481 CHAPTER XLIII. Sympathectomy. Pathology 483 Immediate Results of the Operation 483 Remote Results 484 Choice of ( Operation 484 Surgical Technic for Sympathectomy 4S5 CHAPTER XLIV. Canthorraphy 487 CHAPTER XLV. Bnil.lNC-u VII K I NJECTIONS. Technic 48S xviii CONTENTS CHAPTER XLVI. Preoperative Treatment of the Patient 489 CHAPTER XLVII. Operating Room Technic 491 CHAPTER XLVIII. Postoperative Treatment 493 CHAPTER XLIX. Anesthesia. Chloroform, Ether, or Nitrous Oxide? 498 Local Anesthesia S 01 Technic of Local Anesthesia 502 Intratracheal Insufflation Anesthesia in Thyroid Surgery 506 Pantopon-scopolamin 5°7 CHAPTER L. Postoperative Complications. Shock 5°9 Vasomotor Exhaustion and Paralysis 509 Cardiac Spasm and Eventual Failure 511 Inhibition of the Function of all Organs 511 Deficiency of Carbon Dioxide in the Blood, or Acapnia 511 Morphological Changes in the Ganglion Cells 511 Loss of Vasomotor Control 5 12 Primary Suprarenal Exhaustion S 12 Treatment of Shock and Hemorrhage 5 J 5 Crotti's Technic of Indirect Transfusion 518 Postoperative Hyperthyroidism 5 J 9 Acidosis 5 21 Postoperative Fever • 5 2 3 Postoperative Tetany 5 2 4 Symptoms 5 2 4 Chvostek 5 2 5 Weiss 5 2 5 Trousseau S 2 ^ Erb 5 2 » COXTEXTS xix How Many Parathyroids May Be Removed before Tetany Appears? .... 529 Prognosis 530 Treatment of Tetany 531 Grafting of the Parathyroids 532 Pulmonary Complications 533 Postoperative Dysphagia 534 Postoperative Hematoma 534 Raising of the Scar 534 After-treatment 534 Rules for Goiter Patients 535 CHAPTER LI. The Thymus Gland. Synonyms 536 History and Etymology 536 Embryology 536 Histology 537 Surgical Anatomy of the Thymus 537 Involution of the Thymus 539 Experimental Pathology of the Thymus 540 Skeleton 540 Nervous System 540 Muscular System 541 Interrelation of the 1 hymus to the Organs of Internal Secretion 541 Status 1 hymolymphaticus ^42 1 hymic Tracheostenosis 54.2 Acute Symptoms 54} Chronic Form of 1 hymic Hyperplasia 543 Explanation of the Choking Spells and of Thymic Death 545 Pressure at the Superior Opening of the Thorax 54^ Pressure in the Thorax 546 Spasm of the Glottis 546 Diagnosis of 1 hymus Hyperplasia 54S X-ray Characteristics of 1 hymic Hyperplasia 550 Differential Diagnosis of Thymic Hyperplasia 550 Relation of Thymic Hyperplasia to Basedow's Disease 551 I hymogene Basedow 553 Differential Diagnosis between Thymic and Thyroid Basedow 553 I natment of Thymic Hyperplasia Complicating Graves' Disease 555 Treatment of Thymic Hyperplasia in Children 556 CHAPTER LIE Surgical Technic of Thymectomy. Anesthesia 557 Surgical Technic 557 DISEASES OF THYROID AND THYMUS. CHAPTER I. ANATOMY AND EMBRYOLOGY. ANATOMY. The thyroid gland is an unpaired gland of reddish color. It lies upon the lateral surface of the thyroid and cricoid cartilages and upon the anterolateral surface of the upper end of the trachea which it surrounds like a horsehoe. The thyroid gland consists of two lobes united by a narrow trans- verse portion, the isthmus. The lobes are conical in shape, and measure about 2 inches in length, i\ inches in width, and f inch in thickness. The gland in toto weighs about an ounce. It must be well under- stood that these figures may vary. There are countries where the general average weight may be higher than the one just given, and vet the gland will still be normal. It is customary to call the upper portion of a lobe upper pole, and the lower portion lozver pole, while the portion of the gland between the upper and lower poles may be called the body of the gland. Inwardly, each lobe comes in con- tact with the trachea, esophagus, thyroid and cricoid cartilages, the inferior laryngeal nerve, the inferior constrictor of the pharynx, and the posterior part of the cricothyroid muscle. Its posterior surface is in relation with the carotid sheath containing the common carotid, the internal jugular vein and the vagus nerve; it is furthermore in relation with the inferior thyroid artery, with the parathyroids, and also with the prevertebral fascia and muscles. The anterolateral surface is cov- ered by the sternothyroid, the sternohyoid and the omohyoid muscles; the sternocleidomastoid muscles overlap the outer border of the gland. The isthmus is situated in front of the trachea and covers its second, third and sometimes its fourth ring. It varies in size and width. Usually, it measures about half an inch in breadth and the same in depth. It may even cover the cricoid cartilage, or at least part of it. In such cases superior tracheotomv presents some difficulties. The isthmus may be absent altogether (Fig. i), or may be entirely separated from both lobes, thus forming a lobe by itself. 2 18 AX ATOMY AXD EMBRYOLOGY From the isthmus, or from the adjacent part of either lobe, a narrow strip of glandular tissue is often seen passing in front of the thyroid cartilage upward toward the body of the hyoid bone to which it may or Fig. I. — Thyroid without isthmus and without pyramidal process. Fig. 2. — Thyroid with one pyramidal process. may not be attached. The process is called the pyramidal process (Fig. 2). It is not constant and is found oftener on the left side than on the right. In rare cases the pyramidal process may be double (Fig. 3). Fig. 3. — Thyroid with two pyramidal processes. Fig. 4. — Thyroid gland whose isthmus does not join the two lobes. It has the same structure as the thyroid gland. The pyramidal process represents the vestiges of the thyroglossus duct (Fig. 4). The thyroid gland is in close connection with the trachea and with the larynx by interwoven connective tissue. It has special attachment ANATOMY 19 with the cricoid cartilage through bands of fibrous tissue extending from the isthmus and lateral lobes to the cricoid cartilage. These bands are known as the suspensory ligaments of the thyroid. It is on account of such relation that the latter organ follows the movements of the larynx during deglutition. The entire thyroid gland may be wholly absent, but this is very rare indeed. Accessory thyroids are frequently found in the neck. They are more common in the neighborhood of the hyoid bone, but they mav be found below the thyroid gland as far down as the arch of the aorta and the bifurcation of the trachea. They have the same histological structure as the thyroid gland itself; the)' mav contain colloid or mav show embrvonical structure. Goiter or tumors of any kind can develop from them. A a. Fig. 5. — 1, common carotid; 2, internal jugular vein; 3, superior thyroid artery and vein. Normally the artery originates a little higher up from the external carotid and not from the common carotid, as wrongly shown by the picture; 4, middle vein; 5, imae veins; 6, inferior thyroid artery; 7 and 8, right innominate veins; 9, aorta. Blood Supply. 1 he thyroid gland receives its blood supply from three arteries, the superior, the inferior, and the ima artery (Fig. 5). The superior thyroid artery is the first branch of the external carotid. It runs in a curve forward and downward to the upper pole, and gives off a branch for the hyoid bone, one for the sternocleidomastoid muscle, one for the larynx (the superior laryngeal artery which perforates the thyrohyoid membrane), and one branch known as the cricothyroid artery, passing in front of the cricothyroid ligament just above the isthmus. The artery finally splits into two terminal branches in the upper pole of the thyroid gland, the anterior and posterior branches. 20 ANATOMY AND EMBRYOLOGY The inferior thyroid artery arises from the thyrocervical trunk given off by the subclavian artery. It runs in front of the scalenus anticus muscle, at first upward, then bends inwardly, passing behind the carotid sheath, and terminates in the posterior surface of the thyroid gland. The ima artery comes off directly from the arch of the aorta or from the innominate artery and terminates in the isthmus. It is not constant. Anna Begoune has demonstrated that each artery supplies a terri- tory of its own; the superior thyroid artery supplies the superior half of the lobe; the inferior thyroid artery supplies the inferior half of the lobe. This is of course very schematic and not literally true, as both territories exchange very numerous anastomoses, which in time may grow into an important collateral circulation. If the four arteries are injected, not only the whole thyroid gland, but also the adjoining organs, as the trachea and the esophagus, will become injected at the same time. This is an important fact, as it shows that after ligation of all the thyroid arteries, the gland may still receive some blood from its collateral circulation. The veins of the thyroid gland show considerable variation. They form a rich plexus upon and beneath the capsule of the gland. The superior thyroid vein terminates generally in the thyrohnguofacial trunk formed by the junction of the thyroid, lingual and facial veins. The inferior thyroid vein empties into the internal jugular vein. Not infrequently, as shown by Kocher, there is a middle vein which emerges from the side of the gland, passes transversely outward and empties into the internal jugular vein. From the lower border of the isthmus and both poles there is a plexus of two, three or more veins which go directly downward and empty into the innominate vein of both sides. They are known as the imce veins (Fig. 5). Thyroid veins have no valves. These numerous bloodvessels, be they arterial or venous, pass to and fro, penetrate the gland, and break into smaller branches. They ulti- mately form a capillary network around each follicle and come in close contact with each cell. The blood supply of the thyroid gland is very extensive, and in pro- portion to its size, the circulation here is more extensive than in the brain. This abundant circulation shows that the function of the thy- roid gland must be an important one. Lymphatics. — Forming a network around each vesicle, the small lymphatics resolve themselves into larger collecting trunks which empty either into the prelaryngeal group of lymph nodes located in front of the cricothyroid membrane, or into the cervical group all along the com- mon carotid, or into the pretracheal group below the isthmus. Some of HISTOLOGY 21 these deeper trunks empty into the lymph nodes along the postero- lateral surface of the pharynx and esophagus. The nerve supply comes from the sympathetic (median and inferior cervical ganglion) and from the vagus nerve (superior laryngeal branch). The inferior laryngeal nerve comes in close contact with the gland but does not supplv it. The capsule of the thyroid contains sensory nerves. HISTOLOGY. The thyroid gland has no excretory canal; it belongs to the group of glands of internal secretion. Although this is true, we must, how- ever, admit that the secretion of the thyroid still affects the external type, since the products of cellular secretion empty into the alveoli under the form of colloid, and are only later absorbed into the general circulation. We have, consequently, two distinct processes: one of secretion and the other of absorption. The thyroid gland is composed of connective tissue and epithelium. The connective tissue forms a capsule which surrounds the entire gland, and projects inward, prolongations dividing the gland into lobes and lobules. These lobes contain round, tubular, sacculated, branching or prismatic vesicles or follicles, each one separated b}* more slender septa. In this stroma, be it interlobular or interfollicular, elastic fibers, nerves, blood and lymphatic vessels are found. The normal size ot the alveoli varies from 50 to 300 m- It is not quite uncommon to find in it small foci of lymphoid tissue. The epithelium is cuboidal or cylindrical, and is arranged in one layer all around the wall of the follicle. The follicle in the thyroid gland has no membrana propria. Wegelin, however, has shown that a membrana propria exists in goiter, especially in cases where hyahn degeneration is present. Each cell is provided with a single oval-shaped or round nucleus which contains a thin chromatin network with one or more chromatin corpuscles. The diameter of each nucleus is generally from 5 to 6/z. Acidophiles granulations and fat are found in the cells. Two types of cells are usually described in the thyroid vesicles: the " chief cells," far more numerous, clear and finely granular, and the "colloid cells," more opaque and granular. Differences, however, between these two varieties are not sufficient to warrant differentiating them into two distinct types of cells. The colloid cells seem to be merely chief cells loaded with colloid material which has not yet been excreted into the alveolar lumen. For the majority ot the thyroid cells, the secretion affects the merocrine type. This means that a part only of the cell is used by the secreting process. Once elaborated, the secretion is evacuated into the alveolar lumen by the breaking open oi 22 ANATOMY AXD EMBRYOLOGY the nuclear membrane; then the cells regenerate and become "chief cells," ready to start over the secreting cycle. In numbers of other instances, however, the secretion affects the holocrine type. In these cases the whole cell is used for colloid production. Nothing remains afterward, the whole cell is destroyed. Colloid. — Some follicles are without lumen. The majority, however, contain colloid substance. Colloid may be fluid or thick. This differ- ence in consistency is due to the difference in concentration of the albuminous substances. When filled with thick colloid, the follicle seems to be distended, and when it contains fluid colloid, the follicle does not seem to be under tension. The staining power of colloid is exceedingly variable. In the same microscopic field it is not rare to find alveoli in which the colloid did t W « & ^ Fig. 6. — Colloid with its vacuoles. X 350. not stain at all and others which did take the staining in the most intense manner. We may say in a general way that the thicker the colloid, the more it will stain, although this is not always true, as solid lumps of colloid are not so rarely seen in which the staining has scarcely taken. The thick or solid colloid looks homogeneous, and must be regarded as a product which does not absorb as readily as thin colloid. It is quite common to find vacuoles in the colloid (Fig. 6). These vacuoles are often artefacts due to retraction of the colloid substance when it undergoes coagulation. These vacuoles are then located at the per- iphery of the coagulum and remain in connection with the walls of the follicle through very thin trabecules. Oftentimes, however, they are due to the presence of fat and mucine in the colloid. They are then more or less in the center of the colloid. The colloid most generally enters the general circulation through the EMBRYOLOGY 23 lymphatic spaces and vessels surrounding each follicle. These lymphatics often contain a substance with atypical staining qualities similar to the ones of colloid. That, however, this substance is identical with the colloid is not yet an absolute, demonstrated fact. The amount of colloid found in a gland is by no means a true index of the functional activity of the thyroid. In the newborn, and in Graves' disease the amount of colloid found is scant. The same is true in acute infectious diseases; there the colloid is diminished in direct proportion to the severity of the disease. Nobody, I presume, will contend that in these conditions the functional activity of the gland is diminished. Everything seems to disprove it; the experimental as well as the microscopic findings and especially the increased blood supply. On the other hand, -the colloid is increased in conditions where we know the functional activity of the gland is diminished, as in colloid goiter and in hypothyroidism. Why such apparent discrepancies ? Because, beside "secretion" there is another phenomenon just as important and that is "absorption." The amount of colloid found in a gland depends upon these two processes, and the physiological activity of the thyroid depends largely upon the equilibrium between them. For instance, we may find very little or no colloid in an extremely active gland, because there is at the same time a rapid absorption of the thy- roid products going on. On the other hand, the quantity of colloid may be found materially increased in cases where secretion and absorp- tion are diminished. In these two instances we would draw false con- clusions as to the functional activity of the gland, if we should judge it only by the amount of colloid found. One thing, however, seems to be certain: the amount of colloid and especially its consistency seems to be in direct relation with the increased vascularization. This is not only true in Graves' disease, in acute infectious processes, in thyroids of newborn babies, but has also been shown experimentally. With increased blood supply the colloid loses its thickness and becomes readily absorbable. Desquamation. — Normally, a few cells may decay, lose their connec- tion with alveolar walls, and fall into the lumen of the alveoli where they will gradually disintegrate and be eliminated. These desquamated cells are replaced by new ones. In pathological processes, especially in severe thyrotoxicosis, desquamation may be very marked. As a rule it is always accompanied with thinning or absence of the colloid. It is always ot severe prognosis. EMBRYOLOGY. I he thyroid is primarily a dependence of the esophagus (tuniciers ammocetes) and in its endostyle form is ;i digestive gland of great impor- 24 ANATOMY AND EMBRYOLOGY tance through its external secretion. In its ductless form it is only the atrophic remnant of its ancestor, which, while it has suffered a corre- sponding distortion of function, still profoundly influences the animal's nutrition through the effects of its internal secretion. The thyroid gland is found in the anterior portion of the neck of every vertebrate animal. It is absent in the amphioxus. It originates from an unpaired formation, the tuberculum impar of His, which is formed in the middle line by an evagination of the epithelium of the anterior pharyngeal wall, at the level of the second branchial arch, in or slightly anterior to the first aortic arch. For a long time it was thought that the thyroid gland had a double origin and was formed by the fusion of the median and lateral thyroids, originating from the median and lateral "anlagen." However, Miiller, His, Verdin, and Tourneux, after careful investigations, have come to the conclusion that the thyroid originated only from a single median evagination taking place in the anterior wall of the pharynx, between the three divisions of the tongue, from which place it descends into the neck to its resting place astride the upper portion of the trachea. On a frontal and vertical cut the human embryo, two weeks old, shows laterally of the cephalic extremity a series of branchial arches separated by branchial grooves. In the human embryo of 6 months five branchial grooves are present, the fourth being divided into two. Between the second, third, fourth, and fifth branchial arches on both sides, and between the inferior maxillary and the basis of the heart, there is a triangular space which is called the mesobranchial field of His (Fig. 7). From this field will derive the thyroglossus duct and the thy- roid gland. Laterallv of the mesobranchial field of His are found branchial arches and branchial grooves which altogether form the branchial apparatus. Branchial arches and branchial grooves are separated, one from the other, by a thin wall of tissue covered inside with endoderm and outside with ectoderm. These branchial and mesobranchial elements give rise to very difFerent and very important organs and to very well- differentiated embryonic residues from which thyroid tumors may derive; therefore from an embryological point of view it seems logical to divide the tumors of the thyroid into tumors of mesobranchial origin and tumors of branchial origin. In the mesobranchial field, just in front of the second groove, a median invagination of the walls of the pharynx appears, forming a depression which becomes deeper and deeper, and finally forms the thyroglossus duct. At its lower end this duct bifurcates, forming two terminal buds, which proliferate into a glandular organ (Fig. 7) which later on will be the thyroid gland. In the middle of the second month of intra-uterine life the thyro- EMBRYOLOGY 25 glossus duct divides into two portions, the superior and the inferior. The superior portion, called the lingual duct, extends from the hyoid bone to the foramen cecum of the tongue; the lower portion, or thyroid duct, extends from the hyoid bone to the isthmus of the thyroid gland. This division of the thyroglossus duct into the lingual and thyroid ducts is produced by the hyoid bone, which, at the end of the fifth week, is represented by a cartilaginous mass interposed between the two Fig. 7. — 1, first branchial groove; 2, second branchial groove; 3, third branchial groove; 4, fourth branchial groove; 5, fifth branchial groove; A, thymic portion of the parathyroid; ./', thyroid portion of the parathyroid; B, thymus; C, postbranchial bod) ; 'I'll, thyroid. segments of the thyroglossus duct. Sometimes this interposition does not take place, and in that case the thyroglossus duct forms a continu- ous canal extending from the foramen cecum through the lingual raphe, and passing, as a rule, behind and sometimes in front of the hyoid bone. In few exceptions it passes directly through the body oi the bone. Ordinarily, the thyroglossus duct bifurcates in front of the larynx, forming the isthmus, tin- lobes being formed by tin- two terminal buds. 26 ANATOMY AXD EMBRYOLOGY However, the bifurcation of the thyroglossus duct may take place higher up, as far as the foramen cecum; in that case we shall have two pyramidal processes, one on each side, or we may have two lobes with the pyramids, but no isthmus at all (Figs. 1-4). The thyroglossus duct has a constant and specific structure. It is lined with one layer of cylindrical epithelium provided in places with vibratile cilia. Very rarely is this duct lined with pavimentous epithe- lium. The terminal portion of the thyroglossus, which constitutes later on the thyroid gland, has at first the same cylindrical structure, so that at the end of the fifth or sixth embryonic month the thyroid is formed •-\ mm .•■■•■•..-■ *zzm '■*"+ Fig. 8. — Congenital goiter. Simple parenchymatous goiter fotmed by a cellular mass not yet differentiated into adult alveoli. X 58. by alveoli lined with one single layer of epithelium; their lumen is very small and does not contain colloid; protoplasm is clear, has no vacuoles; nuclei are compact and the chromatin forms a stain instead of a network. Later on this epithelium loses its cylindrical character, and at the end of the seventh month the structure of the thyroid gland has changed considerably; an intense cellular desquamation takes place and fills the lumen of the alveoli, so that toward the end of the intra-uterine life the thyroid is composed of a uniform, non-differentiated mass of cells (Fig. 8) pressed one against the other and containing a few capillary vessels. The nuclei are large, swollen, clear; no colloid is present. EMBRYOLOGY 27 The cause of the desquamation is yet unexplained. A few weeks after birth, however, regeneration of the thyroid takes place; the epithelium shapes itself into epithelial cords which undergo a process of direct division, thus forming new alveoli in which the epithelium becomes cubic or flat. Consequently, it may be said that the thyroid passes through three different stages: i. The embryonic ox thyroglossus stage formed by cylindrical epithelium. 2. The. fetal stage formed by a non-differentiated cellular mass. 3. The adult or vesicular stage. The embryonic and fetal types may leave persistent inclusions in the thyroid. Wolfler has demonstrated that these inclusions of fetal parenchyma are not seldom found in the thyroid, and that they may result in the production of a tumor known as the fetal adenoma. After the thyroglossus duct has formed the thyroid gland with its lobes and isthmus it gradually becomes atrophied and forms a fibrous cord, called by His the thyroglossus tractus, and which extends from the foramen cecum of the tongue to the pyramidal process. Exceptionally, this canal may remain permeable in all its course from the base of the tongue to the thyroid. The thyroglossus duct may leave over its entire course islands of thyroid tissue at the cost of which, later on, accessory glands or goiters may develop. Sometimes the thyroglossus tract does not terminate in the thyroid but extends downward into the anterior mediastinal space, and may even reach the aorta. In that case accessory glands may be left over the entire length of this course. Thus is explained the origin of accessory thyroid glands, and of tumors of the mesobranchial type developed, not only at the base of the tongue and in the cervical region, but also in the mediastinal space. In the same way during the embryological evolution islands of eetodermic epithelium may be left behind, remaining in close contact with the thyroid gland. Later on these inclusions are liable to give rise to tumors with pavimentous epithelium, hence cancroid of the thyroid. \ he dorsal cul-de-sac of the third branchial groove forms the external or thymic parathyroid. The ventral portion of this third groove forms the internal parathyroid. The ventral cul-de-sac of the fifth branchial groove forms the postbranchial or ultimobranchial body. Postbranchial Bodies. -Van Bemmemen discovered in the embryo of the shark and thornback, behind and on each side- of the last branchial arch, a pocket-like formation containing follicles, and resembling the thyroid gland. This glandular organ lies so near the heart that Van Bemmemen called it supraparacardial body. With the exception of the cyclostoma and the temeostiver such organs have been tunnel in other classes of vertebrates, for instance in tin amphibious reptiles, birds 28 ANATOMY AND EMBRYOLOGY and mammalian animals. Because these organs are always situated behind the last branchial arch, Miwa called them postbranchial bodies (Fig. 7). In amphibious reptiles, birds and mammalian animals these postbranchial bodies give rise to follicles with epithelium and vibratile cilia, but according to Miwa, colloid is never found. These colloid bodies have been considered by a few authors as giving rise to the lateral thyroids, which after fusion with the median thyroid were thought to form the thyroid gland. But this has been disproved by Miwa, His, Verdin and Tourneux. In their opinion these post- branchial bodies have nothing to do with the formation of the thyroid gland. They are separate organs whose significance is not yet clear, and which in Verdin's judgment undergo an atrophy and finally disappear. From an embryological stand-point, De Quervain, Delore and Ala- martine were consequently justified in classifying the thyroid tumors in two large classes: I. Tumors of mesobranchial origin. II. Tumors of branchial origin. Tumors of Mesobranchial Origin. These are median tumors in the neck which originate from the thyroglossus duct and from the organs which derive from it, namely, the thyroid gland and the accessory thyroid gland. 1. Tumors of ectodermic origin due to inclu- sion of ectodermic epithelium. Tumors of Branchial Origin. All cancers with pavimentous epithelium. 2. Tumors of endodermic origin due to inclu- sion of endodermic epithelium. 1. From the thyroglossus duct. 2. From the thyroid itself. 3. From the accessory thyroid glands. a. First branchial groove gives fistula in connection with the external auditory canal and the mixed tumors developed in the parotid and submaxillary glands. b. Second branchial groove gives branchial cyst and fistula and all mixed tumors of the lateral region of the neck. c. Dorsal portion of the third and fourth grooves gives parastruma. d. Ventral portion of the fourth or fifth branchial grooves gives the post- branchial tumors. a. Lingual goiter. b. Median, congenital cyst and fistula; benign and malignant. c. Goiters with cylindrical epithelium. a. All benign goiters. b. All malignant goiters. a. All benign accessory goiters. b. All malignant accessory goiters. EMBRYOLOGY 29 This synoptical picture based on embryological considerations is very clear and scientific. It gives the key to the explanation of these very obscure tumors found in the neck and in the thyroid gland, which have so long been a puzzle to the pathologist. Easily explained thereby will be the origin of lingual goiter; of the median and lateral cvsts and fistulae of the neck; of the accessory glands from all along the neck and in the superior portion of the mediastinal space. Easily explained, too, are these puzzling and various tumors in which the thyroid is so rich, as the parastruma, papilloma, postbranchial, mixed tumors, etc. CHAPTER II. PHYSIOLOGY OF THE THYROID. History. — Theories regarding the physiology of the thyroid have been numerous. Wharton thought it was merely a cosmetic organ whose function was to produce a nice, soft, roundness of the neck. Other authors thought that it acted as a mechanical support to the larynx, and protected this organ against cold. Boerhaave thought that it acted as a cushion whose gentle pressure served as a modulator of the voice. Morgagni, Santorini, Winslow and Lalouette thought that the gland was in direct communication with the larynx, and that it probably had an excretory canal emptying into the region of the vocal cords; and that under such conditions the secretion of the thyroid acted as a lubri- cant for these cords. As late as 1870 Ricou believed in the existence of this excretory canal; some other authors believed that the thyroid communicated directly with the esophagus and considered the foramen cecum as the point of outlet of the canal. For quite a long time the thyroid was considered as a mechanical regulatory organ of the blood circulation and was regarded as an arterial reservoir intercalated between the cephalic and the caroticosubclavian systems; filled with blood, the gland was thought capable of compress- ing the carotids, thus diminishing the quantity of blood going into the brain. Compared to a sponge capable of derivating or giving up at will the blood destined to the cerebral organs, the thyroid was then regarded as a safety-vent for the cerebral circulation. There is no need to say that these hypotheses are for the most part purely fanciful and are not supported by any experimental facts. However, it might be incorrect to claim that the thyroid has no effect whatsoever on the cerebral circulation, as this gland receives its nerve supply from the superior laryngeal nerve containing the vasodilatator^ fibers, and from the sympathetic nerve which contains the vasoconstrictory fibers. Experimentation shows that excitation of the central end of the superior laryngeal nerve causes an intense reflex vasodilatation of the thyroid: hence diminution of the quantity of blood directed toward the cere- brum; on the other hand, irritation of the sympathetic nerve causes a vasoconstriction, and consequently an increase of the quantity of blood thrown into the cerebral circulation. It is therefore possible that in certain given conditions this mechanism is called into play and thus RESULTS OF EXPERIMENTAL THYROIDECTOMY 31 mav be regarded to a certain extent as a regulator of the cerebral circulation. One of the most curious theories of the physiology of the thyroid is that of Fomens. According to this author this organ plays an important part in the physiology of sleep; it swells up during sleep because it retains a certain portion of the blood destined to the brain and gives it off again during the period of wakefulness. Evidently this author believes that sleep is due to cerebral anemia. In conclusion we may say that the regulation theory is not sup- ported by any experimental facts nor by surgical experience, as no dis- turbances in the cerebral circulation are noticed after operations. The histological structure of the gland, too, speaks against this theorv; the thyroid is a glandular and not a cavernous organ. All these theories have only an historical interest. Our knowledge of the physiological function, although still incomplete, has become more precise in the last quarter of a century; the thyroid must be regarded as a glandular organ of great importance in metabolism. In 1840 Astley Cooper noticed that thyroidectomy in animals was followed by a peculiar symptom-complex, but he did not pursue his experiences any further nor did he give his observations their correct interpretation. In 1859 Schiff called attention to the dangers connected with thyroid insufficiency. His experimental results, however, passed unnoticed until 1883, when Kocher and Reverdin made their epoch- making discovery. The physiology of the thyroid may be studied from two angles. \ aluable information may be gained by performing a complete thy- roidectomy in animals to see what the outcome will be. Information may be, furthermore, secured by studying the influence of the adminis- tration of the gland itself upon the different organs and functions of the body. Results of Experimental Thyroidectomy. — The thvroid is an organ necessary to life and its absence produces a clinical syndrome which has been called myxedema or cachexia thyreopriva, and which terminates, as a rule, in death. Schiff, Wagner, Horsley, von Eiselsberg and others have shown that extirpation of the thyroid in young animals causes death much sooner than extirpation in adults. Children with total aplasv of the thyroid never reach puberty. The most important symp- toms observed after complete thyroidectomy are a retarded metabolism and an arrest in the growth of the osseous system, myxedematous infiltration of the skin and intellectual disturbances. In young animals the arrest of development is considerable and affects at the same time the skeleton, the nervous system, and the gen- ital apparatus. Young thyroidectomized animals remain small; their 32 PHYSIOLOGY OF THE THYROID bones do not develop; their cartilages and epiphyses do not proliferate; they retain, in fact, their fetal aspect. The skin becomes rough and infiltrated with a mucinoid substance, hence the name myxedema. This mucinoid infiltration is found, too, in muscles, nerves, and other organs. The young animals remain apathetic and dejected; their movements are slow and awkward, while physical activity is a burden to them. The genital organs remain infantile; the testicles do not descend and, as a rule, do not secrete spermatozoids; the ovaries remain small and become sclerocystic. Furthermore, the respiratory exchanges and oxi- dation processes are diminished; the animals become anemic; their temperature is low and the development of the disease is progressive until death occurs. A complete thyroidectomy in adult animals produces the same clinical picture but less intensified. The muscular system becomes weak and paretic; the nervous and psychic functions are disturbed; the skin becomes swollen and edematous, while the hair becomes dry and brittle. The metabolism is diminished, but as these animals have reached normal growth no disturbances of the osseous system are found. Food seems to have a certain influence on the severity of the develop- ment of myxedematous conditions. Thyroidectomized dogs, for instance, seem to stand a cooked-meat diet with impunity, but as soon as they are given fresh meat the symptoms of thyroid insufficiency at once become more severe. Death can be delayed for a longer period if the animals are kept on a milk diet. Apparently, thyroidectomized animals are unable to destroy certain toxic products of a meat diet. After the thyroid has been completely removed its functional insuffi- ciency becomes manifest more or less rapidly, sometimes in a few days, sometimes after a few weeks, and sometimes after many months. Tizzoni, Alonzo and Ughetti did not observe symptoms before nine months, and Horsley waited one and three-quarters years before symp- toms of cachexia appeared in a sheep which had been completely thy- roidectomized. This will explain why there have been authors claiming that thyroidectomy had no efFect upon the condition of the animals. Either these authors did not wait long enough for myxedematous symp- toms to appear or they mistook the lymphatics or submaxillary glands for the thyroid, or if they did remove the thyroid, their operation was not complete, or if it was, accessory thyroids must have been present. Thyroid and Parathyroids. — For a long time great confusion has pre- vailed concerning the correct interpretation of phenomena observed after thyroidectomy, as symptoms depending solely upon thyroid insuf- ficiency were ascribed to parathyroid disturbances, and vice versa. It was thought, too, that the consequences of thyroidectomy were more severe in certain species of animals than in others. Horsley, in 1891, THYROID AXD PARATHYROIDS 33 summing up the results of experimental pathology, found that thyroid- ectomy was not followed by cachexia in birds and rodents, that it took a mild course in ruminants, and that it was of the utmost severity in carnivorous animals. To be sure, everything being equal, symptoms following total thyroidectomy in carnivorous animals are more severe than in herbivorous animals, because, as we have seen, a meat diet seems to cause more symptoms than a milk or herbivorous diet, but this is not the sense of the above statement. Horslev meant that carniv- orous animals became acutely sick and died after a few days in the most acute convulsions, whereas herbivorous animals stood the operation more easily and developed gradually a chronic pathological condition known as myxedema. As we see, he did not at the time separate the svmptoms belonging to thyroid insufficiency from the ones of para- thyroid origin. Thyroid and parathyroids are not only anatomically and pathologi- cally different, but their physiological function is likewise not similar. If in animals the thyroid alone is removed and the parathyroids left in situ, a chronic, slow cachexia, which we call myxedema, takes place; but if the parathyroids alone are removed and the thyroid left in situ, the most severe convulsions appear very soon and the animal dies of tetany in the course of a few days. Now, then, the error made in the interpretation of these symptoms can be very easily explained. In carnivorous animals the parathyroids are found, as a rule, embedded within the capsule in the thyroid tissue itself, while in herbivorous animals the parathyroids are located outside the capsule of the gland. In sheep and goats, for instance, a considerable amount of parathyroid tissue is present outside of the thyroid gland; in rabbits two of the parathyroids have no relation whatsoever with the thyroid: conse- quently, when thyroidectomy in carnivorous animals was perfornu-d. the parathyroids were removed ipso facto at the same time, whereas in herbivorous animals they were left uninjured; hence the difference in tin clinical picture in both species of animals. In one case they devel- oped tetany, in the other myxedema. Pineles, on the strength of his clinical material on the congenital absence of the thyroid, had already come to the conclusion that the parathyroids and thyroid were two entirely different organs, anatomi- cally as well as functionally. In his judgment, if nature wanted to undertake an experiment to demonstrate the independence of the para- thyroid system from the thyroid one, it could not have done it more elegantly and more fully than in thyroid aplasy. We know that in such condition the thyroid is entirely absent, but the parathyroids are pre- served. In X out of 14 cases of thyroid aplasy he was able to demon- strate microscopically the absence of the thyroid and the presence of 3 34 PHYSIOLOGY OF THE THYROID normal parathyroids. Furthermore, he showed that in 4 cases of lingual goiter which had been operated, myxedema followed, whereas no symp- toms of tetany were observed, and for the simple reason that in such cases every bit of thyroid tissue had been removed, but the parathy- roids had remained untouched. To Gley, Vassale and Generali, however, belongs the credit for hav- ing demonstrated beyond doubt that the symptoms observed in animals after strumectomy did not all recognize the same origin, and that ner- vous symptoms and convulsions were due to an injury of the parathy- roids, whereas myxedema recognized as its cause a thyroid insufficiency. Since then these conclusions have been investigated and controlled by a great number of authors and found correct. We can today safely con- clude that the thyroid and parathyroids are two entirely different organs, and that to the insufficiency of one organ belongs a set of symp- toms which differ entirely from the clinical picture due to insufficiency of the other one. Such conclusions are based upon the following rea- sons: After partial extirpation of the parathyroids, tetany does not occur; no lesions of the nerves in the neck, as extensive and compli- cated as they may be, can determine similar symptoms; furthermore, histologically, the parathyroids are different from the thyroid. If the thyroid alone is removed, no tetanic convulsions develop, but myxedema follows; if the parathyroids are removed and the thyroid is left untouched, the clinical picture of parathyroid insufficiency at once becomes acute, but no myxedema follows. The trophic disturbances are due to the absence of the thyroid alone, whereas the acute, convulsive troubles must be referred to the suppression of the parathyroid func- tion. Furthermore, in athyroidism, the thyroid function alone is sup- pressed, whereas the parathyroids remain normal. In postmortems of myxedematous patients and cretins where no vestige of the thyroid could be found the parathyroids were found normal. Finally, para- thyroid opotherapy is often capable of curing tetany, whereas thyroid opotherapy is inefficacious. I know that on the strength of certain experiments made by Gley in 1909-1911, by A. E. Melnikov in 1909, by Iselin in 191 1 (who found that young parathyroidectomized animals which did not succumb to tetany developed a condition similar to rickets and died of cachexia), by Louis Morel in 191 1 (who seems to have demonstrated that after para- thyroid extirpation symptoms of slow cachexia similar to the one seen in myxedema develop), Gley, in the last edition of his Physiology, 191 3, believes there must exist a functional association between these two organs. According to these authors tetany is not the only consequence of the parathyroid insufficiency, but the suppression of these glandules determines cachexia and trophic disturbances of the skeleton, probably POSTOPERATIVE TETANY IN ANIMALS 35 by disturbing the entire chemical metabolism. How? It is not known. Swale, Vincent and Joly do not want to admit that the parathyroids have a specific function of their own. The)' believe that the thyroid and the parathyroids form a unique, physiological system, that the thy- roid is capable of a vicarious function in case of parathyroid insufficiency, and vice versa. In view of the enormous amount of work done in that line by the most competent observers such conclusions seem audacious and presumptuous. They seem certainly contradicted by the clinical facts. Postoperative Tetany in Animals. — The symptoms due to complete parathyroidectomy develop soon after operation and are rapidly fatal. Localized or generalized tetany is the dominant symptom. A few hours or a day or two after parathyroidectomy has been performed, symptoms begin; the gait of the animal becomes unsteady and awkward; an intense tremor develops and later on clonic muscular contractions, tetanic cramps, resembling the contractions seen in tetanus, dominate the pic- ture. Resting apparently quietly for a time the animal is suddenly taken with a convulsive spell, falls on his side, with teeth chattering; rigidity may or may not be present; a few r minutes after everything is over. These spells gradually recur more frequently and the spasmodic contractions become more intensely developed. During the convulsions the animal cries, showing that he suffers; his hind legs are contracted and stiff and in the most severe cases the animal may lose consciousness for hours. During the spell his temperature rises verv high and may reach 109-uo . Respiration is accelerated. During the spells dyspnea is very marked, tachycardia is present; urine is scarce and often contains albumin. The number of red corpuscles is diminished, whereas the pol\ nuclears are increased. Death occurs, as a rule, five to eight days after parathyroidectomy, and takes place during convulsions or coma. If one parathyroid has been left in situ, tetany does not follow or may appear only temporarily. This is so true that Halstead was able in a very elegant and conclusive experiment to show that the removal of the tour parathyroids in an animal was absolutely harmless, provided that one of these glandules was transplanted into the abdominal wall. I he animal lived without showing any pathological manifestations what- ever. Hut as soon as the transplanted parathyroid was removed, marked symptoms of tetany soon appeared and death followed quickly. In some instances tetanv developed, although one parathyroid had been left in situ. This was probably due to the fact that the little glandule had been unduly traumatized or disturbed and had gradually under- gone resorption. If removal of the parathyroids is done gradually and at different periods of time, as soon as the whole parathyroid system is removed, the symptoms become just as acute as if all the pat a tin roids 36 PHYSIOLOGY OF THE THYROID had been suppressed in one sitting. Although the symptoms are less marked in adults than in young animals, the termination is neverthe- less fatal in both. It is during pregnancy that parathyroid insufficiency presents its maximum of development. Adler and Thaler have shown experimentally that the removal of a small portion of the parathyroids in pregnant animals caused severe symptoms of hypoparathyroidism, whereas the removal of the same amount of parathyroid tissue in non- pregnant animals was without effect. Iselin showed that the offspring of rats which had undergone experi- mental lesions of the parathyroids showed a marked congenital tendency to tetany. This latent parathyroid insufficiency was so marked that the removal of one parathyroid only was sufficient to determine the most violent tetany, and which always proved fatal. Pfeiffer and Mayer found in the blood of dogs suffering from post- operative tetany a toxic principle which injected into mice did not cause any disturbance whatever until the parathyroids of these mice had been subjected to trauma. In that case, even if a large portion of the para- thyroids were left uninjured, the mice developed the most severe tetanic symptoms, whereas the controls remained unaffected. Action of Thyroid Administration and Thyroidectomy on Metabolism. — ■ Under normal conditions the thyroid secretion is a physiological product playing a very important part in metabolism, and elaborated in suffi- cient quantities to meet the physiological demands of the organism, but as soon as it is secreted in excessive or insufficient amount, marked pathological symptoms follow; hence, hyperthyroidism and hypothy- roidism. From the beginning of opotherapy it has been observed that if thy- roid preparations are given to animals or human beings, a certain train of toxic symptoms which we call acute thyroidism may sometimes follow, as tachycardia, headache, vertigo, mental excitation, tremor, nausea, vomiting, polyuria, albuminuria, glycosuria, and moderate exophthal- mos. The symptoms observed in such conditions are of two varieties: (i) the ones due to the physiological properties of the thyroid itself; (2) the ones due to adulterated thyroids. This latter condition will be discussed in the chapter on Opotherapy. Some of the symptoms found in acute thyroidism are very similar to those found in iodin intoxication, as cerebral excitation, palpitations, tremor, etc. Ewald believes that a certain number of symptoms seen in acute thyroidism may be due to the excessive or rapid phenomena of disassimilation and to the direct action of the drug on the nervous centers. Thyroid extract injected into normal animals produces at first prostration and somnolence, and soon after tachycardia, tremor, fever, dyspnea, extreme agitation, brilliancy of the eyes, slight exoph- ACTION OF THYROID OX THE CARDIOVASCULAR SYSTEM 37 thalmos, and polyuria. Gradually the animals lose flesh, have diarrhea, melena, polyuria, albumin, and finally sink into a state of stupor, become semiparalyzed in their hind legs, and die. Young animals succumb very much sooner to hyperthyroidization than adult ones. Ballet saw a young dog, five or six months old, die seven days after daily intra- venous injections, whereas adult animals could stand doses three times larger for months. In certain instances, thyroid extract being used in subcutaneous injections, the same authors could witness the development of a real, experimental goiter. Lanz and Trachewski were able to produce an atrophic thyroiditis with thyroid feeding. Canter even saw the develop- ment of a myxedema. Injected subcutaneously, intravenously, or given by mouth, thy- roid extracts have more or less the same influence on previously thyroidec- tomized animals. Trophic disturbances gradually diminish; myxedema becomes less marked; the skeleton grows again; the metabolic exchanges increase; blood becomes normal; urine is secreted in greater quantities, and, in short, the animals have a tendency to become normal again. Action of the Thyroid on the Cardiovascular System. — In 1895 Schoefer saw that an intravenous injection of thyroid extract lowers the blood- pressure and causes a marked dilatation of the peripheric bloodvessels. As this has been found correct by many authors since, the thyroid gland has been regarded as an organ producing vascular hypotension. The theories set forth to explain this physiological phenomenon have been various. Von Cyon sought to explain it by the "depressor nerve theory." In collaboration with Ludwig he found in the cervical region of the rabbit a small nerve formed by the junction of a sympathetic branch and a small fillet coming from the superior laryngeal nerve which, as we all know, is a branch of the vagus nerve. This nerve is called the "depressor nerve." It extends downward into the thoracic cavity, reaches the heart, and terminates in the endocardium of the ventricles and auricles and in the region of the pulmonary artery and aorta. Its fibers are centripetal; excitation of the peripheric end does not produce any effect, but irritation of the central end is painful and determines at once a fall in the blood-pressure, which is caused by a reflex dilatation of the abdominal vessels. At the same tune the heart action becomes retarded. If the two vagi have been cut, the excitation of the depressor nerve has no more influence over the heart action, but produces, just the same, a fall in the blood-pressure. According t<> its discoverer the function of the depressor nerve is to protect the heart against a sudden increase of pressure in the aorta and pulmonary artery. As soon as the blood-pressure exceeds certain limits tin depressoi fibers, terminating in the endocardium, transmit at once the irritation to the 38 PHYSIOLOGY OF THE THYROID centers of the splanchnic nerves, either inhibiting the vasoconstrictor centers or intervening directly on the vasodilatators centers. This causes at once a vasodilatation of the abdominal system. On account of the enormous capacity of this system the blood is deflected from the heart and consequently the blood-pressure on that organ becomes reduced, hence the name depressor given to that nerve; at the same time the cardiac action becomes slower. "Therefore," says von Cyon, "the depressor nerve should be regarded as a means of defense of the heart." At the same time, through its vagal portion, the depressor nerve puts the heart and the thyroid gland in direct communication, so that a mutual and direct influence of one organ upon the other is established. Furthermore, it seems to be an accepted fact that iodothyrin and thyro- globulin increase the excitability of the vagus and depressor nerves, whereas they diminish the excitability of the cardiac accelerators. There seems to be no doubt in von Cyon's mind that this fall in blood- pressure takes place through the depressor nerve. According to Carnot and Georgiewski the fall in blood-pressure can- not be the consequence of the bulbar or spinal paralysis of the vaso- constrictor centers, as it takes place after the bulb and medulla oblon- gata have been destroyed. Neither can it be a question of paralysis of the peripheric abdominal vasoconstrictor centers, as it takes place after ligature of the abdominal organs. The fall of pressure subsists after both vagi have been paralyzed with atropin. Very likely, according to these authors, it is due to direct action of the thyroid secretion on the cardiac musculature. More recently Fiirth, Schwarth, Gautrelet and Lohmann have thought that the hypotensive action of the gland was due to choline. This substance, however, is not found only in the thyroid but also in all the other organs. Lohmann found in the thyroid three substances; one which he called arginine, without action on the pressure; another which he called histinine, markedly hypertensive; and another decidedly hypotensive. The action of the thyroid secretion on the heart, according to Hask- ovec and others, causes a marked tachycardia, increasing with the slight- est effort. This marked acceleration persists even if both vagi nerves have been cut. The frequency of cardiac trouble in goiterous patients is well known, and will be discussed at length in the chapter on Goiter Heart. Action on the Blood. — Soon after complete thyroidectomy in animals a marked anemia is found; the red corpuscles diminish and a leuko- cytosis takes place. It was on account of this anemic condition that the thyroid was for a long time considered as a hematopoietic organ. After thyroidectomy the blood becomes intensely "venous," and accord- ACTION OX THE XUTRITIOX 39 ing to Albertoni and Tizzoni, in the most severe cases of thyroid insuffi- ciency, the amount of oxygen may sink below the half of the normal quantity; of course the amount of CO2 is greatly increased. It is to this venosity of the blood that Herzen, Vassale and Rogowitsch attrib- ute the increased number of respirations of thyroidectomized animals. Vassale thinks that the red corpuscles have lost their capacity for fix- ing oxygen because he found that soon after intravenous injection of thyroid extract the blood loses its venous properties and becomes normal again. This "anoxyhemy" may explain why thyroidectomized animals are so sensitive to slight changes in temperature. This is true, too, of patients suffering from cachexia strumipriva or of a mild degree of spontaneous hypothyroidism. We know that such patients prefer to be in warm rooms, and that even in the hottest day of summer they do not suffer from the heat. The number of red corpuscles is materially diminished and so is the hemoglobin; polvnucleated erythrocytes are not a rare feature. In such conditions the red corpuscles have a fetal aspect, are larger in diameter, and contain several nuclei. In hyperthyroidism the red cor- puscles do not show any modification in quality nor in quantity. Soon after thyroidectomy the leukocytes increase in number but diminish later on. In hyperthyroidism the number of leukocytes is reduced, but hvperlymphocytosis combined with hypopolynucleosis is present. The blood serum of thyroidectomized animals possesses toxic prop- erties, and according to Bianchi, Jacobi and Wassermann its bactericide power is diminished. This explains why insufficiency of the thyroid predisposes to infections. Pagenoff thinks that the toxicity of the serum is caused by a leukomain which probably is nothing more than the thyreoproteid of Notkine. Action on the Nutrition. -After thyroidectomy the nutritional dis- turbances are very marked. The animal's metabolism is reduced, the nitrogenous excretion is diminished, and in the skin a myxedematous infiltration takes place; this edema is hard, does not pit on pressure, and is of a sallow color. According to Virchow this infiltration is caused by an active proliferation of the subcutaneous tissue and to the pres- ence of mucine. In myxedema Horsley has found mucine not only in the skin but in the blood, muscles, carotids, etc. He considers the thyroid as an organ regulating the assimilations and disassimilations; in his judgment, after removal of the thyroid these assimilatory pro- cesses do not take place any more, consequently, albuminates remain in their mucinoid state and are not metabolized. The thyroid regulates the accumulation and repartition <>l fat in the body. It is well known that in hypothyroidism adipose tissue is increased, whereas in hyperthyroidism it is diminished. Lately it has 40 PHYSIOLOGY OF THE THYROID been demonstrated that the thyroid contains a lipase which in thyroid insufficiency is diminished, but is materially increased in hyperthy- roidism, hence the intense lipolytic properties of the serum in Graves' disease. This lipolytic property is found not only in vivo but in vitro, as Youchtchenko has demonstrated. Action on the Osseous System. — Trophic disturbances of the osseous system after total thyroidectomy are so much the more marked that the loss of thyroid function occurs in young individuals. The growth of skeleton ceases, bones remain short and fragile, calcification is incom- plete, and ossification of the cartilages is arrested. Bones of thyroid- ectomized animals compared with those of controls are seen to be at least a third smaller. As pointed out by Gauthier, the fact that certain fractures do not repair normally and that the callus formation is retarded for weeks and months may be recognized as the result of thyroid insuffi- ciency. Thyroid opotherapy in certain of these conditions has proved, indeed, very successful. On the other hand, according to Holmgren individuals affected with exophthalmic goiter at the time of their growth appear to have longer bones than normally. Action on the Nervous System. — In animals which have died following intensive hyperthyroidization no well-defined lesions of the nervous system are found, whereas the cerebrospinal lesions seen in thyroid- ectomized animals have been various and multiple. Albertoni and Tizzoni found peripheric neuritis; Weiss and Rogowitsch found anemia, edema of the nervous elements, and a parenchymatous encephalitis; Schultze and Schwartz saw a leukocyte infiltration in the membranes surrounding the upper portion of the medulla. Herzen and Lowenthal saw a vacuolar degeneration and atrophy of the pyramidal cells and corticalitis of the region of the sigmoid gyrus, which is the motory center of the lower limbs. Capobianco saw vacuolar degeneration in both hemispheres of the cerebellum, in the bulb and in the gray matter of the medulla. Pisenti and Luppo found bulbar hemorrhages. Walter saw that thyroidectomy interferes with the regeneration of the per- ipheric nerve after traumatism, but that as soon as thyroid opotherapy is started the regeneration of the nerves takes place. Walter described marked pathological disturbances in the hypophysis after complete thyroidectomy. Langhans has found a marked degeneration of the muscles in cretins. This degeneration is found in Basedow's disease and may explain the muscular weakness and tremor found in this condition. Modification of the Urine. — In myxedema the quantity of urine is diminished and its toxic properties are increased. According to Pagenoff this toxicity of the urine is due to the same leukomain which he found in the blood of thyroidectomized animals. In the urine and thyroid of MODIFICATION OF THE URIXE 41 Basedow's patients, toxic products have been isolated by Bovnet and Silbert. The excretion of phosphorus in urine diminishes markedly after total thyroidectomy. Sugar, which is very often found in exophthalmic goiter, seldom appears in myxedematous conditions. It is well known that in Basedow's patients alimentary glycosuria is easily produced, whereas patients with hypothyroidism can stand large doses of sugar without showing glycosuria. Albumin is sometimes found in great quantities after complete thyroidectomy, but Corronedi claims that albuminuria is caused bv the fact that with the thyroid the parathyroids have been simultaneously removed, and that albuminuria is a symptom of parathyroid insufficiency and does not occur when the parathyroids have been left uninjured. Robert Hutchinson in a revision of the literature upon the effects of thyroid extractives on metabolism says: "It may be said that the effect of the administration of thyroid is to increase the oxidation of the body; it makes the tissues, as it were, more inflammable, so that they burn away more rapidly. The products of the disintegration of the nitrog- enous tissues appear in the urine almost entirely in the form of urea, uric acid, and the xanthin bases, while the products of the fat destruction are eliminated as CO2 by the lungs and water by the kidneys." Lnderhill and Faiki found that after complete thyroidectomy the ammonia output in the urine was increased even beyond what is observed in starving animals. Nitrogen in the urine is eliminated under the form of kreatin, punn bodies, allantoin. They found that thyroidectomized dogs are incapable of utilizing subcutaneously introduced dextrose in anywhere near the same degree as normal animals; that thyroid tissue fed to normal animals causes a slight increase in the urinary nitrogen excretion, and that this influence soon disappears when the thyroid feeding is stopped. Small doses of thyroid appear to have as pronounced an influence on nitrogen elimination as large ones. How much of the thyroid is it necessary to leave in order to prevent symptoms of thyroid insufficiency? It has been demonstrated experi- mentally by Colzi, von Eiselsberg, Fuhr, etc., that one-third or one- fourth of the entire gland is sufficient to prevent myxedematous degen- eration' Pincles found that one-eighth of the gland was sufficient to prevent thyroid insufficiency in the macacus. The remaining portion oi the gland left in situ undergoes a compensatory hypertrophy winch has been well described by Horslev and Halstead: cells begin to proliferate, become larger in size, and undergo a process of division forming new alveoli \uth colloid secretion. CHAPTER III. BIOLOGICAL CHEMISTRY. In the thyroid Ordtmann found 81.24 per cent, of water, 17.66 per cent, of organic matter, and 0.1 per cent, of inorganic matter, of which iodin occupies the most prominent place. After iodin had been discovered by Courtois in 181 2, Straub, of Berne, suggested that it was the active principle of the "toasted sponges" and "aethiops vegetalis," both of which had been used for centuries in goiter therapy. Ever since its discovery iodin has been universally employed in thyroid pathology. In 1895, very much impressed by the similarity of the effects of iodin and thyroid, Kocher suggested that it would be advisable to examine thyroids for that ele- ment. These researches, which were entrusted to an incompetent research worker, remained, however, negative. More fortunate than Kocher, Baumann in the same year discovered in the thyroid an ele- ment which he called iodothyrin (thyroiodin of Roos). This he consid- ered as the active principle of the gland. Brown states this amorphous substance resists the digestive ferments and is insoluble in a 10 per cent, solution of HC1. Its iodin content varies from 10 to 14 per cent. This nitrogenous compound gives the xanthoproteic reaction. Later researches established the fact that this substance does not exist as such in thyroid, and that it is not the result of an active principle in the gland, but is produced artificially by the brutal action of sulphuric acid on the thyroid and is the result of decomposition of iodized substances contained in the gland. Notkine extracted from the thyroid an albuminous substance which he called thyreoproteid. Given in subcutaneous injections to thyroid- ectomized animals it produces convulsions, dyspnea, and death, whereas given to normal animals it causes symptoms resembling those of cachexia strumipriva. This substance is not normally found in the thyroid, but is a toxic product of metabolism, and is neutralized in the gland itself. Hutchinson, in 1 897, discovered in the colloid two different substances : a proteic one, scarcely active and containing very little iodin, and a non- proteic one, with energic properties, and rich in iodin and phosphorus. Oswald isolated from the thyroid two different substances: the thyreoglobulin and the nucleoproteid. The first one may contain iodin or may not. If it contains iodin, it is called iodothyreoglobulin. The nucleoproteid is free of iodin but contains great quantities of phos- phorus. Both substances enter for the most part into the composition BIOLOGICAL CHEMISTRY 43 of colloid. Normally, the human thyroid contains from i to 9 grams of thyreoglobulin and its amount increases in direct proportion to the quantity of colloid. When injected intravenously the nucleoproteid was found bv Oswald and von Cvon physiologically inactive, whereas the iodothvreoglobulin possesses energetic properties. Its iodin content varies with the species of animal, 1.16 per cent, in the hog, 1.86 per cent, in cattle, and 0.^4 per cent, in the human being. When thyreoglobulin is free of iodin, as in young animals, it may be transformed into iodothvreoglobulin bv adding an iodide compound to the food. This synthesis is possible in the organism only, as Oswald was unable to iodize the thvreoglobulin in vitro. In newborn babes whose mothers had been fed with iodin Nagel and Roos always found iodin in their glands, while thev did not find any in the thyroids of babes whose mothers had not been fed with iodin during their pregnancy. Marine and Lenhart have recorded similar results for animals. The quantity of iodin contained in a gland is dependent upon the quantity of colloid and upon the quantitv of thvreoglobulin contained in the colloid. The quantity of iodothvreoglobulin which can be extracted from the thyroid amounts to a few grams and contains about 0.5 per cent, of iodin. How much of this substance is daily secreted by the thvroid is extemely hard to say, but, according to Oswald, if we take into con- sideration the amount of iodothvreoglobulin which was sufficient to cure the case of myxedema reported by him we may judge that in the adult this amount will scarcely exceed 0.05, which contains about nr mg. of iodin. The action of iodothvreoglobulin must not be compared with iodin, as the latter has entirely different pharmacodynamic properties. Iodin is an inorganic compound while iodothvreoglobulin is an organic albuminous substance. The nucleoproteid of Oswald does not contain iodin but contains 0.16 per cent, of phosphorus and arsenic. Besides these elements leuko- mains have been found by Bourquelot and Lepinois and bromine by Baldi. Chamagne was able to extract from the thyroid very toxic lipoids. Albumoses, leucin, xanthin, hypoxanthin, NaCl, sulphur, oxalate of calcium, and lactic acid are parts of the constituent elements of the thyroid. The dijodthyrosin which Oswald discovered lately has tin- charac- teristic elements of iodized albuminous substances, but has no effect on the circulatory apparatus nor on the nervous system, and does not influence goiter in anv wav, therefore it cannot be considered as the active principle of the thyroid. Kendall isolated a crystalline iodin '60 per cent.' compound from the thyroid in 1914. It is locked in the protein molecule and can !>< obtained only under the influence of carbon dioxid. The administ ration 44 BIOLOGICAL CHEMISTRY of this substance gives all the effects of thyroid administration. If amino acids are injected simultaneously the pulse-rate is enormously affected; otherwise not. In general it affects the growth, mentality, skin, hemoglobin, and metabolism. lodin in the Thyroid Gland. — Iodm is found not only in the thyroid gland, but can also be detected in a great many other organs, as the muscles, suprarenal bodies, hypophysis, liver, kidneys, central nervous system, thymus, spleen, and lymph nodes. We must admit, however, that it is present in the thyroid in larger quantities than in any other organ of the body except in the parathyroids. There, according to Gley and Lafayette, the quantity of iodin is even larger than in the thyroid. Iodin varies with the conditions of life of animals as well as of patients; it varies, too, with localities. In Fribourg, Switzerland, for instance, where goiter is frequent, Baumann found only traces of iodin in 7 out of 26 glands. Their average content was about 2 mgs., whereas 10 out of 27 glands from Hamburg contained more than 4 mgs. In Berlin the quantity was found to vary from 5.3 to 8.1 mgs. This differ- ence was more striking in children. Out of 17 children of Fribourg from one day to seven years old only traces were found. Five times the thyroid contained a quantity of iodin varying from 0.7 to 0.3 mg., whereas in 5 thyroids of children from Hamburg, iodin was constantly present in proportion of 0.1 to 0.45 mg. Iodin content in the thyroid increases if the food contains iodin. The aliments which contain most iodin are asparagus, carrots, beans, mushrooms, and fish. Iodin medications increase, too, the iodin con- tent of the thyroid. After the skin of a dog had been rubbed with iodoform, Baumann found that the thyroid gland of this dog contained 0.3 mg. Smith and Broders found that external applications of tincture of iodin increased to a considerable extent the iodin content of the gland, and that iodide of potash given internally or hypodermically increased the iodin content of the gland very materially. After ingestion of bromides, brome is stored in the thyroid in the same way as iodin. The amount of iodin in the thyroid increases gradually up to middle age and then decreases with old age. Atherton Seidell and Frederick Fenger found (loc. cit.) "That a marked seasonal variation existed in the percentage of iodin present in the healthy, normal-sized glands of the sheep, ox, and hog. There is in general about three times as much iodin present in the months between June and November as in the months between December and May. The seasonal variation in the size of the glands was observed in the case of the sheep and ox, but not in that of the hog. The glands were found to be larger in the months during which the lower iodin content was noticed." Iodin is not invariably present in the thyroid. Miwa, Stoeltzner and Baumann and other investigators have pointed out the frequent IODIX IX THE THYROID GLAXD 45 absence of iodin in the thyroids of children, of dogs fed on meat, and in those of cattle and other animals. They believe that iodin found in the thvroid has no more significance than the traces of copper found in the liver, and that its presence or absence and its quantity are dependent upon the food of the animal. In herbivorous animals iodin is found in greater quantities than in carnivorous, because vegetables contain iodin in greater or less quantity; whereas no iodin or very little is found in carnivorous, since pure meat diet contains no iodin or very little. Animals fed near the sea show a double amount of iodin than do those pastured in inland regions, because vegetable food along the coast is richer in iodin than that found in the interior. Topfer, of Vienna, found no iodin in the thyroids of cattle; Roos, none in the thyroids of dogs, none in that of the wild-cat, none in that of the pole-cat, and found it in but two out of six martens. It was absent from the thyroids of 4 domestic cats and traces only were found in those of 5 others. None was found in 4 out of 11 dogs nor in 2 out of 4 horses. Weiss, after examining the thyroids of 7 children under four and a half years of age, found that the iodin content varied from traces to 0.37 per cent. Wells, in analyzing the thyroids of 6 children from Chicago, found that the glands of 3 had from traces to 0.092 per cent.; the other 3 had 0.11 per cent. Yon Rositzky noticed in children under ten years of age that iodin in the thyroids varied from 0.012 to 0.041 per cent. Oswald, in 5 chil- dren from Basel under seven years of age, found from traces to 0.16 per cent. Charrin and Bourcet found in the thyroids of infants under three months from 0.0004 to 0.0054 per cent. Mendel found no iodin in the thyroids of 4 infants and found 0.07 mg. in others. John found in 27 children from Sweden under four years of age no distinct traces of iodin and in 7 cases from traces to 0.086 per cent. Nigel and Roos found no traces of iodin in the thyroids of 4 newborn puppies. ^ et animals as well as human beings in which iodin was totally absent or found in traces only were in just as good condition as the ones whose thyroids contained a higher percentage of iodin. Never have the chil- dren or animals in which iodin proved to be absent shown any indica- tion of thyroid insufficiency. The hen's egg does not contain iodin when the young chick begins its life, yet its development seems to go on normally. The same is true for the human newborn. It is not pos- sible to detect any pathological difference between animals winch have a high percentage of iodin in their thyroids and those which contain none. I he thyroid free from iodin seems to meet the needs of the body just as well as the thyroid which contains iodin. Thyroidectomy is followed by as severe symptoms in the latter case as in the former. 1 herefore many authors conclude that iodin is not necessary for the physiological activity' of the gland, that it is not the active principle of the thyroid, and that it is onlv an accidental constituent of its secretion. 46 BIOLOGICAL CHEMISTRY Hutchinson corroborated these conclusions. After having prepared an artificially iodized nucleo-albumin from the thymus of the calf, sam- ples of which contained from 4 to 7 per cent, of iodin, he found it inac- tive in the treatment of myxedema and without effect upon the pulse, temperature, or weight of the subjects to whom it was administered. Blum and Hellin also found that iodized albumin was physiologically inactive. They consequently concluded, too, that iodin does not play any important part in the physiological function of the thyroid. Because an organ contains a physiologically active substance it does not follow that its physiological activity is due to that substance; for instance, we know that the thyroid contains arsenic in larger quantities than many other organs, yet nobody will claim that arsenic is the active principle of the thyroid, although arsenical preparations are all very active. In 1899 Roos was the first to take exception to such views and reported the results of experiments tending to show there is a direct relation between the iodin content and the influence of the thyroid upon metabolism. He gave to a dog 5 mgs. of children's desiccated thyroid containing 0.025 P er cent, of iodin. No effects upon the excre- tion of nitrogen nor upon the body weight were noticed. Another dose of 5 mgs. of children's thyroid containing 0.18 per cent, of iodin was found to cause an excretion of nitrogen of about 10 per cent.; and as the same proportion of iodin contained in the thyroid increased, the effect upon the metabolism became proportionately more marked. Von Cyon and Oswald found that thyreoglobulin free of iodin obtained from goiterous calves had no effect upon the circulation, but became active in direct proportion to its iodin content. Marine and Williams in two experiments fed desiccated sheep thyroid containing different per- centages of iodin to dogs and found that the loss of weight of the animal was in proportion to the quantity of iodin in the thyroid fed. Des Ligneris demonstrated that iodin taken by mouth or given externally to young dogs causes in parenchymatous glands an increase of colloid, the folliculi became distended, the epithelium flattened, and the blood supply diminished. The same experiments made upon old dogs had very little or no effect at all upon the amount of colloid; in grown dogs with colloid glands iodin did not increase the amount of colloid. Everybody knows Halstead's classical experiment: If a portion of thyroid is removed, the remaining portion of the gland reacts by secondary hypertrophy characterized by diminution or absence of the colloid secretion, hyperplasia of the epithelium, and increased vascu- larization. But if, soon after partial thyroidectomy has been performed, iodin is administered to these animals no secondary hypertrophy takes place; if iodin is given previously and then only partial thyroidectomy is performed, very little or no hypertrophy takes place. IODIX IN THE THYROID GLAXD 47 Marine and Lenhart not only confirmed these results but went a step farther and claimed there is a constant relation between iodin con- tent and the structure of the gland. The}' demonstrated that although it is true that in Halstead's experiments iodin will prevent secondary hypertrophy, it will not have this effect if a maximum of thvroid is removed; compensatory hypertrophy will then take place just the same. In order to produce these changes the amount of iodin does not need to be very large; the smallest doses are very effective. The same authors believe (loc. cit.) "that the organism retains iodin in the same manner in which it retains iron and calcium. The difference between the maximum and minimum of iodin found to be compatible with the maintenance of the normal histological structure represents the excess of intake or consumption. If iodin falls below a quite constant level, the gland undergoes characteristic and constant histological changes, while if iodin is given these changes, either do not occur, or if they have started, they are arrested. It is of little or no consequence whether hyperplasia occurs in man or animal, or whether it is associated clini- cally with myxedema or exophthalmic goiter. In the presence of suffi- cient doses of iodin all true hyperplasia is prevented." I do not know how far these conclusions are correct, but they cer- tainly do not correspond to what we see in our daily practice. From the above statements we have the right to infer that glandular hyper- plasia found in Graves' disease is due to a "more or less marked lack of iodin," that the severity of the disease is in direct proportion to the diminution or absence of iodin in the gland, and consequently that iodin treatment is the only logical treatment of the condition. Nothing has been less demonstrated than that "lack of iodin" is the cause of Basedow's disease, and that its severity is proportional to its presence or absence; on the other hand, nothing has been better demonstrated than that iodin is not the specific treatment of exophthalmic goiter. More so, in the great majority of cases it is harmful. Yet it cannot be denied that Iodin will prevent secondary glandular hyperplasia, as in Halstead's experiment. Why such inconsistency ? Very likely simply because glandular hyperplasia in Graves' disease and glandular hyper- plasia found as a compensatory process after partial extirpation <>t the gland an- due to two absolutely different conditions corresponding to two absolutely different processes. Similar does not mean identical, and because glandular hyperplasia in both conditions has a histological resemblance, nothing proves that their chemicopathological functions arc tin- same. Although variable in its limits, the highest iodin content per gram is Found in normal glands. Whether these variations are due to varia- tions in the intake or to the consumption within the organism or to 48 BIOLOGICAL CHEMISTRY both is not known. More probably they depend upon the intensity of the chemicobiological metabolism whose intensity varies with each given individual. In parenchymatous and exophthalmic goiter the amount of iodin varies inversely with the degree of glandular hyperplasia; consequently, the lowest amount of iodin will be found with the highest degree of hyperplasia. Yet Oswald, Caro, Smith and Broders, myself and others have observed cases of Graves' disease in which the iodin content was remarkably high. As in marked hyperplastic conditions colloid is generally absent or very much diminished, we can say that iodin varies in direct proportion to the amount of stainable colloid. Aesbacher strengthened these views by finding a diminished iodin content in alco- holic intoxication and in acute inflammatory diseases of the thyroid. This was to be expected, as we shall see in the chapter on Bacterial and Toxic Thyroiditis, that in such conditions there existed at the same time a glandular hyperplasia and a diminution of colloid. Claude and Blanchetiere, however, refuse to see any such parallelism between col- loid and iodin, as they have found high iodin content in glands where no colloid was present. It is very well agreed that colloid glands in general contain less iodin than normal glands, although to this there are many exceptions, as shown by Oswald. In fetal adenoma Marine and Williams found iodin and there, too, the iodin content was in direct proportion to the glandular hyperplasia. The total amount of iodin that a gland may contain depends upon its size, the diet, locality, medi- cation, etc. As regards the iodin content in human thyroids of cretins, no specific observations are recorded, but as these glands are atrophied, we can assume that the iodin content must be low. In old age there is a slight decrease of iodin seemingly proportionate to the degree of senile atrophy. Be that as it may, the fact becomes more and more evident that iodin must not be regarded as purely accidental, but that it plays some important function in metabolism. The merits of having come nearer the solution of this problem certainly belong to Reid Hunt and Atherton Seidell. In extremely elegant and conclusive experiments they demon- strated that if small amounts of thyroid are fed to mice for a few days, these animals acquire a markedly increased resistance to acetonetrile. Thus, a mouse which had been fed with thyroid for nine or ten days recovered from seventeen times the relative amount of acetonetrile fatal to the controls; hence the conclusion that thyroid enables the mouse to "neutralize" or resist in some way doses of acetonetrile which in ordinary conditions are fatal. From another series of experiments it was found that if one part of iodothyrin was fed to a mouse for ten days, it enabled the mouse to resist more than 240 times an equal amount of acetonetrile. IODIX IX THE THYROID GLAXD 49 Up to that time iodin-free thyroids were regarded as being deprived of their physiological activity. \\ ith their delicate tests the same authors were able to demonstrate that this is not the case. They found that iodin-free thyroids have a low degree of physiological activity, that their activity is lower than the thyroids containing iodin, and that their physiological properties increase in direct proportion to the amount of iodin. Consequently, it may be concluded that the activity of iodin- free thyroids is nevertheless largely due to the iodin present in too small quantities to be detected, or that the iodin-free thyreoglobulin has of itself some physiological properties. The latter possibility would explain why in Hunt's and Seidell's experiments certain iodin-free thyroids were more active than thyroids containing small amounts of iodin. It may be supposed that iodin-free or iodin-poor thyroids can meet the ordinary demands of the organism; but if the demands upon the thyroid are not adequate to the function of the iodin-free gland, marked symptoms of hypothyroidism will follow, as shown, for example, by the losses suffered by sheep breeders on account of cretin lambs before the exten- sive use of lodin-containing salt. Continuing their experiments, Hunt and Seidell found that the resistance of rats, mice, and guinea-pigs to morphin is uniformly low- ered after thyroid feeding. In the case of rats there is a close parallelism between the physiological effect of the thyroid as determined by the increased susceptibility to morphin and the percentage of iodin. A similar parallelism was found in general in experiments on mice. Ani- mals which had received thyroid with a higher percentage of iodin showed a better resistance. There is no explanation for the cause of this increased susceptibility. If we sum up the results of these experiments and weigh them, it cannot be denied that a fact stands forth most strikingly, namely, that iodin seems to be of great importance in the thyroid's physiological activity. This is so true that Oswald considers iodothyreoglobulin as the active principle of the secretion, because, according to him, it possesses all the physiological properties of the thyroid. As we know, one of the most important properties of the gland is to cure spontaneous as well as operative myxedema. Now then, Oswald treated a young myxedematous boy, eighteen years old, measuring 131 cms. in length. He gave the boy a daily dose of 0.1 gm. of iodothyreoglobulin for twenty- one months. During that period of treatment the patient grew 21 cms., lost his cretinoid appearance, and improved in every respect, mentally as well as physically. Pick and Pineles have come to the same conclu- sions experimentally. Another property of the thyroid is to increase oxidation of fat and albumin. This property is found, too, in iodothyreo- globulin. Thyroid extract increases the susceptibility of the vagus 4 50 BIOLOGICAL CHEMISTRY fibers to the faradic current; iodothyreoglobulin does the same. Accord- ing to Oswald no other substance in the thyroid has a single one of the same properties as the iodothyreoglobulin, and these properties are due to the iodin combined with a globulino-albuminoid substance. Is it really so ? Is it really to iodin that thyreoglobulin owes its physiological properties and is iodothyreoglobulin the true active prin- ciple of the gland ? The question is not settled: Baumann and Hutchin- son, Oswald, Gauthier and others say, "Yes," whereas Fraenkel, Dreschel, Gottlieb, Chassavant, Hunt, Seidell, etc., claim that the iodized proteids are not the only ones possessing physiological activity. Most probably each camp holds a part of the truth; neither one of the compounds can be considered as representing the whole active prin- ciple of the thyroid gland; there must be other compounds endowed, too, with some physiological properties. This is suggested by the fact that every kind of thyroid preparation, and they are numerous, has some of the physiological properties of the thyroid, and that the thyroid in toto given as medication has succeeded where iodized preparations have failed. If iodin plays an important part in the clinical function of the thy- roid secretion, we must not forget that there are in the thyroid other chemical compounds to w 7 hich not enough consideration has been given. Arsenic, for example, as previously said, exists constantly in the thyroid, and is present in that gland in quantities larger than in any other organ of the body. Certainly its presence is not an accidental one; it must play a part in the physiological activity of the gland. In nature arsenic and iodin do not exclude each other; on the contrary, they are most frequently found associated; sulphurous and iodized waters contain arsenic; algae, for instance, contain iodin and arsenic always mixed together. Furthermore, iodin combined with arsenic is always an excellent thyroid medication. According to A. Gauthier arsenic is found in the thymus, skin, brain, and hypophysis, but nowhere else. Is this only a coincidence, or has it a greater significance than it seems to have at first? The answer is not yet at hand, but it will be inter- esting to note that the thymus, brain, skin, and hypophysis are pre- cisely the organs electively involved in thyroid disturbances. Phosphorus is constantly present in the thyroid. According to Bayer 5 gms. of fresh thyroid contains 0.00102 gm. of P2O5 (pentoxide of phosphorus). Kocher regards phosphorus as playing an important part in thyroid physiology. There seems to exist an antagonistic action between iodin and phosphorus. Brisson, who has investigated the sulphur content of several endo- crine glands, found 0.23 gm. of baryte sulphide per 2 gms. of thyroid. The organs which contain the greatest quantity of sulphur are the suprarenal bodies, testicles, and keratine. CONCLUSIONS CONCERNING THE THYROID FUNCTION 51 In the thyroid Iscovesco found lipoids, which possess a very ener- getic physiological action. According to him there is in the organs of vertebrates a specific and unique lipoid which, injected into the organ- ism of an animal, has the property of localizing its action on the organ from which it originates and on this one only. These lipoids are called homostimulants because the}' exert their action by an elective influence on the medullar centers controlling the organ from which they derive. One of these lipoids, called by Iscovesco thyrol A, injected hypodermi- callv produces exophthalmos, tachycardia, and swelling of the thyroid; another lipoid when given in doses of 2 cgms. per kilogram produces cachexia. The activity of the gland was thought to depend upon its ferments, and lately Youchtchenko showed that the thyroid secretion contains a great quantity of catalase and peroxydase. These ferments preside over the oxygen exchanges in the organism. In carnivorous animals he found in the thyroid a certain amount of lipase, a ferment which intervenes in the metabolism of fat. This would explain certain conditions found in hypo- and hyperthyroidism. In hypothyroidism the peroxydasic and lipasic ferments, being diminished on account of the reduced function of the thyroid, oxydative processes will be diminished, hence the sensation of cold, adipositas, etc.; on the other hand, in exophthalmic goiter the cellular activity being increased, the ferments are in greater quantity; consequently the metabolism is accelerated; hence the sensation of heat, elevated bodily temperature, loss of flesh, etc. In summing up we see that the pharmacodynamic function of the thyroid, as of other organs, the liver, for instance, is not one but is mul- tiple; it seems therefore logical to ascribe to the thyroid several func- tions: an iodin function presiding over the general metabolism; a phos- phorus junction presiding over the thermogenesis and over the vaso- motor)' system regulating the cardiac rhythm; a sulphurus Junction presiding over the nutrition of the skin and the pileus system; and an arsenical function presiding over the nervous function and whose insuffi- ciency causes, according to Hertoghe, migraine. Most likely every one of these functions takes place through a special hormone. Conclusions Concerning the Thyroid Function and its Chemistry. The thyroid is an organ necessary to life and plays an important part in metab- olism. It presides over the nutritional exchanges, over the osseous growth, and regulates the nervous and vascular systems. Its insufficiency causes hypothyroidism. To this condition belong not only myxedema and cretinism, but also a large series of intermediate stages called by Hertoghe "form frustes," and characterized, as we will see later, by disturbances in the sexual apparatus, gastro-intestirral tract, osseous system, etc. These disturbances may be more or less marked; mam of 52 BIOLOGICAL CHEMISTRY them may be present at the same time, or only one symptom may betray a light degree of thyroid insufficiency. Thyroid and parathyroids differ not only embryologically and anatomically, but are also functionally two different organs. Complete removal of the thyroid gland produces chronic nutritional disturbances, as retarded osseous growth, myxedematous infiltration of the skin, marked reduction in general metabolism, with profound psychic dis- turbances. On the other hand, complete parathyroidectomy causes acute nervous conditions, as convulsions, tetany, which soon terminate in death. At the same time, hyperthermy, tachycardia, and dyspnea, as found in acute intoxications, are present. What is the active principle of the gland ? We may say that this active principle is not one but is multiple. The one which we know best is iodothyreoglobulin. It is regarded by many as the real and only active principle of the thyroid. This, however, has not been sufficiently demonstrated. No doubt it plays a very important part in metabolism and controls to a great extent the growth of the osseous system; better than any other, this substance embodies the best, the physiological, action of the thyroid itself. But it is not the only one; there are other substances in the thyroid which are physiologically important; there is a phosphorus principle presiding over the vasomotory system regulating the cardiac rhythm and thermogenesis. We have also seen that there is a sulphurous principle presiding particularly over the nutrition of the skin and pileus system. Finally, there is an arsenical principle which has a certain action over the nervous system. Every one of these prin- ciples represents, we may say, a special hormone. How these different hormones, and very likely others which we have not yet discovered, exert their action and where is not known. Shall we consider them as excitants of the cellular nutrition facilitating the assimilative process, or shall we consider them as substances necessary to the cell itself and its functions, just as traces of zinc seem to be an absolutely necessary aliment for the aspergillus niger? The answer is still not at hand. Biedl thinks that there are in the thyroid two hormones which he calls dissimilatory and assimilatory. According to him the dissimilatory hormones activate the normal activity of the organs, of the heart, of metabolism, of the adrenals, of hypophysis, etc. The assimilatory hor- mones, on the contrary, paralyze a great many organs and functions, as the growth of bones, the function of the pancreas, etc. The fact that thyroid substances resist the action of the stomachal and intestinal digestive ferments shows that its main active principle is more than an albuminous substance. Certainly it is difficult to admit that the ferments as catalase, peroxydase, and lipase found in the thy- roid have no pathological significance and that their presence in that COXCLUSIOXS COXCERXIXG THE THYROID FUNCTION 53 organ is purely accidental. These ferments preside over the oxygen exchanges and intervene in the metabolism of fat. The same may be asserted for the lipoids; they certainly must play some part in the very complicated biological chemistry of the thyroid. Consequently, we see that the thyroid function is not one but is multiple, and is an extremely important one. How does this gland exert its influence over the metabolism ? A great majority of authors believe that the gland has an antitoxic action and that it secretes substances which neutralize poisons resulting from metabolism. This was the opinion of SchifFand seems to be corroborated by the fact that intense bleeding in thyroidectomized animals dimin- ishes the intensity of hypothyroidism symptoms. Intravenous injection of salt solution does the same thing. We may consequently infer that toxic products have been partly eliminated with the bleeding or dis- solved by the physiological solution injected. Notkine believes that the thyreoproteid is the toxin which is the real cause of myxedema, and that the physiological action of the thyroid consists in neutralizing the thyreoproteid contained in the organism. Fraenkel believes that the neutralizing agent is the thyro-antitoxin, Baumann thinks that it is the iodothyrin, and Oswald the iodothyreo- globulin. Von Cvon believes that the principal function of the thyroid is to transform iodin compounds into a harmless organic combination, the iodothyrin; Blum, that the thyroid neutralizes in the gland itself the toxic products of intestinal origin, the enterotoxins. According to him there is in the thyroid an intermediary product which he calls thyro- toxalbumin, whose antitoxic power is due to iodin. As it is possible to obtain from the thyroid various albuminous bodies with a varying iodin content, Blum believes that bodies poor in iodin are the more poisonous, that the ones containing the most iodin are non-poisonous and non-toxic, and that the ones saturated with iodin are harmless. On the nature and quantity of these various by-products reaching the circulation depend the various clinical conditions, as tetany, cachexia, etc. Blum does not make a difference between the thyroid and the parathyroids; he considers the latter glands as the younger forms of the thyroid. According to him iodin never leaves the thyroid to go into the organism, which statement he thought he proved by feeding dogs with an iodin-free diet for months; yet at the end of that time he was still able to find iodin in the thyroid. Cachexia, myxedema, and tetany are the results of an antithyreotoxin, the thyroid being unable to neutralize such products. Dor claims that iodin is transformed into an organic combination which in the general metabolism plays the role of a ferment. Kishi believes that the thyroid neutralizes the toxic prod- ucts of metabolism, especially the ones of muscular origin, and that it 54 BIOLOGICAL CHEMISTRY destroys the nucleoproteids, which are of cellular origin, and which are introduced into the organism with the food. When neutralized, these toxic substances are eliminated later on through the kidneys. Where does this antitoxic power take place ? Does it take place in the thyroid or outside ? Shall we consider this gland as a great chemical laboratory where the most important and most delicate reactions take place? Or shall we consider it as a filter, a sort of "clearing-house" where everything is carefully revised ? As the thyroid is a glandular organ and not a lymphoid one it is difficult to accept the opinion that the detoxicatory action takes place in the thyroid itself. On the other hand, the fact that thyroid given by mouth, rectum, or any other way is physiologically active shows that most probably the thyroid secre- tion exerts its action outside of the gland. This antitoxic theory, however, is not entirely satisfactory. Lindemann, studying the effects of caffeine when injected into the carotid artery of thyroidectomized animals, found that the dose neces- sary to kill a dog so treated was ten times larger than the one neces- sary to kill the control. We have seen that R. Hunt and A. Seidell found that mice which had been fed with thyroid for eight or nine days before were able to stand a dose of acetonetrile ten to twenty times larger than the one necessary to kill the control. How to explain these results ? Of course the partisans of the "detoxicatory theory" will claim that acetonetrile was neutralized and consequently rendered harmless, but Hunt and Seidell do not share the same view and believe that the function of the thyroid in such cases prevented the formation of the poison from mtnle because they found that the thyroid had no effect upon the toxicity of hydrocyanic acid itself, which is the poison resulting from decomposition of acetonetrile. They deem it impossible to think of any way in which such neutraliza- tion could occur, as the amounts of acetonetrile rendered harmless are so out of proportion with the amounts of thyroid fed. In their judg- ment the thyroid seems to alter the metabolism in such a way that the acetonetrile is disposed of without breaking down into its poisonous constituents, as occurs in normal glands. To believe that acetonetrile rendered harmless is out of proportion to the amounts of thyroid fed is no argument against the neutralization theory. Most probably the thyroid hormones do not differ from those of other organs. We know, for instance, that extremely small amounts of adrenalin are capable of causing the most energetic and powerful muscular contractions, the effect in this case being entirely out of pro- portion to the cause. We know, too, that very small amounts of secre- tin are capable of causing an abundant pancreatic and duodenal secre- tion; that all diastases contain a metal or metalloid in absolutely impon- INTERRELATION OF THE ORGANS OF INTERNAL SECRETION oo derable proportions, yet absolutely necessary for their efficacy, though entirely out of proportion to their effects. To be sure, arguments are not facts, and so there is still room for discussion. Were there a direct interaction between poisons and the thyroid, the same results should be expected in all classes of animals. Hunt and Seidell have shown that if the thyroid protects mice against acetonetrile, on the other hand it increases the suceptibihty to these poisons in rats and guinea-pigs. If, then, the thyroid has a neutralizing action, why should it neutralize in the one case and not in the other ? Therefore these authors conclude that when an unusual poison, such as acetonetrile, is introduced into an animal, its fate will depend upon how the animal's metabolism concerning this poison has been affected by the thyroid. The metabolism of mice has been affected in such a way that acetonetrile is rendered harmless, whereas in rats and guinea-pigs it becomes harm- ful. What occurs to acetonetrile is compared by Hunt and Seidell to what happens to methyl and ethyl alcohol (loc. cit.): "When such a poison as ethyl alcohol is introduced into the organism, the metabolism not only renders it harmless but makes it useful for the body in utilizing the energy set free. In the case of methyl alcohol, although oxidation may proceed along similar lines, part of the alcohol is con- verted into poisonous substances (formaldehyde and formic acid). The fate of acetonetrile in the body of the mouse must be compared to the fate of ethyl alcohol, and the fate of acetonetrile in the body of the rat which has been fed with thyroid to that of methyl alcohol." Conse- quently, these authors and others, as G. Gauthier, believe that the thv- roid gland instead of neutralizing the toxic products of metabolism pre- vents their formation. It has, then, a regulating action on the nutritional exchanges. Functional Interrelation of the Organs of Internal Secretion. — It would be a mistake to believe that the thyroid is left entirely to its own resources in its gigantic task, the regulation of the metabolism. It receives material support from other organs. For instance, the suprarenal bodies are indispensable to life; they not only exert an antitoxic action over a certain number of poisons circulating in the blood, as the one resulting from fatigue, but also throw into the blood stream substances which regulate the function of the vasomotors, cardiac, respiratory, and muscular centers. The hypophysis, according to Guerrini, Salvioli and Carraro, has, too, an antitoxic function and regulates the blood-pressure and the cardiac rhythm. Besides its digestive function the pancreas influences metabolism in regulating the production and absorption <>t sugar. Besides their known physiological action the genital glands secrete substances which, carried into the blood, have a favorable action over the vitality and tonicity of the muscular system. We must therefore 56 BIOLOGICAL CHEMISTRY consider these glands with internal secretion as organs whose chief duty is to regulate metabolism. They seem to be dependent upon one another. If one of these organs should become out of order, then more or less important functional disturbances will take place in the other fellow- glands. There is among them an anatomical and functional harmony, a kind of biological synergy, through which the functional equilibrium is maintained. These reciprocal, functional relations have been estab- lished by numerous experiments. After thyroidectomy an hypertrophy of the hypophysis takes place; in myxedematous patients the hypophysis has been found to be increased in size, as a rule. After thyroidectomy the thymus may undergo such an hypertrophy as to cause a sudden tracheostenosis and death. Revivescence of the thymus in Basedow's disease is a common occurrence. Cecca showed that after ovariectomy and orchidectomy an hypertrophy of the thyroid and suprarenal bodies takes place. Tescione came to the same results. Pirera and Soraud believe that between the pancreas and thyroid there is not only a func- tional relation but also a sort of substitution. They found that when the pancreas had been removed the antitoxic function of the thyroid was increased. According to Eppinger, Falta and Rudinger there exists a reciprocal inhibitory action between the pancreas and the thyroid, between the pancreas and the chromaffin system, while, on the other hand, between the thyroid and the chromaffin system a reciprocal, excitatory action is found. The consequences of such facts are easy to foresee. When the thyroid is removed, its inhibitory action over the pancreas having ceased, a hyperfunction of that organ must be expected; but as its excitatory action en the chromaffin system has disappeared, the function of the latter naturally diminishes. In hyper- thyroidism the inhibitory action on the pancreas is exaggerated and a relative insufficiency of the latter organ takes place; hence the intestinal disturbances so frequently seen in that condition. On the other hand, as the excitatory action over the chromaffin system is increased the latter system will be found in a state of hyperfunction. From all these extremely interesting facts we can conclude there is between all the organs with an internal secretion a functional correlation, a sort of physiological team-work. The normal function of one organ is dependent to a certain extent upon the normal function of the others, and when one is out of order it cannot fail to have a pathological repercussion on the others. Endocrinology is a science still in its infancy, but its promises are far-reaching; if fulfilled, it will be one of the richest fields to harvest. CHAPTER IV. PATHOLOGY. Synonyms in Latin: Struma; guttur turgidum. French: Goitre; gros cou. German: Kropf; Blaehals. Italian: Gozzo. Spanish: Papera. English: Goiter; great neck. According to Virchow a goiter is only the continuation of the natural development of the thyroid gland. In a follicle, cellular proliferation takes place by division of the cells, which gradually form solid papillary formations bulging in the interior of the follicle and filling the follicular lumen. Interstitial connective tissue penetrates these papillary forma- tions, carrying with it their vascular supply. Gradually they shape themselves into a more or less follicular form. In this, colloid secretion appears; hence the follicle; hence the goiter. If this process is localized to a part of the gland, then we have a nodular goiter; but if this process takes place all over the gland, then we have a diffuse goiter. Such goiter may become later on a cystic, fibrous, or a calcareous goiter; this depends, however, upon the secondary degen- erative changes which will take place in it. In conclusion, according to \ irehow, a goiter originates bv the subdivision of adult folhcuh into smaller ones; these in turn proliferate and finally form other adult alveoli. Hitzig, in 1894, shared the same view. In 1893 Wolfler modified Virchow's conception as to the origin of goiter. Contrary to Virchow's theory, which claims that goiter is due to hyperplasia, \\ olfler claims that it is due to neoplasia: that it is the consequence of the proliferation of the embryonic epithelium, remaining between adult alveoli, and which is found mostly in the cortical zone of the gland. These embryonic cellular residues, according to Wolfler's theory, are the ones which at one time or another may begin to prolif- erate and form goiter, which Wolfler calls adenoma. In his judgment an adenoma is an epithelial tumor with atypical vascularization, developed from embryonic glandular residues. It m the proliferating process the epithelium keeps its embryological aspect, the consequence of it is a fetal adenoma; but if the epithelium tends gradually toward the adult aspect, it then gives rise to a parenchymatous and colloid goiter. Wolfler distinguishes two kinds of adenoma, the benign and malignant. I hese two theories, although extremely interesting and partly cor- 58 PATHOLOGY rect, do not explain satisfactorily the origin of all the tumors found in the thyroid gland; for instance, they do not explain the origin of goiters with squamous epithelium, and they do not take into consideration at all a number of tumors found in the thyroid gland which have, as we will see later on, a very different origin. I refer to tumors developed from the thyroglossus duct; from the parathyroid; from the postbranchial bodies, etc. In the last few years the study of the embryology of the thyroid has afforded more light on the obscure field of its pathology. This has been true, too, of the ovary, testicle, and kidney. We might say there is a peculiar analogy between tumors developed in these organs and those developed in the thyroid. Tumors developed in the parathyroid and called parastruma are analogous to renal tumors called hypernephroma, and which are developed from the suprarenal bodies. Tumors with cylindrical epithelium originating from the thyroglossus duct find their analogy in tumors developed in Wolfs canal. Mixed tumors of the thyroid originating from the branchial bodies find their analogy in the mixed tumors of the kidney originating from the primitive sclero- myotomata. Langhans, of Berne, and his pupils, Michaud, Verebely and Getzowa, are entitled to a great deal of credit for attempting to clear up this question of the origin of thyroid tumors. Lately De Quervain, in 1909, and Berard and Alamartine, in 191 2, took up this subject, looking at it from an embryological point of view. We call goiter any enlargement of the thyroid gland. If this enlarge- ment shows clinically and pathologically the characteristics which we attribute to benign tumors, then it is called benign goiter; otherwise we call it malignant goiter. If vascular symptoms and congestion are the predominating features, then we regard it as a vascular goiter. If infec- tion sets in in a preexisting goiter, we call it strumitis; but if infection affects a normal thyroid, we call it thyroiditis. The enlargement may affect only a part of the gland or the gland in toto. If the goiter is made up of one or several nodules, we call it nodular goiter. If the enlargement is diffusely distributed throughout the gland, we call it diffuse goiter. We may have a diffuse parenchyma- tous goiter or a diffuse colloid goiter, according to the nature of the thyroid degeneration. In nodular goiter proliferation and the distribution of follicles are very much more irregular and unequal. The nodular goiter is usually colloid or cystic, and has a greater tendency to undergo hyalin, fibrous, calcareous metamorphosis. Hemorrhage takes place more frequently in nodular than in diffuse goiter. The nodular goiter is more common in the lower pole of the gland. It is oftentimes multiple and seldom develops in the pyramidal process. PATHOLOGY 59 A satisfactory clinical classification of the thyroid tumors is not easy on account of the difficult}* of bringing into harmony the clinical with the pathological facts. The classification based on embryology alone is extremely interesting and scientific, but clinically it is confusing, as it mixes up in the same chapter the benign and malignant forms of goiter, which, clinically, are so different. Therefore, I think that until we have something better the following classification will answer the purpose: I. Parenchymatous goiter. II. Colloid. III. Fetal adenoma. I. Epithelial tumors. Pubertv. Pregnancv. II. Connective-tissue tumors. III. Mixed tumors. IV. Dermoids, Teratoma. V. A ccessory goiters. Benign Tumors. I. Physiological | 2. Non-toxic. I 3. 1 hyrotoxic. I Cystic. j Fibrous. Calcareous. Osseous. Malignant Tumors. 1. Malignant adenoma or proliferating goiter. 2. Carcinoma. 3. Metastatic colloid goiter. •I 4. Parastruma. 5. Postbranchial goiter. 6. Papilloma. 7. Cancroid. 1. Fibrosarcoma. 2. Polymorphous-cell sarcoma. 3. Round-cell sarcoma. 4. Myxosarcoma. 5. Endothelioma. 6. Perithelioma. Median cysts. Lingual goiter. Intratracheal goiter. Intrathoracic accessory goiter. ( )\ arian goiter. Inflamma I tONS. Acute I. Bacterial. II. Toxic. III. Parasitical j Non-purulent Purulent. Syphilis. Clironic I uberculosis. \\ oody 1 In roiditis. I 1 h\ roiditis. Echinococcus. 60 PATHOLOGY BENIGN TUMORS. Parenchymatous Goiter. — This type of goiter is formed by glandular proliferation. It is associated with metabolic disturbances, with puberty, menstruation, pregnancy, lactation, and the menopause. Nothing is known definitely regarding the cause of thyroid hyperplasia at these periods. Diffuse enlargement of the thyroid gland, non-toxic in nature is often observed. It is then known as the non-toxic parenchymatous goiter (Fig. 9). When toxic symptoms are present, we call it thyrotoxic parenchymatous goiter. This latter form will be studied in the chapter on Exophthalmic Goiter. Q D % Q Fig. 9. — Non-toxic parenchymatous goiter. X S3- Histologically, the physiological and non-toxic parenchymatous goiter is characterized by an enlargement of all the glandular elements. The number of follicles is increased and they are slightly increased in size. They may contain colloid in slightly larger quantities than nor- mally, or they may not. The colloid is rich in iodin. The number of cells shows an increase in size and number also. The interfollicular connective tissue may be normally developed or slightly increased. Its cut surface is slightly granular as the consequence of the increase in the size of the follicles and their bulging out. The consistency is firm. Iodin generally has a marked therapeutic effect on this form of goiter. PLATE I Colloid Goiter. X 40. FIG. 2 Wolfler's Fetal Adenoma. X lOO. With intrafollicular hemorrhages. BEXIGX TUMORS 61 The histological picture of the goiter taken altogether is a picture of a more or less normal gland in which all the elements show an increase in size and number, but in which the different elements have kept more or less their natural relations, one to another. Colloid Goiter. — Its main characteristic is the increased quantity of colloid. This colloid is generally thick, staining readily. It contains fewer vacuoles than normally, and completely fills the follicle. Its iodin content is diminished. The follicles have lost their normal proportions and show all kinds of form and size. (Plate I, Fig. i.) The epithelium is low or flat; blood supplv of the colloid goiter is diminished, and the interfollicular stroma is more or less abundant, showing, as a rule, extensive hyalin degenera- tion (Fig. 10). Fig. io. — Hyalin degeneration and increased connective tissue of a goiter. First step toward formation of a fibrous goiter. X 40. If the colloid degeneration does not affect the diffuse type, but is nodular, the surface of the goiter is then coarsely lobulated. 1 he con- sistency may be harder or softer than in parenchymatous goiter, and the cut surface, more or less irregularly lobulated, shows a thick, tenacious, transparent material which is colloid. Its color depends upon its con- tent of hemorrhagic blood. It would be erroneous to believe that even in a diffuse colloid goiter every follicle has undergone colloid degeneration. Between the degen- erated follicles there is always a number of normal vesicles and non- differentiated cellular masses of embryonic type, which will proliferate and form new alveoli in order to take up the lost or diminished function of the degenerated follicles. 62 PATHOLOGY Colloid degeneration may affect the entire gland and give rise to a diffuse colloid goiter, or, localized to a small portion of the thyroid, may form a nodular colloid goiter. Colloid nodules may be singles or multiples. The colloid goiter may give rise to a cyst. There are two kinds of cyst, the true, and the false. The true cyst is of follicular origin. Two or more follicles become distended by the colloid secretion, and as a consequence of the continued eccentric pressure on their follicular walls the blood supply is slowly cut off, the alveolar walls undergo atrophy, and finally break and fuse together, forming a larger space filled with colloid (Fig. u). The cyst is formed. It increases gradually in size, takes up a round form, and presses toward the periphery of the surrounding follicles, which owing to the continuous pressure, undergo a connective-tissue degeneration and fuse with the true or follicular capsule of the cyst, thus forming a thick, cystic capsule. A cyst may, furthermore, take its origin from an intrafollicular hemorrhage. The false cyst is the consequence of a hemorrhage which dissociates the stroma of the gland and causes a necrotic, aseptic area. If the hemorrhage is of small size, it gradually becomes absorbed. Pigmen- tation remains for a long time as the only proof of the bloody extravasation. But if the hemorrhage is of some consequence, the hemorrhagic focus being too large to become absorbed, a localized, aseptic Fig. ii.— Walls between large neC rosis takes place and the neighboring colloid alveoli become atrophied • i • *. iy„ ni . n f„^^,:„„ ^ f l PQ _j / tissues begin to proliferate, forming a raise capsule around this hemorrhage; hence the formation of an encapsulated cyst. The size of a true cyst may become enormous. As the ovarian cyst it may be mono- or multilocular and may contain a serous, transparent fluid, which may be red if a recent hemorrhage has taken place, or it may be of chocolate-brown color if the hemorrhage is older. The hemor- rhage is the result of a rupture of one or more small bloodvessels of the wall of the cyst, as a consequence of the chronic endarteritis, or of atrophic changes resulting from mechanical pressure. Crystals of cholesterin are often found, especially in the serous form. The walls of the cyst may be thick or rigid, or may be thin and soft. The inner surface mav be smooth or, as in the ovarian cyst, may and give rise to a cystic forma tion. X 21 BEXIGX TUMORS 63 be covered with papillary formations. It is lined with epithelium derived from the follicles, while there is no epithelial lining in the false cysts of hemorrhagic origin. The walls of the cysts may show calcareous deposits. In both forms of goiter, colloid and parenchymatous, vascular changes may become so prominent that the arteries and veins are con- siderably increased in size and number. In such cases an expansive pulsation is present all over the goiter; a thrill is felt on the main trunks of the arteries; a systolic murmur is heard all over the gland. This form is called, clinically, vascular goiter. It is usually found in connec- tion with exophthalmic goiter; this vascular goiter, however, may be observed in cases in which no thyrotoxic symptoms whatsoever are present. It is then known as the non-toxic vascular goiter. FlG. 12. — Pure fibroma encapsulated in a colloid goiter. X 9. Both forms of goiter may undergo amyloid degeneration, but this is rare. As a result of chronic irritation or inflammation, connective tissue may develop secondarily in a parenchymatous or colloid goiter and thus form a fibrous goiter (Fig. 12). Histologically, this is not a new form of goiter, but only the result of a secondary degeneration. The same is true of the calcareous deposits which oftentimes take place in goiter, and which may convert a nodular colloid goiter into a hard, calcareous lump. Such conditions should be considered as secondary degenerative changes and should not be regarded as pathological entities In themselves. 64 PATHOLOGY I Fetal Adenoma. — This form of goiter is called fetal adenoma because it is formed from embryonic tissue, because it is of congenital origin, ...V s ' Wi i»W, M 1% Fig. 13. — Wolfler's fetal adenoma. X 90. *> . #**.■ ■■ '£#• ■ ,<» *■? • * St &*}\ 1 mM &§ *<*. t * * A it! •/. Fig. 14. — Wolfler's fetal adenoma. Alveoli show a tendency toward the colloid type. X 100. and because the normal parenchyma of the gland does not take any part in its formation. MALIGNANT GOITERS 65 The fetal adenoma develops in the early part of life, but is more common at the time of puberty. It seldom exceeds the size of a lemon, but, as a rule, the adenomata are multiple and may reach twentv or more in number. If in a young individual from ten to twentv vears old, several small, round, mobile, painless nodules with sharp limits and firm consistency are found, one can be almost sure that they are fetal adenomata. Such goiters generally do not give rise to symptoms except when numerous and large in size; they may then cause pressure symptoms. Histologically, this goiter is formed from embryonic cells and embry- onic follicles. The follicles are small and the cells which line their walls have a fetal character. (Fig. 13, and Plate I, Fig. 2.) They are of medium size and stain intensely. The follicles have a very small diam- eter and are uniformly of about the same size. The lumen in the early stage does not contain any colloid, but may do so later (Fig. 14); in further development it may be converted into a colloid goiter. The interfollicular connective tissue is very abundant and seems to have a mucoid aspect. These different forms and varieties of goiters are not found, as a rule, so clearly defined and separated in a goiter as I have described them. Usually, they are mixed together, one form predominating more than the other, and it is this feature which gives to a goiter such a polymorphic, histological aspect. MALIGNANT GOITERS. We distinguish tumors developed from the epithelium and tumors developed from the connective tissue of the thyroid gland. To the first class belong the epithelial neoplasms and to the second, the connective- tissue tumors or sarcomata. One of the chief characteristics of a malignant goiter is its tendency to metastasis. Metastases of malignant goiter, whether of epithelial or connective- tissue origin, may take place through the lymphatics or through the bloodvessels. The general formula applied to malignant tumors when speaking about their mode of dissemination: "Hematogenous route for sarcomata, lymphatic route for cancerous tumors," does not hold good any longer here. Metastases of epithelial malignant goiters occur more frequently in bones than metastases of sarcomata. In both varieties, metastases in the lungs are very frequent. In going over statistics of cancer in general it has been found that cancer of the thyroid occupies the most prominent place- so far as metas- 6(3 PATHOLOGY tases in bones are concerned; then comes the cancer of the prostate. Hassner, for instance, finds that in 140 cases of cancer of the thyroid there were 34 cases of metastases in bones, making 24.3 per cent.; in 1358 cases of cancer of the breast, only 106 metastases in bones, making 7.8 per cent.; in 203 cases of cancer of the uterus, 7 cases of metastases in bones, making 3.4 per cent.; in 247 cases of cancer of the kidney, 9 cases of metastases in bones, making 3.7 per cent.; while in 903 cases of cancer of the stomach not a single metastasis in the skeleton was found. Metastases of malignant thyroid tumors show a marked predilec- tion first of all for the skull, then comes the pelvis, sternum, femur, clavicle, lower jaw, and the shoulder-blade. Metastases in bones, as a rule, are not multiple. Recklinghausen, trying to explain the reason why bony metastases of malignant tumors of the thyroid were so frequent, thought that in bones, on account of the sudden widening of the venous spaces, the blood stream takes a slower course, thus offering the possibility and time to cancerous cells to become permanently settled and then to grow. That may be so, but this theory does not explain why cancers of the thyroid are the ones which develop metastases in bones much more frequently than cancers of the other organs of the body. One peculiarity of these malignant metastases is their ability to revert to the normal type of thyroid tissue; in other words, if a micro- scopic examination of such metastases is made the malignant character of the tumor may have disappeared entirely, or have diminished to such an extent that the microscopic picture is mostly one of normal glandular structure. Cramer explains this by saying that in metastases few cells, partly malignant and partly normal, are carried away into the blood stream, and that cancerous cells, being more resistant than the normal ones, grow first, and only then under their protectorate normal cells proliferate, outgrowing later on the cancerous ones. "Se non e vero e ben trovato." Meyer-Hurlimann and Ad. Oswald had the opportunity to observe a remarkable case of cancer of the thyroid. After *-ray treatment the tumor softened and began to secrete an enormous amount of a serous, brownish-yellow fluid which chemically and physiologically showed the same properties as normal thyroid secretion. This shows that malig- nant degeneration of the thyroid does not deprive the latter organ of its normal function. The faculty of these cells not only to shape themselves into normal alveoli, but also to secrete colloid, raises one of the most interesting problems of ontology and teleology. How is it that malignant cells which cannot be differentiated from normal ones will be carried away by the PLATE II Malignant Adenoma. Large vascular lacunary formations cut transversely and surrounded by cellular masses. This picture is typical too for the malignant adenoma. X 50. Malignant Adenoma. Capillary vessels are formed by an endothelial wall without adventitia. Note their lacunary forms. Note in a the close relation between the tumor cells and the endothelium. X 280. MALIGNANT GOITERS 67 blood stream, and will not only grow upon a strange land but will also not be deprived of their physiological action which is the colloid secre- tion ? A similar feature does not occur in cancerous metastases of other organs. Metastases of the breast do not secrete milk, nor does a metas- tasis of the liver secrete bile, nor does a metastasis of the cancerous kidney secrete urine. Who can give the answer ? That such metastases are capable of normal physiological function is a very well-known fact. Classical is the case of von Eiselsberg who performed a complete thyroidectomy for a malignant tumor. Nothing worth notice followed the operation, but later on, when in a subsequent operation a metastasis was removed, marked symptoms of myxedema soon developed. Malignant tumors of the thyroid seem to have a peculiar tendency to penetrate the walls of the veins even in the early stage of their growth, and it is not uncommon indeed, at operations of cases which clinically seem to be most favorable, to find the thyroid imae veins thrombosed and already invaded by the tumor. It is to the Bernese pathologists, Langhans and his pupils, that we are really indebted for what we know of the malignant epithelial tumors of the thyroid. Their classification is based upon the fact that embryo- logical remnants of various organs may remain included in the thyroid gland and give rise to tumor at one time or another. 1. Malignant adenoma or proliferating goiter. 2. Carcinoma. 3. Metastatic colloid goiter. Epithelial tumors. \ 4. Parastruma. 5. Postbranchial goiter. 6. Papilloma. 7. Cancroid. Malignant Adenoma or Proliferating Goiter. — This has been called adenocarcinoma by von Eiselsberg and malignant adenoma by Kocher. The denomination, proliferating goiter, applied to that form of tumor might be confused with the hyperplastic goiter which is not malignant. Therefore I prefer, especially from a clinical point of view, to adopt the denomination of Kocher: malignant adenoma. Macroscopically, it is represented by a single nodule or growth of a diameter ranging from 10 to 15 cms.; it is seldom larger. I have, how- ever, operated recently a malignant adenoma, involving both lobes and isthmus, very vascular, each lobe measuring about 20 x 15 x 10 cms. Occasionally the tumor may be formed bv more than one nodule. Its surface is lobulated and the capsule is more or less thick. Inwardly, septa divide the parenchyma into lobi and lobuli, while in or near the 68 PATHOLOGY center of the nodule there is a more or less constantly necrotic area giving the tissue a scar-like appearance. The cut surface is like marrow, of a grayish-white color, and more or less cloudy juice can be expressed. Microscopically, the tumor is formed by regular, polyhedric lobuli with round corners, resembling very much normal enlarged follicles (Fig. 15). Between them are found capillaries composed merely of an endothelial wall, with no adventitia, and with no muscular and elastic fibers (Fig. 16). Affecting a lacunary form (Plate II, Fig. 1) instead of a round shape, Cabsul< Fig. 15. — Malignant adenoma. Periphery of the tumor. Above, capsule infiltrated with malignant cells; below, large polyhedric fields of cells, forming solid cellular masses separated by trabecules of connective tissue. X 50. as ordinary capillaries do, they lie in direct contact with the tumor cells. (Plate II, Fig. 2.) In some instances they surround the lobuli entirely, forming then what Minot called "sinusoid." The above microscopic picture found even in a very small particle of a tumor or of a metastasis is pathognomonic for the malignant adenoma or proliferating goiter. Cells have a polyhedric form, and at the periphery of the nodule they are better nourished and younger than in the center. Their pro- toplasm is finely granular and their nuclei are round or oval, measuring from 6 to 10 m. Most of them contain one or more nucleoles. MALIGNANT GOITERS 69 In places, small foci of undifferentiated cells gradually shape them- selves into the form of a circle in which colloid appears, thus form- ing a new vesicle. These neoformed vesicles, when considerable in number and seen at a lower power, give to the field a peculiar, screen- like appearance, characteristic, too, of the proliferating goiter or malig- nant adenoma. Since, later, connective tissue appears between these vesicles, this neoformed tissue has a great similitude with a normal thyroid gland. The scar-like tissue found in the center of the tumor is formed of newly organized connective tissue; it is a product of necrosis. Metastases take place preferably in the cranium and lungs, through the bloodvessels; lymphatic glands are not involved. Fig. 16. — Malignant adenoma. Septa between the lobuli. They are formed by capil- lary vessels. Note lengthened form of cellular fields. This feature is very characteristic of malignant adenoma. X 50. Histologically, the malignant adenoma differs entirely from the ordi- nary cancer. There we have not, as in cancer, irregular epithelial masses surrounded by more or less developed and irregularly shaped frame of connective tissue. As Langhans says, this tumor with its peculiar for- mation, with its neoformed vesicles lined with one layer of epithelium and containing colloid, with the peculiar shape of its bloodvessels, with the irregularity of their disposition, of the construction of their walls, and their intimate relation to the epithelium, recalls rather a normal organ in the course of development than a cancer. Hence the name proliferating goiter given by Langhans. 70 PATHOLOGY Does the malignant adenoma develop from goiterous elements themselves or does it develop from embryonic rests of undifferentiated normal thvroid tissue ? Langhans thinks that the second alternative is likely to be true. Carcinoma. — The cancer of the thyroid is a hard, nodular tumor, as a rule, firmly adherent to the neighboring tissues. The cut surface is of grayish white. Typical cancer juice can be expressed. This carcinoma has a tendency to undergo softening of its constituent parts. Histologically, this cancer shows the usual microscopic picture which is found in cancer of the breast, stomach, etc., namely, the same inter- relations between connective tissue and epithelium which enable us to diagnose cancer. Here, too, as in cancer of other epithelial organs, we have cellular masses irregularly disposed, surrounded by an irregularly developed stroma. The cancer cells, in opposition to the normal cells of the thyroid, have a poorly developed protoplasm; they are small; their nuclei are larger than those of a normal gland and measure from 10 to i6m. In cancer of the 'thyroid, metastases may take place in the sternum, ribs, pleura, kidneys, and in the suprarenal bodies. The cancer does not penetrate the bloodvessels like the malignant adenoma; metastases occur through the lymphatic route: hence, involvement of the cervical and possibly of the mediastinal lymph nodes. It is not always easy to decide microscopically if a metastasis comes from a cancer of the thyroid or not. If in the metastasis vesicles con- taining colloid are found, the diagnosis is easy. If not, the size of the cells and their nuclei, their number and their close relation one to another will arouse a strong suspicion in favor of their thyroidal origin. Metastatic Colloid Goiter. — Metastatic colloid goiter, histologically, does not differ in any way from a simple colloid goiter. There is nothing in its histological picture to arouse the suspicion of malignancy. In the metastatic as well as in the primary tumor we find follicles of different forms, round, oval or elongated. The epithelium of such vesicles may be cuboidal or cylindrical. The colloid material is as abundant and has the same tingible power as the colloid of a simple goiter. It may be strongly colored by the eosin or its coloring power may be diminished or totally absent. Lymphatics and bloodvessels are normal and do not contain metastatic cells. The capsule of the nodule is absolutely intact. The only feature is its metastasizing power. Metastases in the great majority of cases take place through the vascular route; they may, however, occur through the lymphatics. In that case metastases are found in the cervical, mediastinal, and bronchial lymphatic glands. But the seat of predilection of such metastases is in the spinal column, sternum, ribs, and long bones. MALIGNANT GOITERS 71 Tumors of bones due to metastatic colloid goiter form an interesting pathological chapter. Clinically, their true origin is not recognized. Thev are considered as sarcomata, and it is only at the microscopic exam- ination that the error is discovered. Cohnheim, who was the first to report a case of metastatic colloid goiter in bones, considers these tumors as benign; but Recklinghausen and Wolfler do not share the same view and consider them as malignant, claiming that a tumor which is capable of giving rise to metastases is not entitled to the denomination of benign tumor. In Wolfler's judgment this metastatic tendency indicates an increased proliferative energy, which is one of the chief characteristics of malignant tumors. Despite the authority of such men, Bontsch, Honsell, Oderfeld, von Steinhaus, Karl Schmidt, Patel, etc., have taken exception to such conclusions and consider a metastatic colloid goiter as a benign tumor. On the other hand, Kaufmann, Borst and Hanse- mann are unanimous in considering such tumors as malignant. In their judgment the denomination of "benign" applied to a tumor which is capable of metastasis is certainly in contradiction to what we know of benignancy. Langhans, too, considers this tumor as a malignant one. It cannot be denied there are cases in which the metastatic organ was found to be, histologically, a simple goiter, which after surgical removal never gave any recurrence. The only sign of malignancv was its metastatic feature. On the other hand, metastases of benign tumors, as fibroma, myoma, adenoma, have been reported by good authorities. For instance, Cohnheim reported a case of simple goiter in which he was able to find, microscopically, epithelial cords penetrating the walls of a vein and floating freely into the lumen. In such conditions metas- tasis is easily understood. We know that normal organs, as placenta, liver, and suprarenal bodies, whose cells are in intimate relation with bloodvessels, may cause metastases without having shown anv sign of malignancy. Why should not this be possibly the case for the thvroid gland ? At any rate, for some reason or other, a few normal cells are carried away by the blood stream into other organs. Under ordinary circumstances these cells would decay, but for some unknown reason they find a favorable "terrain" on which they grow and finallv develop to the size of a tumor. This feature is no longer to be wondered at since the illuminating experiments of Carrel, who has been able to grow in cultures normal cells of different organs. If we accept Ehrhardt's definition of a malignant goiter, "An intra- or extracapsular tumor whose elements invade the capsule, encroach upon the neighboring tissues and cause metastases," we will see that in the metastatic colloid goiter the encroaching upon the neighboring tissues and the invasion of the capsule by the glandular elements are absent. I he metastatic feature is the only remaining sign of malignancy. 72 PATHOLOGY What strikes us in the history of a real malignant goiter is that there was at first a simple goiter of more or less long standing, that it suddenly began to grow rapidly, and only later on gave rise to metas- tases in the organs. This is not the case of the metastatic colloid goiter; there is here no such history as that of the rapid development of a tumor. Regensburger, in going over the statistics of 58 cases, found that the time which elapsed between the beginning of the metastases and the death of the patient was from 1 to 17 years. In all cases death was not due to the goiter, but to an intercurrent disease. Therefore I am forced to admit that a metastatic colloid goiter may be in some cases a benign tumor. Parastruma or Glycogen-containing Goiter. — Dr. T. H. Kocher, Jr., was the first to describe this form of goiter. It has a nodular appear- ance, grows rapidly and soon becomes adherent to the neighboring tissues; it is very hard in consistency, and rapidly causes pressure symp- toms. The cut curface is gray or grayish white and shows a typical, irregular, alveolar structure. Its cells are large and clear and measure in diameter from 20 to 30 /i. They are polyhedric, sharply outlined with a colorless colloid body, and have no granular protoplasm staining with eosin. Such cells contain gly- cogen in variable quantity, detected by specific stainings. Nuclei are round and vesicular. Smaller granulated cells, staining with eosin, not so sharply out- lined as those previously described, and not containing glycogen, are usually distributed all over the tumor and mixed with cells containing glycogen. The alveoli are separated by septa formed by capillaries which have the same lacunar aspect as the ones spoken about in the prolifer- ating goiter. In between the alveoli glandular canals lined with cylin- drical cells disposed in two or more layers are found. Their nuclei, instead of being at the base, lie at the tip end of the cell near the alve- olar lumen. They are of embryonic origin and correspond to the ves- icles and canals which Kiirsteiner found extending from the lower por- tion of the parathyroid bodies to the upper part of the thymus gland. They have about the same dimensions as the tubuh contorti of the kid- ney, and possess a high, clear, cylindrical epithelium with a nucleus lying at the upper tip end of the cell. Such canals may be found even in the thymus itself; they disappear at birth. On the other hand, Getzowa discovered in normal thyroids residues of aberrant parathyroids containing glycogen and glandular cells, resembling entirely those above described. We know that the human parathyroids usually contain glycogen; that they contain sometimes glandular canals lined with a high, clear, cylindrical epithelium whose PLATE III Struma Postbranchialis. Nodule A sharply outlined from the rest of the gland. Note how staining A differs from staining of thyroid epithelium B. A forms a cellular mass suggesting alveoli formations in places. X 62. FIG. 2 m Cancroid. Typical cancerous pearls. X 70. MALIGNANT GOITERS 73 nuclei lie at the upper pole of the cell. Therefore it seems safe to con- clude that a tumor containing glycogen and whose cylindrical cells have a nuclei at the tip end of the cell instead of at the base, is derived from the parathyroid bodies; hence the name parastruma. Parastruma gives metastases in the cervical, mediastinal, bronchial glands, lungs, and bones. Metastases may or may not contain glyco- gen but possess the same characteristic cells; they contain, too, a great quantity of mucine not found in the parathyroid bodies. Postbranchial Goiter. — Macroscopically, this tumor is composed of large nodules of more or less irregular surface, sharply outlined from the rest of the gland. The cut surface is alveolar, shows fine granulations and is of a grayish-brown or grayish-red color. This tumor grows very rapidly. *» » » w I,' • 4 Fig. 17. — Struma postbranchialis. Large cells resembling liver cells. Note large homogeneous body of protoplasm with round, vesicular nuclei containing small corpuscles of chromatin and in places an eccentric nucleole. X 700. The alveoli are very small and seldom have a diameter of more than 100 ft. The cells measure from 1 5 to 30 n, and show a large homogeneous, refringent protoplasm. They are polyhedric; their nuclei have about the same size as the nuclei of normal thyroid glands; they are round, vesicular and contain small corpuscles of chromatin; a small eccentric nucleole is almost always present. Such cells stain intensely with acids and do not contain fat or glycogen. They resemble greatly the cells of the liver or suprarenal bodies. T heir vesicular arrangement and their colloid content show their true origin, and prevent mistaking them for the liver's or the chromaffin system's epithelium. 74 PATHOLOGY Metastases are found in the lungs, liver, in the lymphatic glands of the neck and of the mediastinal space, and occur through the lymphatic vessels. Getzowa has found in normal thyroid glands groups of cells having exactly the same histological appearance as the cells described. They are polyhedric, with an abundant granulated protoplasm, staining intensely with eosin. (Plate III, Fig. I.) The cells are sharply outlined and resemble the liver cells (Fig. 17). They form solid cellular groups, and in places beautifully formed vesiculi in which there is found col- loid. They are embryonic residues of the postbranchial bodies, hence the name postbranchial goiter. Papilloma. — Papilloma are usually small in size, and may have a diffuse or nodular form. The nodules are small, smooth in surface, with a firm, fleshy consistency. The cut surface is finely granulated, grayish red, and may show a lobular structure. The tumors may be solid or cystic. In the cystic form the most striking and arborescent papillary formations may be seen sprouting from the walls of the tumor into the interior of the cyst (Fig. 18). Papilloma begins to develop in a small follicle lined with one layer of epithelium; this is the first indi- cation of a papilla. It gradually grows larger, and in a later stage subdivides into smaller branches which subdivide themselves again, giving, finally, rise to the most com- plicated arborization (Fig. 19). In places the branches of the arborization meet together and form vesicles in which colloid may be found (Fig. 20). Capillary vessels penetrate only later in the axis of the papillae and of its arborization. The cells are generally large and provided with abundant proto- plasm which is granular, not refringent, and stains readily with eosin. Cuboidal or cylindrical, they may be sometimes very high and may reach 40,11. The nuclei are round or oval, lying at the base of the cell or at its tip. They contain a nucleole staining with eosin. This tumor makes metastases especially in the lymphatic glands, Fig. 18. — Papilloma partly cystic and partly solid. In the solid portion the papillae fill up entirely the whole space. In the cystic portion exquisite arboriza- tions are seen. MALIGNANT GOITERS 75 and has a great tendency to encroach upon the neighboring tissues. Metastases have the same histological picture as the primary tumor. Fig. 19. — Papilloma. This low power shows plainly the arborescent formations. X 17. JSBSEem MPISr^ ,* oi a t\ .*' -•• •' Fig. 20. — Papilloma. Low cylindrical epithelium and alveoli formations containing colloid, x 125. '(■) PATHOLOGY In such tumors lymphoid masses may be found, many of them pos- sessing a distinct germinal center. The fact that cells with nuclei at the upper end are found, shows that they very likely take their origin in the Kiirsteiner canals, described in relation with postbranchial goiter. Cancroid. — This tumor never reaches enormous dimensions. It has an irregular surface, is very hard in consistency, and may occur in normal thyroid gland as well as in preexisting goiter. The cut surface is white, a marrow-like color, and is finely granular; the granulations are formed by the cancerous nest sticking out, and can be readily expressed. ^ Fig. 21. — Cancroid. Broad, solid, cellular cords of irregular size and form, embedded in more or less loose connective tissue. X 44. Histologically, this tumor gives the same microscopic picture as the cancroid developed in the skin, mouth, pharynx, esophagus, and other organs containing a cuboidal epithelium. It is formed by broad, solid cords of irregular size and form (Fig. 21) embedded in a more or less loose connective tissue and formed of polyhedric cells provided with an abundant protoplasm. This protoplasm is finely granular and does not take eosin easily. It contains in its center a very large vesicular nucleus which contains a few small nuclei of chromatin. (Plate III, Fig. 2.) Cancer pearls are numerous; the blood supply is not diminished, and stroma is generally highly developed. MALIGNANT GOITERS 77 Owing to the fact that such tumors have always a close connection with the pharynx or larynx, Langhans thinks that this tumor has its starting-point in the epithelium of the pharynx, larynx or in remnants of the thyroglossus duct. The fact that this tumor always develops and perforates at the same place, namely, near and behind the first tracheal ring, seems to support this theory. On account of its com- munication with the larynx or pharynx this tumor is oftentimes the seat of inflammation and has a tendency to necrosis. Being given its anatomical relations it involves earl}' the sympathetic and inferior laryngeal nerves. This tumor is rare. Tumors of Connective-tissue Origin. — Sarcoma of the thyroid gland occurs sometimes in earl)' life, but in the greatest majority of cases it is to be found between fifty and sixty years. Molf thinks that he found a suitable explanation for this in the fact that in advanced age epithelial elements undergo atrophy, thus allowing the connective tissue to grow with energy. Sarcoma develops with preference in nodular goiter, where the con- nective tissue may be found more or less abnormally developed and undergoing degenerative and metaplastic changes. It may reach larger dimensions, being formed by a mass of conglomerated nodules, more or less large in size. Sarcoma grows extremely rapidly. In the early stage it is mobile and sharply limited, but later it becomes adherent to the neighboring tissues, muscles, trachea, esophagus, etc. Hence the diffuse limits, loss of mobility, difficulty in swallowing, irradiating pain in the ear, in the arm, etc. The common carotid is displaced backward; exceptionally, it may be completely surrounded by the tumor. Sarcoma is soft in consist- ency, friable, exudes little juice or none on its cut surface, which is grayish white in color. Its blood supply is generally increased. It has a great tendency to undergo necrosis, fatty degeneration, or calcification. The varieties of sarcoma mostly found in the thyroid gland are: 1. Fibrosarcoma. 2. Polymorphous-cell sarcoma. 3. Round-cell sarcoma. 4. Myxosarcoma. 5. Endothelioma. 6. Perithelioma. 1. Fibrosarcoma. — This variety is the most frequent. It is gener- ally of harder consistency than the round-cell sarcoma, but it may be soft also. Its outer surface is lobulated and its cut surface is grayish white or yellowish white, but it may be of a brownish-red color it the blood supply is very well developed. This form of sarcoma is less malig- nant than the round-cell sarcoma. Histologically, it does not differ 78 PATHOLOGY from the picture of fibrosarcoma in general; the cells form a long spindle in which nuclei are found. Spindle cells alternate with masses of gen- uine connective tissue; hence the name fibrosarcoma. 2. Polymorphous-cell Sarcoma. — This sarcoma is a mixture of spindle, round, and pyramidal cells. Giant cells may be present also. In fre- quency this form of tumor comes next to the spindle-cell sarcoma. 3. Round-cell Sarcoma. — The round-cell sarcoma forms a soft, rap- idly growing tumor. As it is generally composed of several lobes its outer surface is lobulated. The cut surface is generally white and con- tains necrotic areas. A white, milky juice exudes. The blood supply of the round-cell sarcoma is generally intensely developed. The cells Fig. 22. — Round-cell sarcoma. The small, round sarcomatous cells are seen penetrating between the alveoli; many of them are already about destroyed. X 50. of this form of sarcoma penetrate between the follicles of the thyroid gland and surround and destroy them entirely (Fig. 22), so that the microscopic examination of a well-developed tumor shows only round- cell sarcoma. No trace of a follicle is found except at the periphery of the tumor, where the folliculi have not been entirely destroyed. The round-cell sarcoma has two kinds of cells: the small and the large. The small cells are composed of a nucleus with a thin layer of protoplasm. They resemble lymphoid-tissue cells very much. The variety with large round cells contains abundant and granular proto- plasm. The nucleus is large and oval. The latter variety is less malig- nant than the sarcoma with small round cells. PLATE IV ** Endothelioma. Endothelial cells of a vascular lacuna. Note enormous dimensions acquired by the endothelium a; blood, b. X 280. MA LIGXA N T GDI TERS !9 4. Myxosarcoma. — Myxosarcoma is a rare tumor and does not differ materially from fusocellular sarcoma. It is formed by fusiform sarco- matous cells and abundant mucinoid tissue. 5. Endothelioma. — Macroscopically, the endothelioma is sharply out- lined; only later when the capsule and neighboring tissues have been invaded by the tumor does it become diffuse in its limits. The surface is more or less coarsely lobulated because the tumor may be composed of one or more nodules of different sizes. Its capsule, more or less thick, is composed of connective tissue in which bloodvessels have been partly obliterated; hence the frequent areas of necrosis found throughout the tumor. The cut surface differs strikingly from the cut surface of other varieties of sarcoma. Connective tissue irregularly disposed forms, a framework in which large vascular lacunes are found containing liquid Fig. 23. — Endothelioma. Cavernous portions of the tumor. X 60. or coagulated blood (Fig. 23). Fibrin at different stages of organization is seen forming gray masses which have been called by Langhans "rubber colloid." The microscopic picture seems to be at first very complicated. This tumor is composed of capillary vessels with a single layer of epithelium; little by little the epithelium begins to proliferate; the capillary vessels become larger and finally form large (Plate IV) vascular lacunes filled with blood in which the epithelium has acquired enormous dimensions. I his endothelium may be desquamated, and in places fills entirely the vascular cleft, thus forming solid cellular cords and nests. In places large endothelial cells are found containing in their protoplasm one or several red corpuscles undergoing degeneration and finally forming homogeneous little lumps known as Russell's corpuscles. This shows the exquisite phagocytic power of endotheliomata. SO PATHOLOGY The cells are variable in form. They may be polyhednc, round, or have a spindle form; protoplasm is more or less abundant and stained heavily with eosin. The nuclei are generally large and contain one or two small corpuscles of chromatin. Connective formations between the vascular lacunes are more or less abundant. Metastases take place through the bloodvessels and have the same characteristics as the primary tumor. 6. Perithelioma. — Such tumors originate by proliferation of the outermost part of the wall of the bloodvessel. The endothelium is always normal, its outermost part only showing the beginning of the proliferation. The microscopic picture is very typical. It consists of a capillary vessel of more or less large diameter with an absolutely normal endothe- lium. All around this lumen there are multiple layers of cells forming a thick mantle to the bloodvessels. These mantles may be separated or may fuse together, forming what is called a plexiform angiosarcoma. When fusion between the mantles has not taken place, capillary vessels and thyroid follicles may be found. The cells may be more or less large and of different forms. The protoplasm stains readily with eosin, and its nucleus contains many small nucleoles of chromatin. Such tumors are generally very hard. Combination of Various Forms of Malignant Goiter. — Carcinoma and sarcoma may occur at the same time in the thyroid gland. This occur- rence, however, is exceedingly rare. Such tumors are formed with cells of the carcinomatous and sarcomatous type irregularly mixed together; hence the name carcinoma sarcomatodes. Schmorl has seen carcinomata sarcomatodes occur in a relapsing cancer of the thyroid gland. In the metastasis the sarcomatous type of cells only was found. Mixed Tumors. — These tumors are characterized by their extreme polymorphic aspect, as they contain connective and epithelial tissues, cartilage, bone, etc. They have been called osteochondrosarcoma and osteochondroadenoma, etc. They constitute the first stage in the develop- ment of teratoma, with the difference that they do not contain any well-differentiated organ like the latter one. These tumors, although found mostly in old people, seem to be con- genital. They undergo malignant degeneration only in old age. Women have them more often than men, and they are found, too, in animals. Their size varies from the size of a fist up to the size of the head of a fetus. Their surface may be smooth, but is mostly grossly lobulated. They are firm or hard in consistency, although some portions may be soft. As a rule the tumor has sharp limits except in advanced stages of malignancy. Their walls are often infiltrated with calcareous deposits, so that a saw is necessary to cut them. In the cut surface the carti- MALIGNANT GOITERS 81 laginous and bony formations are found mixed with softer areas formed by sarcomatous or cancerous degeneration. These tumors produce metastases in the lungs, heart, suprarenal bodies, liver, stomach, and intestines. The lungs are mostly affected. The histological picture of the metastasis is the same as that of the original tumor; bone, cartilage and other tissues may be found in it. Histologically, osseous and cartilaginous tissues are found diffusely mixed with thyroid elements; the alveoli may proliferate intensely and their epithelium in places may become cylindrical. Colloid is also present in alveoli. The most common form of degeneration of connective tissue is the fusocellular sarcomatous type. Blood is supplied bv vascular lacunes whose thin walls will explain easily why hemorrhages are frequent in such tumors. Hyalin and reticular cartilage are more or less constantly found in mixed tumors of the thyroid. Their distribution throughout the tumor is capricious and does not follow any rule. The osseous elements have not, like normal bones, a lamellous structure; the osseous corpuscles are not as well formed as the normal ones. As a rule the structure of these bony formations affects the spongiform type; the eburneous type is rare. No medulla is found in the trabecules. Solarno, of Milan, reported, in 1914, a case of osteosarcoma devel- oped in the left lobe of the thyroid. The tumor was enucleated but recurred quite rapidly. It was formed, histologically, of sarcomatous and osteoid elements. The pathogen}' of such tumors can be explained by the theory of metaplasia; in other words, they are due to an abnormal and incoherent proliferation of normal glandular elements. Such conception is based on indisputable facts of substitution of one tissue by another; for instance, the ossification of a scar tissue in the abdominal wall after a laparotomy is a well-known fact. While assistant to Professor Kocher I remember that eight to ten months after a median laparotomy for a gastric cancer we removed a large ossification which had developed in the old scar; histologically, it proved to be ossified connective tissue. Cohnheim explains the origin of such tumors by the inclusion theory. In his judgment some non-differentiated cellular elements of other organs are accidentally mixed and held among the thyroid cells at the time of their embryological formation. For a long time they remain inactive, but in later periods of life, for some unknown reason, they begin to proliferate and develop into these peculiar tumors. Dermoids and Teratoma. -These tumors ait- exceedingly rare; three or four cases have been reported in the literature. I hey represent ;i step further in the development of mixed tumors. In the latter ones 6 82 PATHOLOGY the elements are mixed together without order and are represented by a cellular, non-differentiated mass; whereas in dermoids and teratoma, these elements are organized into rudimentary organs as skin, hair and other well-developed tissues. Personally, I came across one case (Fig. 24). The dermoid in itself was a very small nodule about the size of a small nut, mixed among other colloid nodules. There was no infiltration of the neighboring tissues, and the only feature which attracted my attention was its white, transparent appearance. Microscopically, it proved to be skin with sebaceous and sudori- parous glands. (Plate V, Figs. 1 and 2.) Accessory Goiters. — An accessory goiter is a goiter developed in an accessory thyroid gland. r t\ .1 We distinguish two kinds of accessory goiters, tig. 24. — Dermoid cyst. & . . Natural size. tne f a ^ se ar >d the genuine. If a goiter nodule gradually becomes separated from the main body of the thyroid, so as to be wandering, possibly quite far from the mother-land, while retaining with it a connective-tissue connection, this wandering goiter is called false accessory goiter; but if the accessory goiter nodule has no connection whatsoever with the thyroid or the goiter, then it is called genuine accessory goiter. Genuine accessory goiter takes its origin in residues left at the time of the formation of the thyroid. We must remember that after the thyroglossus duct has proliferated and formed the thyroid gland, it gradually becomes atrophied and leaves as vestiges a fibrous cord called the thyroglossus tract, which extends from the foramen cecum of the tongue to the pyramidal process of the thyroid, passing between the mylohyoid and the geniohyoid muscles. This duct may leave along its entire course islands of thyroid tissue, at the cost of which later on accessory glands or goiters may develop. Sometimes the thyroglossus tract passes behind or in front, or even through the hyoid bone, and may extend downward into the anterior mediastinal space as far as the aorta. In that case accessory glands may be left over the entire length of this course and thus will be easily explained the origin of accessory glands and of tumors of the mesobranchial type, developed not only at the base of the tongue, in the hyoid bone, and in the cervical region, but also in the mediastinal space. Accessory goiters may be influenced sympathetically by pathological disturbances of the thyroid gland itself; they may undergo compensa- tory hypertrophy after partial or complete thyroidectomy; finally, they may give rise to the same variety of tumors as the gland itself. Conse- quently, whenever the presence of an accessory goiter is suspected, the PLATE V M \ • VJ* VH* few %»«&< c < Dermoid of Thyroid. Skin with (a) stratum corneum; &, stratum mucosum; c, stratum conjunctivum. X 3°°- FIG. 2 Dermoid of Thyroid. a, sebaceous glands; b, stratum pilosum. X ioo. MEDIAN CYSTS ' 83 th) r roid gland should be thoroughly examined, as the treatment will depend greatly upon the conditions found. If the thyroid is function- ally' intact, excision of the accessory goiter can be done safely; but if symptoms of thyroid insufficiency are present, a partial operation onlv on the accessory goiter must be performed. The most important varieties of accessor)' goiters are the median cysts and lingual goiters; then come the intrathoracic, the intratracheal, and ovarian goiters. Median Cysts. — Median cysts are located above or under the hvoid bone; more rarely they are located in the body of the hvoid bone itself. Although variable in volume, they seldom exceed the size of an egg. Thev are round or oval in shape, elastic in consistency, often show fluctuation, being, as a rule, firmly attached to the hvoid bone; they are more or less immobile; pressure is painless. They originate from an incompletely obliterated thyroglossus duct (Fig. 25), giving off a secre- tion which gradually distends the canal until a cyst is formed. They are seldom congenital. As a rule they develop in the first three decades of life and are more frequently' observed at the time of puberty. The following case will serve as a good illustration of such a condition: Miss H. C, aged twenty years, referred to me by Dr. J. F. Baldwin, of Columbus, Ohio. A year before the patient noticed a small lump under the chin, growing slowly but gradually; no pain; no disturbance of any kind. Examination showed that between the hvoid bone and the thyroid cartilage, in front of the thyrohyoid membrane, there was a lump the size of a walnut, with smooth surface, elastic, and slightly mobile laterally, but immobile in the upward direction; pressure was absolutely painless. Thyroid gland was normal and independent of the tumor. Diagnosis. — Cyst of the thyroglossus duct. Operation confirmed the clinical diagnosis and showed a cyst dark in color, situated between the hvoid bone and the thyroid cartilage in front of the thyrohyoid membrane. The thyroid cartilage was dis- placed downward, forming a part of the lodge in which the cyst was located. The cyst was attached firmly to the hvoid bone and was solidly embedded in it. It was carefully dissected out and removed. The walls of the cyst were thin and contained a dark tluul rich in choles- terin. At the microscopic examination the walls of the cyst were found to be lined with a ciliated, cylindrical epithelium disposed m one, two, and, in places, three layers. The epithelium lining these cysts is not always cylindrical, bur may be pavimentous. The cystic contents may be a clear or bloody fluid containing cholesterin. The median fistula may be complete or incomplete. In rlu- great 84 PATHOLOGY majority of cases it is not congenital, but appears after birth. If com- plete, the fistula extends from the foramen cecum of the tongue to the skin, FlG 25 ._Diagram showing the various locations of cystic or solid tumors developed from the thyroglossus duct, i, intralingual; 2, sublingual; 3, suprahyoid; 4, infrahyoid; 5, prethyroid. its external orifice being found on the middle line of the neck between the hyoid bone and the jugulum. Its external opening may be punctiform or LINGUAL GOITER 85 may be wider. Its lumen may be unique or multiple. Oftentimes the walls of the fistula are so thickened as to become easily palpable under the skin, especially in the region of the hyoid bone. It passes in front of the incisura of the thyroid cartilage and in front of the thyrohyoid ligament and forms intimate relations with the hyoid bone, while passing behind, in front, or through the bod}' of that bone. The epithelium lining the canal may be cylindrical or pavimentous or both together; secretion is variable and may be reduced to a few drops a day or mar be quite abundant; in that case irritations and eczematous conditions of the skin may follow. Fistula and cyst may in rare instances undergo malignant degeneration. The only rational treatment is their removal. Lingual Goiter. — Lingual goiter is not infrequently found. Accord- ing to Smyth, 67 cases have been reported in the literature. Out of this number 61 were in females. Although found at all ages of life, they seem to be most frequently reported at the time of pubertv. For a long time they may remain unobserved, but when they begin to grow the symptoms rapidly become marked. The tumor is always found at the root of the tongue in the region of the foramen cecum, and is usually median. The size varies between the size of a cherry and that of an egg. Its consistency is variable; it may be hard, soft or cystic, according to the pathological changes which have taken place in it. Although embedded in the muscular fibers of the tongue, it may have a slight mobility per se, and has always, except when inflamed or degenerated, very sharp limits. Under the chin a diffuse swelling may be seen, but toward the pharynx and larynx the tumor is well outlined. Lingual goiters are exceedingly vascular. Large, numerous blood- vessels penetrate the goiter from the neighboring tissues. The mucous membrane of the tongue is congested and filled with dilated blood- vessels; consequently a slight traumatism may cause quite an impor- tant hemorrhage; as a result the operation will be a bloody one. Histologically, these tumors are the same as simple goiter. The symptomatology of such tumors has very few characteristics of its own. Patients complain of a sensation of fulness and tension in the upper part of the neck as if a foreign body were localized in the pharynx and could not be swallowed despite continued efforts at degluti- tion. If the tumor is superficially localized, the epiglottis being con- stantly irritated, coughing spells may ensue. Deglutition and respira- tion are, as a rule, interfered with only when the goiter h;is reached hum dimensions. There is often a certain difficult) of speech: the patient articulates as if the tongue were infiltrated and swollen. At the same time the flow of saliva may be increased; expectorations oi blood due to ulcerations of the lingual mucous membrane may occur. 86 PATHOLOGY Diagnosis is not always easy. In discussing the differential diag- nosis of lingual tumors the possibility of a lingual goiter should always be borne in mind. The mere inspection of the buccal cavity with a frontal mirror is not sufficient, as in many of the reported cases the tumor could not be seen by direct inspection. But indirect examination with the laryngoscopic mirror will show in the region of the foramen cecum a tumor bulging more or less and covered with a congested and vascular mucous membrane. Intrabuccal, monodigital examination combined with outside manipulation will readily discover the tumor; as palpation is painless, its limits will be easily outlined. The tumor may bulge slightly under the chin. Lymphatic glands of the cervical region are not involved. In a syphilitic gumma the limits are more diffuse and the tumor has a tendency to show a softening of its central portions. In malignant tumors the limits will be infiltrated and diffuse. The age of the patient and the course of the disease may be of some help in differentiating the diagnosis. Dermoids and cystic tumors of branchial and salivary origin sometimes found at the basis of the tongue may not be differen- tiated, clinically, from a lingual goiter, as their consistency and other anatomical features may recall those of a lingual goiter to such a degree that their true nature is recognized only at the time of the opera- tion. Angiomas are more spongy, more irregular in outline, of purple color, and show usually venous extension to one of the lateral sides of the pharynx. Surgery is the only rational treatment for such conditions. Before removing radically, care should be taken to ascertain the presence of some other source of thyroid secretion, as cases of myxedema have been reported from various sources as a consequence of a radical extir- pation of a lingual goiter. The operation can be made from within or without the mouth. The choice of the route will be dictated by the case itself. If the buccal route is chosen, and if general anesthesia is not used, the tongue and pharynx are carefully novocainized, and a rapid enucleation is made while the tongue is held in extreme tension. The free hemorrhage is controlled by deep sutures. If the cervical route is chosen, a transverse incision is made in the region of the hyoid bone and the goiter is dissected out. It will rarely be necessary to divide the lower jaw. While bloody, these operations for lingual goiter are quite successful. No fatalities have been reported. Intrathoracic Accessory Goiter. — Accessory thyroid glands are not infrequently found in the thorax. Wolfler called attention to this, and Wagner found quite frequently small accessory goiters in the thoracic cavity of dogs. I remember finding at an autopsy of a patient a tumor the size of a small egg situated at the bifurcation of the trachea. His- tologically, this tumor was a simple colloid goiter. OVARIAN GOITER s7 These tumors have been found in close relation with the aorta, and therefore have been called aortic goiter. While assistant to Professor Kocher I remember seeing an aber- rant intrathoracic goiter which during coughing spells became entirely cervical and disappeared again into the chest. The majority, however, of these tumors are autopsy findings. Few may grow so large that marked symptoms of dyspnea and impairment of circulation follow. The symptomatology of such tumors does not differ from the symptomatology of intrathoracic goiter, which will be discussed in a later chapter. Ovarian Goiter. — Ovarian tumors showing both grosslv and histologi- cally the typical structure of a struma colloides have been reported by numerous authors more than once. A great many of such tumors are teratomata in which the thyroid tissue has taken the upper hand, but in others no teratoid formations can be found, so that the tumor seems to be composed purely of thyroid alveoli with their typical normal structure. Possibly such tumors are due to metastatic colloid goiters. \\ e know that a simple colloid goiter is liable to make metastases in bones and other organs. Why not, then, in the opinion of some authors, admit that such metastases could take place in the ovary: Thus the question is proposed, but I would not dare to answer it. I should rather be inclined to consider the above theory as improbable. Similar tumors have been found in the testicles. One should not forget there is a series of tumors which might be mistaken for an ovarian goiter, and which are, indeed, tumors of an entirely different nature, such as adenoma, cystadenoma, adenocarcinoma, endothehomata, etc.; in these, too, the colloid formation may be very abundant and the histological picture may resemble that of goiter. Pick was the first to contend that these ovarian goiters are all teratomata, whether they contain or do not contain embryonic rests of other organs; the thyroid elements possessing more vitality out- grow the other embryonic tissues and finally destroy them. 1 his process results finallv in the production of a colloid tumor. In support of his contention. Pick cites Saxer's case, in which a single well-formed tooth was found in an otherwise healthy ovary. In Pick's judgment this can be explained only on the theory that a teratomata had started to develop, that the tooth above was able to grow, and that the remainder of the embryonic tissues was absorbed. Pick's views on the etiology of ovarian goiters are. so to speak, universally accepted. \\ althard examined three ovarian goiters which were apparently composed of thyroid tissue only. x et, after making "complete serial sections" of all of these three tumors he found in one 88 PATHOLOGY case cartilage, in the other squamous epithelium, and in the third seba- ceous and sweat glands. In every case the findings were purely micro- scopic; it would have been utterly impossible to detect them macro- scopically. These facts of Walthard's very strongly support the teratoma theory. The iodin content of such tumors might be of diagnostic value, since we know that in goiter, iodin more or less is always present. To be pathognomonic it should be demonstrated that iodin does not exist in any others except in those of thyroid origin. I think that this fact has not been thoroughly established. At any rate the amount of iodin found in these thyroid-like tumors is so infinitesimal (0.000225 S m - iodin in 16 gms. of ash, by Robert Meyer) that its presence is of com- paratively little significance. A. P. Jones has shown that the presence or absence of iodin in colloid material can be determined by the behavior of the colloid with the Mallory's anilin-blue-orange connective-tissue stain. G. W. Outerbridge, after applying the same staining method to ovarian goiters, found that these tumors contain without doubt a certain amount of iodin. Such tumors may reach a very large size and are very often accom- panied by ascites; they are coarsely lobulated, and may be partly cystic and partly solid. The only case which it has been my good fortune to see, reminded me at once on its cut surface of a colloid goiter; the histo- logical examination confirmed my presumptions. Clinically, most of these ovarian goiters are benign; some of them, however, may undergo malignancy. Concomitant ascites must be regarded as a suspicious symptom. Yet it is no certain proof of malignancy, since we know that ascites sometimes accompanies benign ovarian tumors or non-malignant pediculated fibroids of the uterus. From all that we know of the physiology of the thyroid gland, if these ovarian goiters are truly of thyroid parenchyma, then there can be no doubt that these tumors are endowed with an internal secretion. CHAPTER V. INFLAMMATIONS OF THE THYROID. Inflammations. I. Bacterial 2 Toxic. 3. Parasitic. Acute Non-purulent. Purulent. Syphilis. Chronic. - Tuberculosis. Ligneous or woody thyroiditis. Chagas thyroiditis. Echinococcus. History. — As earl)' as the eighteenth century a number of descrip- tions of purulent and non-purulent thyroiditis were given by Carron, Walter, Hedenus, Conradi and Bischof. The disease was called by some "cynanche thyroidea," and "angina thyreoidea;" it was called by Walter "struma inflammatoria;" Franck called it "thyreophyma acutum," and Baillie, "inflammatio glandulae thyroideae." Hedenus, Franck and Conradi seem to have realized in their descriptions of the disease that there was a difference between inflammations of a normal thyroid and inflammations of a goiter, as Conradi, in 1824, objected strenuously to the name "struma inflammatoria" applied indifferently to any infectious disease of the thyroid. In 1840 Weitenweber fully appreciated the difference between the two conditions and called inflam- mation of the normal thyroid "thyreo-adenitis," and inflammation of a goiter "struma inflammatoria." In 1857 Bauchet published a very complete article on both forms of inflammation. As Conradi did, Bauchet also considered the non-purulent form of thyroiditis as the fore stage of the purulent form. In 1878 Kocher, speaking of the etiology of infectious diseases of the thyroid, made a great step forward in claiming that all inflammations of the thyroid were of a metastatic nature; and the correctness of such views was demonstrated bacterio- logically by Tavel in 1892. In 1895 Mvgind, dividing thyroiditis into two classes, the "simplex" and the "suppurativa,'' claimed that the first one was not always a fore stage of the second, but was in many instances a disease sui generis. Ewald, in 1896, although admitting that the thyroiditis simplex might be of "idiopathic or metastatic" origin, did not recognize for it an entity of its own, bur looked upon the non-suppurative thyroiditis as the fore stage of the purulent form. The same was done by von Eiselsberg. In [894 De Quervain, in an 90 INFLAMMATIONS OF THE THYROID eloquent and scientific article, took up this question again and shared entirely Mygind's views. In his judgment the non-purulent thyroiditis is a disease sui generis, sharply defined clinically as well as pathologically. Before discussing these views let us have a clear understanding of the terms we use. We call thyroiditis an inflammation of a normal thyroid gland, and strumitis an inflammation of a goiter, no matter what its variety may be. When we speak of a primary thyroiditis or of a primary strumitis we mean an inflammation which apparently seems to occur spontaneously in a normal thyroid or in a goiter; nowhere in the organism can a focus be found which might explain the origin of the infecting agent. Secondary thyroiditis and secondary strumitis, on the other hand, are infections whose infectious agents have been trans- ported metastatically from a well-defined infected focus in the body, as pneumonia, typhoid fever, etc. Strictly speaking, however, there is no such thing as a primary infection of the thyroid. If one examines care- fully and critically the so-called "primary thyroiditis," or "primary strumitis," it will always be found that the patient was previously predisposed to infection by some gastro-intestinal disturbances, some chronic intoxications, as syphilis, tuberculosis, saturnism, etc. Thy- roiditis and strumitis are all of metastatic origin, ergo, secondary; nevertheless we shall preserve these two distinctions for the sake of convenience and clearness. We distinguish two kinds of thyroiditis, bacterial and toxic. Bacterial Thyroiditis. — Bacterial thyroiditis is caused by the settle- ment of the microorganism itself in the thyroid; toxic thyroiditis is due to the inflammatory reaction of the thyroid when in contact with chemical poisons or microbic toxins circulating in the blood. I cannot bring myself to consider with De Quervain and Mygind the non-purulent form of bacterial thyroiditis as a class apart, a disease sui generis. The same microorganism, according to its violence on one side, and the means of defense of the body on the other, will in one case determine only a non-purulent thyroiditis; whereas in another case it will produce suppuration. Even if a small purulent focus has started, it may not necessarily continue to evoluate but may regress and finally be absorbed. Such cases will be catalogued as non-purulent thyroiditis because clinically we have no positive means of distinguishing the puru- lent from the non-purulent forms in their incipent stage. In that respect very instructive is the case reported by Breuer. His patient, without any apparent cause, was taken suddenly sick with acute thyroiditis developed in the left lobe of the thyroid gland. Swelling, local and referred pains, difficulty in swallowing, fever, etc., were present; in short, the clinical picture was identical with the one of primary non-purulent thyroiditis. Four or five days afterward everything had subsided, but in BACTERIAL THYROIDITIS 91 the following weeks he began to show symptoms of exophthalmic goiter, and seven months afterward died from the consequences of this disease. Postmortem showed in the left lobe a small encapsulated abscess which proved to be of staphylococcus origin. And yet this case had been labeled in good faith, and could not be called anything else than "non-purulent thyroiditis." A bacterial, non-purulent thyroiditis, in my judgment, is only a phase of a process whose last act is suppuration. This suppurative stage may or may not be reached; we have no means to know beforehand, what course a given thyroiditis will take, whether abscess will form or not. This is certainly true in typhoid, diphtheria, puerperal infection, cholera, influenza, pneumonia, and erysipelas. Therefore, if we are willing to say that in acute thyroiditis the inflammatory process, accord- ing to the virulence of the microorganism and the individual resistance of the patient, may never go further than the non-purulent stage, and that the same process, when conditions of virulence, resistance, etc., are changed, may pass over to the purulent stage, all well and good (the distinction between the non-purulent and the suppurative stage is needed anyway for the sake of clearness in describing the disease); but to make of the non-purulent stage a disease sui generis does not seem to me rational. It might be permissible to put under this separate heading the forms of thyroiditis consecutive to infectious diseases whose bac- terial etiological factors are still unknown, as in scarlet fever, measles, parotitis, and acute inflammatory rheumatism; these forms of thyroid- itis do not suppurate. As we do not know if in such circumstances thyroiditis is due to the microbes themselves, too mild to reach the suppurative stage, or to their toxins, it might be more simple and non- committal to regard them for the time being as diseases sui generis, but certainly some day there will be more light upon this subject, and I feel confident these forms of acute thyroiditis will be classified as toxic forms of thyroiditis. According to the foregoing considerations we will admit that bac- terial thyroiditis may evoluate in two stages, the non-purulent and the suppurative forms. Bacterial thyroiditis may be parenchymatous or interstitial. In the parenchymatous form the epithelial elements are mostly involved, whereas in the interstitial form the connective tissue is mostly inflamed. Bur, as a rule, both forms of thyroiditis are mixed together, one predominating more than the other. If we should consider a goiter as the result of an infectious process, the goiter in itself would be a thyroiditis, and strumitis would then become only an epiphenomenon of a previous infection. Indeed, one can- not fail to see there must be a connection between goiter and strumitis; 92 INFLAMMATIONS OF THE THYROID in regions where goiter is endemic, strumitis is mostly found, whereas thyroiditis is rare. The opposite is true of countries free from goiter. One of the greatest laws which infections seem to follow with predi- lection is, they localize preferably on the site of diminished resistance. Now, then, as we know that in all infectious processes of the body the thyroid is put to a very great task, being seemingly the great labora- tory where the products of thyroid secretion are destined to neutralize or render harmless the poisons of metabolism, it is not illogical to admit that after a long illness the gland is in a state of exhaustion and becomes an easy prey for infection. When strumitis occurs in cases in which acute infection has apparently not previously existed somewhere in the body, we are then compelled to admit that goiterous degeneration has created a predisposition to infection. Indeed, goiter with its degenera- tive and hemorrhagic processes forms a suitable "bouillon" for the growth of microorganisms which happen to be wandering in these regions. We may consequently conclude that a local pathological disposition of the thyroid forms a locus minor is resistentice, and thus may encour- age acute inflammation to settle in the thyroid. The mildest degree of local disposition is found in thyroid parenchymatous hyperplasia, but as soon as thrombosis, hemorrhages, and regressive metamorphoses, as fatty and colloid degeneration, take place the local disposition of the tissues for infection is greatly increased. This is so true that typhoid bacilli, in order to be able to produce a thyroiditis, must have a great virulence or they must develop in a gland already degenerated. Roger and Gamier were unable to produce experimental thyroiditis by inject- ing typhoid bacilli in the thyroid arteries of the normal gland of rab- bits. Traumatism also is an etiological factor. Of course, beside local disposition, the virulence of the microorganism is of great importance. Yet we must say there are in the body very few organs which are less susceptible to metastases of all sorts than the thyroid; for instance, metastases in that gland from malignant tumors are of the utmost rarity; even tuberculosis, which is one of the most common diseases, very rarely settles in the thyroid. Certainly, this relative immunity must not be an accidental one; very likely, under normal conditions, the thyroid gland has a powerful bactericide action, capable of warding ofF infections. If it is a well-accepted fact that a preexisting goiter is a predisposing factor of great importance in the etiology of strumitis, what about thyroiditis? Is there, perchance, a small goiterous nodule there also, too small to be detected clinically, and which becomes the point where infection sets in ? The problem is not easily solved. We really have no means to decide, clinically, when the thyroid ceases to be normal and begins to become pathological. Bassot, in postmortems ETIOLOGY 93 of pregnant women who died soon after deliver)', found the thyroid three or four times larger than normally, and yet in many of these cases the histological picture was one of a normal thyroid gland. De Quer- vain found that in a gland weighing 50 gms. or more the histological picture may have been one of an absolutely normal thyroid gland, whereas in glands weighing between 20 and 30 gms. unmistakable signs of diffuse colloid degeneration might be seen. Therefore neither weight nor size is a positive criterion when it comes to deciding whether the thyroid gland is normal or not. Etiology. — Kocher is the first who brought light into the etiology of thyroiditis. In the farsightedness of his genius, although at the time he did not have bacteriology to support his theoretical views, he claimed that every acute thyroiditis or strumitis was due to metastasis of an infectious agent located somewhere in the organism, or originating from the intestinal canal. Later, bacteriological findings proved the correct- ness of such views. Thyroiditis and strumitis may occur spontaneously without any apparent cause, or as a complication of another infectious process. They happen especially during convalescence from an acute illness, and are less frequent in chronic cases. Infection may take place in three different ways: (1) by contiguity. An infection localized in the neighborhood, as for instance, in the case of cervical adenitis, may extend gradually over to the thyroid; this mode of infection is more apt to cause a perithyroiditis or a peristrumitis than a genuine thyroiditis or strumitis; however, the fact is possible, and has been observed; (2) by direct inoculation, as in a puncture with a needle or an injury with a knife; (3) by the hematogenous route. As the thyroid has no excretory canal and does not come into contact with a mucous membrane of any sort, if an inflammation sets in, and if the possibility of an infection by direct traumatism or by propagation from the neighboring tissues has been excluded, there remains only one pos- sible way by which the microorganism might have traveled, and that is by the hematogenous route; bacteria thus thrown into the blood current settle in the thyroid. If an infected focus exists somewhere in the body, thyroiditis or strumitis may be caused by the direct metastasis of the same micro- organism causing the primary infection; but it may be caused, too, by a microorganism of an entirely different nature from that of the primary focus. A mixed infection may even be present. The number of microorganisms incriminated as etiological factors oi thyroiditis or strumitis is a very large one. Osteomyelitis and metastatic meningitis cannot compete with thyroiditis and strumitis so far as the diversity of microorganisms as etiological factors, fhyroiditis and stru- 94 INFLAMMATIONS OF THE THYROID mitis have been found to follow not only pneumonia, typhoid, tonsil- litis, puerperal infections, gastritis, enteritis, pyemia, but also scarlet fever, diphtheria, malaria, influenza, smallpox, measles, cholera, dysen- tery, mumps, and inflammatory rheumatism. All the infections of the gastro-intestinal tract especially, but particularly of the intestine, have been incriminated in the production of thyroiditis. The microbes mostly found in such conditions are the streptococcus, the staphylococcus, the Bacillus coli in pure culture or associated with anaerobic organisms. The symbiosis of the latter microorganism with streptococcus is fre- quently found in gangrenous thyroiditis. Typhoid bacilli are found, too, as etiological factors of thyroiditis and strumitis. Out of 1700 cases of typhoid fever Liebermeister and Hoffmann found 15 cases of thyroiditis and strumitis with six abscesses. Pneumococcus has been found in acute infections of the thyroid fol- lowing pneumonia, and streptococcus after erysipelas and puerperal infection. As said before, traumatism may be an adjuvant etiological factor of great importance in thyroiditis. It does not need to be a direct injury of the thyroid, as a puncture with a needle or knife, but indirect injury is sufficient to cause thyroiditis. This is well illustrated in the case of Schoninger, who reported that a girl, aged three years, after being attacked and nearly choked to death, developed an acute thyroiditis. In that case it is well to assume that a hemorrhage was the consequence of the direct traumatism, forming in that way an excellent "bouillon of culture" for bacteria to grow upon. The same explanation holds true in goiter. Schoninger reported another case of a girl who, while lifting a heavy weight, felt a sharp pain in the region of the thyroid, and soon after developed a strumitis. Similar cases of thyroiditis and strumitis were observed, too, by Kocher in men whose profession it was to carry heavy loads on their heads and necks, and in officers of the army whose duty it was to cry out loud orders, while their uniforms fitted their necks tightly. Cold seems to have been in some cases etiologically responsible for thyroiditis. Thyroid inflammations have been found at every stage of life, from the young child to the old adult. Demme saw a congenital strumitis in a newborn babe, and Berard a strumitis in an old man, aged seventy- five years. A case of mine was in a woman, aged seventy years. But the period of life in which they are most frequently found is between fifteen and sixty years. Women are more often affected than men, and this may be explained by the activity of their sexual apparatus. Each period of their genital life, as puberty, menstruation, pregnancies, menopause, is an occasion for congestive reactions in the thyroid, and consequently predisposes to goiter development and infections. SYMPTOMS 95 Pathology. — In a great majority of cases inflammation is localized to one lobe while the rest of the gland remains normal, but cases have been reported in which infection extended to both lobes and the isthmus. The isthmus and the pyramidal process are less frequently involved. In the early stage of the development of the infection, namely, in the non-purulent stage, the capsule is furrowed with distended, partly thrombosed veins; the glandular tissue is extremely congested, dark red, and spangled with punctiform hemorrhages. In places small infarcts are seen. Parenchyma, as well as interstitial connective tissue, is involved. Under the spur of the infection the epithelium begins to proliferate; the cells may increase in size and number to such an extent as to become multistratified and to form papillary projections into the alveolar lumen; at the same time a more or less intense cellular des- quamation may take place. The colloid becomes vacuolated, thinner, loses its staining power, and in many alveoli disappears entirely. The lymphatic spaces are distended; cells of connective-tissue origin pro- liferate; infiltration with leukocytes is more or less marked. According to De Quervain, besides these elements of connective- tissue origin giant cells are found which should not be confused with tuberculous giant cells. They are seen around very thick, seemingly unabsorbable lumps of colloid, and have very likely a phagocytic action. They are the same ones which are found around foreign bodies, and probably have the same significance. In the purulent stage suppuration takes place in one or more of the small hemorrhagic areas. As in pyelonephritis the gland may become entirely dotted with small abscesses which may remain independent ot each other, or may fuse together gradually, forming finally a large puru- lent collection. In thyroiditis the abscess is never very large. In stru- mitis its size depends upon the dimensions of the preexisting goiter, and may attain large dimensions, especially in cystic goiter. Pus varies in consistency and color. It may be thick or thin, yellow, brown or red, according to the amount of blood which it contains and to the nature of the infecting agent. As a rule it is found serous, brown- ish, and hemorrhagic in streptococcus infection; thick and greenish in pneumococcus infection. The purulent pouches when multiple may communicate or may not. In rare instances a gas due to gas-producing organisms is found in the abscess. Symptoms. The clinical aspect of thyroiditis and strumitis varies with the previous condition of the patient and with the virulence of the microorganisms. Clinically, the types of thyroiditis and strumitis fol- lowing influenza, typhoid, cholera, inflammatory rheumatism, pneumonia, and erysipelas do not differ so very much one from another. I hc\ have about the same intensity, the same course, the same symptomatolog} . In tonsillitis and malaria they seem to have a milder course. 96 INFLAMMATIONS OF THE THYROID Pneumonic thyroiditis, as a rule, takes place during the defervescing period of pneumonia, evoluates mildly, has very little tendency to sup- puration: if it suppurates, the signs of purulent production are slow to appear. Acute thyroiditis develops rarely during the acute period of pneumonia. However, Vitello's case proves that this is possible, although in his case a mixed infection was present: the diplococcus was associated with other microorganisms. Typhic thyroiditis, too, takes place during the convalescing period, is longer in its evolution, and does not frequently reach the suppurative stage. Out of 15 cases of thyroiditis, Liebermeister found abscess for- mations six times. Geza Galli reported lately a very remarkable case of strumitis developed twenty-one years after the patient had had typhoid fever. The incised abscess proved to be, bacteriologically, a pure cul- ture of typhoid bacilli. The author does not say whether the patient was a typhoid carrier. Puerperal thyroiditis occurs, as a rule, between the tenth and four- teenth day from the beginning of the infection. As a rule in thyroiditis as well as in strumitis the debut of the dis- ease is very sudden and is frequently accompanied by chills and high fever. The patient complains of pain in the region of the thyroid, with a sensation of constriction of the throat. A deep, continuous, and paroxystic pain, although more or less diffusely distributed over the cervical region, is most marked on the side of the affected lobe; it is exaggerated by pressure and by movements of the head, especially by extension, which compresses the gland between the spinal column and the superficial cervical muscles; therefore in order to relax these muscles the patient holds his head flexed. The pain is also increased by the up-and-down movements of the larynx during the act of swallowing; shooting pains never fail to be present in the back of the ear, occipital region, shoulder, and occasionally in the lower jaw. These referred pains are an early symptom, and are complained of by the patient long before any swelling in the thyroid is noticed. The sensation of con- striction in the throat is due to mechanical pressure on the esophagus and to peri-esophageal edema. The pain in swallowing may be so intense as to prevent the patient from taking any nourishment. In later stages, especially when infection is localized to both lobes, the windpipe is compressed and may be displaced. As peritracheal inflam- mation may extend to the mucous membrane of the windpipe and of the larynx, laryngotracheitis accompanied by coughing spells takes place, thus increasing the dyspneic symptoms, which may become very alarming, because in thyroiditis the patient has not had time, as in simple goiter, to get used to the diminished caliber of the windpipe. One of the peculiarities of thyroiditis is its liability to cause marked SYMPTOMS 97 cardiovascular symptoms; tachycardia may be more or less accentuated, heart action being between 120 and 140. What strikes the attention at once is the disproportion between temperature and pulse-rate; the heart action remains rapid even if the temperature is not elevated. This tachycardia becomes more accentuated with a physical effort, but may appear without any cause, and is then liable to cause the most annoying cardiac palpitations. It is of thyrotoxic origin. Blood-pressure is low- ered and, as in Parisot's case, may be so low as to cause symptoms of collapse, which may become very alarming. These cardiovascular symptoms follow a parallel curve with the inflammation of the thyroid, reaching their maximum when the phleg- masia is at its highest and gradually diminishing with the retrocession of the inflammation. As a rule they disappear only when the inflamma- tion of the gland has subsided for quite a long time before. Besides these manifestations, symptoms of less importance may be found, as hoarseness due to involvement of the inferior laryngeal nerve; sympathetic symptoms are rare. The patient complains of roaring in the ears and vertigo; he is extremely agitated and may become delirious. Nausea and vomiting have been rarely reported and they have been erroneously attributed to pressure on the pneumogastric nerves. They are most likely of thyrotoxic origin. Fifteen to twenty hours after the debut of the infection a diffuse swelling located between the sternocleidomastoid muscles makes its appearance. It is closely related to the larynx and goes up and down with it during deglutition. In a great many instances the swelling involves one lobe, and in some others it may be found extending over both lobes, one side being more swollen than the other. The isthmus and processus pyramidalis are seldom involved. If the gland was previ- ously absolutely normal, the size of the swollen lobe will not exceed that of an egg. Of course, if there was previously a goiter, then the size of the swollen lobe will vary accordingly. The tumor, especially in early development, is hard in consistency. The veins of the neck are dilated; the patient's face is congested and may become cyanotic; the region of the thyroid is swollen, hot, and tense; in some instances infiltration of the cervical region may become so marked that it is no longer possible to outline the limits of the thyroid; a diffuse, board-like wall covers the entire region of the neck. Palpation must be done very carefully, as it is exceedingly painful and may provoke suffocating spells. Objective as well as subjective symptoms increase very rapidly t<>i ;i few days until they reach their maximum; if, then, thyroiditis remains in the non-purulent stage, it subsides rapidly and disappears in a f( \\ days or in two or three weeks. According to Ewald the non-purulent 7 98 INFLAMMATIONS OF THE THYROID form is found in 25 per cent, of the cases of acute inflammation of the thyroid. In some instances, after a period of rapid amelioration, the disease retrocedes more slowly and may be protracted over a period of several weeks. The gland may recover its previous normal condition, or a few indurated areas, which in time will be converted into fibrous goiters, may be left as the only living witnesses of the past phlegmasia. Exceptionally, after a remission of a few days, if the infection has been confined to one lobe only, the opposite side may become involved and acute symptoms begin all over again. But in many instances the infection instead of retroceding, progresses until an abscess is formed. The skin becomes more and more red and swollen until fluctuation becomes manifest. If the abscess is not incised, it mav open spontaneously outside, leaving a fistula which may last quite a long time — seven years in P. Franck's case. In some instances the abscess may rupture into the trachea and the esophagus. Death is not necessarily the consequence of such an accident, as cases have been reported in which, after spontaneous rupture of the abscess into the trachea, recovery was uneventful. If the abscess fuses downward into the mediastinal space, it causes a diffuse, purulent mediastinitis which is most invariably fatal. In some rare cases of thyroiditis called by Lebert thyroiditis dissecans, a portion of the thyroid gland is found spontaneously severed from the body of the gland, soaked in a fetid, reddish serosity similar to the one found in phlegmon. This glandular sequestrum swims loosely in the purulent cavity; it is often formed by colloid nodules, showing that instead of a thyroiditis we have in reality a strumitis. Similar cases have been reported by Lowenhardt, Kern, Knuppel, Eulenberg and Middledoiff, and considered as acute massive gangrene of the thyroid. The special cause of such powerful infections must certainly be looked for in the malignant virulence of microbes such as streptococcus and anaerobic bacilli of putrefaction. Besides these acute forms of gangrene there are others, less obstrep- erous, less dangerous quoad vitam, but very much more unpleasant on account of their long duration. They are infections, occurring in old goiters with fibrous or calcareous nodules whose blood supply is precari- ous, and consequently are soon isolated from the gland and converted into foreign bodies. As soon as surgical or spontaneous drainage is estab- lished, suppuration does not stop until total elimination of the foreign body has occurred, and this may take months or years. Diagnosis. — Inspection and palpation of the cervical region are so easy there should be no difficulty in making the correct diagnosis. If there is any doubt left, the up-and-down movements of the larynx will clear up the question; the latter symptom is always present except in DIAGXOSIS 99 cases in which inflammation has become so far advanced that a diffuse infiltration extends all over the neck. Congestion, especially in women, is not an uncommon feature at the time of their menstruation or pregnancy, but in such cases pain, fever, and all the other general symptoms found in acute thyroiditis will fail to be present. If a sensation of constriction in the throat, and even respiratory disturbances, are complained of, it will not be difficult to put them in relation with some nervous and hysterical condition of the patient unless a goiter large enough to satisfactorily explain these symptoms should be present. It may become extremely difficult to differentiate a hemorrhage tak- ing place in a goiter from a strumitis. Spontaneous hemorrhages are very rare in a normal thyroid, whereas they are often seen in goiter. Hemorrhage may take place in a nodule which is so small that the patient is unaware of its presence, and yet such swelling may cause an enlarge- ment of the entire lobe, so that the pathological picture may be mis- taken for thyroiditis. The history and development are of great value in differentiating inflammation from hemorrhage. If acute swelling of the thyroid has taken place in connection with some infectious process, the probability will be in favor of thyroiditis, but if the swelling has no relation whatsoever with an infectious process, and perchance has appeared after a physical effort or traumatism, it will be reasonable to admit that we have to deal with a hemorrhage. Local pain and fever, although possibly present in hemorrhage, are less marked than in acute infection, and when present complicate that much more the diagnosis, as in the following case of mine. A young woman, aged eighteen years, had a small goiter for which she was being treated by an osteopath. After severe manipulations of the neck she complained of pain and sen- sation of constriction in the cervical region. The right lobe, in which goiter was developed, had increased rapidly in size and was very painful to pressure. The temperature was ioi°; the skin of the neck was warm but not infiltrated. After three days everything subsided, but the goi- ter remained a little larger than before. In this case, after some hesita- tion, I made the diagnosis of hemorrhage in a colloid goiter following traumatism. As the patient did not consent to an operation at any time I never had the opportunity to confirm my diagnosis, although in all probability it was correct. In conclusion we may say that in hemorrhage the symptoms reach their climax more rapidly and subside more quickly than in thyroiditis. To mistake acute thyroiditis for tuberculosis or syphilis is hardly possible. Miliary tuberculosis of the thyroid is only an incident of a more important process, namely, generalized miliary tuberculosis; there- fore it has no clinical interest, and is, as a rule, a postmortem find- 100 INFLAMMATIONS OF THE THYROID ing. Small localized tuberculous foci might be confused with thyroid- itis, but their chronic character and the lack of general symptoms will afford the correct diagnosis. The same is true of syphilis. Differential diagnosis between strumitis and malignant goiter, although, as a rule, without difficulty, is sometimes not easy. For instance, a rapidly growing sarcoma has been mistaken for an acute infection more than once, because in such instances the symptoms have been very much the same. The skin may be warm, red, infiltrated, painful to pressure, and even fever may be present. I saw in Charleston, W. Va., a man, aged forty-five years, a foreigner speaking not a word of English, French, German, or Italian, so that it was impossible for me to get any information so far as the history of his case was concerned. In the right lobe was found a large tumor with diffuse limits; very adherent to the neighboring tissues; scarcely sensitive to pressure and firm in consis- tency. Yet on deep pressure there was a sensation of elasticity. The skin was infiltrated and red; he had no temperature. Although the patient had become very emaciated, he looked to me as being pro- foundly toxic rather than cachectic, and despite the diagnosis of malig- nant tumor made by several other physicians, I concluded the patient was suffering from a slow-developing strumitis, and advised operation, which later confirmed the correctness of my views. On account of the difficulty in swallowing, and because of the pain and sensation of constriction in the throat, non-purulent thyroiditis might be confused with tonsillitis, but an intrabuccal examination will settle the matter. An acute cervical adenitis might be mistaken for thyroiditis or strumitis, but their localization and anatomical relations with the other organs of the neck will soon throw some light upon the subject. In the diffuse cervical phlegmon the inflammation is more superficial; the infiltration is more diffuse and deglutition is less painful. In rare instances a mistake might be possible with laryngochondritis. It is not only of theoretical interest to decide if in a given case we have to deal with thyroiditis or strumitis, but it is also important from the prognostic point of view. Experience shows that thyroiditis is more apt to be non-purulent, whereas strumitis will terminate by suppura- tion. Consequently, not only the duration but the course of the disease and the dangers connected with it may be predicted to the patient or his family. In order to decide if we have to deal with a thyroiditis or strumitis the history of the case will be of great assistance, as it will indicate whether the patient has previously had a goiter or not. If the patient lives in a country where goiter is endemic, not too much stress should be placed upon his answer if negative, as the chances are great that his thyroid might contain a few unobserved goiterous nodules. This is so PROGXOSIS 101 true that Kocher saws he has never seen a case of genuine thyroiditis. All the acute cases which came under his observation were developed in an already degenerated thyroid. The size of the swelling is of good differential diagnostic value. In thyroiditis the tumor rarely exceeds the size of an egg, whereas in stru- mitis the size will depend upon the volume of the goiter. In thvroid- itis, infection involves from the start the entire lobe. Strumitis, even if developed in a small nodule, remains for a time localized to this nodule; only later the inflammatory processes extend to the entire lobe. If inflammation involves both lobes, the chances are that we have to deal with a thyroiditis, or if one lobe is affected and after subsiding the inflammatory symptoms appear on the other side the chances are that we have to deal with a thyroiditis. Prognosis. — The prognosis of acute infection of the thyroid depends very much upon the virulence of the microbes and upon the condition of the patient at the time the infection takes place. If suppuration does not take place, the inflammatory symptoms subside rapidly; sometimes even small abscesses regress spontaneously, but, as a rule, if suppuration sets in, the process will go on until spon- taneous or surgical drainage has taken place. During this period the inflammatory process may endanger the life of the patient on account of the septicemic phenomena due to resorption of infectious materials taking place as long as the abscess under tension has not been opened. It may endanger life on account of pressure symptoms causing asphyxia, and on account of a possible perforation into the trachea, esophagus, pleura, and mediastinal space. The dangers of suffocation cannot be better illustrated than in the case of P. Franck. When he was a mere boy he was taken ill with strumitis. The dyspneic symptoms became so alarming that the life of the child was in danger. The best physician in the neighborhood, called in to see the young patient, declared pom- pously that "a nerve in the child's neck had been ruptured," and that death was imminent. The mother, who had more medical "horse-sense" than all the medical academy of that time, thought that the swelling in the neck had something to do with the choking of her child. She called in the barber of the corner and told him to make an incision with his razor in the swelling. The barber did so, and at once a Stream oi pus rolled out, the dyspneic symptoms ceased, and so was saved the life of P. Franck, who at the beginning of the nineteenth century became a surgeon of great repute. As a result of this incision a fistula remained for seven years before closing spontaneously. So far as death is concerned, non-purulent th\ roiditis is very much less dangerous than the purulent form. According to Robertson s sta- tistics, 12 out of 96 cases died; ^4 were non-purulent thyroiditis, with 2 102 INFLAMMATIONS OF THE THYROID deaths; 41 were purulent, with 9 deaths; 1 was gangrenous, with 1 death. It seems, however, that with our present knowledge of surgery that the death-rate ought to be reduced. A serious and frequent sequelae of thyroiditis is the development of exophthalmic goiter. Treatment. — In non-suppurative thyroiditis the treatment will differ according to the infecting agent; for instance, rheumatic thyroiditis will be amenable to treatment with sodium salicylate; thyroiditis consecu- tive to malaria will be greatly benefited by quinine; thyroiditis due to influenza will also derive benefit from salicylate. For the other forms of thyroiditis we have no specific remedies; the treatment must be symp- tomatic. As a rule we might say that in every form of thyroiditis, except the malarial form, salicylate should be used because many of such acute cases seem to be in relation with some rheumatic condition. As non- suppurative thyroiditis subsides spontaneously no surgical interference will have to be considered unless the inflammation should have taken place in a diffusely enlarged parenchymatous or colloid gland causing dyspneic symptoms. In that case the surgeon may be called upon to perform a tracheotomy or, better, thyroidectomy. When the abscess is formed, it must be opened and drained, and by the way, it is not always easy to tell whether the abscess is present or not. Fluctuation, which is really about the only reliable sign betraying the presence of pus, is not always detectable because the abscess may be deeply situated and surrounded by a hard, thick capsule of peristru- mitis, or because small abscesses may be difFusely spread throughout the gland, so that if one should wait for fluctuation to appear before inter- fering surgically, he might overlook the psychological moment for operation and thus allow his patient to run undue risks so far as compli- cations and death are concerned. On the other hand, one might be so misled as to take a pseudofluctuation for a real one, and on the strength of such findings may be induced to operate, expecting to find an abscess. Great will be his surprise to find only a much-congested gland. Very suggestive of abscess formation will be the fact that inflam- mation is no longer localized to the lobe itself, but has extended difFusely to the neighboring tissues. Very suggestive, too, of an abscess forma- tion is the presence of a very hard lobe whose central portion seems to be soft. The blood count and temperature may be of help, as in non- suppurative thyroiditis temperature climbs gradually, and when it has reached its climax, gradually comes down in lysis, whereas in abscess formations the temperature remains high and takes a septic curve. It would be a mistake to rely upon an exploratory puncture as a means of deciding whether the abscess has formed or not, because if the puncture is negative, it does not mean that pus is not present, but TOXIC THYROIDITIS 103 means only that the needle did not strike the purulent pouch or that the pus is too thick to be aspirated. If symptoms are so alarming as to necessitate an immediate operation the exploratory puncture only means precious time lost. If they are not, there will be enough time left to make a correct diagnosis without endangering the life of the patient by an exploratory puncture, because this puncture is bv no means a harmless one. It may determine a sudden hemorrhage into the goiter and, consequently, cause severe choking spells in a very short time. Hence the following rule: If at any time one wishes to make an exploratory puncture, everything should be in readiness for an immediate subsequent operation if it should become necessary. In conclusion we may say that the diagnosis of abscess cannot always be made with certainty, and that it is better to operate a little too soon than too late. If the abscess is still very well encapsulated, and if the infiltration with the neighboring tissues is not such as to render the operation extremely difficult, the removal of the tumor in toto is the most feasible thing to do; but if for some reason or another the sur- geon must be parsimonious with the thyroid tissue, as in a case of bilat- eral thyroiditis, incision of the purulent pouch and drainage is the logi- cal procedure. It is nearly impossible to set down hard-and-fast rules, as indications will vary with each given case. Judgment and experience will be the surgeon's best guides. Toxic Thyroiditis. — As we have a toxic hepatitis and a toxic nephri- tis, so we have also a toxic thyroiditis. It is caused by chemical poisons and bacterial toxins, whereas the bacterial thyroiditis is caused by the microorganism itself. Experimentally, it has been very well demon- strated that chemical poisons such as phosphorus, nitrate of silver, iodin, turpentine, and pilocarpine cause a toxic thyroiditis characterized histologically by hyperplasia, degeneration, and desquamation of the epithelium and sometimes by increase, but more often diminution or absence of colloid, and more or less marked hyperemia. As a rule leukocyte infiltration is less frequent than in bacterial thyroiditis. In nicotine and lead poisoning no alterations are present. Although mostly absent, swelling in such toxic conditions may be more or less marked; it is a well-known fact that acute lodism may be- followed by acute swelling and inflammation of the parotids. The same may be true for the thyroid as in Lublinski's case-, in which the thyroid became swollen and inflamed during treatment with K.I. Ever) symptom subsided after the medicament was discarded. When once it was found that the thyroid was so susceptible ro chem- ical poisons it was only logical to conclude thai bacterial toxins mighl have the same effect upon that organ, hence the experiment undertaken by Roger and Gamier, Crispino, lorn, De Quervain and others, fhey 104 INFLAMMATIONS OF THE THYROID found that the introduction ot bacterial toxins into the general as well . s into the thyroid circulation had on the thyroid about the same influ- ence as the chemical poisons, as hyperemia, proliferation, and desquam- ation of the epithelium, diminution or absence of colloid and its increase in the lymphatic vessels. According to De Ouervain a pure culture of a virulent microorganism injected into the artery of the thyroid may ss through the thyroid without leaving any marks of its passage, but, on the other hand, may cause disparition of the colloid, desquamation of the epithelium, and the appearance of polynuclear leukocytes in the alveoli. After these findings it became evident that a step further should be made and that the relations between thyroid and infectious diseases in man should be thoroughly - investigated. Sokolow was the first who, in 1896, tried to work out these relations. He tound that in acute dis- s, fatty degeneration ot the follicular epithelium with desquama- tion took place. M tiller in the same year reported about the same findings. In 1900 Roger and Gamier reported the result of the examina- tion ot forty thyroid glands which had been taken from patients who had died from measles, scarlet fever, diphtheria, acute gastro-ententis, typhoid, cerebrospinal meningitis, peritonitis, rabies, and smallpox, and in nearly every case they tound marked histological changes in the thyroid. Even diffuse hemorrhages were present in three cases. In some instances the epithelium had proliferated to such an extent as to form papillary formations projecting into the alveolar lumen. The cellular protoplasm was tound granular, nuclei were swollen and stained with difficulty. Hand in hand with proliferation a cellular desquamation was noticed. The colloid, thin in places, was absolutely absent in others. The interstitial connective tissue showed very" little pathological changes except in thyroids of patients who had died from tuberculosis. In such instances the authors found a diffuse sclerosis of the thyroid, the alveoli being choked by the increased connective tissue. In their opinion this sclerotic process was the result of tuberculous toxins. They concluded that in infectious diseases, according to the gravity and duration ot the infectious process, after a period of functional stimula- tion leading to hyperthyroidism symptoms, the thyroid, injured by per- tent and deleterious irritations of toxic nature, may finally be put in a state ot more or less complete functional inhibition; hence hypothy- roidism. Torri shared the same v'u Kashiwamura, in i^ci, relating the results of his investigations on 53 thyroids from patients dead from various infectious diseases, tried to disprove the findings of B ger, Gamier and Torri. He did not find the same typical changes described in the epithelium, colloid and connective tissue, and concluded that, owing to the fact that the physi- TOXIC THYROIDITIS 105 ognomy of the thyroid is already so variable in normal conditions, it would not be safe to draw conclusions derived solely from its histolog- ical appearance; in other words, it is difficult to decide what belongs to the normal histology and what belongs to pathology. De Quervain, Crispino. Sarbach, Serrafini, Vitry and Giraud. on the other hand, found that a manifest relation between the thyroid and infectious diseases exists, and according to their researches the pathological changes are mostly in proportion to the severity of the disease. De Quervain, in ti gating the condition of the thyroid in 45 cases, in which the cause of death was tuberculosis, cancer, cardiac, liver and kidney diseases, peri- tonitis, puerperal infection, diabetes, scarlet fever, smallpox, measles, diphtheria, typhoid, and pneumonia, found changes in the epithe- lium characterized by proliferation, desquamation, fatty degeneration of the desquamated cells, thinning, diminution or absence of colloid, increased vascularization in the gland in toto, and some pathological changes of the connective tissue with, in certain cases, leukocyte infil- tration. In patients who died from cancerous cachexia, diabetes, neph- ritis. Addison's disease, and uremia no pathological changes of the thy- roid were detected. S a roach's conclusions, after investigating 67 cases, were as follows: 1. Acute infections may produce in the thyroid, histological altera- tions, characterized by increase in size and in number of the alveolar cells, their desquamation and degeneration, liquefaction and diminu- tion of the colloid, and hyperemia. The connective tissue remains intact. : Alcoholism can determine similar alterations in the gland. Chi :>nic pulmonary tuberculosis produces a sclerosis of the thyroid with secondary atrophy of the alveoli. 4. Nephritis, uremia, cancerous cachexia, and sarcoma do not produce any alterations of the thyroid. rr and Esmonet, treating the epithelium of the thyroid with osmic methods, tound that normally the epithelium is exempt from fatty degeneration, whereas in infections and cachectic conditions, as in cancer. leukemia, and tuberculosis, the epithelial elements have undergone a marked fatt _ neration. Finally, Gregor, in 26 thyroids of children who had died of scarlet fever, tound, too, the same pathological char _ reported by all authors. Consequently, from all this wide and carefully conducted research work \vc can safely conclude that the thyroid does not remain indifferent in the presence of the important pathological phenomena taking place in the organism. It reacts more or less constantly to even - infectious process by some degree of hyperplasia which is often clinically deu able. It is then know: -Kptom. 106 INFLAMMATIONS OF THE THYROID The question arises whether, in a given case, we have to deal with a bacterial thyroiditis or a toxic one, and I must say that the differ- entiation between the two is certainly not easy. We might say that in toxic thyroiditis, as the entire gland is flooded with toxins, the damages will be diffuse and spread all over the gland. Furthermore, as the toxins are diluted in the blood, their damaging power being diminished, patho- logical changes, except in severe intoxication, will be more or less mild. Consequently, the immediate clinical symptoms will be much less marked than in bacterial thyroiditis, and swelling of the thyroid may not be present at all, although a slight enlargement may easily escape unnoticed. In that respect the researches of Gamier are extremely interesting. Taking systematically the measurements of the neck in 20 cases of scarlet fever he found that mil cases the circumference of the neck was increased from 1 to 2 cms., yet no clinical symptoms were present. Very likely if more attention should be given to this phase of the ques- tion we should find that Vincent's thyroideal symptom in infectious diseases is present more often than we think. If toxic thyroiditis has a less noisy symptomatology and pathology than bacterial thyroiditis, it does not follow that it is a harmless occur- rence, as this form of thyroiditis seems preferably to injure the physi- ological function rather than the anatomical elements of the thyroid. Frequently there is found an acute Graves' disease grafted upon a seem- ingly innocuous infection, as tonsillitis, etc. Even myxedema has been the consequence of such toxic conditions. Tuberculosis of the Thyroid. — It is classical to say that tuberculosis of the thyroid is rare. Rokitansky, in 1861, denied its existence; but a few years later Lebert discovered the first case, and lately Arnd, in looking over the literature, found 44 cases which seemed to be undoubt- edly of tuberculous origin. Of course tuberculous foci occurring in miliary tuberculosis have not been included in the list, as they are without interest; they have no entity per se, but are only the conse- quence of a generalized process extended to the entire organism. Follicular tuberculosis of the thyroid, secondary to a primary focus localized in another organ, is more frequent and better known. Lebert, in 1862, was the first to call attention to it, and since then other pathol- ogists have studied it. Chiara thinks that it is common in the acute form of tuberculosis, 3 out of 4 cases (what a small number to draw con- clusions from), but rare in the chronic form, 4 out of 96 cases. Fraenkel and some other authors have confirmed these results, which were, how- ever, only postmortem findings. The caseous form of tuberculosis of the thyroid is rare. The first case was published by Bruns in 1893. It was that of a woman, aged forty-one years, with a large goiter growing rapid!)' in size. The tumor TUBERCULOSIS OF THE THYROID 107 was hard, painful to pressure, had diffuse limits, and caused shooting pains and dyspnea. Bruns considered the case a malignant one, but was very much surprised at the operation to find only a caseous tuber- culous goiter. A few other cases have been reported since, and in conclusion it may be said that caseous tuberculosis in goiter forms a tumor, more or less hard in consistency, painful to pressure, with dif- fuse limits and a tendency to infiltrate neighboring tissues. Diagnosis is verv seldom made before the operation. Localized areas of tuberculosis may be found, too, in a simple goi- ter; no clinical or pathological symptoms betray their presence, and they are revealed only by a careful microscopic examination. Ruppaner was the first to describe such a condition, and reported 3 cases of col- loid goiter in which he was able to detect such tuberculous lesions. \ on Werdt, in going over 444 cases of simple goiter, found similar conditions three times. Out of 29 exophthalmic goiters he found 1 with tuberculous areas. Arnd found 3 cases, Hedinger 10, out of 608 goiters. The tubercu- lous lesions are found in the nodular goiter itself or in the normal paren- chyma between the nodules. Hedinger thinks that tuberculous lesions in conjunction with goiters are more frequent than is thought, because these lesions, being so little apparent, easily escape attention unless looked for in seriated slides; they are really microscopic findings. Besides these massive as well as tiny tuberculous lesions a more or less marked sclerotic condition may be encountered in the thyroid, due to a chronic toxic irritation from the tuberculous toxins. In certain instances sclerosis may become so developed that a condition of canceriform appearance known as woody thyroiditis follows; the tumor is hard like wood, has diffuse limits, is in the great majority of cases painful to pressure, and rapidly causes marked dyspneic symptoms. Its true origin, as a rule, is not recognized and the diagnosis of malignant tumor is nearly always made. Some authors seem to think there is an indisputable relation between goiter. Basedow's disease, and tuberculosis. The impression gained from the small amount of experimental work along this line is that the thyroid is peculiarly resistant to tuberculous infections. Pinoy, injecting guinea-pigs with tuberculous bacilli, found only once the thyroid gland infected with tuberculosis; therefore he concluded that the thyroid, as well as the pancreas and other glands, shows a special resistance to tuberculous bacilli. Torrin and Tomellini, on the other hand, injecting directly into the thyroid artery an emulsion of tubercular bacilli, found in each case the corresponding lobe infiltrated with tuberculosis. Shimo- daira repeated the same experiment, but in one series injected heavy doses of tubercle bacilli and in the other series small doses. He found 108 INFLAMMATIONS OF THE THYROID that in the first series of experiments the gland was infected with tubercle bacilli while in the other it was not. Therefore he concluded that unless overpowered by number the thyroid gland shows a special resistance to tubercle bacilli. Many seem to believe that the thyroid has an immunizing influence against tuberculosis, not only for the gland itself but also for the entire organism. Morin, working in a sanitarium for tuberculosis in Leysin, after examining several hundred tuberculous patients, came to the con- clusion that the disease undergoes a more acute and malignant course in cases in which the thyroid is atrophied; whereas in cases in which a thyroid hypertrophy or even a goiter exists the course of the disease is milder. I do not know how far these conclusions are justified, but it is, nevertheless, a fact that myxedematous patients are easily the prey of tuberculosis, as shown by McKenzie, who out of 71 cases of myxedema found that 20 were tuberculous. This, however, could be explained by the retarded metabolism and the diminished resistance of the patients. Costa goes so far as to pretend there is an etiological relation between goiter and tuberculosis. Goiter, in his judgment, is due to the reaction of the gland against tuberculous toxins. If he meant that the thyroid may react to tuberculous toxins by toxic thyroiditis, all well and good; otherwise he must have been the victim of coincidences, because we see too many cases of goiter in which no tuberculous lesions are found, and vice versa. Let us remember that Hedinger found 10 microscopic tuberculosis cases out of 608 cases. Goiter and tuberculosis are among the most common diseases, and if there were any etiological relation between the two, it seems that this fact could be easily demonstrated, as thou- sands of cases are seen each year. In the many hundreds of cases of goiter which I have seen, pathologically as well as clinically, tubercu- losis associated with goiter was only an accidental occurrence. On the other hand, the relation of cause to effect between Basedow's disease and tuberculosis cannot be denied. It is not uncommon to find a Graves' disease grafted upon a case of early tuberculosis; even marked exophthalmic symptoms may develop in the course of advanced tuber- culosis. From the cases I have seen, however, I could not say that tuberculosis was of more frequent occurrence in the history of my Base- dow's patients than any other acute illnesses, as typhoid, pneumonia, tonsillitis, etc. I shall take up again these relations between acute infectious diseases and Graves' disease in the chapter on the Etiology of Exophthalmic Goiter. Syphilis of the Thyroid. — It is only recently that attention has been turned to syphilis of the thyroid. Only very few cases worth any ere- WOODY THYROIDITIS 109 dence have been reported. Demme, according to \\61fler, found a syphilitic gumma in the thyroid of a newborn. In 1889 Gamier described syphilitic alterations in the thyroids of five newborn, characterized bv interstitial sclerosis and alveolar atrophy. Lancereaux found about the same alterations. Recently, Poncet, Leriche, Berard, Favre and Savy have made important contributions to this subject. Histologically, lesions of the thyroid may involve the interstitial as well as the parenchymatous elements. The interstitial connective tis- sue has a marked tendency to abnormal proliferation, spreads through- out the gland, and terminates by a sclerosis of the organ. In the early stage, epithelioid nodules and giant cells are frequently seen in it. Diffuse leukocyte infiltration is the rule. Woody Thyroiditis. — It was Riedel who, in 1896, first described a form of thyroiditis which he called "eisenharte strumitis," or "iron- hard strumitis." Riedel's patient was a man, aged forty-two years, who had a tumor, developed in the thyroid, extremely immobile and causing alarming dyspneic symptoms. He diagnosed it as a cancer of the thyroid and attempted the removal of the tumor, but at the opera- tion the difficulties were so great, the adhesions with the neighboring tissues so intense, that a radical operation had to be given up. He, however, removed a piece of the tumor the size of a walnut and to his great surprise after a few months the patient was entirely cured. Micro- scopically, no malignant elements were found; the whole thing was simply the picture of a chronic inflammation. On account of the extremely hard consistency of the tumor. Riedel called it "eisenharte strumitis." In the same year Cordua, of Hamburg, reported a similar case. In 1898 Jeannel, of Toulouse, reported a case in which he made a diagnosis of cancer of the thyroid; later, it proved to be a case of "eisenharte strumitis." In 1901 Ricard reported a similar case in which the diagnosis of cancer of the thyroid had been made and which proved to be a case of "woody thyroiditis." Silatschek, of Innsbruck, and Spannaus, of Breslau, reported lately similar cases. This form of thyroiditis, called by Riedel "eisenharte strumitis," or "iron-hard strumitis," and by Delore and Alamartine "La thyroidite ligneuse," "woody thyroiditis," has always been mistaken for a malig- nant tumor, and yet between these two forms of disease the clinical differences are such that a differential diagnosis can often be made. First of all, the woody thyroiditis is found in younger people, that is, those between thirty and forty years of age. Men are more often afflicted with it than women. The disease evoluates extremely rapidly, in a few weeks or months. The region of the thyroid is painful and shooting pains are intense. One of the earliest symptoms is dyspnea, which may become so rapidly alarming that death seems imminent, and 110 INFLAMMATIONS OF THE THYROID in many instances tracheotomy is the only salvation. The dyspneic symptoms are due to the fact that the trachea is compressed between the lobes of the inflamed thyroid. The trachea is not displaced unless there has been a goiter previously. Pressure symptoms on the inferior laryngeal nerve show up early. The inflammation extends over the entire gland and seems to occur more frequently in normal thyroids than in goiter. Like a drop of oil, it spreads and infiltrates all the organs found between the superficial and prevertebral fascia, thus forming a gangue in which everything has become solidified : thyroid, trachea, esophagus, neurovascular cords, sternocleidomastoid muscles and muscles of the subhyoid triangle all form only one mass. Vainly, one would try to find in it a plane of cleavage. The tumor is absolutely hard like iron or wood, hence, its name. Its surface is smooth, being irregular only when a goiter existed previously. The larynx, immobilized by the diffuse infiltration, does not go up or down with deglutition; cervical lymphatic glands are very seldom involved. The common carotid is lost in the midst of the infiltration, whereas in a cancer of the thyroid, especially if there has been a previous goiter, it is displaced backward. All these symptoms taken together give to the disease a physiog- nomy which differs from the one of malignant tumors. The extreme hardness, its regularity of surface, its marked diffuseness of limits, the involvement of the gland in toto will remind one more of woody thy- roiditis than of a cancer of the thyroid, especially if the disease is found in a young individual, and if it has evoluated rapidly and caused early dyspneic symptoms, entirely out of proportion to the size of the tumor. Pathologically, the gland is transformed into a fibrous, whitish, extremely hard mass. If a goiter has existed previously, it is embedded in the fibrous mass. The cut surface is dry and no juice can be expressed, as can be done in cancer. Histologically, the parenchyma is choked by a sclerotic connective tissue of interstitial and capsular origin; alveoli in places have disappeared; there is no abscess nor any tendency to suppuration. In the remaining alveoli, desquamation and either thinning or absence of the colloid is present. In such cases the idea of scirrhus must be soon discarded, as spon- taneous healing has been observed, and a complete cure without relapse followed partial extirpation. Fibromata of the thyroid have not the same anatomical and clinical aspect either; they are encapsulated with- out tendency to infiltration. As a rule the disease affects individuals who have been in excellent health previously, with no typhoid, pneumonia, or other infectious dis- ease as a preliminary stage. In some instances, it is true, tuberculosis and syphilis have been found as a concomitant complication, so that they might be considered as an etiological factor; but the fact remains that PARASITIC THYROIDITIS 111 cases of woody thyroiditis, where apparent concomitant infection could be discovered, do exist. This fibrous, sclerotic process is not peculiar to the thyroid only, but had also been found by Riedel in the pancreas and by Mickulicz and Kuttner in the submaxillary and lacrymal glands. The same sclerotic process is known, too, in the digestive apparatus, especially in the stomach and gall-bladder. I remember finding in a postmortem a stomach which had seemingly undergone the same kind of sclerotic degeneration as the one described above in the thyroid, and which is known as the "leather-bottle" stomach. The stomach was transformed into a canal about 40 cms. in length, 10 to 12 cms. in width in the cardiac region, and 6 to 8 cms. in the pyloric region. This canal was extremely hard, its walls were thick, and all the epigastric region was diffusely involved by the same sclerotic condition — no metastases of any kind; no ulcerations of the mucous membrane of the stomach. Macroscopi- cally, I made the diagnosis of "limtis plastica," which was considered at the time as a peculiar form of malignancy, but histologically it proved to be a chronic inflammation. Bacteriologically, nothing has been found to enlighten us on this subject. Mycosis, and especially actinomycosis, might be incriminated in some cases. In view of the extreme diffuseness of the lesions, surgical treatment which intends to be radical is extremely dangerous, as extirpation can- not be complete without sacrificing important organs as the common carotids, vagus nerve, and the jugular veins. On the other hand, infiltra- tion of the walls of these vessels makes the attempt dangerous as they are very friable; ligatures cut through as if in butter. If the dyspneic symptoms become so alarming as to endanger the life ot the patient, the best treatment is a cuneiform resection of the isthmus in order to liberate the trachea from its compressing ring. If an operation is decided upon, then, according to Delore and Alamartine, an excision of a small portion of the tumor seems to be sufficient to assure complete recovery. Iodide of potash is an excellent adjuvant, and x-ray treatment seems to be, according to Silatschek and Barjon, specific for this disease. If syphilis is suspected, an intense antisyphilitic treatment should be started at once. Parasitic Thyroiditis. — In 1907 Chagas, working in the Institute of Manghuinos in Rio de Janeiro, discovered a new parasite which he called " Schizotrvpanum cruzi" in honor of his chief, Oswald Cruz. According to Chagas this living organism causes a parasitic thyroid- itis, accompanied by the most severe symptoms, and is very often fatal. The geographical distribution of this disease is not entirely worked out. It is found in Brazil, especially in the State of Minas Geraes. It 112 INFLAMMATIONS OF THE THYROID is transmitted to human beings and to domestic animals by the bite of a hematophagus insect, the " Conorrhinus megistus." This hemip- terus lives in the cracks of windows and walls of old huts; it is not found in new houses, consequently the disease is mostly found among the poorer class of people. The insect bites during sleep. Its bite is absolutely painless and does not cause any inflammatory reaction. It is not uncommon to see a dozen or more of these insects biting at the same time a sleeping infant without waking it. The parasite is found in the blood under different forms, according to the stage of its evolution. It can be culti- vated on blood agar. The period of incubation after its bite is about ten days. According to Brumpt, other insects can also act as hosts, especially the bed-bug (Cimex lectulanus), the excreta of which are highly infectious. Parasitic thyroiditis may be acute or chronic. The acute form is found mostly in children under one year of age. The thyroid is swollen, skin is infiltrated not only in the neck but over the face, and a crepitus on pressure is present. Fever is persistent, high, 103 , with only slight morning remissions. Cervical glands, spleen, and liver are enlarged. The disease lasts about fifteen to thirty days, and terminates, as a rule, in death. Only exceptionally does it take a chronic course in very young children. The chronic form is found in older and more resistant children and in adults. If the disease does not terminate fatally, it lapses into a chronic form characterized by goiter, often of very large size, and symptoms due to partial or total loss of the thyroid function dominate the scene. According to the degree of thyroid disturbance the symptoms may be slight, moderate, or very pronounced. It is possible, therefore, to meet with cases which are practically indistinguishable from the usual type of goiterous individuals seen in endemic localities in Europe. It is impossible to distinguish such cases from the true endemic goiter by blood examination, since the trypanosoma, which is said to cause the goiter, disappears from the blood after the acute symptoms have sub- sided; the true infectious origin of this goiter can be ascertained by inoculation methods. Chagas described five different forms which the disease may take: 1. The pseudomyxedematous form: the thyroid is enlarged, the enlargement being confined, as a rule, to one lobe only; the skin shows a mucoid infiltration and has a bronze color, similar to the color charac- teristic of Addison's disease; irregular and intermittent fever is present. 2. The myxedematous form: symptoms of hypothyroidism are extremely marked. 3. The cardiac form: found mostly in adults and characterized by myocarditis, arrhythmia, and bradycardia. HYDATID CYST OF THE THYROID 113 4. The nervous form: caused by the localization of parasites in the central nervous system; spasmodic motorv disturbances are frequently seen in that form. 5. The subacute form: characterized by periods of exacerbation alternating with periods of remission; the prognosis of this form is severe. Postmortem shows enlargement of the thyroid and of the cervical glands; cardiac hypertrophy with a pericardiac, pleuritic, peritonitic, serous exudate is frequent. Liver, spleen, and suprarenal bodies are enlarged. Histologically, what dominates in both forms, acute and chronic, is sclerosis due to an exaggerated development of connective tissue. The alveoli are choked and atrophied. In the acute forms, proliferation and desquamation of the epithelium, thinning or absence of the colloid, hyperemia, leukocyte infiltration, in short, the same lesions found in all the other forms of acute thyroiditis are present. In chronic cases the connective tissue is very abundant and cystic forma- tions of more or less large size are found in great numbers. The same inflammatory reactions and cystic formations can be found in the myo- cardium, muscles, nerves, testicles, ovaries, cortex cerebri, etc. In the acute form, as the parasites are numerous, a simple drop of blood taken from the finger or lobule of the ear will show the parasite when colored by the Giemsa method. In the chronic forms 5 to 10 c.c. of blood injected into the vein of a dog, monkey, or cat will kill the animal after a certain period of time: the schizogonic form of the parasite will then be found in the lungs. Most significant analogies between what Chagas calls the endemic Brazilian goiter in its chronic form and our own endemic goiter cannot be denied. In both cases there exists the chronic enlargement of the thyroid gland with its accompanying conditions of cretinism and myx- edema. Beyond doubt the Brazilian infection is much more severe and the mode of infection and infectious agent totally different, but these conditions do not change the fact that a chronic goiter is developed from an infectious basis. This is, in my judgment, a very strong argu- ment in favor of the infection theory of our endemic goiter. Hydatid Cyst of the Thyroid. — Hydatid cysts of the thyroid are extremely rare. L. A. Landiver went over the literature and found 29 cases, to which he adds 2 of his own. The hexacantic infection takes place through the hematogenous route. Direct inoculation occurs only in a very extraordinary condition, as in Minert's case — there the cervical wound was licked by a dog. The pathological characters of the hydatid cyst do not differ from those of a simple cyst. The parenchyma undergoes sclerosis on account of compression. If the hydatic cyst becomes infected, we have then the 114 INFLAMMATIONS OF THE THYROID symptoms of a cystic strumitis. Clinically, the diagnosis of hydatid cyst is seldom made, as the only symptom pathognomonic of its pres- ence, namely, the "hydatid fremitus," has never been perceived. Treatment, of course, must be surgical. CONGESTIONS OF THE THYROID. Possibly more than any other organ the thyroid is exposed to conges- tions of various origin, physiological or pathological. These congestions have a great clinical importance. Physiological congestions are observed most frequently in women and especially during their genital life. Premenstrual congestion of the thyroid is among the most frequent premonitory symptoms of the first menstruation. Mothers often worry over this "physiological goiter." Not all have the wisdom of the one mentioned by Goethe, who said to her daughter: "Do not worry, my child, Venus has touched thee with her enchanted hand." Of course, in such conditions congestion is accompanied with true glandular hypertrophy. When once the menstruation is well estab- lished, congestion of the thyroid may subside more or less entirely. In many cases, however, it reappears each month with the menstrual period, and in dysmenorrheic patients it may, indeed, be very marked, as if the thyroid were trying to exert a vicarious function. That congestion in the thyroid takes place during the first sexual relations is a fact known since antiquity. It was a popular custom among the old Roman matrons to measure the circumference of the neck before and after marriage, and, as Berard says, "More than one Roman husband measured the virginity of his wife by the length of the thread rolled around her neck." Later on, during pregnancies and especially during delivery, the thyroid is again the site of congestion. This increase in volume is partly due, of course, to hypertrophy of the glandular elements, but active and passive congestions play a very important part in it also. After delivery, hypertrophy and congestion retrocede gradually, but, as a rule, the volume of the thyroid never goes back to its normal size. At the menopause there is again occasion for congestions of the thy- roid; they are the last "flaring up" of the genital process, which is going to be set at rest forever. Too often, however, these congestions of the menopause are of bad augur, as they are the premonitory symptoms of a malignant goiter. In young boys these same transitory congestions are seen at the time of puberty. TRAUMATIC LESIOXS OF THE THYROID 115 Congestion following physical effort is a well-known fact, and is of frequent occurrence. Already Lalouette and Maigmen were aware of that fact. They demonstrated experimentally that in dogs, after a prolonged and fatiguing run, the thyroid became a third larger. This increase in size was due to venous congestion. These congestions due to physical effort are seen in all walks of life — singers, officers, workmen lifting heavy weights are especially liable. Congestions in congenital goiter will be taken up in the chapter reserved for that subject. Pathological Anatomy. — \ erv little was known of the congestive lesions in man until De Quervain, Berard, Ball and others approached this question experimentally. What strikes the attention at first is a marked dilatation of the vessels of the capsule, which are abnormally distended and filled with black blood. On the cut surface the alveoli and capsular vessels are dilated and bulge out. Microscopically, beside the intense vascularization and the interstitial hemorrhages, what im- presses one is the fact that the alveoli contain no colloid or very little, whereas the intra- and perilobular lymphatics contain a great quantity of it. At the same time a more or less intense desquamation of the epithelium is present. Symptoms. — As a rule the only symptom seen in congestion of the thyroid is a swelling of the thyroid. Palpation shows an enlarged gland, soft or firm, and slightly painful to pressure. It is only when a goiter of quite large size is present that the congestions of the thyroid are liable to cause dyspneic symptoms. The prognosis of such conditions is extremely benign. After a few days or weeks the congestive symptoms retrocede and the gland is restored to normal condition. In the newborn the prognosis is not always so simple, as we shall see in the chapter on Congenital Goiter. Treatment. In the great majority of cases expectation is the only reasonable treatment. If during pregnancy the dyspneic symptoms become so marked as to endanger the life of the patient, thyroidectomy, Cesarean section, or an abortion may be given serious consideration. The nature of the intervention, of course, will depend upon the case. TRAUMATIC LESIONS OF THE THYROID. On account of its natural vertical as well as lateral mobility, and on account of the protection afforded to it by the muscles of the cervical region, the thyroid gland is seldom involved in traumatisms ot rlu- cervical region; however, injuries of that gland may occur and may be of such importance as to endanger the life of tin- patient and to call for immediate surgical help. 116 INFLAMMATIONS OF THE THYROID Contusions. — When a goiter more or less large in size is present, the traumatism does not need to be a great one in order to determine intra- parenchymatous or intracystic hemorrhages. When this occurs, the increase in volume is sudden and may cause marked dyspnea. But when the thyroid is normal, the traumatism must be a severe one to determine lesions in the thyroid. This occurs mostly in strangulation, hanging, and other severe accidents bearing directly upon the thyroid. The consequences of such injuries to the gland are multiple; the most important are the intra- and periglandular ecchymosis and hemorrhages. The concomitant disturbances in respiration, phonation, and degluti- tion are nearly always due to fractures of the laryngotracheal carti- lages. Thyroiditis may be the consequence of such contusions; even development of myxedema has been reported by Guerlain-Dudon as the result of a direct traumatism of the thyroid by the wheel of a wagon. Most likely in that case the gland underwent connective-tissue degeneration. Wounds. — At the time when thyroid surgery was not so far advanced, modifying as well as aspirating punctures were in great vogue. Some- times they gave rise to very troublesome accidents. Aspirating punc- tures of an abscess or cyst often determined hemorrhages a vacuo; injec- tions of modifying substances, as tincture of 10dm for instance, were always most dangerous, and quite a number of sudden deaths have been reported after the use of such punctures. Today these thera- peutic measures have been almost entirely discarded. Wounds caused by sharp instruments are more serious. They occur, as a rule, in attempts to commit suicide, and are mostly situated in the upper portion of the lobe near the vascular pedicle, thus causing profuse hemorrhage. Such wounds, of course, are accompanied by injuries of the superficial veins, of the vessels of the capsule, and in some instances of the vascular cord; even the laryngotracheal canal may have been opened. In all these traumatisms the hemorrhage is profuse, and death occurs if surgical help is not brought in time. Before the antiseptic period, wounds inflicted with fire-arms, because of hemorrhage and suppuration, were more dangerous than they are today. This, however, was not always the case. At the battle of Cerisoles, commanded by the Duke d'Enghien, under Francois I, the young Swiss, Philip von Hohendax, who despite his youth had quite a large goiter, was struck in the neck with a large pick. The goiter, fortunately, was a large cyst, so that the accident proved a lucky one, as it cured the patient of his goiter. Wounds by our modern rifles with their small, thin bullets have proved more than once to be benign unless such injuries are accompanied by severe injury of other organs. On account of its speed and small size the bullet goes easily through the TRAUMATIC LESIOXS OF THE THYROID 117 thyroid, making only a very small hole, and unless a vessel of impor- tance is struck at the same time the hemorrhage is not of great conse- quence, and is stopped automatically by the glandular debris formed by the passage of the bullet. Infections of such wounds are very uncom- mon. During the late war between Japan and Russia many of such cases were observed, but frequently no ill effects followed. Treatment. — If surgical interference is thought necessary, the first indication is to widen the wound by a large incision, in order to be able to get a better view of the deep tissues. The second, to put hemostats on all the bleeding vessels and ligate them. The third, to clean out thoroughly the surgical field if it is necessary. The fourth, to sew up the injured gland either by continuous or interrupted sutures. The fifth, only in very rare instances, when a lobe has been smashed into pieces, the resection of that lobe is to be given serious consideration. The sixth, to leave a small drain for twenty-four to forty-eight hours or longer if necessary. The seventh, to sew up the skin. CHAPTER VI. ANATOMICO-PATHOLOGICAL RELATIONS OF GOITER TO THE SURROUNDING STRUCTURES. Structures with which a goiter may come in contact are: i. Sternocleidomastoid, sternohyoid, sternothyroid, and omohyoid muscles with their cervical fasciae. 2. Larynx and trachea. 3. Pharynx and esophagus. 4. Bloodvessels, common carotid, superior and inferior thyroid arteries, internal jugular vein; in intrathoracic goiter both innominates, the arch of the aorta and basis of the heart may come in contact with the tumor. 5. Nerves: vagus with its superior and inferior laryngeal branches; sympathetic. 6. Sternum, clavicles and superior opening of the thorax. 7. While extending upward a goiter may come in contact with the hyoid bone, the digastric, hyoglossus and mylohyoid muscles, the submaxillary gland, and the hypoglossus nerve. 8. While developing laterally, a goiter may fill the posterior triangle of the neck, compress the spinal accessory nerve and go as far as the anterior border of the trapezius muscle. 9. Owing to the fact that the thyroid gland lies on a hard surface, formed by the transverse processes of the cervical vertebrae, covered by the deep muscles of the neck, a growing goiter most naturally develops forward, laterally, and downward; its upward extension is less fre- quent, and is found mostly in certain large parenchymatous goiters, and in those developed in the upper poles or in the pyramidal process. 10. The relations of a goiter to the surrounding structures will differ notably if we have to deal with a diffuse parenchymatous goiter or a nodular one. 11. A diffuse parenchymatous goiter, unless of unusual dimensions, occupies the position of the normal gland, and consequently has no material influence on the surrounding structures. On the whole, it retains the shape of the normal gland. Only in very voluminous goiters do we see the upper poles extend upward as far sometimes as the angle of the jaw and then come in contact with the thyroid cartilage, the hyoid bone, the mylohyoid and digastric muscles, and the hypoglossus PLATE VI .ikf 1 ^ Cross-section of the Neck Showing the Relation of a Goiter to the Surrounding Structures. RELATIOX OF GOITER TO SKIX AXD MUSCLES 119 nerves. In its downward growth the goiter grows alongside and in front of the trachea and esophagus, in front of the carotid sheath and of the vagus and sympathetic nerves. Anteriorly, the two hyperplastic lobes and isthmus cover a more or less great portion of the trachea, of the cricoid and thyroid cartilages. The processus pyramidahs partici- pates, as a rule, only in a moderate degree in the hyperplasia. Laterally and in front the goiter is covered by the muscles of the cervical region. If hyperplasia is more or less evenly distributed over the whole of the thyroid, there is practically no displacement of the trachea and esoph- agus; displacement of the latter organs takes place only when one lobe of the gland is larger than the other one. However, displacement or compression of the windpipe is seldom severe with diffuse parenchy- matous goiters. In that type of goiter we do not find the intense dyspnea and the same intensity of choking spells that we encounter in nodular goiter. If, however, the hyperplastic goiter grows around the trachea and esophagus so as to form a "circular goiter," then dyspnea and dysphagia may be quite marked. Because diffuse parenchymatous goiter, especially when it has reached large dimensions, compresses the large vascular trunks on both sides, and because, too, such goiters more than any others, except the thyrotoxic, are subjected to congestions, impairment of the venous circu- lation of the neck is not uncommonly seen. It does not, however, reach the same degree of intensity as in intrathoracic goiters. Nerves are very rarely injured by the diffuse parenchymatous goiter; the inferior laryngeal nerve, however, may show some symptoms of compression. Not infrequently does the diffuse parenchymatous goiter extend downward behind the sternum. When it does, it is only in a moderate degree, and especially in cases where the thyroid is situated abnormally low (thyroptosis of Kocher). Entirely different are the relations of the nodular goiter to the sur- rounding structures. Of course here, again, such relations are deter- mined by the size of the goiter. (Plate VI.) Relation of Goiter to Skin and Muscles (Plate VI). — In certain forms of goiter, especially in pendulous goiter, the skin may become so distended and elongated as to form a real pedicle. At first, during the slow but progressive growth of the goiter, the cervical muscles covering the goiter undergo a certain amount of hyper- trophy, thus forming a powerful muscular belt whose spasmodic con- traction during choking spells can but increase their intensity. I his is proved by the fact that the transverse section of this muscular belt relieves dyspnea very materially. Later, however, when the nodular 120 ANATOMICO-PATHOLOGICAL RELATIONS OF GOITER goiter has reached voluminous dimensions on account of prolonged pressure and displacement the muscles finally undergo atrophy and degeneration; the muscular fibers become thin, pale, friable, dissociated, sometimes hardly recognizable. The sternocleidomastoid muscles, too, participate in this atrophy, although in a lesser degree. Relation of Goiter to the Larynx and Trachea ( Plate VI). — Already in 1817 Aepli, then Soemmering in 1820, and others called attention to the various forms of deformation of the trachea most frequently seen in connection with goiter. In 1861 Demme gave a magistral description of the pathological trachea in goiter and insisted especially on the "sabre-sheathed" trachea (Fig. 27). These deformations were thought to be of purely mechanical order. In 1878, however, Rose, although admitting that the etiology of tracheal deformations was partly mechan- ical, insisted that a great number of sudden deaths seen in such condi- tions was due to the sudden collapse of the walls of the windpipe on account of their degeneration and atrophy. The microscope showed that not only congestive lesions of the mucous membrane were present, but that also a marked fatty degeneration of the cartilaginous rings of the trachea and of the elastic and muscular fibers of the posterior membrane had occurred. Demme, Eppinger, Berard and others have more or less confirmed these findings. Indeed, it seems logical to admit that an organ which is constantly undergoing pressure is bound to undergo atrophy and degeneration in the course of time. At any rate, one who has seen goiters knows that the "ribbon-shaped" trachea is not rare, and that mechanical and secondary alterations intervene to form such a trachea. Tracheal deformations in nodular goiters are found in about 50 per cent, of the cases. This has been confirmed by O. Wild with trache- oscopy, and PfeifFer with radiography. The effects of pressure on the windpipe are manifold: 1. If the nodular goiter develops in one lobe, the other one being more or less normal, the trachea assumes a curved direction with the convexity toward the sound side (Fig. 26). At the same time the trachea and larynx rotate around their long anterior axis because the latter one is held more or less firmly by the thyroid suspensory ligament and the hyoid bone, whereas the posterior border is free from such attach- ment; it rotates along the anterior border and in the opposite direction of pressure. 2. If a nodular goiter is developed in each lobe, and if these two goi- ters are more or less of the same level, the trachea may be so compressed on each of its sides that the walls of the trachea may come in contact one with the other and form what we call the sabre-sheathed trachea (Fig. 27). This form of deformation of the trachea, although possibly RELATION OF GOITER TO LARYXX AXD TRACHEA 121 less frequent than the former, is infinitely more dangerous, and is the one which may prove fatal. This is easily explained. Although as the result of pressure the walls of the trachea may have undergone consid- erable atrophy, as long as the trachea remains in intimate connection with the goiter, the latter playing the role of a splint, there is no chance for the tracheal walls to be sucked in during inspiration. But let us remove the goiter, then atrophied, degenerated, and having lost their normal resistance and elasticity, the walls of the trachea are unable to withstand successfully the changes of air-pressure in the bronchial tube; Fig. 26. — Unilateral compression of the trachea by a nodular goiter. Fig. 27. — Bilateral compression of the trachea taking place at the same level. Sabre-sheathed trachea. they float in and out; expand during expiration and collapse during inspiration: hence suffocation. The more laborious the inspiration is, the tighter is the suction. Every surgeon has probabl} more than once experienced such a tracheal collapse during operation. At any rati. everyone who does thyroid surgery should be acquainted with such an eventuality, and should know how to guard his patient against it. 3. If two nodular goiters develop in each lobe, but at different levels, then the trachea assumes an S-shape analogous to the scoliosis ol the spinal column (Fig. _ v 122 ANATOMICO-PATHOLOGICAL RELATIONS OF GOITER 4. If a goiter develops in the isthmus, its size does not need to be very large to produce symptoms of pressure. As the isthmus is firmly attached to the cricoid cartilage by the thyroid suspensory ligament a goiter developed in the isthmus will naturally not be able to wander far even if it attains a large volume; it is kept in front of the windpipe, where compression takes place anteropostenorly, which fact is soon betrayed by marked dyspneic symp- toms (Fig. 29). In such conditions the large diameter of the tracheal lumen is frontal, whereas in the sabre-sheathed trachea it is sagittal. Such a goiter is called struma mediana or median goiter. In its further development the median goiter may Fig. 28. — Bilateral compression of the trachea taking place at two differ- ent levels, thus forming the S-shaped trachea. Fig. 29. — Pressure on the trachea and esoph- agus taking place anteroposteriorly. gradually sink downward and become intrathoracic. This goiter rarely develops in the isthmus alone; as a rule it develops at the junction of the lobe with the isthmus. 5. A goiter developed in the processus pyramidalis is a rare feature. It is situated in the middle line or a little outside of it, high up in front of the larynx, and is quite superficial. Let us call this form of goiter pyramidal goiter (Fig. 30). 6. In certain cases, especially in newborn, each lobe of the thyroid may extend behind the trachea and esophagus to such an extent as to come into contact one with another; trachea and esophagus are then surrounded with a ring of glandular tissue. That is the circular goiter (Fig. 50). We shall study it in a chapter by itself. Besides the trachea the larynx may, too, be compressed and dis- placed by a large goiter. Such modifications of positions of the larynx RELATION OF GOITER TO PHARYNX AND ESOPHAGUS 123 and changes of consistency of its cartilages are apt to cause phonetic disturbances, due only to a rupture of the anatomical, statical, and muscular equilibrium; the vocal cords may be normal but the points of insertion are slightly displaced; hence a slightly disturbed synergical action of both cords. As can be easily foreseen, all these pathological modifications of the laryngotracheal tube give rise to congestion of its mucous membrane, and as these irritations are eminently chronic, the mucous membrane becomes edematous, thickened, and congested. The clinical importance of these lesions cannot be ignored. Take, for instance, cases in which tracheo- FlG. }o. — (inner developed in the pyramidal process. stenosis is so developed that the patient has barely enough lumen left for respiration. Suppose now that for some reason an active or passive congestion takes place in the tracheal canal, the mucous membrane at the level of the tracheal stricture becomes so edematous that the respi- ratory lumen becomes insufficient, suffocation follows, and death may ensue. Relation of Goiter to the Pharynx and Esophagus (Plate \ I I. — In ordinal)' goiters the pharynx and esophagus are seldom involved. Deglu- tition is interfered with only when the goiter has become adherent to the walls of the esophagus either because of a strumitis or because of a 124 ANATOMICO-PATHOLOGICAL RELATIONS OF GOITER fibrous or malignant goiter. There, too, as in the trachea a long, con- tinuous pressure on the esophageal walls may cause such an atrophy as to perforate them, and yet such goiters may not be malignant at all; but, of course, this is rare. Relation of Nodular Goiter to Bloodvessels (Plate VI). — In large goiters the common carotid is displaced posteriorly and laterally; it may even be found in the posterior triangle of the neck. I have seen it more than once not far from the anterior border of the trapezius. The carotid is then found enlarged, has sometimes a tortuous course, is subcutaneous, and is felt as a tense, expansive cord. When the common carotid has contracted, intimate relations with the capsule of the gland, on account of strumitis or for any other rea- son, this posterolateral displacement of the vascular trunk is easily understood; yet such displacements happen in goiters in which no inflammation whatever is found. It then finds its explanation in the anatomical relation between the thyroid gland, the common carotid, and the superior thyroid artery- In undergoing upward enlargement the goiter seems to grow in the angle formed by the carotid and the superior thyroid artery. As the latter is firmly fixed by its two terminal branches to the thyroid it holds tightly the common carotid to the posterolateral surface of the goiter in the same manner as if someone should carry somebody on the back or over the shoulders by holding him tightly by the arm. The more the goiter grows, the tighter becomes the relations between the goiter and carotid, consequently the more the carotid will be displaced laterally and posteriorly. At the same time it becomes elongated; in voluminous goiters this elongation of the common carotid may be sometimes quite marked. Wolfler saw a case in which the carotid formed around the goiter a segment of a circle whose radius was 6 cms. The displacement outward of a carotid has a very important diag- nostic value, because it is caused by goiter and by nothing else. In tuberculosis or malignant tumors of the cervical lymph nodes the common carotid, instead of being displaced outward, lies in the center of the tumor. Again, anatomy will give us the reason for it: normally, the lymph nodes are found all around the vascular cord of the neck, conse- quently in tumors of the cervical ganglions the common carotid must naturally lie in the middle of the tumor. The superior thyroid artery loses its normal anatomical relations only in large-sized goiters. In that case, very much increased in size, this artery follows a sinuous course, separated, to a more or less extent, from its normal anatomical neighbors, namely, the inferior constrictor of the pharynx and the superior laryngeal nerve. The point of election for its ligation is the superior pole. RELATION OF GOITER TO NERVES 125 Lving directlv on the prevertebral fascia the inferior thyroid artery may be easily compressed and displaced by a growing goiter. In partly intrathoracic goiters this artery is covered entirely by the tumor and is consequently of difficult access for ligation. As a rule the safest place to ligate the inferior thyroid artery is inside the carotid sheath, between this sheath and the thyroid gland. The ligation of the artery near its point of entrance into the thyroid is dangerous, inasmuch as the para- thyroids and the inferior laryngeal nerve might easily be injured. In large goiters the veins of the neck are distended because the return flow of blood is impaired by compression on the large venous trunks or because of some pathological disturbances in the right heart; as a result of it an intense venous congestion is seen in all the cervical region — the anterior jugular vein, the superior thyroid, the imce veins, and all the capsular veins may be so distended that the gland seems to be the site of an angioma. These imae veins must be known to the surgeon, as they are the ones most apt to allow an air embolism. In all these conditions the distended veins are friable and thin. They have lost their elasticity: hence, the frequent venous parenchymatous hemorrhages which may sometimes become alarming. Relation of Goiter to Nerves (Plate VI). — The nerves which are mostly involved in voluminous goiters are the vagus and the sympathetic. Compression on the vagus trunk itself does not give rise to any special symptoms. Its branch, the superior laryngeal nerve, even when materi- ally compressed and displaced, does not cause appreciable functional disturbances. On the contrary a slight injury to the inferior laryngeal nerve, which is another branch of the vagus, has the most unpleasant consequence, as it may mean for the patient total loss of voice. After thyroidectomy this symptom may be the only living witness of the awkwardness or ignorance of the surgeon. As a rule this nerve is com- pressed in the inner and posterior angle of the tumor, and as a result of this, paralysis of the corresponding vocal cord may follow. I he same thing may happen if the goiter has been the site of a hemorrhage or strumitis, because the nerve becomes adherent to the capsule: hence again causing functional disturbances. That the sympathetic nerve may be invoked in large growing goiters is made clear by its anatomical relations. It may Income compressed on the prevertebral surface or it may be constantly traumatized with each pulsation of the inferior thyroid which comes in contact with it and the middle cervical ganglion. Traumatism of the cardiac branches of the sympathetic may account, too, for some forms of tachycardia. The hypoglossus, spinal, and phrenic nerves and the cervical and brachial plexus may be involved, too, by the large growth of the goiter. CHAPTER VII. CLINICAL SYMPTOMS AND DIAGNOSIS. CLINICAL SYMPTOMS OF GOITER. A great many goiters, at least for a considerable period of time, have no history. They do not betray their presence by any mechanical or functional symptoms. In their early stage, when symmetrically placed, they give to the neck a soft roundness called "swan-neck," and considered in many countries as one of the attributes of feminine beauty. Many of the great artists of the past centuries shared the same views, as one can easily convince himself, if he care to, by visiting certain museums. Although sometimes a slight apathy, thickening of the tegu- ments, constipation, chilliness, etc., indicate a slight degree of thyroid insufficiency, while in other cases a slight tachycardia, nervousness, impatience in disposition, abruptness of movements and brilliancy of the eyes betray the first symptoms of hyperthyroidism, these patients are absolutely unaware of their condition and would sneer at one who would tell them that they are sick. At the time of puberty especially, and later on with each menstrual period, young girls often complain of constriction of the neck, of chok- ing sensation, of coughing spells; during sleep they are frightened with distracting nightmares; in daytime they easily get tired, complain of palpitation, nervousness, tremor, etc. All these symptoms, partly mechanical, partly thyrotoxic, are due to a slight parenchymatous goiter which so often accompanies puberty. In the great majority of cases they subside; in others, however, they progress and evoluate into a permanent parenchymatous or nodular goiter, be it toxic or not. A goiter may cause mechanical and functional symptoms. Mechanical Symptoms. — The mechanical disturbances can be easily foretold after our study of the relations of a goiter with the neighboring tissues. We must remember that the symptoms are not always in direct proportion to the size of the goiter; a small median or retrosternal goiter will cause far more serious symptoms than a voluminous goiter hanging in front of the thorax. Dyspnea. — One of the main symptoms which causes the patient to seek medical attention is dyspnea. It may be produced: I. By direct pressure on the trachea. DYSPHAGIA 127 2. Bv an injury of the inferior laryngeal nerve, causing paralytic conditions of the vocal cords. 3. Bv venous congestion of the cervical region and the upper part of the mediastinal space following pressure upon the nervous trunks. Dvspnea is a slow-developing symptom. For a long time the patient is not aware that he is getting out of breath easily, that while talking he must stop frequently to draw a deep breath of air. In time he becomes conscious that he is no longer able to climb up stairs or to do any physi- cal exercise without losing his breath. Gradually respiration becomes more and more laborious, and when finally, on account of pressure, the lumen of the trachea has become greatly narrowed a long, loud, whist- ling inspiration is heard: that is the tracheal stridor. Stridor is mostly inspiratory, but may be expiratory also. Dyspnea may be constant or paroxystic. When the trachea is greatly constricted, a slight physical exertion, a simple movement of the head, or a catarrhal congestion of the laryngotracheal tube, or any sudden pressure from without, is suffi- cient to cause attacks of asphyxia. When compression, even of moderate degree, is of years' standing, a permanent congestion of the entire respiratorv apparatus takes place, and, as a consequence of this catarrhal condition and of the tracheal stenosis, emphysema and bronchiectasy develop. Furthermore, when the blood circulation in the lower por- tion of the lungs becomes sluggish, there is a marked tendency to bron- chitis, bronchopneumonia, etc. As the result of pressure upon the large cervical and intrathoracic venous trunks, stasis takes place in all the upper venous system, hence vertigo, headache, congestion of the face, nose-bleeding, somnolence, etc. Like stridor, dyspnea is more frequently inspiratory than expiratory. Dysphagia. Difficulty in swallowing is especially noticeable in the retrovisceral and intrathoracic goiters. The patient seldom complains of pain in swallowing; he may, however, have some difficulty in swal- lowing solid food, yet in uncomplicated goiters an absolute impossibility of doing so is not known. The voice in large goiters is characteristic; it has a thick, guttural, impure tone, as if the vibrations were muffled. 1 his is due to the con- gestion of the mucous membrane of the laryngotracheal tube and ro the slight displacement of the points of insertion of the vocal cords. and on that account they cannot ring true. If to that we add a muscular insufficiency, we will understand why dining the speech of markedly goiterous patients, changes in the voice appear so brusquely, why cer- tain sounds are not uttered, win "slips of the voice" occur, the whole thing making, as Berard says, a motley mixture of couacs and silences which are very peculiar and characteristic. Berard considers tin 111 as vocal awkwardness. Only in the later stages are they due to paretic or paralytic conditions of the vocal cords and constitute then the bitonal voice. 128 CLINICAL SYMPTOMS AND DIAGNOSIS Symptoms Due to Injury of the Inferior Laryngeal Nerve. — Bilateral paralysis of both inferior laryngeal nerves is found only in malignant goiters. In the benign form of goiters, injury of the inferior laryngeal nerve is nearly always unilateral; it then determines tonic contractions of the vocal cords of the same side, which give to the voice a bitonal character. It may cause, too, coughing spells and spasm of the glottis, which may be so marked as to cause the most alarming symptoms of suffocation. Cough of recurrent nerve origin differs clinically from the one resulting from compression on the bronchotracheal tube. We can say with Varay that they constitute two distinct types: 1. The cough of recurrent type. 2. The one of compression type. The "recurrent cough" is dry, loud, and not accompanied with expectoration. It comes on mostly by spells. The "compression cough" is sonorous, deep, cavernous, with a grave, metallic sound, resembling the cough of a dog choking with a bone in his throat; it is really a "bark- ing cough." Brought on by slight physical effort, it does not seem to annoy the patient as much as the noise would indicate. When compression on the inferior laryngeal nerve is only slight, it manifests itself by a metallic sound of the voice, due to a paretic condi- tion of the vocal cord involved. As long as the inferior laryngeal nerve has not been destroyed the patient remains exposed to sudden and unexpected spasms of the glottis because the constrictor muscles of the glottis resist longer than the dilatators; the latter are put out of func- tion a long time before the former. On the other hand, when the pro- cess of irritation or paralysis of the recurrent nerve retrocedes, as Rosen- bach and others have shown, the dilatator muscles are the last to recuperate their function. Paralysis of the recurrent nerve, as a rule, takes place gradually; it may, however, be sudden, as in cases in which a brusque compression due to an intracystic hemorrhage occurs. When paralysis of the nerve is complete, then there is a paralysis of the corresponding side of the glottis; the vocal cord of the paralyzed side takes an "intermediary" position, and as the vocal cord of the sound side does not go beyond the middle line, phonation is, of course, impossible; hence complete aphonia. Later, however, the sound vocal cord increases its radius of excursion, swings over the middle line in order to come into contact with the paralyzed cord: aphony then disappears, the patient may even seem to have regained his normal voice; his singing voice, however, never returns. In goiter, injuries of the inferior laryngeal nerve are relatively fre- quent. They are mostly characterized by symptoms of slight impor- tance, and according to statistics, the frequency of such lesions varies IX JURY OF THE IXFERIOR LARYXGEAL XERYE 129 from 7 to 35 per cent, of the cases. Lesions of the inferior laryngeal nerve predominate on the left side as a rule. Avellis found that out of 150 recurrent laryngeal paralyses, 46 were on the right side, 92 on the left, and 12 were bilateral. B. Mathews out of 289 partial or complete paralyses found 93 on the right side, 162 on the left, and 17 bilateral. Predominance of paralysis on the left side may be accounted for bv the fact that the left inferior laryngeal has a longer course, and is more exposed to pressure not only in the mediastinal space but also in the cervical region, as it is more superficial than the right. Although the frequency' of pressure symptoms on the recurrent nerves is in direct proportion to the size of the goiter, Mathews found some exceptions: small goiters, hardly large enough to be recognized, may produce symp- toms of paralysis, whereas large ones may not cause any. Men are about three times as liable as women to have paralysis of the inferior laryngeal nerves. The trunk of the vagus nerve itself is seldom involved bv goiters except in strumitis and cancers. In rare instances the slowness of the pulse and respiration have been interpreted by some authors as due to mechanical traumatism of the vagus nerves. So far as the sympathetic nerve is concerned it is not always easv to recognize clinically the symptoms which belong to mechanical com- pression of the sympathetic nerve itself; if, however, the sympathetic symptoms are localized on one side of the face only then the diagnosis of compression on the sympathetic side can be made with certainty. 1 he symptoms of excitation of the sympathetic are a unilateral exoph- thalmos with dilated and sluggish pupil, enlargement of the palpebral fissure, and redness of one cheek more marked than the other. The symptoms of paralysis are ptosis of the eyelid, thus producing a smaller palpebral fissure, myosis, on account of the dilatator muscles of the pupils, redness of the ear, and abundant perspiration on the paralyzed side. In extremely rare cases the spinal nerve is involved; a torticollis, or wry-neck, due to spasmodic contraction of the trapezius and sterno- cleidomastoid muscles, is then the consequence of it. The lesions of the hypoglossus nerve occur only in goiters developed from the thyroglossus duct. In such conditions a paresis and an atrophy of the corresponding side of the tongue have been observed. Symptoms of compression of the superficial cervical plexus are found sometimes in voluminous goiters and are characterized by irradiating pains toward the auriculotemporal and occipital regions. When pressure takes place on the deep cervical plexus, pectoral neuralgia and painful formications along the arm and hand have been reported. The phrenic nerve, especially in retrosternal goiters, may be caught and compressed in front of the scaleni muscles; 9 130 CLINICAL SYMPTOMS AND DIAGNOSIS this is rare, however. In such conditions hemispasm of the diaphragm will be present, followed later by paresis or paralysis of that muscle. Functional Symptoms. — Functional symptoms can be divided into two large classes: the symptoms of hypothyroidism and those of hyper- thyroidism. They will be studied in separate chapters. The goiter-heart will be studied in a chapter by itself. DIAGNOSIS OF GOITER. In the great majority of cases, diagnosis of goiter presents no diffi- culty. First of all the history of the patient puts us at once on the right scent by telling us if the patient comes from a country where goiter is endemic or not, if other members of his family are affected with it or not, or if he complains of mechanical or thyrotoxic symptoms. When dealing with a tumor of the neck, the two important things which we have to decide are: i. Is the tumor in the thyroid? 2. What is its nature? i. Is the Tumor Developed in the Thyroid? — Inspection shows the form, volume, and position of the goiter. It shows the condition of the skin of the neck, whether there is any congestion of the face, any collateral circulation on the neck or thorax, any dyspnea, any symp- toms of irritation or paralysis of the sympathetic, or whether any thyrotoxic symptoms as tremor, exophthalmos, etc., are present. There is one symptom which is pathognomonic for tumors of the thyroid: that is, the up-and-down movements which the tumor follows during deglutition. As the thyroid is intimately connected with the cricoid cartilage through its suspensory ligament, the tumor is bound to follow the larynx in its up-and-down movements. This symptom sel- dom fails. Only when the goiter is extremely large or when it has a long, loose pedicle, these up-and-down movements may be doubtful. But even then a little trick may solve the problem. By placing the patient's head in hyperextension and asking him to swallow, it would be very surprising if these up-and-down movements are not obtained; exceptionally, however, when the tumor has developed at the cost of an accessory thyroid gland, or when a malignant tumor or a strumitis has walled in all the organs of the cervical region, then these up-and-down movements will not be detected. Palpation must be done methodically. We must begin by ascer- taining if possible the exact position of the thyroid and cricoid carti- lages and the trachea to see if they are displaced on one side or the other. When that is done the two lobes, isthmus and pyramidal DIAGNOSIS OF GOITER 131 process are carefully investigated separately, their consistency, their surface, their mobility, and their relation to surrounding structures being carefully noted. We shall find that in the greatest number of cases the goiter is more mobile transversely than vertically, that during deglutition the tumor slips out of the palpating hand to follow the up-and-down movements of the larynx. We must then endeavor to outline the inferior limits of the tumor. The best way to do so is to palpate with the thumbs, the palms of the hands and fingers reposing on the shoulders. The patient is requested to flex his head forward and laterallv in order to relax the muscles of the side subjected to examination. This facilitates, too, the palpation of the retrosternal region. With some care and skill it will then be possible to fish out of the thorax quite a number of partially intrathoracic goiters which were never suspected before. When a goiter is a multinodular one, pressure on each nodule separately may reveal the one which is causing most of the pressure symptoms. Palpation will, furthermore, show that the common carotid is pos- sibly displaced laterally and posteriorly; in that case it is felt pulsating subcutaneously. The condition of the superior thyroid arteries is ascer- tained. If a goiter shows pulsation, we must determine if this pulsation is only transmitted or if it is really an expansive one. Percussion over the thorax is intended to show if there is a dulness caused either by an intrathoracic goiter, a thymus hyperplasia, or any other mediastinal tumor. It conveys, too, some information as to the condition of the lungs and the size of the heart. Auscultation will tell us if a systolic murmur is present oyer the gland, especially at its upper poles. It will tell us, too, if there is compression upon the trachea by the tumor. In that case we shall hear, especially over the manubrium sterni, a rough inspiration followed by a prolonged, loud expiration, unmistakably accompanied with tubular breathing. I consider this finding as an excellent sign of compression. Finally, auscultation will inform us as to the true condition of heart and lungs, the knowledge of which is of the utmost importance when it comes to prognosis and treatment. Laryngoscopic Examination. Laryngoscopy examination shows the condition of the vocal cords. This examination should be made as a routine procedure before operation, if only as a protection to the surgeon in order to avoid being held responsible for an injury to the inferior laryngeal nerves which existed prior to the operation. I rache- oscopy is seldom indicated. An x-ray, if deemed necessary, will then terminate the examination and corroborate or disprove many of the clinical findings. It will add, furthermore, precious information about the size of the intrathoracic 132 CLINICAL SYMPTOMS AND DIAGNOSIS goiter, if there is any, about the displacement and compression of the windpipe, about the presence of thymus hyperplasia, etc. 2. What is its Nature? — When once we have decided that the tumor is of thyroid origin we must then decide what its nature is. In diffuse parenchymatous goiter the gland in toto is enlarged, of firm consistency, and finely granular. The gland has more or less kept its normal, gen- eral outlines unless the diffuse enlargement should affect one lobe more than the other. By closer examination it is not uncommon to find small nodules of harder consistency spread throughout the gland. In colloid goiters the gland has lost its regular form, and colloid degenera- tion is more marked in one lobe than in the other; hence the irregularity in the form of the thyroid. The surface is lobulated, nodular on account of the presence of colloid nodules of different sizes; consistency may be firm, but in cases in which the colloid nodules are large and of different volumes the consistency may vary considerably, being firm in places, hard in others, and soft in others. Fibrous goiter is characterized by its hard consistency, and differs from the calcareous goiter by its small size, though this is not always the case. Cystic goiter is not difficult to diagnose, especially when it has attained a certain size; its surface is smooth, the tumor is mobile, elastic, or fluctuating. When fluctuation is present the diagnosis of cyst is almost certain. I say almost certain because a pseudofluctuation sometimes seen in some colloid nodules may lead one to believe that he has to deal with a cystic tumor when such is not the case. Vascular goiter is of rare occurrence except in exophthalmic goiters. In that case the diagnosis is easily made. In genuine vascular goiter the tumor is soft and can be reduced in size by compression. A marked vascular murmur is heard over the gland and especially at its poles. Thrill and expansive pulsation are present. In a great majority of cases the differential diagnosis between goiter and any other condition is hardly necessary. When the tumor is median, a cyst developed from the thyroglossus duct might be confused with a median goiter. But, as a rule, this cyst of thyroglossus duct origin lies in exactly the middle line and is found mostly between the hyoid bone and the thyroid cartilages, whereas a median goiter is situated below the cricoid. Congenital cysts of the neck of thymic origin are located along the anterior border of the sternocleidomastoid; they are independent of the trachea and larynx and do not follow their up-and-down movements during deglutition. The same is true of tuberculous glands; their anatomical relations, their consistency, their pathological characters, and the history of the development of the disease differ entirely from those of goiter. GOITER-HEART 133 GOITER-HEART. That there exists a relation between goiter and the heart was, of course, observed long ago. Rose first thought that the goiter-heart in connection with stenosing goiters was due to pressure of the blood- vessels on the thorax. Kocher not only admitted this fact as an etiolog- ical factor, but added that impairment of the respiration was also a cause of goiter-heart, and called it dyspneic goiter-heart. Schrantz believed that goiter-heart was caused by venous stasis in the thorax, causing a hyperemia of the heart muscle, and consequently an excitation of the cardiac ganglions: hence, increased cardiac activity, then, hypertrophy, dilatation, and degeneration of the muscle. Wolfler took a similar view. Kraus designated as goiter-heart the cardiovascular symptoms caused not by the mechanical pressure but by the exaggerated function of the thyroid gland and its action on the regulating cardiac apparatus. Kocher shared this same view and differentiated this goiter from the mechanical goiter-heart. To Minnich we owe an excellent contribution on the question of goiter-heart of pneumonic origin. There are two separate and distinct varieties of cardiac disturbances that may occur in connection with goiter, the mechanical goiter-heart and the thyrotoxic goiter-heart. Kocher distinguishes a third form which is rare: this condition of the heart is caused by compression of the large vessels and nerves by a large goiter. This goiter is then called cardiopathic goiter. The Mechanical Goiter-heart. — It is easy to understand that being given their anatomical relations with the thyroid gland, the vagus and sympathetic nerves may be mechanically traumatized by a large goiter. These lesions, however, are rare; when present they are mostly unilateral. Bilateral compression on the vagus and sympathetic by a simple goiter, to my knowledge, has never been observed except in malig- nant goiters. Far from me, however, be the idea that is not possible. Furthermore, there are a great many goiter-hearts in which traumatism of the vagosympathetic system cannot be rightfully incriminated on account of the small size, location, etc., of the goiters. It we stop to consider the close anatomical relations of the vagus and sympathetic, it is hardly admissible that traumatism can center its effects on one nerve and not on the other. It seems to me that both must be injured at the same time. If that is the case, since the vagus is a moderator and the sympathetic an accelerator of the cardiac action, these two nerves should counterbalance their action. It is true that nutation with the faradic current of the sympathetic produces physiologically a slight acceleration of the cardiac action, whereas the same nutation ol the 134 CLINICAL SYMPTOMS AND DIAGNOSIS vagus produces a moderation. Surgical experience shows, on the other hand, that division of both vagi or both sympathetics has no effect, or very little, on the frequency of cardiac action. Goiter-heart is really the appanage of goiter. It is not found in the malignant degeneration of cervical ganglions, in Hodgkin's disease, etc., where certainly the chances for having an involvement of the sympathetic and vagus are great. Why is it ? So the theory that considers pressure on the vagus and sympathetic nerves as the etiological factor of goiter-heart is, in my judgment at least, not tenable. The pressure on the bloodvessels of the thorax as advanced by Rose is a very important etiological factor of goiter-heart. It causes a stasis in the thorax combined oftentimes with respiratory disturbances, so that a stasis in the right auricle and ventricle is the natural conse- quence of it: then follows a dilatation, and after more or less time a degeneration of the heart muscle. The impairment of respiration, as Kocher and Minnich have pointed out, may also cause goiter-heart. In order to understand the development of such pathological condi- tions we must study the physiology of respiration and circulation. Normally there is in the thorax a negative pressure. This negative pressure is always constant, and is never reduced to zero even in forced expiration. The consequence of it is that the extrathoracic pressure is higher than the intrathoracic one. For this reason the blood is aspirated toward the thorax; this fact is called the thoracic suction. During diastole the heart increases actively the size of its chambers, and by so doing creates a vacuum which produces a sucking effect on the blood of the tributary vessels. With Minnich let us call that ventricular suction. Thoracic and ventricular suctions are two of the main factors in the thorax which aspirate the blood toward the heart. Of course other important factors come into play, but they are without importance so far as the explanation of goiter-heart is concerned. During inspiration the thorax increases its capacity, hence the nega- tive pressure increases and consequently the thoracic suction increases, too. During expiration the thorax contracts, the lungs expel the air contained in the alveoli; as a result the negative pressure is diminished, and, ipso facto, the thoracic suction. As a consequence of this fact there is normally during inspiration an increased quantity of blood aspirated toward the right auricle and ventricle. During expiration this quantity is diminished. During these physiological phases the quantity of blood, and conse- quently the pressure in these chambers, would soon run above normal GOITER-HEART 135 if there was not a compensatory process to prevent such excess. This compensation is furnished by the capillaries of the lungs. During inspiration they follow the expansion of the lungs, increasing their capacity, so that the blood running toward the heart is partly side- tracked. Bv this process the pressure in the right heart is maintained normal. Minnich called this fact the pulmonary compensation. The effects of respiration on the left heart are quite different and very much less marked, because of the size and of the thickness of its walls; however, during inspiration the pressure in the left auricle and ventricle diminishes in a moderate degree, and during expiration increases in the same proportion. These few physiological explanations will enable us to understand what happens in cases of stenosis due to goiter or any other obstacle to respiration. In inspiratory dyspnea, when a patient takes a deep breath in order to get enough air, the thorax expands to the maximum, so that the negative pressure in the thorax is greatly increased. In such conditions the blood is aspirated toward the right heart with great speed, but unfortunately, on account of the goiter-stenosis, the lungs do not follow the expansion of the thorax. Consequently the capillary bloodvessels of the lungs do not dilate; in other words, pulmonary compensation does not take place; the blood is not side-tracked in proportion to the stream running to the right heart, hence the dilatation of the right heart. The consequence of this is that the pressure in the pulmonary artery diminishes, and as a result there is, too, a diminution of pressure in the pulmonary vein, in the left auricle, and in the left ventricle. It the musculature of the right heart is still in good condition it will com- pensate by overwork the rupture in the balance of pressure between the right and left heart, and we shall then have an hypertrophy of that section of the heart. If the musculature is degenerated we shall have failure of compensation and its results. In expiratory dyspnea during the effort of expiration the negative pressure is considerably diminished. For this reason the blood is kept back in the tributary veins: the volume of blood coming to the right heart is considerably diminished, but with the following inspiration all this blood which has been kept back flows toward the right auricle and ventricle and would soon overwhelm this segment of the heart if this compensation of the lungs did not take place and side-track the surplus of blood. But suppose the expiratory dyspnea is of long standing, caus- ing emphysema, bronchiectasy, and chrome catarrh of the respirator] apparatus, then in that case the capillaries of the lungs undergo patho- logical changes, and the compensation cannot take place normally; the right heart is soon overwhelmed by the quantity of blood running into 136 CLINICAL SYMPTOMS AND DIAGNOSIS it, and the consequence is a dilatation of the right auricle and right ventricle. So the final results of an inspiratory and expiratory dyspnea are the same; they cause a dilatation of the right auricle and right ventricle, and finally disturb the whole cardiac svstem. Goiter-heart has an insidious development. The goiter may be present for many years before the patient is aware of the changes which are going on. For a long time the patient does not notice that the tone of the voice is changing and that he easily gets out of breath. He attrib- utes the cause of all his troubles to chronic catarrh of the trachea and lungs. Later he complains of vertigo, headache, congestion of the face, epistaxis, palpitations, dyspnea, at the slightest physical effort; edema and anasarca are the terminal stages. At that time the volume of both cardiac chambers is markedly increased, caused by hypertrophy and dilatation. In the early stages there is generally a slight systolic murmur to be heard at the apex, betraying a mitral insufficiency caused bv the stasis in the small circulation. Later the second tone of the pulmonary valve becomes weak. In late stages systolic and diastolic murmurs may be heard on all its orifices. Arrhythmia is present. The liver, spleen, and kidneys become congested; anasarca terminates the scene. By this time the pathological changes in the heart are so extensive and so irrep- arable that the entire therapeutic arsenal has become powerless. Goiter-heart is not always present in all cases of stenosing goiter. The reason must be found in the resistance of the heart itself. It is a well-known fact in medicine that one heart may resist certain patholog- ical conditions better than another; this is due to individual resistance and to the existence or non-existence of previous or concomitant intoxications or infections. The influence of age certainly should not be neglected. Other things being equal, a young heart will offer more resistance than an old one. The majority of well-developed cases of stenosis come on between the ages of forty and sixty; consequently the pathological changes in the heart will be more common at that period of life. The purely mechanical goiter-heart is not frequent. It is usually combined with thyrotoxic goiter-heart. The Thyrotoxic Goiter-heart. — To this class we do not ascribe only the goiter-heart found in the well-developed exophthalmic goiter but also all the intermediate stages. As Wolfler says: "It is easy to go progressively from a simple goiter to a well-marked Graves' disease: goiter with tachycardia; goiter with tachycardia and tremor; goiter with tachycardia, tremor, and psychic disturbances; goiter with tachycardia, tremor, psychic disturbances, GOITER-HEART 137 exophthalmos, etc., until we get the complete clinical picture of a well- developed Graves' disease." The)' are only different stages of the same process. The thyrotoxic goiter-heart may be caused by any kind of goiter. The parenchymatous goiter is the most common cause, but a cystic or colloid goiter, even a cancerous or sarcomatous goiter may give rise to a thyrotoxic goiter-heart. Cystic and colloid goiters do not cause a thyrotoxic goiter-heart as such, but their presence seems to incite the remainder of the gland to overfunction. In such cases the goiter becomes " Basedowified." The same explanation accounts for the rare cases in which exophthalmic symptoms develop in cancer or sarcoma of the thyroid gland. The fundamental symptom of the thyrotoxic goiter-heart is the increased heart action. This symptom never fails. It is found in the fruste forms, and may remain for a long time after the patient is practi- cally cured of the other symptoms of exophthalmic goiter. In some cases the patient is not aware of the increased heart action, but in the great majority of cases he complains of palpitations. These may come on gradually or by spells. Oftentimes the slightest muscular exertion increases the action of the heart considerably. The pulse rate may reach 120, 150, and frequently more. The heart action is not only increased in frequency but in intensity as well. Often the whole cardiac region shows a pulsation, and the beating at the apex is strongly marked. After a longer or shorter period of duration of the disease the heart area is increased. This increase, it is found, involves mostly the left ventricle. The apex beat is outside the mammillary line; the transverse diameter of the area of cardiac dulness is increased; fluoroscopic exami- nation confirms these clinical findings. The heart lies transversely on the diaphragm. In a later stage when the thyrotoxic intoxication is far advanced the right ventricle shows a marked dilatation and the area of cardiac dulness is found extending 1, 2, 3 cms., and sometimes 4 cms., outside of the right sternal edge. In many casts I have been surprised to find the difference in the ana of cardiac dulness before and after exercise. Before exercise- the heart limits were only slightly increased, but after exercise they were consid- erably enlarged. I consider this symptom very valuable before an operation to show the resistance of the heart to the surgical attempt. If after exertion dilatation of the heart is present, and it the In ait action increases considerably, and especially it myocarditis is present, one should "Pray the Lord before attempting the operation." In thyrotoxic goiter-heart the pulse is frequently soft, and dicrotism is often observed. In advanced cases the pulse may become regular. 138 CLINICAL SYMPTOMS AND DIAGNOSIS blood-pressure mav be increased, but it is generally normal. When thyrotoxicosis is well developed the carotid arteries are distended and beat violently. The veins are enlarged, too, and show a venous pulsa- tion. This vascular erethism is not due to the cardiac impulse, but seems to be merely localized in the vessels of the head and neck, because it does not extend to the abdominal aorta nor to the radial or other arteries. Oftentimes the patient feels the pulsation all over the head and complains of roaring in the ears. The cardiac impulse may be so intense as to shake the whole body synchronously with the heart beat. Palpation of the neck gives a thrill, especially over the thyroid arteries. Auscultation frequently gives a systolic murmur not only just over the arteries but also all over the thyroid gland. This murmur, espe- cially in the supraclavicular spaces, is sometimes continuous, and forms what we call the "bruit de none." The thyroid gland shows not only a transmitted but also an expansive pulsation. As a rule the mechanical goiter-heart and thyrotoxic goiter-heart are seldom separated clinically. Of course there are goiter-hearts which are purely of mechanical origin, but even then there exists between the mechanical goiter-heart and the Basedow-heart a series of intermediary symptoms which are caused by the thyroid hyperfunction, and are con- sequently of thyrotoxic origin. Therefore the etiology of thyrotoxic goiter-heart and of Graves' disease is the same. There is no difference between the thyrotoxic goiter-heart described in the chapter on Graves' Disease and the one complicating any colloid, cystic or malignant goiter. The thyrotoxic symptoms disappear with thyroidectomy, or at least are greatly benefited, providing the operation takes place before the cardiac muscle has become irremediably altered. These facts are of great importance. From them derives the first very clear indication: if a goiter cannot be cured, or at least held back in a harmless state by ordinary medical means, it should not be allowed to wait until the thyrotoxic and vascular symptoms of goiter have gone too far before performing thyroidectomy. Furthermore, these facts are of great diagnostic value and of great help to the surgeon in deciding if the operation can be done, also how and when. When in goiterous tracheostenosis the pathological disturbances in the heart and in the small pulmonary circulation have not damaged these organs to such an extent as to become permanent, surgical inter- ference gives brilliant results. More than once I have seen cases of intrathoracic goiters with marked dyspnea, venous congestion of the cervical region, irregular pulse, headache, vertigo, etc., entirely relieved of all these symptoms after operation. The most remarkable case was that of a woman with a totally intrathoracic goiter displacing the aorta and compressing the basis of the heart. This patient had what I thought GOITER-HEART 139 was a marked degree of myocarditis. To my surprise the day following the operation the pulse had become regular and has remained so ever since. But when a dilatation of the right heart has already taken place, when tachycardia, arrhythmia, congestion of the liver, spleen, and gen- eralized edema are present, an operation in such cases can only termi- nate by failure, and, what is worse, in death. This is so true that when Kocher reported the results of 3000 operations for goiter he said that the only real danger which he still feared in goiter operations was cardiac collapse. His advice was then to operate a goiter as soon as possible and to discard any thyroid or iodin treatment when a goiter-heart was present. CHAPTER VIII. INTRATHORACIC GOITER. We call intrathoracic goiter a goiter which lies in the thorax. That variety of goiter may be partly intrathoracic or totally so. If we should call intrathoracic every goiter whose inferior poles dip more or less into the superior opening of the thorax, we should regard as intrathoracic many goiters not worthy of that denomination. Such goiters do not extend down into the mediastinal space; their inferior limits can be outlined more or less easily during swallowing or coughing. We apply to such a class of goiters the name struma profunda or deep goiter (Fig. 35) and reserve the term of partly intrathoracic (Figs. 32 to 36) to goiters whose greater portion lies in the mediastinal space and whose remaining portion lies in the cervical region. As the name indicates the totally intrathoracic goiter (Figs. 39 to 41) lies completely in the thorax; now and then there is not even external evidence of thyroid enlargement in the cervical region. Intrathoracic goiter takes its origin either in the lower poles of the thyroid or in the isthmus; more seldom it develops in accessory thyroid glands. When originating from the lobes or isthmus the intra- thoracic goiter remains, as a rule, connected with the body of the thy- roid by a pedicle; if it develops from an accessor)' thyroid gland it has no relation whatsoever with the thyroid. These latter forms of goiter are rare. Intrathoracic goiter does not seem to develop oftener in the lobes than in the isthmus. A goiter has a tendency to become intrathoracic for three chief reasons: 1. The thyroid gland normally goes up and down with respiration, with swallowing and coughing, hence the tendency to drop. 2. The goiter is more or less forced into the thorax by the various movements of rotation and especially by flexion of the head. 3. By the natural action of gravity. In short-necked people with a well-arched thorax the thyroid lies abnormally low, and a goiter developed in that gland is bound to become intrathoracic very soon. This abnormally low situation of the thyroid has been called by Kocher thyroptosis (Fig. 43) and is accompanied at the same time by a laryngoptosis. According to von Eiselsberg this thyroptosis is frequently found in patients with emphysema. Kreuz- IXTRATHORACIC GOITER 141 fuchs claims that, on the whole, an isthmoptosis \s more frequently found than a ptosis of the entire gland itself. In rare instances the isthmus seems to form a big body per se, being connected with the lobes by only a thin bridge of connective tissue containing bloodvessels, and thus forming what Gruber calls glandule? tripartita'. In such glands the isthmus is very apt to sink into the superior opening of the thorax as soon as it grows in volume. At first a deep goiter extends only partly behind the sternum and underneath the first rib. It moves freely up and down with the larynx. Later, when the goiter has descended into the thorax and has grown more voluminous, it escapes out of the thorax only in forced respiration or coughing. But as the goiter continues to grow there finally comes a time when it can no longer escape the superior opening of the thorax; it then lies in the superior mediastinal space and becomes more or less completely intrathoracic; in such conditions the up-and-down move- ments with the larynx have more or less lost their entire amplitude. We can consequently conclude that the great majority of intra- thoracic goiters have been at one time cervical: only the ones which originate from an intrathoracic accessory gland, or which are developed at the cost of an extremely ptosed isthmus or lobe, are intrathoracic from the start. If two separate nodular goiters in the same individual become mediastinal they form a double intrathoracic goiter. Intrathoracic goiters vary from the size of an egg to that of a large fist. They may be nodular and irregular in shape when they are formed by an aggregate of colloid nodules, but they may also have a smooth surface with a round or oval shape when formed by a cyst or by a unique colloid nodule. Histologically all the pathological varieties seen in simple goiter are found, too, in intrathoracic goiter. That an ordinary goiter dips by its inferior poles more or less low into the superior opening of the thorax is seen quite frequently, and according to statistics and my own experience it occurs in about 25 to 35 per cent, of all goiter cases; on the other hand, a partly intrathoracic goiter occurs in about 15 to 18 per cent, of the cases. In this class, too, we find the diving or plunging goiter which has been so well described by the French authors and called goitre plongeant. This plunging goiter may be median or lateral; it owes its name to the fact that at times it is cervical and at others intrathoracic: during coughing or forced expira- tion it springs up suddenly above the manubrium sterni and then disap- pears into the thorax again. Such goiter is liable to become incarcerated at the superior opening of the thorax and then canst- very alarming suffocating spells. One of the most striking specimens of plunging goiter which I have seen was while 1 was the assistant to my master, Kocher. It was developed in a retroclavicular accessory thyroid gland on the 142 INTRATHORACIC GOITER right side, had no connection whatsoever with the thyroid, and with each coughing used to play in the most exquisite way the game of "Now you see me; now you don't." In fact, it was the only symptom which had brought the patient to seek surgical attention. Totally intrathoracic goiter includes all cases of goiter which lie in the thoracic cavity, showing no signs, more or less, of external enlarge- ment of the gland. This is the true intrathoracic goiter. It occurs in about 6 or 7 per cent, of the cases of goiter. Intrathoracic goiter may in rare instances be congenital, but as a rule it is found in middle age about the fortieth year of life. My young- est case of totally intrathoracic goiter was a girl, aged about thirteen years, while my oldest was seventy-five years. It is more frequently found in men; it is of benign nature, but, of course, may undergo malig- nant degeneration. As ordinary goiter is by far more frequently seen in women than in men, it may seem peculiar to find intrathoracic goiter more frequent in men than in women. The reason is that men begin hard work very young and continue it all their life, more so than women. Hence the tendency for ordinary goiter to become intrathoracic. Intrathoracic goiter developed in the isthmus lies in the middle line and is called the median intrathoracic goiter (Plate VII, Fig. i). A goiter developed in one of the lobes lies laterally of the middle line, and for that reason is called lateral intrathoracic goiter. Relation of Intrathoracic Goiter to Neighboring Tissues. — The median intrathoracic goiter lies in front of the large vessels and is bounded by the manubrium sterni in front, by the trachea and esophagus behind, by the arch of the aorta or innominate artery below, and laterally by the lungs. The lateral intrathoracic goiter (Plate VII, Fig. 2) is bounded in front by a portion of the sternum and costal cartilages, behind by the first three vertebrae with their costal insertions, inwardly by the trachea and esophagus, and laterally by the pleural membrane. A very impor- tant relation of intrathoracic goiter is its relation to the large intra- thoracic vessels; it may he in front, which is less frequent, or behind them or laterally too; the median intrathoracic goiter nearly always lies in front of these vessels. When situated behind the vessels it is called retrovasal; when in front of them it is called prevasal. In conclusion we may say with Wolfler that the portion of the thorax in which intrathoracic goiters can be found is limited in front by the manubrium sterni and the adjacent portions of the clavicles and of the first three ribs; behind, by the first three thoracic vertebrae with their costal insertions; laterally, by the parietal pleura; below, by the arch of the aorta, the innominate, and the basis of the heart; above, by the superior opening of the thorax. From this it follows that an intratho- racic goiter may come in contact with very important organs, such as PLATE VII Relation of a Median Intrathoracic Goiter to the Surrounding Structures. Cross-section of the Upper Part of the Thorax, Showing Relation of" a Lateral Intrathoracic Goiter to Surrounding Structures. SYMPTOMS 143 the right and left innominate artery and veins, the common carotids, the arch of the aorta, the basis of the heart, the thoracic duct, both vagi, the inferior laryngeal, phrenic and sympathetic nerves, the trachea and the esophagus. On account of such dangerous vicinity it will be easilv understood that intrathoracic goiter may have a most striking symptomatology. In intrathoracic goiter as well as in cervical goiter the trachea may be displaced or compressed, or both together. If the pressure is of long standing the walls of the trachea may become atrophied. In median intrathoracic goiter, pressure takes place anteroposteriorly. In lateral intrathoracic goiter, pressure takes place laterally. If the windpipe is compressed laterally on each side by two nodular goiters, compression may be so marked that the two walls of the trachea may come in con- tact with each other and form what we call the sabre-sheathed trachea (Fig. 27). If the two nodular goiters are at different levels then the trachea assumes an "S" shape (Fig. 28). Beside the trachea the goiter mav exert pressure on one of the main bronchi. More seldom com- pression of the upper portion of the lungs may be found. Kreuzfuchs more than once had opportunity to determine such compression with the jv-rays. In one of my cases compression on the right lung was so marked and had been of such long standing that gangrene of the apex followed and caused an empyema. All the large vessels of the thorax, even the superior vena cava, aorta and basis of the heart, may undergo compression and displace- ment from intrathoracic goiter. Thus on fluoroscopic examination the tumor mav appear to pulsate and may then be taken for an aneurysm. Yet, closer examination will show that this pulsation is not an expan- sive one, but is only transmitted by the aorta or the other large vessels of the mediastinal space. Injury to the inferior laryngeal nerve happens more frequently on the left than on the right side. Wolfler thinks this is due to the fact that the left inferior laryngeal nerve is more superficial than the right. That may be true in some cases; in others, however, Kienbock's explan- ation is more satisfactory. In his judgment, as the intrathoracic goiter presses and displaces the aorta toward the left side, it puts the inferior laryngeal nerve on the stretch, hence the injury to the recurrent nerve. This is to be expected, as we know experimentally that traction on the nerve is the equivalent of compression. Symptoms. — The symptoms produced by intrathoracic goiter do not differ in any way from those described in conjunction with cervical goiter, except that they may be more intense and that suffocating spells may be caused by the slightest physical effort, or come on spontaneously, especially dining the night. While in bed the patient cannot find a 144 INTRATHORACIC GOITER comfortable position for sleep as the recumbent position causes a con- gestion of the cervical region, soon followed by suffocation; on the other hand, pillows are of no use because they flex the head, causing the chin to press upon the goiter which, in turn, compresses the trachea, hence again bringing about suffocation. Such patients spend their nights in an arm-chair like asthmatic or cardiac patients. In one of my patients dyspnea was so marked that I had to operate on her in a sitting posi- tion, and had to keep her in that position until the goiter was fished out of the thorax. When dyspnea is intense there is during inspira- tion a sucking-m of the suprasternal and the epigastric regions; this phenomenon is called by the French authors tirage. In intrathoracic goiter the auscultative findings differ naturally with the situation — the volume and the relation of the goiter with the neigh- boring tissues. If a bronchus of secondary importance only is com- pressed, respiration in the corresponding portion of the lung will be diminished in proportion to the compression. If one of the main bronchi is totally compressed, a complete silence will be found in all the cor- responding regions of the lungs. If stenosis of the tracheobronchial tube is incomplete a loud, whistling inspiration and a prolonged expira- tion with tubular character will be found, especially over the sternum and on the spine. Emphysema and bronchial catarrh are of common occurrence. If the lungs themselves are compressed there is, in the area of pressure, diminished respiration accompanied with rough inspira- tion and prolonged expiration, and tubular breathing. More than once such conditions have been considered as incipient tuberculosis. Certain movements of the head increase dyspnea, whereas certain others afford an easier respiration. These facts soon become known to the patient and it is not so rare to find a patient going about carrying his head always in the same posture, as if he were suffering from a boil on the neck. When of long standing these abnormal positions may even produce secondary deformations of the skeleton. Kronlein, for instance, reported a case in which intrathoracic goiter had produced a scoliosis of the spine. A symptom which is considered very valuable for diagnosis by Wolfler and Kocher is not only the displacement of the windpipe later- ally, but also a ptosis of the larynx in toto and a diminution of its up-and-down movements: the radius of its excursions is reduced as if something were trying to hold it immobile. Laryngoptosis may some- times reach such a degree that the cricoid cartilage lies at the level of the incisura sterni (Fig. 43). Fixation and ptosis of the larynx are of great diagnostic value in intrathoracic goiter. Symptoms of compression on the sympathetic nerve are much more frequent in intrathoracic than in cervical goiter. SYMPTOMS 145 Pressure on the subclavian and innominate veins, and on the superior vena cava produces a congestion of the neck and head, hence roaring in the ears, vertigo, cyanosis, etc. In some cases the compression of the big venous trunks is so marked that the return flow to the heart is greatly impaired. In such cases a collateral circulation is established by means of the superficial veins of the thorax and inferior portion of the neck; the)- become distended and the blood reaches the heart through the superficial anastomosis which joins the superior and inferior caval Fig. 31. Partially intrathoracic goiter wuli a marked collateral circulation. Fig. 32 I Ik- goiter after us removal, I Ik- portion below the clavicle was intrathoracic. systems. These veins mav sometimes attain enormous dimensions and be so numerous as to cover the entire upper portion ot the thorax, forming what is known as the caput medusa- (Fig. 31). The arm on the corresponding side may become edematous. In some rare instances compression on the large arterial trunks may diminish or suppress the pulsations of the carotid and radial artery on the side involved, lo In- exact, I must say that these symptoms produced by the interference of the arteriovenous system are not pathognomonic of intrathoracic goiter only, but are seen in any sort of mediastinal tumor. 1(1 146 IN TRA THORA CIC GO I TER The intrathoracic goiter more than any other goiter is apt to cause cardiac disturbances and give rise to what we call mechanical goiter- heart, w T hich is often combined with thyrotoxic goiter-heart. This ques- tion has been thoroughly discussed in the chapter on Goiter-heart. Difficulty in swallowing is found more often in intrathoracic goiter than in cervical goiter. These disturbances are caused not only because of compression, but also on account of displacement of the esophagus. Pressure of long standing on the esophagus determines chronic inflam- matory conditions in the musculature and in the esophageal mucous membrane, hence the difficulty and pain which the patient complains of in swallowing. Interference with the inferior laryngeal nerve, whose branches partly supply the esopha- gus, may sometimes account, too, for much difficulty in swallowing. Kreuzfuchs and other authors have described a symptom which is not pathognomonic for intrathoracic goiter alone, but is very often found in any other mediastinal tumor; it consists in the forward displacement of the manubrium sterni. Normally the manubrium and corpus sterni, although sometimes forming a slight angle, are on the same level. In intrathoracic goiter or any other mediastinal tumor, the manubrium happens not infrequently to be dis- placed forward so as to form a difference in the level between the manubrium and the gladiolus. This difference may vary from a few millimeters to a centimeter. If the cartilages of the first and second ribs participate, too, in this forward displacement, the whole thing forms a characteristic "moon-like" picture which, according to Kreuzfuchs, is more often seen in malignant intrathoracic goiter. Dulness over the sternum is always present, except in a few cases in which the intrathoracic goiter is of very small size and covered by emphysematous lungs. Gentle percussion is best suited to bring out the outlines of intrathoracic goiter. As a rule a dulness with a down- ward convexity will be found, a point of good differential diagnostic value, as in aneurysm this dulness will rather show an upward convex- ity. This will, of course, be confirmed by the x-rays. Another symptom of great diagnostic value is the displacement of such dulness by forced respiration: it goes downward with deep inspiration and upward with expiration. As a rule the dulness over the sternum is smaller than the Fig. 33. — Ten days after the operation. SYMPTOMS 147 goiter itself, because the concomitant emphysema which is always present in tracheostenosis prevents the outline of the true limits of the true tumor. In lateral intrathoracic goiter dulness is localized over the manubrium sterni, over the cartilages of the second, possibly of the third rib, and over the sternoclavicular articulation; the side will depend upon which side the goiter has originated. If the intrathoracic goiter is median the dulness will be found mostly over the manubrium sterni. In normal individuals auscultation over the manubrium sterni will, as a rule, show a faint indication of respiration, or no respiration at all. But if an intrathoracic goiter is interposed between the sternum and the trachea, and with still greater reason if the trachea is compressed, auscultation over the manubrium sterni, as a rule, will reveal a loud inspiration and a prolonged expiration accompanied with marked tubular breathing. X-ray examination should really become a part of the routine exam- ination in anv suspected intrathoracic goiter. It not only confirms the clinical findings, but completes them. Sometimes, when it is difficult to decide on which side of the thorax the intrathoracic goiter is located, A-rays will show it. The fact that there is a double intrathoracic goiter may escape clinical detection; the v-ray, however, will nearly always give you this information. Furthermore, it gives precise indication on the situation, form, etc., of the trachea. Finally, it may prevent the surgeon from overlooking conditions of the thoracic organs, which may have great influence on the success of the operation, such as tuberculosis, pleural exudate, etc. Normally, in the dorsoventral skiagram, the shadow may be divided into three parts: a cervical, a mediastinal, and a cardiac shadow (Figs. 34 to 4 1 )- In intrathoracic goiter the shadow of the cervical and mediastinal portion is much increased. Laterally the shadow may reach the inner third of the half of the clavicle. Downward it may cover the base of the heart, extending to the middle of the manubrium sterni and to the cartilage of the third rib. Upward, when the goiter is partially intra- thoracic, it extends and fuses with the shadow of the cervical goiter. The tone of the shadow of the intrathoracic goiter, as a rule, is regularly distributed, dark and opaque; its contour is convexed laterally and sharply marked, as a rule, because of the contrast with the shadow ol the lungs, which is clear. Instead ol being regular and convexed, how- ever, the contour may be undulated and irregular, indicating a nodular goiter or a malignant tumor. The shadow of the aorta and of the vena cava may be absolutely covered by the goiter, and not uncommonly the arch of the aorta is found displaced toward the left side and downward. 148 INTRATHORACIC GOITER According to its variety the shadow of the intrathoracic goiter may be median or lateral. In the median the trachea is absolutely covered Fig. 34. — Normal skiagram of the mediastinal space. Fig. 35. — Skiagram of a struma profunda or deep goiter. SYMPTOMS 149 Fig. 36. — Skiagram of a partly intrathoracic goiter. J, intrathoracic goiter; B, aorta. Fig. 37. — Skiagram of a partly intrathoracic goiter. Mote compression and displacement of the windpipe. 150 TN TRA THORA CIC GO I TER Fig. 38. — Skiagram of a partially intrathoracic goiter. Fig. 39. — Skiagram of an almost totally intrathoracic goiter from patient Fig. 40. SYMPTOMS 151 by the goiter and no shadow of the windpipe is seen in the skiagram. In the lateral intrathoracic goiter the shadow mav be mostly devel- Fig. 40. — Almost totally intrathoracic goiter. Note youth of patient ( fourteen years). Fig. 41.— Skiagram <>t a totally intrathoracic goiter: ./, intrathoracic goiter; B, aorta. 1 he goiter alter removal is shown in lig. 42. oped on the right side or on the left side of the mediastinal space, accord- ing to the position of the goiter. In that case the aorta may be seen displaced toward the left side, tin- windpipe may be followed more or 152 INTRATHORACIC GOITER less in its entire course and may be displaced or compressed or may be both together. In a few instances the trachea may be followed to its bifurcation. In intrathoracic goiter not only skiagraphy but fluoroscopy is of the utmost importance. A fluoroscopic examination will reveal the pulsa- tions, the up-and-down movements of the goiter during inspiration and deglutition. The shadow of the goiter is not infrequently seen pulsat- ing; these pulsations, however, are not expansive, but are transmitted from the neighboring large vessels, especially from the aorta. Up-and-down movements synchronous with the act of swallowing are pathognomonic of a tumor developed in the thyroid gland; this symp- tom never fails, except in an abnormally large incarcerated intratho- racic goiter or in malignant degeneration. On the fluoroscopic screen the goiter is clearly seen rising with the trachea and larynx, but the aorta remains immobile. In a few instances the aorta is seen rising with the goiter; this does not mean, however, that the aorta is adherent to the goiter, but only that the pressure from the goiter on the aorta being released the normal elasticity of the aorta brings this large vessel into its normal position again. The best way to observe these up-and- down movements is to have the patient swallow water, or, better, to have him take a very deep inspiration, hold it for a few seconds, and then perform a quick expiration. In so doing the intrathoracic goiter goes downward during deep inspiration and comes upward with expira- tion. Sometimes, according to Kreuzfuchs, a small intrathoracic goiter located behind the manubrium sterni or behind the sternoclavicular articulation may escape notice on the skiagram, but becomes fluoro- scopically detectable while the patient is taking a deep inspiration, because the nodule emerges laterally from the shadow of the sternum. Diagnosis. — The diagnosis of a partially intrathoracic goiter is, as a rule, not difficult. In that case we have to deal with a patient who has had for a longer or shorter period of time a goiter. He complains of dyspnea and palpitations, and more recently may have had spells of suffocation. We find a cervical goiter. Our first duty is to outline its inferior limits. If we do not succeed we ask the patient to cough or to swallow. In that way if the goiter lies only behind the episternal notch the palpating finger will be able to outline its inferior limits; but if the goiter extends farther down we shall not know how far down the goiter reaches. We shall have to rely upon percussion and ausculta- tion. We must see if there is any congestion or puffiness of the face; if there is any collateral circulation in the neck, thorax, and arms; if there is any difference between the radial and carotid pulse on each side; if there is any irritation or paralysis of the sympathetic nerve; any fixation or ptosis of the larynx; any displacement of the windpipe, DIAGXOSIS 153 or any difficulty in swallowing, etc. These symptoms and the x-ray picture will terminate the examination, and as a result diagnosis of partially intrathoracic goiter will always be made. But with a goiter which is totally intrathoracic, diagnosis is very much more difficult. Here we shall have to rely mostly upon the mediastinal symptoms. The first thing to do is to ascertain that the thyroid gland is in its normal position, and that the two lobes and isthmus are normally situ- ated, since a missing lobe is a feature of enormous diagnostic value. In the latter condition, Wiihrmann claims that there is a depression of the skin between the sternocleidomastoid muscle and the larvnx. Another symptom of great importance is the feeling with the finger of an impact above the episternal notch during expiration, swallowing, or coughing. This impact is caused by the intrathoracic goiter rising with the larvnx. The presence of a pedicle extending from one lobe or isthmus down- ward behind the sternum is a clue of great diagnostic value. If, further- more, the palpating finger is not able to feel, as is normally the case, the tracheal rings of the windpipe behind the episternal notch, but finds, on the contrary, a mass interposed between the sternum and the trachea, and if this mass moves up and down during swallowing, the diagnosis of an intrathoracic goiter is certain. But such symptoms as those above mentioned may not be present, or may be doubtful, and then the diag- nosis becomes greatly difficult. In such cases we must decide: i. \\ hether we have to deal with a mediastinal tumor, and if so, 2. \\ hat is its nature ; That we have to deal with a mediastinal tumor will be shown by the subjective symptoms described by the patient, as well as the objec- tive ones found in the course of our examination, such as congestion; puffiness of the face and neck; collateral circulation of the thorax; dimin- ution or disparation of the radial pulse on one side; possibly edema of one arm; well-defined dulness over the upper portion of the thorax; forward displacement of the manubrium sterni; paresis or paralysis of one or both inferior laryngeal nerves, and, an unmistakable shadow on the skiagram. These mediastinal symptoms will not always be all pit-sent, but in the great majority of cases there will be enough of them to warrant a sure diagnosis. When once the diagnosis of mediastinal tumor is made with cer- tainty, we must decide if we have to deal with an intrathoracic goiter or nor. In that direction the history of the patient may furnish pre- cious indications. lie may have previously had a goiter which has "disappeared." Indeed, it is not infrequent to see patients who believe that they have been cured of a goiter because their neck seems to be free from it; nevertheless tin- goiter is still present but has become intrathoracic. 154 INTRATHORACIC GOITER The symptoms which will be of great value in deciding if a mediastinal tumor is a goiter or not are: i. Dyspnea, which is entirely out of proportion to the cervical goi- ter, if there is any, or with the size of the mediastinal tumor, as shown Fig. 42. — Totally intrathoracic goiter. by the skiagram and percussion. The suffocating spells, especially at night, speak for goiter, as also does the fact that flexion, or extension, or lateral movements of the head increase dyspnea or cause suffocation. Fig. 43. — Intrathoracic goiter accompanied with thyro- and isthmoptosis. These suffocating spells may be stopped or greatly benefited by pulling the larynx upward or by displacing it laterally; on the contrary, in other conditions these procedures may accentuate the suffocating spell. DIFFERENTIAL DIAGNOSIS 155 2. A ptosis of the larynx, and diminution of the radius of its excur- sions, or its entire fixation. In mediastinal tumors other than intra- thoracic goiter, ptosis and fixation of the larynx are less frequently seen. 3. The absence in the cervical region of one lobe or the isthmus (Figs. 42 and 43). This symptom is of great diagnostic value. 4. The feeling of an impact behind the episternal notch when the patient swallows. 5. Stenosis of the trachea in the region of the fifth, sixth or seventh cartilaginous rings of the trachea, detected either by laryngoscopy or tracheoscopy. 6. If symptoms of hyperthyroidism are found in connection with this mediastinal tumor, as tachycardia, tremor, exophthalmos, nervousness, etc., the chances are great that we have to deal with an intrathoracic goiter. 7. The fluoroscopic examination will be of enormous value, espe- cially if it is able to show the up-and-down movements of the shadow synchronous with the act of swallowing. In that case the diagnosis becomes certain. Differential Diagnosis. — Sometimes the difficult)' is to decide whether we have to deal with an aneurysm or an intrathoracic goiter, since even fluoroscopic examination will not always solve the problem. Symptoms may be much the same in both cases, pulsations being transmitted to the intrathoracic goiter by the innominate or the arch of the aorta. These two conditions have been mistaken one for the other more than once. It would seem that in doubtful cases auscultation of the heart and aorta would throw the necessary light upon the diagnosis, yet it is not always so, as auscultation of an aneurysm may be entirely negative. Here the physical and skiagraphic examination will be of great help. If the shadow is located more or less to the left of the mediastinal space the diagnosis between aneurysm and intrathoracic goiter is most diffi- cult; but if it is located to the right, and if sympathetic and laryngeal nerve symptoms are present on the right side, too, the chances are great that we have not to deal with an aneurysm, but with a goiter, unless we should be unlucky enough to meet with an aneurysm of the innomi- nate. Each of the symptoms above mentioned should be given careful attention and its relative value duly considered in order to arrive at a safe diagnosis. Kreuzfuchs says that a shadow of an intrathoracic goiter differs from the shadow of an aneurysm by the fact that there is an angle between the shadow of the vessels and the tumor, and that at the fluoro- scopic examination during the act of swallowing these two shadows separate from each other in the case of goiter. If it were always possible to determine on the fluoroscopic screen, if pulsation seen in the tumor 156 IX TRA THORA CIC GOT TER is an expansive instead of a transmitted one, diagnosis would then be made easier, because we know that an aneurysm expands in every direc- tion; whereas in transmitted pulsations such a movement takes place always in the same direction. Unfortunately this is not always possible; more than that, one may come against cases of true aortic aneurysm where no pulsations whatsoever can be detected, because the aneurysm is accompanied by diffuse inflammatory or syphilitic mediastinitis. Lateral fluoroscopic examination is of great help in deciding if we have to deal with an aneurysm or a mediastinal tumor, because in the latter condition there is no clear space between the spine and the tumor, whereas this "clear space" exists in aneurysm unless the aneurysmal sac has acquired large dimensions and a pen-aortitis due to frequent hemorrhages has taken place. A large and flat aorta might be mistaken for a mediastinal tumor, but in that case a lateral view of the patient will clear up the diagnosis. Fig. 44. — Lateral radiogram of a normal heart: A, spica; B, aorta; C, heart; D, diaphragm. Fig. 45. — Lateral radiogram of an aneurysm. Syphilitic or tuberculous mediastinitis must be differentiated from the intrathoracic goiter. Both varieties of mediastinitis are located mostly in the posterior superior mediastinum, whereas intrathoracic goiters are seen in the superior anterior mediastinum. Skiagraphic examination shows that in mediastinitis the shadow is more diffuse and somewhat linear, whereas the shadow of a goiter is more round and convex down- ward. In tuberculosis of the mediastinal space the skiagram will show enlarged tracheobronchial glands at the hilum of both lungs. In syphilitic mediastinitis (Fig. 46) Wassermann and specific treatment may clear up the diagnosis. Hypertrophy of the thymus may have to be differentiated from an intrathoracic goiter. This thymic hyperplasia occurs mostly during the early years of life. However, in adults it may persist and is especially DIFFERENTIAL DIAGNOSIS 157 found in combination with goiter. The x-ray picture of thymus hyper- plasia is absolutely different from the picture of intrathoracic goiter. The diagnosis of thymus hyperplasia, contrary to all that has been written, is possible in a great majority of cases. Clinical examination must be always accompanied by this skiagraphic examination. Normally a skiagraphic mediastinal shadow (Fig. 34) measures from 2.5 to 3.5 cms. under the arch of the aorta, from 3 to 3.5 cms. at the arch of the aorta, and from 5 to 6 cms. at the conus arteriosus. The shadow of this region is dark, opaque, and regularly distributed, and has definite limits. FlG. 46. — Syphilitic mediastinitis. Note the location of the shadow. In thymus hyperplasia there is a shadow which overlaps laterally the normal mediastinal shadow (Figs. 47 and 48). It may affect one lobe more than the other, or may affect both lobes in the same- proportion. The thymic shadow is more or less triangular; from the basis ot tin- heart it extends upward on each side in a Straight line, or follows to some extent the contour of the mediastinal shadow; it covers the auricles, which seem to be overdistended, and forms an angle between them and the ventricles; hence, too, an enlargement of the auricles which is not in proportion to the rest of the heart. The character of this thymic shadow differs from the cardiac and mediastinal shadows. It is thin. 158 INTRATHORACIC GOITER transparent, soft, and regularly distributed; its edges, as a rule, are sharply limited and linear. Fig. 47. — A, intrathoracic goiter; B, thymus hyperplasia. Findings corroborated by postmortem. Fig. 48. — A, thymic shadow. PROGXOSIS 159 Prognosis. — The prognosis of an intrathoracic goiter depends upon many factors. A lateral intrathoracic goiter may sometimes cause pulmonary symptoms; a median intrathoracic goiter will compress the trachea anteroposteriorly, and consequently give dyspneic symptoms much earlier than the former one. Compression of the windpipe and of the bronchial tubes cause a stubborn catarrh which resists every medical treatment. Intrathoracic goiter more than any other is apt to cause choking spells, but one of the most tragic terminations of an intrathoracic goiter is "sudden death," which will be discussed in the chapter on Goiter Death. Even free of symptoms, an intrathoracic goiter is still dangerous to the patient because a hemorrhage may take place, an acute infection or a malignant degeneration may develop in it, and so endanger the life of the patient. In skilful hands the prognosis of the cases treated surgically is excel- lent. Out of his last 77 cases of intrathoracic goiters, Kocher lost but 1 case. Autopsy showed advanced sclerosis of the coronary arteries of the heart. CHAPTER IX. GOITER DEATH. In patients suffering from tracheobronchial stenosis, any congestion of the respiratory apparatus or any physical exertion increases the short- ness of breath; even talking taxes their strength to the utmost, and it is not unusual for them to stop in the middle of a sentence to get breath: inspiratory stridor is then more or less always present. With a little care, however, such patients may get along for years without choking spells, inasmuch as they adapt themselves to the smaller caliber of the trachea and to the diminished oxygenation of the blood; yet, disregard- ing the fact that such patients are more liable than others to have pneumonia, their lives are otherwise always endangered because a slight catarrh, or any other trifling cause, may determine a dangerous choking spell which may terminate in death. Sudden death is one of the most tragic and often one of the most unexpected endings of those afflicted with goiter, especially with the intrathoracic variety. One who has seen many goiter patients with choking spells knows, for instance, that these patients learn by experience that twisting of the head in certain ways increases dyspnea, whereas earning the head in some definite manner makes respiration easier, because in so doing they unconsciously relax certain muscles, thus diminishing the direct pressure upon the goiter, which in turn allows respiration to take place more freely. If, however, during sleep they should make a false move- ment of the head so as to twist or compress the trachea, the}' at once awaken in need of air and try to find again the stereotyped position in which respiration is easier, and which Rose calls " Die letzte Stellung." If they succeed, all well and good: the spell will soon be over. But if they do not, and if there is at the same time a congestion of the larynx and a catarrhal condition of the windpipe, and if there is added to this as the consequence of congestion an active and passive venous stasis in the goiter, which results in an increased volume of the goiter itself, and in turn in an increased pressure on the windpipe, then the efforts of the patient to get his breath are useless: the tracheal stenosis has become complete and death must ensue. As said before, these choking spells and this type of goiter occur most frequently with the forms of intrathoracic goiter, among which the plunging goiter must be given due consideration. As we know, this GOITER DEATH 161 goiter has a long pedicle, and has a wide range of excursion, since it can wander from the cervical region into the mediastinal space, and vice versa. Suppose, now, that a sudden hemorrhage, or that an active or passive venous congestion takes place in that goiter, then at once the latter increases in size, and on that account can no longer escape the superior opening of the thorax: it becomes incarcerated behind the ster- num. The tighter the incarceration the more marked are the congestive symptoms, hence the increased pressure upon the windpipe, hence suffo- cation and death. In fact, any sudden increase in the volume of any form of goiter is liable to cause sudden death. In pregnant women during deliver}" the violent efforts of expulsion cause an intense swell- ing of the goiter, w r hich in turn compresses the windpipe. The same is true of sudden hemorrhages or acute infections taking place in colloid or cystic goiters. The same is true, too, of these intense venous conges- tions occurring in goiters of newborn babies. All these deaths occur by the same mechanism, namely, by the compression of the windpipe. This process is made worse by the spasmodic contraction of the cervi- cal muscular belt, especially that of the sternocleidomastoid muscles acting as auxiliary muscles of respiration during the dyspneic spell. In such conditions the goiter plays the part of a hard ball pressed violently against the trachea. This is especially true in cases in w T hich the cervical musculature has not yet undergone atrophy. In some cases pressure on the windpipe and on the venous trunks is only moderate; the laryngotracheal catarrh is not marked; the inferior laryngeal nerves are not traumatized, yet during menstruation, preg- nancy, physical effort, or on account of an increase in the volume of a goiter due to hemorrhage or infection, a brusque hyperemia and congestion of the laryngeal mucous membrane takes place and an edema of the glottis follows. The patient becomes cyanotic and fights for air; this suffocating spell may soon be over or may terminate in death. This form of sudden death has been especially observed in pregnant women, and very likely because the renal filter in pregnancy is often at fault. But there are cases of sudden death in which there is no compres- sion at all, where there is no softening of the windpipe, where the bron- chial or tracheal catarrh is absent, where the renal function is normal, and where the cervical muscular belt has no murderous intentions, yet the patient dies suddenly of suffocation. "This acute choking spell without any tracheal stenosis surprises the patient," says Kronlem, "without warning, like a thief in the night." The patient may previ- ously have had a slight shortness of breath or may have been entirely well; his voice may have been entirely clear; he may have been sleeping quietly, when suddenly he wakes and rushes to the window to get fresh 11 162 GOITER DEATH air. He can scarcely speak, and a long whistling stridor shows that the patient is in danger of choking. From this spell he may recover in a short time, or he may not. In such conditions death is due to the spasmodic contraction of the glottis, through stretching of or pressure on the inferior laryngeal nerve by the goiter. As Kraus and Krishaber have shown, the choking spell due to compression of the inferior laryngeal nerve is not at all caused by paralysis of the nerve but by its excitation. When the nerve is paralyzed there is no longer danger of glottic spasm. Indeed, we know that the dilatators as well as the constrictor muscles of the glottis are all sup- plied by the inferior laryngeal nerve. But we must remember, too, that the constrictors, being stronger than the dilatators when irritation of the recurrent nerve following pressure takes place, closure instead of dila- tation of the glottis occurs: hence spasm of the glottis. And let us not forget that pressure on the inferior laryngeal nerve does not need to be bilateral in order to cause this spasmodic condition, because the aryten- oid muscle is an unpaired muscle. As Dieulafoy rightfully says, "This muscle, which arises from the posterior surface and outer border of one arytenoid cartilage and is inserted into the corresponding parts of the opposite cartilage, always has the same effect, namely, that of bringing its two insertions together when it contracts, thus closing the glottis." It is the only muscle in the organism which exerts its action simul- taneously on both sides of a symmetrical organ. Accordingly, excita- tion of one of the recurrent nerves will determine, on the one hand, constriction of the interligamentous glottis by the action of the lateral crico-arytenoid muscles and of the thyro-arytenoid muscle on the corre- sponding side, and on the other hand, the complete occlusion of the respiratory glottis by the bilateral action of the arytenoid muscle. Respiratory and vocal troubles result from this combined action. There are, however, cases of goiter death in which the laryngoscope shows an absolutely normal function of the vocal cords; the voice is normal; there is no sabre-sheathed trachea; compression of the wind- pipe is only moderate; symptoms of bronchial catarrh are lacking, and no plunging goiter can be incriminated, yet the patient suddenly drops dead without a sign of warning. Death occurs without a struggle. This is the " Tod ohne kampf of the Germans and "la mort sans phrases" of the French. In such conditions death is absolutely unex- pected; the patient, while talking, reading, or drinking, suddenly dies. It is a goiter-heart death; the heart simply stops. Of course tracheotomy is useless and medicine is powerless in the presence of such a tragedy. The postmortem will show a dilatation of the right ventricle, and dila- tation and hypertrophy of the left ventricle, fatty degeneration of the cardiac musculature, brown atrophy, and myocarditis. These are the causes of death. CHAPTER X CIRCULAR GOITER. The circular goiter is a goiter which surrounds more or less com- plete!}' the trachea, or both the trachea and esophagus (Figs. 49 and 50). The inner portions of both lobes of the thyroid gland grow graduallv inwardly until they come in contact, one with the other, thus forming a ring of glandular tissue in which the esophagus and trachea are caught (Fig. 51). Such goiters are found in the newborn as well as in adults, and are mostly of parenchymatous nature. Symptoms. — Among the most strik- ing symptoms caused by a circular goiter are dyspnea and dysphagia. On account of its anatomical relations, this form of goiter is easily liable to cause disturbances of the inferior laryn- geal nerves. It also frequently causes sudden death. Circular goiter does not need to be very large to cause dyspneic symptoms. In 1854 Maurer reported a case of a child who was suffering from dyspnea. Examination of the neck did not present anything abnor- mal, yet the postmortem revealed a small, circular goiter encircling the trachea. While demonstrating anatomy at the Ohio State Medical College in 191 5, I found a most striking example of circular parenchymatous goiter. The gland in toto was scarcely more than twice its normal size. From the inner and posterior angle of each lobe there sprang at sharp angles laminae of thyroid tissue which passed behind the esophagus, and came in contact with each other. I was unable to ascertain if during the life of the patient symptoms wire present. Diagnosis. Diagnosis is not always easy. When a parenchymatous goiter of moderate size causes dyspneic symptoms which seem to be out of proportion to the size of the goiter, and especially when one <>i ^■I^KS^fc. ^^^m^^^M^^^H^^p^^^^ Id \ ^^v m ^ / Fig. 49. — Congenital goiter. Natural size. Anterior view. 104 CIRCULAR GOITER both inferior laryngeal nerves are involved, the possibility of a cir- cular goiter should never be overlooked. Palpation may convey the Ton que. Esopna^us Goiter Trachea Fig. 50. — Circular goiter surrounding the trachea and esophagus. Autopsy of a new- born. Natural size. Posterior view. impression that the lobes of the thyroid seem to disappear behind the esophagus and windpipe. Laryngoscopy, tracheoscopy, and esophagos- copy may reveal a circular compression of the esophagus and windpipe. Fig. 51. — Pressure upon windpipe and esophagus by a circular goiter. Treatment. — The treatment of circular goiter must be surgical. Great care should be taken to avoid injuring the inferior laryngeal nerves. INTRATRACHEAL GOITER 165 RETROTRACHEAL OR RETRO-ESOPHAGEAL GOITER. This variety of goiter is developed at the cost of an accessory thy- roid nodule, and is located behind the esophagus or windpipe. It is entirely independent of the main body of the thyroid. This form of goiter is rare and the main symptoms which it causes are dyspnea and dysphagia. INTRATRACHEAL GOITER. Intratracheal goiter is very uncommon. With this, too, women are much oftener afflicted than men, and every recorded case has occurred between the ages of twelve and thirty-five years. The only symptom which brings the patient to the physician is an increasing dyspnea which may develop quite rapidly in a few weeks or may take a slower course. Laryngoscopy and bronchoscopy are the only two means of making a correct diagnosis. A subglottic tumor will be seen filling, to a more or less extent, the lumen of the trachea. It may be round, cylindrical, or oval in shape, with smooth surface, and covered by an intact mucous membrane. It is implanted by a broad basis on the tracheal wall. Its average size is about 2.5 cms. in length to 1.5 cms. in thickness, and it is nearly always located in the upper part of the trachea between the cricoid cartilage and the first five tracheal rings. Radestock, however, reported a case in which postmortem showed the tumor located at the mouth of the right bronchus. Intratracheal goiter does not seem to show predilection for any special portion of the walls, since it is found in the anterior, posterior, and lateral walls of the windpipe. Suspicion of an intratracheal goiter will be aroused when dyspneic symptoms cannot be accounted for. If, in a young individual complain- ing of dyspnea, laryngoscopy and bronchoscopy show a subglottic tumor with smooth surface, round or cylindrical in shape, and with a broad basis, the diagnosis of intratracheal goiter can be made with great probability. As said before, the site of the tumor on the walls of the trachea is of no diagnostic value. Differential diagnosis will have to be made with other conditions as possibilities. Enchondroma is far more rare than intratracheal goiter. A mistake might possibly be made with a sarcoma, as it has, too, a broad, large basis and smooth surface, but the sarcoma grows very much more rapidly, and thus causes more intense dyspneic symptoms than the intratracheal goiter. The origin of such tumors must be referred to embryonic residues included in the tracheal walls at the time of their development. In one instance, however, Paltauf showed microscopically that the intra- tracheal goiter in his case undoubtedly took its origin from a goiter developed in the isthmus of the thyroid gland, and which had penetrated through the tracheal walls. CHAPTER XI. CONGENITAL GOITER AND GOITER IN CHILDREN. CONGENITAL GOITER. If systematic examination of the neck of all newborn were made, certainly many more congenital goiters would be detected than actually are. Congenital goiter was described for the first time by Fodere in 1796. This author was already impressed by the relation which existed between congenital and parental goiters. Hausleutner, in 18 10, Martin, in 1840, von Ammon, in 1842, Pflug, in 1875, devoted quite a good deal of attention to this question of congenital goiter and goiterous ante- cedents, but it is to Virchow and Demme that we owe the most careful study on this subject. Reviewing 642 cases of goiter, Demme found 37 congenital goiters; out of 2292 goiterous patients Diethelin saw 25 congenital goiters; out of 1996 goiters Richard found 43 cases of con- genital goiter; and in 1909 Thevenot reported 133 cases of congenital goiter taken from the literature and from his own personal experience. Vascular and parenchymatous goiter are the two most frequent varie- ties seen in the congenital form of goiter. Colloid goiter is very much less frequent. Cystic goiter is rare, but when present may attain enor- mous volume as in Hecker's case reported in 1868, where the tumor was so enormous that it prevented the normal course of labor. Addelmann and Hubbauer saw a congenital cystic goiter whose dimensions were 1^ times the size of the head of the newborn. Every once in a while it has been found that the congenital goiter had undergone sarcomatous degen- eration. Many of the congenital goiters reported in literature as being of very large size were, as a rule, teratomata. Such large tumors are not seldom associated with other pathological conditions resulting from malformations or retarded development as hare-lip, situs inversus, etc. The etiology of congenital goiter is the same as that of ordinary goiter. In the vascular form, however, the mechanical influences during labor and delivery such as hyperextension of the head in face presenta- tion, persistent occiput posterior positions, pressure on the fetus from uterine contractions, and prolonged labor and deliveries, intervene to a great extent as adjuvant etiological factors by increasing the conges- tion of the thyroid gland. On the other hand, congenital goiters have a great obstetrical interest. Situated between the chin and the sternum, they prevent flexion of the head during the passage of the fetus through CONGENITAL GOITER 167 the pelvic route and hence cause face presentation. Sometimes, espe- cially in shoulder or buttock presentations, the umbilical cord winds around the neck, thus increasing the congestion of the goiter. Finally, these congestive conditions are apt to occur during normal labor in conjunction with all pelvic deformities. Parenchymatous goiter is, more strictly speaking, the true form of congenital goiter. The influence of heredity, especially on the mother's side, cannot be denied. Out of 53 congenital goiters Demme found that in 37 the parents had goiter, while in 23 cases the mothers alone were goiterous. Out of 43 cases Richard found 22 in which the mother had goiter, but in 1 only did he find goiter in both parents. In the 7 cases which I have seen and in the 9 cases reported bv Riibsammen in each case the mothers had goiter. Furthermore, congenital goiter is far more prevalent in regions where goiter is endemic, but this is no longer surprising as soon as we admit that the causes which produce it are the same as the ones which produce endemic goiter. Syphilis or tuberculosis cannot be regarded as playing any part in the etiologv of congenital goiter. Commandeur seems to think that congenital goiter is not found in primiparae, as the 5 cases reported bv him occurred in multipara. This statement, however, has not been confirmed. Histologically the congenital goiter does not differ materially from the forms seen in adults except that its vascularization mav be more intensely developed. Its volume is, of course, variable, but seldom exceeds the size of an egg. As a rule congenital goiter is entirely cer- vical; in some instances, however, it has been found intrathoracic. Congenital goiter may affect the circular form (Figs. 49 and 50), in that case it is most dangerous, as it may cause fatal spells of suffocation. Symptoms. — Even' congenital goiter does not necessarily produce symptoms. Many of these goiters remain latent and subside rapidly with or without treatment. In other instances, however, thev grow and finally attain a large size. These goiters, as a rule, are not the dan- gerous ones, because everybody is aware of their presence, and since their symptoms are not alarming there is plenty of time to apply medi- cal treatment which, as a rule, is thoroughly successful. To be sure, they may disturb the little patient by their volume, and they may cause dyspnea and dysphagia; in the latter case the baby will refuse to nurse. In other more benign forms of congenital goiter, interference with respi- ration is only moderate and causes what is known as the asthma neona- torum. These cases, however, properly handled can be satisfactorily managed. I his is not true of the fulminating forms of congenital goiter. Often- times in that form of goiter the little child is born dead; if not, the accidents develop rapidly; cyanosis is intense; dyspnea is quite marked; 168 CONGENITAL GOITER AND GOITER IN CHILDREN stridor with supra- and infrasternal tirage is present; the mouth and trachea are filled with mucus; the voice is hoarse; the wailing is weak, the cry rasping and shrill; the eyes are protruding, and death soon follows. Treatment of Congenital Goiter. — To a certain extent the treatment of congenital goiter may be prophylactic. For instance, if to a goiterous woman who is known to have already borne goiterous children, thy- roid extract is administered with caution during her pregnancy, the development of congenital goiter may be prevented. When the swelling is mostly of congestive nature it soon retrocedes spontaneously; at any rate, ice applied over the region of the thyroid will be beneficial. When, however, the enlargement is mostly of paren- chymatous nature, and when the symptoms are not too alarming, medi- cal treatment should be started at once. The following lodin ointment is very effective and easily used: Kal. iodat. . Aq. dest. Lanolin . Vaseline . Tinct. of iodin 5-0 IO.O 30.0 70.0 10 drops. The 6 cases which I have seen, and which were so treated, responded beautifully to the treatment. It goes without saying that medical treatment will have no effect upon a cystic goiter. When the child is born in a state of apparent death all the known means for resuscitating a baby should be employed. Warm baths for the lower half of the body and ice-water on the cervical region may be beneficial, while, as in one instance, the forward pulling of the lower jaw may put a stop to suffocation. Sometimes by grasping the thyroid tumor between the fingers and pulling it upward and forward, one may be able to bring back respiration. In that case pressure is due to incar- ceration of the goiter at the superior opening of the thorax. If this maneuver has succeeded the little patient may do better if he is kept lying flat on his back, with a pillow under his shoulders and the head in hyperextension. If, however, everything has failed, one should no longer hesitate. A transverse incision should be made over the tumor, and the goiter liberated and resected, unilaterally or bilaterally as the case may be. If hyperplasia involves the isthmus more than the remainder of the gland, isthmectomy may be all that is necessary. If, at the same time, thymus hyperplasia is present, thymectomy must be done quickly. It should always be borne in mind that the operation is in itself dangerous, as the little patients do not stand shock or hemorrhage. GOITER IN CHILDREN 169 Yet there is nothing else to be done. The mortality in the few cases that have been reported varies from 6 to 8 per cent. Tracheotomy is more dangerous, and, as a rule, fatal on account of the bronchopneumonia which follows. Furthermore, if we remember that in such conditions the trachea is covered by an enlarged, congested isthmus, extending from the larynx to the sternum, and through which one will have to go, and if we remember that below there are the thymus and the innomi- nates, and that in children the windpipe is small, soft and easily eludes the knife, and if, finally, we remember that the operation must be done quickly, since the child is dying, then anyone will easily understand that tracheotomy under such conditions is one of the most difficult operations a surgeon can be called upon to perform. GOITER IN CHILDREN. Goiter in children is not at all rare, especially in regions or countries where goiter is endemic. As in adults, so in children, all varieties of goiter are found; the parenchymatous form, however, is more fre- quently seen than any other. Goiter may be localized to one lobe only or it may involve the entire gland. When nodular the goiter originates nine times out of ten in the right inferior pole. The nodules may be unique or multiple. The goiter may even be intrathoracic. Simple goiter in children must not be considered as a mere incident. It is often accompanied by a constitutional syndrome showing a general depreciation of the little patient. As a rule these children are below the standard of health and development; they look frail and become fatigued easily. So far as treatment is concerned the same rules apply as those for any goiter seen in adults. CHAPTER XII. SIMPLE GOITER AND PREGNANCY. During pregnancy the thyroid gland undergoes nearly always an increase in volume which remains more or less marked all through the puerperal period. According to Seitz, this increase in volume occurs in 65 to 90 per cent, of all cases of pregnancy. Out of 718 pregnant women seen by Rubsammen, 89.5 per cent, of the cases showed a glandular enlargement. According to Lange, thyroid hyperplasia in pregnant women was found in 108 out of 133 cases, and when goiter existed previ- ously it always increased in volume during pregnancy. Von Graaf exam- ined 654 pregnant women during the second half of their pregnancy; 48.7 per cent, of them showed a thyroid enlargement. The same author, examining 256 pregnant Viennese women, found that 44 per cent, of them had goiter. Of course many of these women had had goiter prior to their pregnancy. This, however, does not disprove anything, since he then found that 38.5 per cent, of these goiterous women showed a marked increase in the volume of their goiters during pregnancy and delivery. According to Freund and Lange, hyperplasia takes place sooner in multiparae than in primiparae; it appears in the fifth month in the former and in the sixth month in the latter. It begins to retrocede a few hours after delivery and keeps on decreasing in size for weeks after. The thyroid, however, never returns to its normal size. Lactation seems to be devoid of any influence over the volume of the thyroid. The increase in volume is due to hypertrophy and hyperplasia of the parenchymatous elements; colloid and cystic nodules, when present, are only slightly involved. According to Seitz, the increase in volume is due to the action of placental products upon the thyroid. This gland- ular hyperplasia appears to be intended to destroy the products of auto- intoxication and changes in the serum caused by pregnancy, and it seems that women who do not show any hyperplasia of the thyroid are very apt to have albuminuria and eclampsia afterward. That the latter part of the supposition is not simply based on coincidence was shown by Lange. Indeed, if in non-pregnant cats one-fifth of the thy- roid is removed, no ill effects whatever are observed, but if the cats are pregnant the same operation causes at once albuminuria and nephritis. Thyroid opotherapy undertaken in such animals causes the symptoms to retrocede at once. Nicholson obtained the same results; the treat- ment with thyroid extract of four pregnant women with albuminuria TREATMENT 171 and eclampsia gave very good results. Seitz, Doderlein and others believe, however, that eclampsia is of parathyroid origin. Whatever the cause mav be we must admit that the thyroid hyperplasia in preg- nancy is a phvsiological process, most likely intended to deliver the organism of waste products taking their origin in the mother and in the child. Perhaps, too, this hyperplasia is intended to counterbalance the temporarily lost function of the ovary. In the majoritv of cases during labor, and especially during deliv- erv, the goiter increases materially in size. Sometimes it acquires such dimensions that bursting of the neck seems to be imminent. Dyspnea and cyanosis are very marked. It is seldom, however, that the dyspneic svmptoms become such as to necessitate surgical intervention. During labor and delivery pains, on account of the pressure from the goiter, the carotid pulse disappears, as shown by taking the pulse at the tem- poral arterv. Guvon considers this phenomenon as an attempt of nature to regulate the cerebral circulation. In goiters of long standing the goiter-heart is always present and must be regarded as a bad complica- tion. In other conditions tachycardia may become a very troublesome and alarming symptom. Treatment. — In all pregnant women the condition of the thyroid should receive careful attention. If this gland is found manifestly enlarged or altered, and if evidence of thyroid insufficiency is found, the active principle of the gland in some available form should be admin- istered. On that point everybody agrees. Small doses should be given, and may be continued for several weeks or months. As it has even been found that thyroid opotherapy started in the early period of pregnancy prevents thyroid hyperplasia, and furthermore, as it has been shown experimentally that it prevents albuminuria and nephritis in pregnant thyroidectomized cats, it might be worth while to undertake a series of experiments in order to find out if it would not always be advisable to feed pregnant women with thyroid extract, in order, possibly, to prevent some of the dreaded complications of preg- nancy as albuminuria, eclampsia, etc. In every case of pregnane) complicated with goiter, be it simple or thyrotoxic, or both together, the wishes of the parents regarding the life of the child should always be carefully ascertained, and the situation explained to them. Where children have been lost previously, and the parents are desirous of offspring, all possible means should In- used to continue the pregnancy without, of course, undue risk to the mother. As soon, however, as pregnancy is terminated the physician or obstetrician should consider it one of his first duties to have the patient seek surgical advice and treatment in order to remedy permanently the thyroid condition. 172 SIMPLE GOITER AND PREGNANCY When pregnancy complicated with simple goiter only has reached an advanced stage no one should become unduly alarmed, the course of the pregnancy should be allowed to go on, and in the great majority of cases everything will terminate to the entire satisfaction of the patient as well as of the attending physician, even if during labor dyspnea and cyanosis seem to threaten at first to become alarming. If, however, on account of that goiter the patient has previously lost a child, and if the symptoms have been such as to endanger the life of the mother, elective Cesarean section before labor should be selected. In cases in which, before labor, the dyspneic symptoms are marked, and when there is congestion of the cervical region with "caput medusae" highly developed, it is logical to assume that dyspnea will be greatly increased during labor. In such conditions, elective Cesarean section can be made before the labor pains have started. If labor and dilata- tion are already far advanced, pituitrin, judiciously administered, may greatly accelerate labor and shorten its duration. If dilatation is more or less complete, forceps may be necessary. If dilatation is not far enough advanced, but engagement is well started, a vaginal Cesarean section may save both mother and child. As in these cases the sole object of surgical intervention is "to do everything quickly," the induc- tion of labor with elastic bags is, of course, to be rejected, as it is too slow and too uncertain a process, and adds to the mother's nervous- ness, and, furthermore, exposes her to rupture of the uterus in delivering a child through a partially dilated cervix. Thyroidectomy in such conditions should be undertaken only as a necessity, as the operation is rendered extremely difficult by the enor- mous active and passive congestion of the entire cervical region; further- more, the thyroid during pregnancy is in a state of compensatory hyper- trophy, consequently, it is difficult to judge how much gland should be removed and how much should be left. Thyroidectomy will be a much safer process after the obstetrical period is over. Tracheotomy must be considered only as a life-saving device. In all these cases the administration of an anesthetic is a very seri- ous matter, and should be given the greatest care and attention, for it may prove disastrous. When possible, surgical intervention should be done under local anesthesia. CHAPTER XIII. CLINICAL ASPECT OF MALIGNANT GOITERS. In 90 per cent, of the cases, malignant goiter develops in an already preexisting goiter; consequently it is more frequently found in regions where goiter is endemic. A malignant tumor developing in a normal thyroid is rare; it is nearly always a tumor of connective-tissue origin, as sarcoma, endothelioma, etc. Malignant degeneration of goiter occurs mostly between the ages of forty and sixty years. To be sure, cancerous goiters have been found in younger people, even in children ten to twelve years old, but these cases are certainly not common. If we glance over Schmidt's, von Straaten's, Carranza's, and Carrel's statistics we find that: 24 occurred from 20 to 30 years of age = 5 per cent, of all malignant cases; 91 occurred from 30 to 40 years of age = 19 per cent, of all malig- nant cases; 219 occurred from 40 to 60 years of age = 44 per cent, of all malig- nant cases; 76 occurred after 60 years of age = 16 per cent, of all malignant cases. Sarcoma is more frequently found in young people, cancer in old ones. Malignant goiter is more frequently found in women than in men, and occurs mostly at the menopause, hence the absolute necessity of removing any goiter which begins' to grow at that time of life. Infectious diseases seem to have a certain etiological influence on the development of malignant tumors of the thyroid. It is not so infrequent, for instance, to find that malignant degeneration follows an acute spell of grippe. Relations to Surrounding Structures. — In advanced malignant goiters the skin is infiltrated, swollen, adherent to the deep layers, and is some- times of a livid red, while underneath the veins are dilated, even throm- bosed. I he diffuse malignant infiltration may extend to the neck, muscles, and other cervical organs. In the majority of cases the deformations of the larynx and trachea found in malignant goiter, as compression and deviation (Fig. 52), existed previously and were started by the goiter itself. To be sine, such deformations may have become more accentuated since the malignani degeneration of the goiter occurred, but they are not typical of malig- 174 CLINICAL ASPECT OF MALIGNANT GOITERS nancy. The only feature which is characteristic of malignancy is the invasion of the tracheal walls by the tumor; in advanced cases it may even perforate them. Of course this perforation is facilitated by the previously existing atrophy of the windpipe due to the pressure from the goiter itself. Fig. 52. — Pressure upon windpipe by a malignant goiter. The esophagus, too, becomes involved by the malignant degenera- tion. It seldom becomes perforated by the tumor. Compression may become so marked as to reduce considerably the size of the esophageal canal, hence dysphagia, and in the last stage, starvation. The carotid sheath is usually found adherent to and choked by the tumor. In advanced stages the malignant infiltration may involve the large vessels, erode them, and cause a fatal hemorrhage, as in the cases reported by Oser, Lebert, and Coulon. Such termination, however, is exceedingly rare. Less resistant than the arteries, the veins are fre- quently invaded by the malignant tumor, and it is not infrequent to COURSE AND SYMPTOMS 175 find them perforated and filled with cancerous masses. In one of my cases in which the cancer extended deep downward into the mediastinal space, not onlv the imae and jugular veins were thrombosed, but the carotid and the vagus were also involved, so that dissection was wholly impossible; veins, arteries, and nerves had to be removed with the tumor. In another case I found the junction of the subclavian and jugular veins completely thrombosed and perforated by the tumor. When malignancv has reached a certain stage, one or both inferior laryngeal nerves will nearly always be involved. The one on the left side is more often involved than the one on the right side. Both nerves may be involved at the same time. As told above, the vagus and sym- pathetic nerves may become so embedded in the tumor that their removal with the tumor is rendered necessary. This removal, however, does not materially influence the immediate postoperative prognosis, especially when resection is unilateral. In cancer the involvement of the lymph nodes takes place earl)'. The ones which are affected at first are the cervical, found along the carotid sheath; only later, the mediastinal lymph glands become involved. As a rule malignant lymph nodes are small, round, hard, and form a chain along the carotid sheath. In a later period they grow and fuse together with the goiter itself. In some forms of malignancy the lymph nodes are large, soft, and remind one of a malignant lympho- adenoma. Involvement of the lymph nodes in some forms of malignancy may be totally absent. Course and Symptoms. — The development of cancer may be acute, subacute, or latent. In the acute or fulminating form the development of the malignant tumor is extremely rapid. In three or four weeks it may reach such a development so as to cause alarming symptoms of suffocation, since the tissues soon become caught by the diffuse, malignant infiltration. This form of malignant tumor occurs in young people, and is often mistaken for acute thyroiditis. It is often impossible to differentiate it clinically from woody thyroiditis. In the latent form the gland is hardly modified in form, size, and con- sistency, but numerous metastases are found in the lungs, bones, etc. The thyroid origin of such metastases is usually discovered at autopsy or when the microscopic examination happens to be made from a lump removed bv operation. This form of malignancy is rare. Usually the development of malignant tumor follows the subacute type. It occurs in patients who previously had goiter, winch may haw- been stationary for years. Some day, however, without any apparent cause, it begins to enlarge and to grow with comparative rapidity. It soon interferes with respiration, the voice becomes rough, harsh and 176 CLINICAL ASPECT OF MALIGNANT GOITERS rapidly bitonal; deglutition is slightl)/ difficult; shooting pains especially toward the ear and along the cervical and brachial plexuses are complained of. Little by little the limits of the goiter are less sharply outlined; the tumor becomes adherent to the muscles and other neighboring tis- sues (Fig. 53) and grows downward toward the mediastinal space. The goiter loses its previous softness and becomes hard. This is a symptom of great diagnostic value. Gradually respiration becomes more difficult, a barking cough is frequent, and paroxysmal choking spells soon dominate the scene. These suffocating spells are always horrifying to witness. The face and neck are congested; the veins are dis- tended; the eyes protrude, and the patient makes desperate efforts to get his breath. His hands massage his neck as if he were trying to remove the pressure. The choking spells suc- ceed one another, and gradually the tracheostenosis grows tighter (Fig. 52), the tracheobronchial catarrh becomes more and more tenacious, and finally the end comes. Percussion, auscultation, ;c-ray, and laryngoscopic examination will give the same information as that of intra- thoracic goiter. On the anterior and superior por- tion of the thorax when the malignant tumor has already progressed beyond a certain degree, there is a collateral circulation, showing that the return flow of blood toward the heart is impaired. At the same time edema of that entire region may be present, and especially when the superior vena cava has been involved. Sometimes one may run across a cancer of the thyroid in which pulsations synchronous with the heart beat are distinctly perceived, so much so that one thinks of an aneurysm. This is due to the fact that the veins of the thyroid, being thrombosed to a more or less extent, the return flow of blood is greatly impaired, and the impact of each new arterial arrival of blood is strongly transmitted through the congested and solid tumor. This form of cancer is called aneurysmal cancer (Figs. 54 and 55). Dysphagia is among the first symptoms to betray the presence of cancer of the thyroid. Not infrequently this compression is accom- Fig. 53. — Malignant goiter beyond operative stage. COURSE AXD SYMPTOMS 177 panied by spasm of the esophageal musculature. In such conditions, the swallowing of liquids, especially when cold, is as difficult as the deglutition of solid food. Compression of the inferior laryngeal nerves, of the vagus and espe- cially of the sympathetic is frequently seen in malignant tumors of the thyroid. Symptoms caused by the injury of each one of these nerves have been studied when describing intrathoracic goiter, consequently, there is no need to go over them again. Not infrequently patients complain of intense neuralgia in the arm, fingers, and occipital region of the side corresponding to the tumor. These shooting pains are due to compression of the cervical and brachial plexuses. Fig. 54. — Malignant vascular Fig. 55. — Two weeks after goiter. operation. Metastases must be carefully looked for; they may be found, or at least suspected, especially in the skeleton and lungs. The blood formula in malignant tumors of the thyroid does not differ in any way from the one found in malignant tumors of other organs. Symptoms of thyroid insufficiency in connection with malignant degeneration of the thyroid are not so frequent as one would expect. The reason for this is mostly because the entire gland is seldom involved. There remains nearly always enough gland to meet the physiological requirements. And then, too, we know that malignant cells of the thy- roid have not lost their physiological properties: they are still capable of normal function. 12 ITS CLINICAL ASPECT OF MALIGNANT GOITERS Symptoms of hyperthyroidism, as tachycardia, tremor, even exoph- thalmos, have been noticed quite frequently in connection with malignant tumors. Diagnosis. — When no tumor is seen in the cervical region, diagnosis is difficult. In that case all the symptoms discussed in the chapter on Intrathoracic Goiter must be searched for. Diagnosis of a malignant intrathoracic accessory thyroid gland is seldom thought of. In differential diagnosis between tuberculous lymph nodes, malignant branchioma, can- cerous lymph glands symptomatic of cancer of the esophagus, pharynx, or even stomach, aneurysm of the aorta will have to be discussed. Too often, however, the true diagnosis becomes patent only at the operation. Very much easier is the diagnosis of malignant degeneration of the thyroid gland when a tumor is present in the cervical region. In that case we have to deal with a patient who has had a goiter before, and which may not have given him any trouble thus far. Some day, how- ever, without any apparent reason, the goiter begins to grow rapidly, and soon interferes with respiration and deglutition. Note, furthermore, that the patient is of middle age, that perhaps it is a woman undergoing menopause. Note, too, that the goiter has lost its softness, and has become irregular in surface and peculiarly hard in consistency. This is enough to warrant a diagnosis of malignancy. If we add to this, that the goiter has lost its sharp limits, that shooting pains are present, that the inferior laryngeal nerve has become involved, then the diagnosis of malignancy becomes more or less certain. Rapid increase in volume of a goiter, which has remained inactive for a long time, and changes in its consistency, are two excellent signs of malignant degeneration. What is true of the uterus is true, too, of the thyroid. If after menopause has taken place, a uterus which has remained in a quiescent state for some time, begins without apparent reason to bleed, the chances are great that we have to deal with a malig- nant degeneration of that organ. The same is true of the thyroid. If a goiter, after a period of apparent inactivity, begins to grow, we must be on the lookout for every symptom tending to betray the malignancy of such a change. Hemorrhages taking place at different intervals in a goiter might convey the impression that some malignant changes are taking place in that goiter, as there, too, we shall find a rapid increase in volume, hard- ness in consistency, slight diffuseness of its limits, shooting pains, slight temperature, etc., but further development will very soon show (in a few days) which one of the two conditions (hemorrhage or malignancy) we have to deal with. Actinomycosis, tuberculosis, and syphilis might cause the same, but these conditions are far more rare than malignant degeneration. The woody thyroiditis spoken of in the chapter on TREATMENT 179 Strumitis might be mistaken for a malignant degeneration, but the mis- take will be only beneficial to the patient, as an early operation may save his life. Differential diagnosis between carcinoma and sarcoma of the thy- roid is not always easy. Sarcoma, as a rule, grows more rapidly, reaches larger dimensions, is softer and has a smoother surface than carcinoma. In sarcoma the skin is less adherent and its limits are not quite as diffuse as in cancer. Treatment. — There is only one treatment — the knife. All the other means are palliative measures only, and all are disappointing. Even the "knife" does not always fulfill its promises; we might even say that it seldom does. Let us hope, therefore, that the time is not far distant when biological chemistry will give us an easier and more effective measure than surgery, capable of curing this terrible disease. Vv hy is it that cancer of the thyroid as well as cancer of other organs has been for so long considered beyond surgical reach ? Simply because all these cases are operated too late, hence disastrous immediate results; hence high mortality. We have in late years learned to know that cancer can be fought with some chances of success if it is operated early, namely, before the capsule of the gland has been invaded, before the veins have become thrombosed, and before the lymphatic glands have become involved. When the neoplasm is so encapsulated that it has not yet spread outside of its capsule, and consequently, has not involved the neighboring tissues, the chances for a happy outcome are good; at least, we can hope that the patient will enjoy a comfortable and peace- ful life for a year or two before any relapse occurs. Even that gain, though short, is it not worth our utmost efforts ? Life is not so long after all that we should squander it lavishly. We can properly say that the outcome of a cancer case lies within the power, not of the surgeon, but of the family physician. He is the one who sees these cases first; he is the one to treat them for months and months for simple goiter, before he realizes that something very serious is undermining his patient. He is the one who should conse- quently be educated to know such conditions, to differentiate them, and to make a very quick decision when once his doubts have been aroused. Every physician should always have in mind the possibility of a cancer in connection with any rumor. This possibility should haunt his brain in every case: he should be a "cancero-maniac." The satisfied and dangerous optimism which is too often found, and which unfortunately too frequently finds its excuse in ignorance, should be discarded ami replaced by an alarming pessimism. In that start' of mind, the physician will be able to catch the significance of any slighr physical change in the tumor, the meaning of any apparently slighr and insignificant s\ mp- 180 CLINICAL ASPECT OF MALIGNANT GOITERS torn. Too often, indeed, these little prodromic symptoms are not paid enough attention, yet they exist. It is for us to train our senses to perceive them, and to utilize them for early diagnosis. Cancer, as a rule, does not appear like a thunderbolt in a clear sky, nor does a vol- cano emit its devastating lava without betraying its intentions by some previous uneasiness, some premonitory, earthly rumbling. To be sure, sometimes the early development of a cancer is insidious; in that case we are powerless. Then, too, the patient is too often guilty of an unpar- donable negligence against which he should have been educated. Can- cer is one of the few conditions in which it is not necessary to wait until diagnosis is certain. Suspicion is enough to warrant surgical interven- tion. When we have to deal with a patient of middle age whose goiter, without any apparent reason begins to grow, to cause some shooting pains, to become hard, especially if this patient is a woman about the time of menopause, why wait until the entire cervical region has become as hard and rigid as a board, until the patient is choking to death, in other words, why wait until it is too late to operate ? In a great many such cases an early operation, even when the diagnosis of cancer is still uncertain, will strike the neoplasm in its embryo, so to speak, and cure the patient. Even if an operation should be performed for a condition, which, later on, proves not to be malignant, no harm will be done, as the patient will be relieved of his goiter, and may be saved from a future malignant degeneration of that tumor. Expectation and procrastina- tion can only be fatal. They allow the newly starting neoplasm to reach a stage beyond which the words of Dante sound like a terrible condem- nation: "Lasciate ogni speranza voi ch' . . . . Lose all hope, you who . . . ." In operations for cancer of the thyroid large incisions must be used. The surgeon must be able to have a good view of the field, and an easy access to the organs. There is no need to increase the difficulties of the operation by a narrow incision. Cosmetic results are of secondary importance. If the neoplasm is still within the capsule and has not reached it, the operation will be a simple one; it will not offer more difficulty than the ordinary goiter. If, however, the malignant tumor has invaded the capsule and the neighboring tissues, the operation becomes extremely difficult. It may necessitate large sacrifices, as the resection of the internal jugular vein, the common carotid, the sympathetic and vagus nerves. The windpipe and esophagus may be so adherent as to necessi- tate their partial resection. The lymphatic glands and the tumor itself may extend so deep behind the sternum as to render a radical operation impossible. In such conditions the immediate results are disastrous; the mortality is very high, and, according to the statistics of Brown- TREATMENT 181 Potter, in 1900, the total mortality for thyroid operations for cancer varied between 72 and 85 per cent., according to the stage of the devel- opment of the cancer. In such conditions not infrequently relapse of the tumor is noticed already a few days after operation. In the most favorable cases, however, relapse occurs only two or three years after; exceptionally it may not appear at all, as in the cases of Roux and Kopp in which relapse had not occurred six years after an operation for a cancerous goiter in which a partial resection of the trachea had proved necessary. In 1900 Madelung reported 100 cases of malignant tumor of the thyroid; 59 times death followed the first month after operation; 39 times relapse occurred in the sixth month after operation while in the 2 remaining cases death occurred later. When the malignant degeneration involves both lobes, and when the necessity of a complete removal of the tumor subsists, the surgeon must not hesitate to sacrifice the entire gland regardless of the myxedematous consequences. Between the two evils, better choose the lesser one. Myxedema, if it does occur, can be easily taken care of by thyroid opotherapy. On the other hand, total thyroidectomy does not neces- sarily expose the patient to hypothyroidism, because accessory thyroid glands may be present which may be capable of supplying the deficiency of the removed thyroid. Sometimes unsuspected metastases may be present; we know that such metastases are physiologically active, as illustrated by the well-known case of von Eiselsberg's. Concomitant unilateral resection of the internal jugular, of the common carotid, of the sympathetic and vagus nerves, with the tumor seems to be without importance so far as the postoperative course is concerned. When the malignant degeneration has spread throughout the entire cervical region, and when the cervical organs have become embedded in a hard, diffuse, cancerous gangue, no relief should be expected from surgery. The patient has to be more or less abandoned to his fate; at the most, relief may be sought through some palliative treatment. Among the most important of these palliative forms of treatment are x-ray, radium and tracheotomy. Tracheotomy has proved extremely disappointing, so much so, that there are surgeons who prefer to let their patients die their own death. Such views are to a certain extent warranted, because tracheotomy 111 such conditions is an extremely difficult operation. The veins art- enlarged and dilated; the skin is infiltrated; the cancerous mass sur- rounding the trachea is thick, hard, and non-clastic; the trachea itself is compressed, displaced, invaded by the tumor and rendered hardly recognizable (Fig. 52). Add to this, that the patient is choking, that the operation must be done quickly without anesthesia, vou will then 182 CLINICAL ASPECT OF MALIGNANT GOITERS understand why a surgeon might hesitate before attempting trache- otomy. Such difficulties, however, should certainly never deter a sur- geon worthy of the name, if the results expected from such an interven- tion are thought likely to be satisfactory. But as said before, results are very disappointing. A great many patients die during the operation, a great man)' others die a few hours after, and many of those who sur- vive, die a few days after, either because compression of the windpipe takes place low in the thorax, or because bronchitis or broncho- pneumonia follows. When dysphagia is very marked, feeding of the patient must be done with an esophageal canula. Gastrostomy may become necessary. HYPOTHYROIDISM— MYXEDEM A. Synonyms. — Cachexie pachydermique; Cachexia Thyroidea; Cachexia Thyreopriva, or Strumipriva. In 1875 William Gull reported to the Clinical Society of London 5 cases of a disease characterized by a swelling of the skin, and a more or less complete apathy of the patient. The title of his paper was, "A Cretinoid State Supervening in Adult Life in Woman." {Clinical Society Transactions, Vol. 7.) William Ord, in 1877, published 6 other new cases which he called myxedema on account of the edematous infiltration of the skin. Char- cot, in 1879, reported other cases, and called the disease, "cachexie pachydermique." All the cases reported up to this time were found in women only. Savage, in 1880, was the first to report a case of myxedema in the male. In the same year Madden called attention to the fact that in myxedema an atrophy of the thyroid gland was constantly present, but he did not see any etiological relation between these two conditions. He thought that atrophy was due to a vasoconstriction of the gland itself. At about the same time Kocher, of Berne, and Reverdin, of Geneva, called attention to the results supervening after complete removal of the thyroid gland. Kocher gave to the clinical syndrome resulting from complete thyroidectomy the name of Cachexia Strumipriva; Reverdin called it Operative Myxedema. The Kocher-Reverdin Controversy. — The publications of Kocher and Reverdin, appearing so nearly at the same time, have given rise to a long discussion as to whom the priority of the discovery really belongs. As the subject, so far as I know, has never been threshed out in Eng- lish medical literature, and as it seems only just to give to each the credit to which he is entitled, I think it will be of interest to go to the bottom HYPOTHYROIDISM— MYXEDEMA 183 of this controversy. The medical public shall be the judge. Here are the facts : i. In 1874 Kocher published a case in which after total extir- pation of the thyroid, psychic and physical disturbances followed. In reporting the case in his "Pathologie et Therapeutique du Goitre," pub- lished in the Deutsche Zeitschrift filr Chirurgie, Kocher said, "The future will show if relations exist between total extirpation of the goiter and the subsequent status of the patient, and what their nature will be." 2. On the 7th of September, 1882, while going to Geneva to attend the Congress of Hygiene, Kocher happened to meet Jacques L. Reverdin. Their conversation naturally drifted to surgical matters, and among them, goiter surgery. When asked by Reverdin if he had noticed anything out of the ordinary after his goiter operations, Kocher said that he had seen one of his patients sink into a marasmic condition similar to cretinism, and that he was endeavoring to find the cause of such conditions, as it might prove of great importance so far as surgery of goiter was concerned. 3. Six days after this conversation Reverdin made a short com- munication to the Medical Society of Geneva which I shall transcribe in extenso: Out of 14 operations for goiter there were 3 deaths, one from pneumonia, one from nervous symptoms, and the third, a malig- nant goiter, from suffocation. In patients who recovered, Reverdin noticed two or three months after the operation, weakness, paleness, and anemia; two of them showed an edema of the face and hands with- out albuminuria. In one patient the pupils were contracted; this patient had a dejected appearance, and his face became similar to that of a cretin. In the majority of patients this condition took a long time before disappearing, and in three of them this condition was still present after one year. Reverdin mentioned the fact that nobody had described such a condition before, but that Kocher a few days ago had told him that he had observed one similar case. "Is this condition,'''' asked Rever- din, "due to traumatism of the sympathetic nerve, or to disturbances of the thyroid gland in its hematopoietic function?" On account of such results Reverdin states that he has modified his technic. He used to perform total thyroidectomy when this was possible; now he saves a portion of the capsule of the gland. In one case where one lobe only of the thyroid had been removed, no secondary symptoms followed. 4. On the \th of April, 1883, Kocher reported the results of 101 operations for goiter at the Surgical Congress of Berlin. In tins com- munication Kocher gave a masterly description of a condition which he called cachexia thyreopriva. This description based on about 30 cases of cachexia thvreopn va was so completely and so clinically true that nothing of importance has been added to it since. Not only did Kocher 184 CLINICAL ASPECT OF MALIGNANT GOITERS give a full clinical description of that condition, but he also went a step further and recognized as an etiological factor of the disease, total thyroidectomy, and that physical as well as psychic disturbances seen in patients were due to a lack of thyroid function. With his marvel- lous and exquisite clinical sense, he claimed that there was a direct relation between thyroid insufficiency, cretinism, and idiocy. 5. On the 15th of April, 1883, namely, 11 days after Kocher's paper at the Surgical Congress of Berlin, Reverdin, in the Revue Medi- cate de la Suisse Romande, began the publication of an article which was continued in the same journal on the 15th of May, 1883, and again on the i$th of June, 1883. These publications have since been united in one fascicule with the date, "April 15th, 1883." on the cover. This fact might mislead the judgment of the reader who is not aware of the combination of articles appearing in three different successive months and given the date of the first article. I shall summarize these three articles. 6. In the first portion of the article in the Revue Medicale of the 15th of April, 1883, his first article, Reverdin discusses the etiology and symptomatology of goiter, and their relations to the neighboring tis- sues. Then follows the report of 9 operations for goiter. In Case 8, a few months after total thyroidectomy, this eminent surgeon noticed an edema of the face and hands, loss of strength, and dejected appear- ance. The other cases in which total thyroidectomy had been performed, and which survived, were all reported as being in excellent condition. No other reference to myxedema was made. 7. In the Revue Medicale de la Suisse Ro?nande of the 15th of May, 1883, his second article, Reverdin adds the report of 13 other cases, making 22 in all, of goiter operations. In the foureenth case which had undergone total thyroidectomy, Reverdin was told by the family that the patient had lost strength and had swollen face and hands. As Reverdin saw this patient only from afar on the street, he could not control the truth of such statements. However, in April, 1883, when revising his cases, Reverdin did see him, and then the patient had com- pletely regained his health. In Case 16, soon after total thyroidectomy, tetany occurred, which Reverdin considered as a symptom of hysterical origin. (At the time the real significance of tetany was not known.) Some time after the operation the patient became afflicted with "troubles bizares." He gave no other description of these symptoms. Thus out of 22 operations, 17 were total extirpations; 2 deaths occurred; 3 cases showed some peculiar symptoms which we know now were of myxedematous origin; all the other cases were reported in excellent condition. Summing up the results of his operations, Reverdin concluded the H I r P0 TH I r ROIDISM—M I 'X EDEMA 185 article of May 15, 1883, in the following manner: "Total extirpation of the thyroid in goiter presents great advantages. It prevents relapse; when the gland presents several nodules of colloid or cystic nature, if the larger ones only are removed, the other small nodules are bound to grow, hence relapse of goiter. Total extirpation becomes a necessity when a diffuse, parenchymatous degeneration involves the entire gland. In such conditions partial thyroidectomy is not practicable. When the entire gland is pathologically involved, and when the condition of the patient does not warrant total extirpation in one sitting, total extirpa- tion of the gland must be made in two sittings. Another advantage of total extirpation is to leave a large, clean cavity which heals up more readily than the one left by partial thyroidectomy. In the latter condi- tion mortification of the glandular tissues left prevents prompt healing. On the other hand, total extirpation is more dangerous than partial thyroidectomy because the inferior laryngeal nerves are more easily injured." On page 273 of the same article of the 1 5th of May, 1883, when speak- ing of partial extirpation of the thyroid, Reverdin says, "Partial extir- pation of the thyroid is not a method of choice, but a method of neces- sity." In Case 19 Reverdin decided to perform a partial thyroidectomy because of the condition of the patient and says, "One might be driven against his will to perform a partial thyroidectomy. In conclusion when it is possible, total extirpation is certainly better so far as relapse is concerned; however, there may be cases in which prudence may oblige the surgeon to choose partial thyroidectomy before or even during operation." The great advantage as seen by Reverdin in partial thy- roidectomy is to diminish the chances of injury to the inferior laryngeal nerves. No reference whatsoever to myxedema. 8. In the Revue Medicale de la Suisse Romande of the 15th of June, 1883, his third article, Reverdin deals at length with the results of thyroidectomies, giving supplementary information of Cases 8, 10, 11, and 14, which are cases in which myxedematous symptoms occurred after total thyroidectomy. (Why was such supplementary information not given before with the report of the cases, if such cases were really intended at the time to serve as the clinical working material from which the description of operative myxedema was to be derived?) In the same article Reverdin admits having read the resume of Kocher's communi- cation to the Surgical Congress of Berlin on the 4th of April, [883, and then gives a splendid description of the condition which he calls Oper- ative Myxedema. In that article he clearly establishes the analogy exist- ing between spontaneous myxedema of the adult and that following total extirpation. On the other hand, contrary to his previous state- ments, made four weeks before in the Revue of the [5th of May, 1883, 186 CLINICAL ASPECT OF MALIGNANT GOITERS Reverdin concluded finally that a partial thyroidectomy should be per- formed whenever it is possible, reserving total extirpation of the thyroid for cases in which it cannot be avoided. Such are the facts and such are the data in which these various events occurred. From them we can draw the following conclusions: i. Already in 1874 Kocher had been impressed by the peculiar physical and psychic conditions shown by his completely thyroidec- tomized patient. He did not at the time, however, recognize their true nature and origin. 2. When Reverdin and Kocher met on the 7th of September, 1882, and exchanged privately their views on goiter surgery and espe- cially on its remote consequences, we can assume from what both said, that each one of these illustrious surgeons was becoming aware of the fact that a certain curious and peculiar condition developed after opera- tions for goiter, but neither one seemed at the time to have recognized its true significance. 3. The only official document on which Reverdin can possibly base his claim to priority of the discovery of myxedema is the short communication which he made to the Medical Society of Geneva on the 13th of September, 1882, and which has been reviewed above in extenso. Since then all that Reverdin wrote on that subject was pos- terior to what Kocher said on the \th of April, 1883, at the Surgical Con- gress of Berlin, and is consequently of no avail so far as priority is concerned. 4. In examining attentively Reverdin's report made at the Medical Society of Geneva on the 13th of September, 1882, and which has been transcribed above, we can draw the two following conclusions: (a) The few remarks made by Reverdin cannot possibly have the pretension of a description of the disease as he mentions only, "the edema of the hands and face without albuminuria," and in one case, the "cretinoid appearance." Others had called attention to this condition a long time before him. Gull, for instance, in 1873, and William Ord, in 1877, who called that condition myxedema, and Charcot, in 1879, who created the denomination pachydermic cachexia. (b) He did not see clearly that thyroid insufficiency was the etiologi- cal factor of myxedema. He did not know whether the gland or the sympathetic system was to blame. 5. After his report of September 13, 1882, Reverdin continued, nevertheless, to perform total extirpation of the thyroid. His last was performed on November 17, 1882, namely, over nine weeks after his communication to the Medical Society of Geneva. It is to be regretted that Reverdin did not give the reports of all his cases of thyroid opera- tions up to the time of his publication on April 15, 1883, as Kocher did HYPOTHYROIDISM— MYXEDEM. 1 187 up to April 4, 1883. On the other hand, Kocher, too, performed a complete thyroidectomy on November 27, 1882, and another one, his last, on January 16, 1883. From these facts what logical conclusions can we draw? Simply that at that time neither one had realized the exact significance of the disturbances seen after total extirpation of the thyroid. Kocher discovered their real meaning only when in January, February, and March, 1883, he reviewed his thyroidectomized patients and saw the results. So far as Reverdin is concerned, if he had discov- ered the real significance of total thyroidectomy and its direct relation to myxedematous symptoms, he could never have written what he did in the Revue Medicate de la Suisse Romande, May 15, 1883, namely, that total extirpation offered great advantages, and that partial thyroidec- tomy was not yet a method of choice, but a method of necessity. (See above.) Yet four weeks after, on June 15, 1883, in the Revue Medi- cate de la Suisse Romande, Reverdin says just the opposite. In his judgment, partial thyroidectomy should be given the preference, and total extirpation of the thyroid should be practised only when for some reasons it becomes necessary. Why such a sudden change? Out of Reverdin' s 22 thyroidectomies, 3 cases, possibly 4, showed unmistakable myxedematous symptoms. All the other cases were reported, in excellent condition. Without injustice it can be said that there is certainly a disproportion between this meager clinical material to work with, and the splendid clinical description of operative myxedema given by Reverdin on June 15, 1883. When once Kocher became convinced that myxedema was the result of total extirpation, he remained consistent with his conclusions. He never practised complete thyroidectomy again, and never advocated it under any circumstances except in malignancy. He gave his masterly description of myxedema which holds true today, and finally drew up the rules which in thyroid surgery have been the guide of each succeed- ing school of surgeons ever since. To posterity the name of Kocher will always be intimately associated with the thyroid subject, and to him belongs the credit of having, so to speak, discovered myxedema and its true significance. It would be unfair, however, not to give Reverdin justice and honor, as he certainly did suspect a part of the truth inde- pendently, and perhaps would have seen it all had he not been antici- pated by Kocher. At any rate, his work, coming so soon after the one of Kocher, gave Kocher's conclusions more strength, and was certainly of great help in convincing the surgical public of the dangers ot total thyroidectomy. Etiological Relationship between the Various Forms of Hypothyroidism. —If we compare the different forms of hypothyroidism, we shall see that there is between them an undeniable relationship, and despite 188 CLINICAL ASPECT OF MALIGNANT GOITERS the fact that sometimes notable differences exist between them, their etiological origin is one, namely, a diminished, or a suppressed thyroid function. Consequently, these different forms of hypothyroidism are only varieties of the same disease. Let us consider, for instance, operative and experimental hypothyroidism. In these forms the thyroid has been entirely removed. The results of this total thyroidectomy in human beings as well as in animals are the same: the metabolism is greatly disturbed; a myxedematous infiltration of the skin takes place; the nervous system is deeply affected, and the intelligence is considerably reduced. If thyroidectomy has been per- formed in young animals, the growth of the skeleton and the develop- ment of their central nervous system are affected. In short, we have a complete physical as well as psychic degradation of the individual. In adult hypothyroidism, too, the symptoms are so strikingly similar to the ones found in operative and experimental myxedema that it is impossible not to see between them a close relationship. Since the cause of operative and experimental hypothyroidism is the loss of the thyroid's function, the same etiology is found in adult hypothyroidism; the differ- ences between them are only differences of degree. In operative and experimental hypothyroidism, as the thyroid has been abruptly and com- pletely surgically suppressed, the clinical symptoms are very much more acute and rapid, whereas in adult myxedema where the thyroid has undergone a slow process of atrophy and degeneration, the symptoms are chronic and slow; ultimately, however, the results are the same, namely, a well-characterized hypothyroidism. Consequently, from an etiological point of view, operative and adult hypothyroidism can be identified. The first one is caused by the sudden, the second, by the slow suppression of the thyroid function. Suppose, now, that we go a step further and consider infantile myx- edema. At the first glance, between this form of myxedema and the adult one, the differences are great, since in infantile myxedema we have an arrest in the intellectual development, namely, idiocy, and an arrest of physical development, namely, nanism. These two symptoms give to infantile myxedema a physiognomy of its own which is not found in adult myxedema. Consequently, at a superficial survey, these two diseases seem to be entirely different, yet if we go back to what we see in experi- mental or operative myxedema we shall see that the relationship between these different forms is a close one. Hoffmeister and von Eiselsberg, after performing complete thyroidectomy in newborn rabbits, sheep, and goats, observed, besides the symptoms of myxedema usually found in adults, an arrest of physical development characterized by nanism and an arrest of intellectual development characterized by idiocy. Complete thyroidectomies performed in young children between eight and ten HYPOTHYROIDISM— MYXEDEMA 189 years of age, as reported by Bruns, Kocher, and Combe, give the same results. Consequently, we must conclude that these different forms of myxedema recognize the same etiology, and that the differences which exist between them are only due to the fact that in children the loss of thyroid function occurred at a time when the physical and intellectual growth were in the making: hence, nanism and idiocy. The sooner after birth the loss of thyroid function takes place the more marked will be the thyroid insufficiency. What about endemic cretinism? There, too, as we shall see later in the etiology of that disease, the condition is caused by thyroid insuffi- ciency aggravated by a noxious condition of endemic origin, which most probably exerts its nocive influence on the thyroid and on the entire organism not only during fetal life, but also through generations, so that, hereditarily speaking, that thyroid gland is normally below par. We may then conclude that operative, adult, infantile hypothyroidism and cretinism have the same relationship between them; they are only degrees of the same disease. The good results obtained by thyroid opotherapy in every one of these conditions corroborate these views. What is of importance is not so much the presence or absence of the thyroid but its loss of function, and especially the period of development at which the thyroid ceased to functionate. Nomenclature. — The denomination "cachexia thy reopriva," or "cach- exia strumipriva," given by Kocher, is a far better one than "myxe- dema," as the latter evokes in the mind one symptom only, namely, the mucinoid infiltration of the skin. It was adopted at a time when noth- ing was known of the etiology of the disease, and when the condition of the skin was the most striking symptom attracting the attention of observers. Furthermore, we know that in myxedema mucinoid infiltration of the skin is not always present. Consequently, this denomination is, strictly speaking, defective, yet it has become so common in the medi- cal literature and has acquired such a stronghold that it would be diffi- cult to change it. On the other hand, if the denomination "cachexia thyreopriva" stands on a solid etiological basis, it nevertheless does not fulfil all the requirements, as it applies only to those forms of myxedema where the gland is absent. It does not apply to these cases of function- all)' insufficient thyroid glands. Consequently, this denomination, too, is insufficient. If one reads the medical literature on myxedema, one cannot but be astonished at the great number of synonyms invented to designate the same thing, as "cretinism," "idiocy," "idiocy with pachy dermic cach- exia," "cretinoid pachydermia," "cretinoid myxedema," "myxedema- tous dystrophia," "infantile myxedema," "myxedematous infantilism, 190 CLINICAL ASPECT OF MALIGNANT GOITERS "spontaneous infantile pachydermic cachexia," "atrophic cretinoid myxedema," "pachydermic cachexia," etc. To the reader who is not familiar with all these matters, these different denominations are most confusing. Each one of these denominations seeks to set forth the side which struck most forcibly the mind of the observer who invented it, but none of them stands on a solid physiological and etiological basis. It seems to me that, as we know today, all those various and differ- ently designated forms of diseases have a common origin, namely, absence or insufficiency, or inefficiency of the thyroid function, it would be much more rational, clear, and simple to classify them as follows: I Surgical. i ._ , • i I. Athyroidism. L, • . I Or cachexia thyreopriva. | Or cachexia strumipriva. These denominations would apply to cases in which the thyroid has been surgically totally removed or is congenitally absent. II. Hypothyroidism. Surgical. ( r r -i n lnrantile. Spontaneous. < . , . 1 { Adult. ~ I Infantile, rruste. < . •. Adult. These would apply to cases in which the thyroid gland, although partly or even entirely present, has become functionally insufficient, as after partial or total thyroidectomies, or where the thyroids are degenerated, etc. TTT „ . . - J Endemic. 111. Cretinism. < r .. ( Sporadic. By endemic cretinism we understand the peculiar forms of thyroid insufficiency found in connection with endemic goiter. By sporadic cretinism we mean that condition of cretinism which occurs in regions where goiter is not endemic. CHAPTER XI V. PATHOLOGY OF THE VARIOUS FORMS OF THYROID INSUFFICIENCY. Thyroid. — For a long time the etiological relation between the con- dition described as myxedema and the thyroid was not recognized, but after the researches of Ord, Olive, Schiff, Kocher, and Reverdin, it became known that an absolutely sine qua non condition for the develop- ment of myxedema was a lesion of the thyroid. This is so true that the English Commission appointed in 1884 to study the etiology of myxe- dema concluded that the only lesion which was constantly found in that disease was thyroid atrophy. "Without lesions or absence of the thyroid, no myxedema," says Kocher. Hypothyroidism is a result of hypofunction of the thyroid either because the gland is partially or totally absent or because it is degenerated. At any rate, in hypothy- roidism, the thyroid is never normal. In some cases of congenital athyroidism, microscopic examination shows no vestiges of the gland whatsoever. In such cases we have to deal with a congenital defect. An inflammatory process which would have destroyed the thyroid alone is hardly probable. This is evidenced by the fact that no traces of inflammation are discovered, and by the fact that the parathyroids are found absolutely normal. Indeed, if we remember how closely the parathyroids are related to the thyroid, and if we were to suppose that athyroidism were due to an inflammatory process, then the small parathyroid bodies would no doubt show some sympathetic symptoms, either clinically or microscopically. Such, how- ever, is not the case. The parathyroids are always found normal. This fact proves, furthermore, that the parathyroids embryologically develop independently of the thyroid gland and that their presence does not prevent hypothyroidism from taking place. In some cases, however, it seems reasonable to admit that some toxic infectious influences have brought about the condition of athyroidism. In the great majority of cases of hypothyroidism, however, the thy- roid is present. A mass of sclerotic connective tissue takes the place of what was gland before; it is hard and of a yellowish color. The epithelium of the alveoli is degenerated, and a thick colloid is present. Von Eiselsberg found in counting the number of cells of the alveoli, that they were greatly reduced in number and size as compared to the cells 192 VARIOUS FORMS OF THYROID INSUFFICIENCY of normal follicuh. Langhans believes that the gland has undergone an interstitial inflammation with leukocyte infiltration and endarteritis. The process, in his judgment, resembles the one seen in cirrhosis of the liver. In Stilling's case the entire gland had undergone a fatty degen- eration and was represented by a mass of fat; the thyroid arteries were not present. In certain conditions the connective-tissue degeneration of the gland is so thorough that scarcely any traces of that organ can be found. Such cases might be mistaken for congenital athyroidism. Most probably the cases reported by Maresch, McCollum, and Fabian belong to that class. In cases regarded clinically as congenital athy- roidism, the presence of alveoli in the connective tissue of the cervical region have been detected microscopically. In many cases of hypothyroidism and cretinism the thyroid, instead of being absent or atrophied, is, on the contrary, enlarged, but degener- ated. In cretinism we can say that in 25 per cent, of the cases the thy- roid is absent or atrophied, and in 75 per cent, of the other cases the gland is enlarged and degenerated. Microscopically, the acini are poorly developed, the normal elements of the gland are reduced and atrophied, and an intense colloid degeneration has taken place. As a rule, besides the degenerated portion of the gland, other parts are present which appear to be entirely normal. H. Vogt claims that a number of cases of cretinism have been found in which the thyroid was absolutely normal, and Bircher, examining the thyroid glands of 16 cretins, found the majority of them mostly normal. Skin. — The infiltration of the skin with a mucine-like substance is a feature which is bound to strike the attention of the observer. It is to that condition that the disease owes its name, myxedema. A marked hypertrophy of the connective tissue of the chorion is present while the sebaceous and sudoriparous glands are atrophied. The connective tis- sue has an embryonic character; its fibers are dissociated, forming spaces in which a substance very rich in mucine is present. This semifluid substance filling up the interstitial spaces gives the entire skin a trans- parent appearance. The question whether this substance is really mucine or not is not yet settled. According to Halliburton, the quantity of mucine is fifty times larger than normally. On the other hand, Prud- den in the majority of his cases did not find mucine. Some authors seem to think that the infiltration of the skin is not of mucinoid origin, but that it is due to an ordinary edema localized in the most superficial layers of the skin, hence the reason why this edema does not pit on pressure. Microscopically, the connective fibers of the chorion have a gelatinous aspect and are swollen. The lymphatic spaces are enlarged, and the nuclei of the endothelial walls voluminous. The majority of authors consider this process as a return to the embryonic stage. How- OSSEOUS SYSTEM 193 ever, Virchow does not share this view. He believes that instead of being regressive, this process is an irritative one, similar to the one seen in phlegmasia alba dolens, and elephantiasis. It resembles a granu- lation tissue containing an increased number of fibers and nuclei, and partlv infiltrated with an amorphous liquid of more or less mucinoid appearance. Ewald considers myxedema as a trophic disturbance and a degeneration of adipose tissue. Osseous System. — In congenital athyroidism and spontaneous infan- tile hvpothvroidism one of the most striking pathological findings is the retarded growth of the osseous system. Periosteal, as well as endo- chondral ossification, is extremely retarded. The epiphyses remain thin and cartilaginous. Cases have been seen where ossification was not completed at the forty-fifth year. The marrow of the bones shows a considerable fattv degeneration. These disturbances are so constant that thev may be considered as typical of congenital athyroidism, con- genital hypothyroidism, and cretinism. The perichondrium as com- pared to the normal one is very poorly supplied with bloodvessels; the osteoid tissues, too, are very poorly irrigated. In congenital athyroid- ism and spontaneous infantile hypothyroidism the bones remain so short that, after growth is supposed to be terminated, the patient is and remains a dwarf. The thickness of bones, however, is less affected than their length. That all these osseous disturbances are due to the fact that the centers of ossification do not appear in due time is easily demonstrated by the x-rays. In a ten-year-old child, for instance, no traces of ossification were found in the capitulum ossis Hamatum, when thev should have been present normally between the fourth and sixth months after birth. Dieterle has given a synoptical tableau showing when points of ossification appear normally in the various bones of the hand. This tableau is of great interest and help. It is as follows: ./:v. Ossification appears in Newborn Shaft of the phalanges, metacarpi, radius and ulna 4 months 5 6 7 " 8 12 i ', years 1 2 2 " Z\ " A " 3 " 13 Capitatum, I [amatui Body length. 50 cms. 60 cms. Epiphysis of the radius 75 cms. Basilar epiphysis ol the proximal phalanges Basilar epiphysis of the terminal phalanges ( )thcr basilar epiphyses 85 cms. 95 cms. ioo cms. VARIOUS FORMS OF THYROID INSUFFICIENCY Ossification appears in Body length. Os lunatum Multangulum majus and minus 108 cms. Os naviculare no cms. Distal epiphyses of the ulna 117 cms. 130 cms. Os pisiforme 135 cms. 194 Age. 3i years 4 5 Sh 6 7 8 9 10 11 12 13 " Sesamoid, hamulus ossis hamati 150 cms. 16-17 years Disparition of epiphyseal lines of ringers and metacarpi . 165 cms. 18 years 19 " > Disparition of all epiphyses 170 cms. 20 " 170-180 cms. Of course the pathological disturbances in the skeleton depend upon the time of life in which the thyroid insufficiency began to manifest itself; the sooner after birth the hypofunction of the thyroid takes place the more marked will be the disturbances in the osseous system. The pathological changes will be found mostly developed in the bones which were still cartilaginous at the time the thyroid insufficiency started to develop. For that reason the fibrous bones of the cranium are the least affected; they continue to grow to a certain extent while the development of the other bones is arrested, hence a disproportion between the head and the skeleton, and hence a macrocephalous on the body of the dwarf. The growth of the bones of the skull, however, is far from being normal; the large fontanelle remains open and synostosis of the cranial bones is considerably retarded. Kyphotic and scoliotic anomalies of the spinal column are quite frequent. Some authors, as Bourneville and Hertoghe, have claimed that in congenital athyroidism and spontaneous infantile hypothyroidism, deformation and retarded ossification of the osseous system were due to rickets. But in rickets we have to deal with an osteoporosis and a deficient calcification, whereas, in athyroidism and hypothyroidism, simply with an arrest of ossification. In rachitism the epiphyseal lines, instead of being linear, as in thyroid insufficiency, are irregular, and have a "saw-tooth" outline; furthermore, in rickets the appearance of the points of ossification is not retarded as in hypothyroidism, but takes place in due time. Nervous System. — Whitewell found in examining the brains of myxe- dematous patients that the nervous cells were irregular, their prolonga- tions reduced in number and their nuclei not staining as readily as the . GEXITAL APPARATUS 195 normal ones; vacuolization was present and neuroglia was increased. It seems that these pathological findings are not specific for hypothy- roidism inasmuch as they are also found in other pathological conditions. Nowhere in the central nervous system can alterations specific for hypo- thyroidism be found. Stud}' of the brains of cretins has not been done sufficiently to enable us to draw practical conclusions from it. Their weight has been found to van* between iooo and 1400 gms. Micro- scopically, nothing typical has been found. Vascular System. — Von Eiselsberg found experimentally atheroma- tous degeneration of the bloodvessels of thyroidectomized goats. The same results have been found clinically since. Very advanced athero- matous conditions of the large bloodvessels have been reported fre- quently in very young myxedematous individuals. Even amyloid has been found without apparent cause. Genital Apparatus. — -In congenital athyroidism, infantile hypothy- roidism, and cretinism the genital apparatus, as a rule, is not sufficiently developed; even if the cretin reaches an advanced age, the genital apparatus remains of the infantile type. Their genital capacity is nega- tive: "Nemo dat quod non habet." These congenital disturbances are, of course, in proportion to the degree of thyroid insufficiency, and with the period of life in which such insufficiency has taken place. In hypo- thyroidism of milder degree the genital apparatus is better developed. Such individuals are even able to procreate, although ordinarily, their offspring come into this world cretins, hydrocephalus, or dead. The hypophysis in cretinism and hypothyroidism has been reported from various sources as being pathological. Normally, its weight varies between \ and I gram, consequently all that is found above or below these figures may be considered as pathological. Rogowitsch and others found experimentally that the hypophysis after extirpation of the thy- roid underwent an hypertrophy. This was regarded by these authors as a vicarious function of the hypophysis toward the thyroid gland. Schonemann, however, did not confirm such views. In examining 112 hypophyses of goiterous individuals he found that the hypophysis was atrophied in direct proportion to the goiterous degeneration of the thy- roid gland. On the other hand, Boyce and Beadles, Bourneville and Bricon, Pisenti and Viola and Ponfick found that in cases of hypothy- roidism the hypophysis was hypertrophied. The alterations found in the hypophysis involve the anterior lobe of the gland only. Abnormal connective-tissue development, fatty or colloid degeneration, necrosis and Ischemia of the cells, diminution of then" number, distention of the little gland by a plasmatic fluid, all these pathological conditions may be found at the same time, or separately. Chromophil cells seem to be decidedly increased in number, are enlarged, and remind one of the cells with colloid degeneration. 196 VARIOUS FORMS OF THYROID INSUFFICIENCY The thymus has up to this time not been paid much attention. In a few cases, however, it was found hvpertrophied, as in Bayon's case. On the other hand, Pineles and Bernheim Kasser reported a hypo- plasia of the thymus in cases of congenital athyroidism; in that case the thymus was microscopically free from lymphocytes and Hassal's corpuscles, whereas the connective tissue was highly developed. This might be considered as a counter-balance of what we find in Basedow's disease, where the thymus is hyperplastic. Researches on pancreas, suprarenal bodies, and other glands of internal secretion have not yet been made. Surgical Athyroidism and Surgical Cachexia Strumipriva. — These conditions come on, as a rule, after total extirpation of the gland and may appear in a few weeks, months, or even a few years after thyroidectomy. Young people are much more markedly affected than old ones, and the pathological picture is more marked in cases of long standing than in those of more recent date. The clinical picture following total thyroid- ectomy differs according to the period of life in which the loss of thyroid function takes place. Symptoms. — At first the patient feels weak and tired. The lassi- tude following slight physical exertion is extreme, as shown for instance, by the patient of Reverdin's, who, although a great walker, could not, after having undergone total thyroidectomy, walk more than one or two miles without being completely exhausted. Pain and heaviness in the limbs, tremor of the extremities, a sensation of cold are the most usual complaints of such thyroidectomized patients. Their movements become slow and awkward; they lose their capacity for doing fine or precise work; they lose the coordination of their movements. If the patient is a barber he drops his scissors or razor unexpectedly; if a seamstress, she can no longer do fine needlework, etc. Naturally, this awkwardness reaches its maximum when the hands become edematous. At the same time the intellectual power diminishes; the memory becomes weak; speech is difficult or slow; the patient becomes apathetic. At first, especially if it is a child, the patient may try to conceal his handicap; as, for instance, the young girl spoken of by Kocher, who in school made desperate efforts to keep up the pace with her schoolmates. The patient, however, soon realizes that something is wrong with his intelligence, and becomes silent, shy, and self-contained. When the disease is well established the face is large and swollen. The eyelids, especially the inferior ones, show a semitransparent sacci- form swelling, which one is always surprised to find does not pit on pressure. As these edematous eyelids partially cover the line of vision the eyes look small and sunken. The nose is large; the lips thick, hang- ing, and cyanotic; the ears are enlarged and thickened; the lines of the SYMPTOMS 197 face being puffed, have lost their mobility and are without expression, and hence give an air of stupidity which recalls cretinism. The skin of the hands, feet, and of the body gradually becomes swollen. This edema is more pronounced in the morning, and differs from the edema of kidney and cardiac diseases by the fact that it does not pit on pres- sure. The skin is dry, shows a yellowish-white, dirty color, and scales easily; perspiration is more or less suppressed; the hair is scarce; the patient "looks old." The swelling of the skin extends to the mucous membranes; the tongue is thickened; the patient becomes anemic; the blood shows a diminution of red corpuscles, and a relative increase of leukocytes; this leukocytosis increases with the degree of the disease. The pulse is small and the heart, as a rule, shows no changes. The temperature is lowered, the circulation, respiration, and digestive func- tions become less active. Sensibility to pain and touch is diminished. In short, the mental as well as the physical processes are considerably reduced, more or less. If total thyroidectomy has been performed in a young child, its growth stops and its intellectual faculties regress rapidly. This is very well illustrated by the case of Dr. Sick, who in 1867 performed a com- plete thyroidectomy in a ten-year-old child. This boy, who was extremely intelligent, gradually lost his mental and intellectual energy to such an extent that when seen by Bruns, eighteen years after, he had the appearance of a perfect cretin. He was incapable of rudimentary work, and could not answer the most elementary questions. His stature was the same as at the time of the operation; his head only seemed to have developed and was out of all proportion to the rest of the body. Kocher, Combe, and others have reported similar experiences. If total thyroidectomy is performed in a later period of physical development, the symptoms of hypothyroidism will be less marked. These symptoms pre- sent their minimum when growth and sexual development are terminated. The condition then becomes harmless, quoad vitam; it affects only the patient's efficiency and often renders him incapable of attending to his business, thus forcing him to give it up, such as the barber who con- stantly dropped his scissors or razor; the seamstress who could not remember measures; the maid who dropped everything which she picked up, or the student who had become unable to remember the simplest facts of mathematics. When hypothyroidism affects a severe form the patient dies either from the condition itself or from an intercurrent disease. In other instances after a more or less prolonged period of development, hypo- thyroidism may regress spontaneously, become less severe, and 111 a h \\ instances may even disappear entirely. Indeed it has been demon- strated in a great main casts by many authors that total extirpation ot 198 VARIOUS FORMS OF THYROID INSUFFICIENCY the thyroid is not always followed by cachexia strumipnva. At first this seems not in harmony with the classical belief that the complete removal of the thyroid causes hypothyroidism. This inconsistency, however, is only apparent, for we know now that this failure to follow the rule is due to the fact that the gland has not been entirely removed, a small portion of it having been left, as the processus pyramidalis, for instance. It may also be due to the presence of accessory thyroid glands, which are, as we know, not uncommonly found in the cervical or mediastinal regions; as soon, however, as these accessory glands are removed, cachexia strumipriva follows. Cases of hypothyroidism have been known to develop after the removal of a lingual goiter. More perplexing are the cases of "partial" thyroidectomy followed by a well-defined hypothyroidism. Why is it so ? We must remember that certain individuals have just enough thyroid to meet the ordinary physiological demands. They are constantly verging on thyroid bank- ruptcy. Therefore it will be easily understood that the removal of a portion of that gland puts them at once in thyroid physiological inferi- ority. In other cases postmortem has shown that after partial thyroid- ectomy the remaining portion of the gland has become atrophied and invaded by the connective tissue to such an extent that the glandular elements have been partly destroyed: hence, again, producing functional insufficiency. It goes without saying that so far as thyroid insufficiency is concerned it does not matter what portion of the gland is removed; in ordinary conditions, if any part of either of the two lobes or isthmus, or if any accessory thyroid gland remains, hypothyroidism is not to be feared. Spontaneous Adult Hypothyroidism (Fig. 56). — This is eminently a chronic disease. It progresses slowly and it is only after years have elapsed that it reaches its maximum. Etiology. — Excitement, traumatic lesions of the neck, numerous pregnancies, especially when accompanied with much loss of blood intrapartum, tuberculosis, alcoholism, and syphilis, have been thought to be the cause of spontaneous adult hypothyroidism. Most likely all these conditions should not be regarded as the primum movens. They have most probably supervened in conditions of hypothyroidism already existing, although latent. As said before, in certain patients as long as conditions remain normal the thyroid is barely physiologi- cally sufficient; but as soon as it is overtaxed it becomes momentarily or permanently insufficient to the task: hence thyroid insufficiency. Spontaneous adult hypothyroidism is often found in conjunction with goiter (Fig. 56). Among the most important causes of spontaneous adult hypothyroidism are acute infectious diseases. This etiological factor is being recognized more and more every day. We have seen in ETIOLOGY 199- the chapter on Strumitis and Thyroiditis that the thvroid does not remain indifferent in the presence of acute infectious diseases as typhoid, malaria, acute inflammatory rheumatism, pneumonia, etc. It reacts more or less intensively, and in many instances, may even reach sup- puration. After the acute inflammatory stage is over, the process is by no means terminated. An insidious, treacherous, chronic inflammation remains, characterized by a diffuse production of connective tissue whose ultimate result is the destruction of the secreting epithelium of the gland, hence thyroid insufficiency. This influence of infectious dis- ease is very well illustrated in one case reported latelv bv Achard: myxedema developed in a child ten years old some time after measles, and after forty-two years' duration of the disease the patient died. The postmortem showed no traces whatsoever of thvroid tissue. Fig. 56. — Spontaneous adult hypothyroidism. The thyroid gland is barely palpable. Spontaneous adult hypothyroidism, although found everywhere, is far more frequent in regions where goiter is endemic, and in individuals whose thyroid is congenitally insufficient on account of their goiterous parentage. It is rare in the tropics, occurs frequently in cold climates, and is very common in certain countries, especially in France and Swit- zerland. It is less common in North America. Cases of spontaneous adult hypothyroidism have been reported among negroes. It is more common in women than in men. Prudden, in 1888, found 145 cases — 32 men and [13 women. Heinzheimer, in 1894, out of 150 cases, found 10 men and 1 17 women. (In 23 cases the sex of the patient was not given.) The predisposition of women to spontaneous adult hypothyroidism is clue to frequent congestions and toxi-infectious dis- turbances of the thyroid during sexual life, such as menstruation, pug- 200 VARIOUS FORMS OF THYROID INSUFFICIENCY nancy, menopause. It is more common between the ages of 30 and 50 years. Symptoms. — As the patient has reached his complete physical and mental development the symptoms found will correspond to the ones seen in operative myxedema of the adult; the skeleton is normal, and the disturbances of a psychic order are not so marked as in infantile hypothyroidism. The organs are not anatomically but only functionally disturbed. The debut of the disease is insidious, slow, and progressive. With- out apparent cause, more often during the convalescing period of an acute infectious disease, a progressive weakness, physical apathy, and an intellectual torpor combined with anemia are observed. The true significance of such conditions, as a rule, is not understood and the patient is treated for anemia. Under medical treatment and rest these conditions are improved or retrocede entirely, but after a few weeks or months they relapse again, and then they follow their slow but pro- gressive course, which may last ten, twenty or even forty years. In the full development of the disease the face is swollen, the lips are thick and everted, especially the lower one, and the nose and mucous mem- brane of the nasopharynx are swollen, too. This swelling compels the patient to breathe with open mouth while sleeping, hence causing loud snoring. The tongue is thick, chin plump, and on account of the swell- ing of the eyelids the eyes seem to be smaller; the cheeks are flabby and the lines of the face have a remarkable immobility; this altogether gives the patient an air of stupidity. His forehead is often wrinkled and his eyebrows are elevated in order to raise the swollen lids above the line of vision. In opposition to what is seen in cardiac and renal diseases, where edema obliterates the wrinkles of the face, in myxedema it exaggerates them. The skin is yellowish white, waxy, with a slight redness on both malar regions. The myxedematous infiltration is not evenly distributed over the body; there are places in which it is more prominent than in others, for instance, in the supraclavicular spaces, abdomen, neck, and thorax. For lack of perspiration the skin is dry and scales off easily. The sebaceous secretion is scarce and skin eruptions of different kinds are often present. The hands and feet are thick and clumsy, the fingers have the shape of small, round sausages, and move with difficulty; hence the name "spade-hands" of Gull. The patient does not use them with ease, hence producing awkwardness. The feet become deformed and edema- tous, and the legs become round and thick, and have a pachydermic appearance. The hair and eyebrows are thin and brittle, while in the axillary and pubic regions the hair falls out. SYMPTOMS 201 The symptoms evidenced by the nervous system are very striking. Thev consist in a weakened memory, slow mental processes, diminution of the capacity of coordination, and diminished activity of the organs of sense and of the reflexes. The patient answers questions slowly and becomes irritable if pressed with them. Although he may usually be of a gentle disposition, he will at times show remarkable bursts of rage. Any mental or physical exertion is a burden to him; his speech is slow, but not stammering or monosyllabic. His slowness is due to a slow pro- cess of ideation. His voice is more or less husky on account of the edema of the laryngeal mucous membrane. The organs of special sense are quite often affected: hearing, sight, taste, and the sense of smell are diminished. Deafness, to a greater or less degree, is common, and is not onlv due to infiltration of the mucous membrane, but also seems to be of central origin. Tinnitus is quite frequent, and is the source of much complaint on the part of the patient. The sense of touch is reduced and the patient is sensitive to cold. This sensation of cold is not only purely subjective, but is also objective, as the central tempera- ture of the body is lowered and varies between 95 ° and 97 ° F. The extremities, lips, and nose are cold and cyanotic; the circulation is slow and the pulse varies between 50 and 65. As a rule the heart shows no abnormality. The red corpuscles may be slightly diminished, and the hemoglobin content reduced. But just as for Graves' disease, the most charac- teristic changes concern the white cells, so here, too, as shown by Kocher, we find a leukopenia, a hyperlymphocytosis, and a hyperpolynucleosis. The coagulability of the blood, on the contrary, as shown by Kottmann, is reduced in hypothyroidism, whereas it is increased in hyperthy- roidism. This is a point of very good differential diagnostic value. The urine is diminished and its specific gravity varies between 1000 and 1015. The nitrogenous exchanges are low. Menstruation when present may be profuse or scarce, but very often is suppressed. The patient com- plains quite often of rheumatic pains in the hands, feet, and back. The clinical picture of spontaneous adult hypothyroidism is not always so complete; many cases have been described in which only a few of the above symptoms recorded as characteristic of hypothyroidism have been found. These cases are called fruste, larvatc, or incomplete hypo- thyroidism. They were described by Brissaud and Tiberge and called by Hertoghe, benign hypothyroidism. They art- more frequent than one would expect. We shall study them in another chapter. In senility the thyroid gland becomes atrophic, undergoes a diffuse sclerosis, and tends gradually to destroy the epithelial elements of the gland itself, hence hypothyroidism. According to Horsley, old age is only a form of mitigated hypothyroidism. He believes that tin- people that enjoy 202 VARIOUS FORAIS OF THYROID INSUFFICIENCY a green old age owe this happy condition to a thyroid which has remained normal. The points of resemblance between senility and a slight degree of hypothyroidism are more than one. The changes in the face, the falling out of the hair, the dryness of the skin, the production of adipose tissue, the diminution in the function of the nervous system, of the sensorial, intellectual, and genital spheres, all these symptoms found in advanced old age, according to Horsley, point toward a thyroid insufficiency of moderate degree. In both cases the nutritional exchanges are dimin- ished; the pulse is slow; the temperature is low and a sensation of cold is present. "The only differences," says Ewald, "is that in old age there is a constant atrophy of the intestinal tract which is not present in hypothyroidism." It these views are correct, thyroid opotherapy should be of great value in preventing old age, but I am afraid that this theory, although extremely interesting, is a sister to the Brown-Sequard theory, and we know that the promises of this have not been fulfilled. They who are dreaming the dream of Faust and Ponce de Leon, the dream of eter- nal youth, must still put their trust in something else than in the feeding of testicular or thvroid extract. CHAPTER XV. CONGENITAL ATHYROIDISM, SPONTANEOUS INFANTILE HYPOTHYROIDISM, AND CRETINISM. In this class we shall include all these conditions which have been labelled at various times as "sporadic cretinism," "congenital or infan- tile myxedema," "idiocy," "pachydermic cachexia," "cretinoid pachv- dermy," "cretinoid idiocy," and "infantile myxidiocy." In children thyroid insufficiency takes place at a period of their development when intelligence and growth are incessantly undergoing changes, consequently, hypothyroidism in children will differ from that of adults. Nanism, or arrest in the physical development, and idiocy, or arrest in the mental development, are the chief differential charac- teristics. Here, too, as in the previously described forms of thyroid insufficiency, all stages will be found. If at birth the thyroid is totally absent, nanism, idiocy, and other hypothyroidism symptoms will reach the maximum of development. This is the congenital form of athyroidism. If thyroid insufficiency develops at a later period, when the body has already undergone a cer- tain evolution, and when the intelligence has already awakened, nanism and idiocy will be less marked. The child will not be an idiot, but only an imbecile. If thyroid insufficiency develops at a time when the physi- cal and intellectual developments have already reached an advanced growth the symptoms will be less marked, nanism will be only sketched; the intellectual disturbances will be less noticeable, and then the little patient will not be called an idiot nor an imbecile but simply a retarded child. Finally, if the thyroid insufficiency is of a mild degree only the symptoms of thyroid insufficiency will be benign, too. Let us call this condition fruste infantile hypothyroidism. Etiology of Congenital Athyroidism and Spontaneous Infantile Hypothy- roidism. — In countries where cretinism is not endemic, cases of cretin- ism are found which resemble closely the endemic form, yet they do nor recognize entirely the same causes. They are due solely to the absence of the thyroid or to its insufficiency. Exogenous influences from water and soil do not intervene as etiological factors. Such conditions are met with in congenital athyroidism and spontaneous infantile hypo- thyroidism. Congenital athyroidism clue to a complete absence of the thyroid must be regarded as a malformation; it is a congenital delect whose 204 ATHYROWISM AND INFANTILE HYPOTHYROIDISM cause is still very obscure. Probably, as in other forms of congenital malformations, something interfered with the normal development and arrangement of embryonic cells. This congenital thyreo-aplasia is not special to certain countries, has no relation whatsoever to endemic cretinism, and differs from the endemic hypothyroidism by the fact that there is no endemic goiter or cretinism in the ascendants. In spontaneous infantile hypothyroidism (Fig. 57) the thyroid is always present; it may be either atrophied or even hypertrophied, which latter condition occurs very seldom. Hypertrophy, however, is never excessive. The cause of that form of hypothyroidism may be dated back to infec- tious diseases of the mother during pregnancy. We know that the placenta is permeable to microorganisms, therefore it is logical to admit that it is that much the more easily permeable to their toxins which are liable to cause an acute toxic thyroiditis of the fetus in utero. Later, this thyroiditis takes a chronic form, the thyroid under- goes atrophy, hence a thyroid in- sufficiency after birth. Tuberculosis and syphilis have been incriminated, too, as a caus- ating factor of infantile thyroid atrophy. Alcoholism of the mother during pregnancy has been found, too, as a cause of thyroid insuffi- ciency in the child. We know that it has been experimentally demon- strated that alcoholism has a damaging influence over the thyroid, consequently it is permissible to assume that in cases of severe alcoholism of the mother during pregnancy, alcoholic intoxication of the mother may damage the thyroid of the fetus in utero. Severe and prolonged congestions of the thyroid due to dystocia during delivery have in some instances been followed by thyroid insufficiency. Girls are more often affected than boys. When hypothyroidism appears during the first years of infancy, after the child has been seemingly normal, the cause of such thyroid insufficiency may be found in the acute diseases which are the appanage of childhood, such as enteritis, whooping-cough, measles, and pneu- monia, etc. Cretinism. — Etiology. — According to Kocher the name "cretin" comes from the French word "Chretien" (Christian), the intention being Fig. 57. — Spontaneous infantile hypo- thyroidism, with some other polyglandular symptoms. CRETIXISM 205 to convey the idea of innocence and simple-mindedness. Bayon thinks that the word "cretin" comes from the Rhaeto-Romanic word "cret," which means cripple, cretin, or dwarf. Others think that it is derived from the word "creta," which means chalk, because of the color of the skin. The following anecdote related by St. Lager might confirm Kocher's idea, namely, that the word "cretin" comes from the French word "Chretien." "A mayor of a village received one day a circular letter asking him to fill up an enclosed blank purporting to establish the number of disabled people of the town. After filling the columns concerning the blind, the lame, the hunchbacks, the lunatics, etc., the mayor stumbled upon the column 'cretins.' 'Cretins? What is that." Everybody in the office was consulted, but nobody knew the meaning of the word cretin. Finally, the policeman was sent for and consulted. After thinking a while, 'By George,' said he, 'that is a typographical error. They ask you how many Christians (Chretiens) there are in your town.' The problem was solved. So the mayor wrote in the column of 'cretins,' 'We all are.'' Cretinism is a peculiar clinical form of thyroid insufficiency, and belongs to the same pathological class as surgical, congenital, infantile, and adult hypothyroidism. Many of the symptoms of thyroid insuffi- ciency seen in these conditions when compared with those seen in endemic cretinism show such a striking similarity that a parental relation between them cannot be denied. Although in everyone of these conditions we find disturbances of the skin, of the osseous system, and of the genital and nervous apparatus, yet a closer examination shows that there are between them fundamental differences. In endemic cretinism, for instance, pathological changes of the skin are present, but they have not the same character as those seen in myxedema. Scholz says that the skin of the cretin cannot be even called "pseudomyxedematous." Bircher claims that in 60 per cent, of his cases of cretinism, myxedema of the skin was not present. Osseous disturbances of the skeleton in endemic cretinism differ from those seen in congenital athyroidism. In the latter condition endochondral and periosteal ossification is consid- erably retarded. Ossification in the epiphysis and synchondrosis takes place only very late in life. The fontanelles remain open for a consid- erable period of time, as seen in the postmortem of the "Pacha de Bicetre." In cretinism the retarded ossification is very much more irregular; only certain epiphyses and synostoses undergo normal ossifi- cation, whereas others do not. Sometimes we may see premature syn- ostosis, hence disproportion between different parts of the skeleton. In endemic cretinism it is remarkable that the diminution of cere- bral power is not always in proportion to the disturbances seen in other systems of the organism. The course of the disease is different, too. 206 ATHYROIDISM AXD INFANTILE HYPOTHYROIDISM In endemic cretinism, after a certain period of time, the disease seems to remain stationary, hence the long life of the cretins. In congenital athyroidism the disease is progressive and death takes place at a much earlier period than in endemic cretinism. As said before, no cases of congenital athyroidism have been known to live longer than thirty years. The results of opotherapy show that there are differences between congenital athyroidism, infantile hypothyroidism, and endemic cret- inism. In the first two conditions the results of opotherapy are bril- liant, whereas in endemic cretinism they are doubtful. Von Wagner claims that in endemic cretinism he has obtained brilliant results with thyroid opotherapy. On the other hand, Scholz, Kutschera, Bircher, and others claim that their results have been more or less negative. As to the etiology of cretinism, we shall see in studying the causes of endemic cretinism and goiter that there is a marked divergence of opinion among writers. Some, as Kocher, von Wagner, von Eiselsberg, Langhans, and Seigirt, believe that this endemic cretinism is solely due to thyroid disturbances. "Without disturbed function of the thyroid, no cretinism," says Kocher. He believes that the same noxious causes producing other forms of hypothyroidism intervene during fetal life and cause cretinoid degeneration. This noxious agent primarily injures the thyroid, and secondarily all the organs. On the other hand, Bircher, Kaufmann, Scholz, Kutschera, and Dieterle believe that the thyroid disturbances are not solely the cause of the disease, but that there are other determining causes of cretinic degeneration. One thing is certain: in every cretin the thyroid gland is not always atrophied, but is, on the contrary, in some instances, hypertrophied. Besides degenerated portions, such enlarged glands often possess others, which seem to be normal, and which, so far as we can judge by their histological appearance, are undoubtedly capable of function. After going over cases of cretinism in which microscopic examination of the thyroid has been performed, we must conclude that there is not always a striking parallelism between the intensity of cretinism and the histo- logical disturbances. As cretinism does not respond to thyroid opo- therapy as readily as other forms of thyroid insufficiency, and on account of the above-mentioned reasons we can conclude with Ewald, Kutschera, Bircher, etc., that endemic cretinism is a physical as well as an intellec- tual degeneration not solely due to thyroid insufficiency, but to some additional damaging influences on the other organs of the body as a consequence of the endemic; in other words, the pathological agent of endemic cretinism is polytrope and not monotrope. This means that in order to have a true cretinism we must add to the disturbed thyroid function other causes. One of the most important of these causes is the fact that "the endemic" has been exerting its nocive influence upon ATHYROIDISM, INFANTILE HYPOTHYROIDISM, CRETINISM 207 the organisms of these individuals throughout successive generations. The union of all of these conditions gives, then, rise to the true or endemic cretinism, whereas surgical and congenital athyroidism, spontaneous infantile, and adult hypothyroidism are caused only by a thyroid insufficiency and by no other cause. In cretinism, as in the other forms of hypothyroidism, all degrees of development can be met with. If the noxious agent is of benign type the thyroid insufficiency will be a moderate one, and that condition may remain stationary throughout life. But if the damaging agent is more perfidious and affects individuals already in instable thyroid equilibrium, cretinism will be more severe. All the various stages found between the mild and the most severe forms of cretinism are only links of the same chain, and Fodere was indeed correct when he said, "Goiter is only the first degree of a degeneration whose last manifestation is cretinism." The endemic includes the true endemic cretinism, endemic goiter, endemic deaf and dumbness, and endemic feeble-mindedness. In opposi- tion to what is seen in other forms of hypothyroidism, males are more often affected with cretinism than females. Symptoms of Congenital Athyroidism, Spontaneous Infantile Hypothy- roidism, and Cretinism. — As the symptomatology of congenital athyroid- ism, spontaneous infantile hypothyroidism, and cretinism, endemic and sporadic, on the whole resemble each other very much, I shall give the clinical description of these conditions in the same chapter in order to avoid unnecessary repetitions. I shall dwell on their respective charac- teristics in the chapter on Differential Diagnosis. W hen any of the above-mentioned types of thyroid insufficiency has reached its full development the clinical picture is so striking, so charac- teristic that a glance is sufficient to make the correct diagnosis. When one has seen one case he has seen what is peculiar to all cases, no matter what the particular type may be. In the first place, there is on the small body of the dwarf, for such the patient will be, an enormous head entirely out of proportion to the rest of the bod)'. If we add to this a vague, lifeless, stupid look with a cretinoid physiognomy the first impression is complete. As for details we may note that the skull is deformed, voluminous in the occipital, and narrow in the frontal regions, and that the anterior fontanelle is still persistent even in individuals fifteen to twenty years old. The face is round, in "full-moon," and without expression, the forehead low, receding, and furrowed with numerous wrinkles. The nose is wide at the basis, but short and retrousse; in a word it is what we call expressively the "saddle-nose." The ears are thick and everted. Both malar regions are prominent; the cheeks, flabby and hanging, while the lips are thick, cyanotic, and everted. I he 208 ATHYROIDISM AND IN FAX TILE HYPOTHYROIDISM mouth is wide and open. The tongue, so thick that it is too large for the oral cavitv, protrudes for much of the time from the mouth. Some- times it hangs out constantly and a continuous flow of saliva may be seen running out at the corners of the mouth. This macroglossia is not due to muscular hypertrophy but is caused by an abundant deposit of fat and mucine between the muscular fibers; it is a sort of hpomatous macro- glossia. In regions where goiter and cretinism are endemic the teeth are decayed, but in countries where goiter and cretinism are only spo- radic the quality of the teeth of these cretins, according to Bayon, does not differ very much from that of the teeth of normal children. Of course in congenital hypothyroidism teeth are absent, second den- tition does not in most cases take place, and if it does, it occurs only very late, say at the ages of twenty-five to thirty years. The neck is short, and Hpomatous masses are found in the supraclavicular spaces. The thorax is flat; the abdomen large and hanging, and has the shape of a "frog-belly." Umbilical hernias are very often present. The arms, legs, hands, and feet are very stocky, and the swollen fingers can be moved only with difficulty. The feet are short and deformed and too broad for their length; the toes are swollen, and hence produce a peculiar, unsteady and obviously difficult gait. The skin is pale and sallow, semitranslucid, recalling a little the clinical picture of the phlegmasia alba dolens. Even in a very advanced period of life the skin remains unbearded; the hair of the pubis and axillary regions does not grow, while the eyebrows and lashes are always spare and thin. The mucous membranes of the larynx, esophagus, and intestinal tract are edematous. The genital organs, atrophied and arrested in their development, retain the infantile type. If the male cretin reaches the adult age, his testicles and penis are considerably smaller than normally. The same is true for the uterus and its appendages in the female cretin. With such a hypoplasy of the genital apparatus, sexual appetite is not present. The genital functions are more or less suppressed, and only after the thirtieth year do the genital organs seem to develop sufficiently to functionate, but fortunately these cretins are usually sterile. Nanism is one of the earliest and most striking symptoms in athyroidism and spontaneous infantile hypothyroidism. The expected growth of the skeleton does not take place, or if it does, it occurs very slowly. Normally the length of the skeleton is 172 cms. for man and 160 cms. for woman. In cretins the skeleton varies from 60 to 120 cms. in length. For example, the Pacha de Bicetre, nineteen years old, was only 90 cms.; the cretin of Batignolles, thirty-one years old, was 1 meter and 10 cms. long; the cretin of Francotte was 84 cms. long when twenty-one years old; and the one of Combe, 80 cms. when fifteen years old. The bones are thick and deformed, as in rickets, and deformities ATHYROIDISM, INFANTILE HYPOTHYROIDISM, CRETINISM 209 of the ribs and pelvis are frequently found. Kyphotic and scoliotic anomalies of the spine are quite common. The skull of the cretin is flat and low, and wider than it is high. The bones of the skull are thick, and prognathism is a characteristic feature. All cases of congenital athyroidism are idiots. If athvroidism or hypothyroidism occurs at a later period of bodily development, then the degree of idiocy is in direct proportion to the period of development in which the thyroid function has become totally insufficient. In congenital athyroidism and in the most marked forms of cretin- ism the little patients live a purely vegetative life; thev eat, breathe, and sleep, and that is all. They do not even have the instinct of conser- vation, for although suffering from hunger and thirst the)' do not have the intelligence to take the food that is placed near them, and if thev should not be actually fed, they would starve to death. Thev sit for hours, motionless, inert, and entirely unconscious of the surrounding world, insensible to good or bad treatment, and incapable of recogniz- ing even their parents. They are indeed what Roesch calls the "man- plant." If hypothyroidism manifests itself some time after birth, namely, after the child has undergone a certain degree of physical and mental development, the symptoms will be less accentuated. Such little patients do recognize their surroundings, and may even smile when thev see their parents, thus showing that their cerebral system is able to register impressions, although m a very rudimentary degree. It is the vestiges of their earl\', but too soon interrupted cerebral education, that thev show when they manifest signs of pleasure or discontentment, or when, for example, they make efforts to grasp toys lying nearby. Cer- tainly they have sensations. Their psychic vacuum is not absolutely complete and they may even have perceptions. The)' have the instinct of conservation, since, if food is placed near them they will take it. The)' manifest their emotions, and possibly their perceptions, too, bv grunts and growls. As a domestic animal may be taught, so may they be taught to be clean, and they may even be trained to do things which require only a rudimentary intelligence, such as to earn' wood or water. The\' correspond to what Roesch calls the "man-animal." Of course between these extreme forms of hypothyroidism and cretinism and the fruste forms all degrees are found. But, to continue, the organs of sense show a greatly diminished function; the senses <>t smell, taste, and touch are not acute; sensibility is considerably reduced. The cretin will stand for hours in the full glare of the sun and show no signs of being discom- forted by it. Indeed, then" eyes do not seem to be ar all affected by the intense light. The)' hear and speak with difficulty, and quite often are deaf and dumb. Sometimes the speech consists only in a few inarticu- 14 210 ATHYROIDISM AND INFANTILE HYPOTHYROIDISM late sounds which are understood only by members of the family; when more highly developed many seem to have an especially great difficulty in pronouncing the consonants. Their memory is weak. They are unemotional, and in their affections resemble animals. If anyone has been unkind to them they do not forget it. On the other hand, they rejoice very much when, as Kocher says, "they see a friend of their stomach." They are very sensitive to cold, for not only is the central temperature reduced, but the peripheric circulation is also diminished. The blood-pressure is low; pulse small and easily depressible. Their muscular system is always poorly developed; their strength is in propor- tion to their stature and their movements are slow and awkward. The "frog-shaped" belly which is often found in cretins is no doubt caused by this general relaxation of the musculature, and this relaxed condition plays an important part, no doubt, in the etiology of hernias which are so frequent in cretinism. Since they show a profound dislike for any physical effort, they sleep most of the time, and for hours will sit motion- less in the same place. More than once in the hospital ward I have found them sitting at the same place where I had left them hours before, in exactly the same posture, and totally indifferent to the external world. Their appetite is moderate, and they have a natural aversion to meat. Their digestion is bad, and, as a rule, they suffer from constipa- tion. Cretins show great sensitiveness to the effect of alcoholic drinks. In regions where cretinism is endemic, every little town, so to speak, has its "cretin" (Fig. 82), and one of the greatest amusements of the unmerciful and heartless youth is to give a glass or two of wine to these poor creatures in order to intoxicate them and then to enjoy their contortions and queer faces. Differential Diagnosis. — Since the symptoms of endemic and sporadic cretinism, congenital athyroidism, and spontaneous infantile hypothy- roidism are so much alike, differential diagnosis is sometimes very diffi- cult. In the majority of cases, however, it can be made. Life in congenital athyroidism is ordinarily short. Death occurs most usually during the first two or three years. According to Ewald no case of congenital athyroidism is known to have lived longer than thirty years, whereas some endemic cretins have acquired notoriety by reaching the ages of fifty or sixty years, and even eighty-six years. In congenital athyroidism and spontaneous infantile hypothyroidism the myxedematous infiltration of the skin is very much more marked than in endemic cretinism. On the other hand, in the latter condition the retarded growth and deformations of the osseous system are less marked than in the former. A consideration of value in differentiating congen- ital athyroidism from cretinism is the fact that the latter condition occurs when goiter is endemic. To be sure, there are sporadic forms of cretin- DIFFERENTIAL DIAGNOSIS 211 ism seemingly occurring in regions where no endemic is present. As a rule, however, we nearlv always find in the ancestors of endemic and sporadic cretins, endemic goiters or other cretinoid conditions, serving as telltales. In countries where cretinism is endemic, individuals who have goiter, who are of small stature, and at the same time have a certain mental deficiencv are called "cretins." This appellation is not exact, as such individuals are not actually "cretins" but cretinoids. They represent a higher step in the scale of cretinism where, m fact, all degrees of cretinic degeneration may be found. Certain individuals may, at the first glance, appear to be normal physically and mentally, yet their stature, which is slightly under normal, their wide face, with low forehead, and the prominence of the malar bones, the slight touch of "saddle-nose" and their limited intellectual power show that these individuals have been stamped, although lightly, with the endemic. One need only to walk through certain Swiss valleys to become convinced of the fact that there are many thus afflicted. Indeed, we may go so far as to say that in certain districts the entire population is marked with the endemic. In the first year of life it is extremely difficult to diagnose cretinism or any other form of hypothyroidism. At that age the child lives a purely vegetative life; it is even difficult to decide whether the child is normal or not. In fact the onlv symptom which might point toward thvroid insufficiency is a thick tongue, protruding from the mouth, or unusually thickened integuments. Sometimes the disease takes such a slow course that the child reaches the second or third year before any- body realizes that something is wrong with it. When studying the embryological development of the thyroid we saw that the thyroid gland at birth is formed by a mass of non-difFeren- tiated cells. No colloid is present, and only in a later period do these cells shape themselves into normal alveoli. During this cellular anarchy it is permissible to assume that the function of the thyroid is greatly disturbed, and that it is in a state of hypofunction. Some authors, as Langhans, Kaufmann, and Bircher, go so far as to claim that tin- fetal thyroid is normally physiologically inactive. They regard tin* maternal hypertrophy of that gland as a compensatory process caused by the lack of thyroid function in the fetus. Although it is highly probable that the function of the thyroid during fetal life is diminished, it is, never- theless, difficult to admit that the gland is in a state of complete physio- logical negativism. Let us not forget that there is a period, the vesicu- lar stage, during fetal life when well-formed alveoli containing colloid are present. Nothing proves that the thyroid at that time does not functionate. Furthermore, it is a well-known fact that pregnant women afflicted with hypothyroidism see their symptoms of thyroid msuffi- 212 ATHYROIDISM AND INFANTILE HYPOTHYROIDISM ciency improve greatly during pregnancy. This is most likely due, not only to the hyperplasia of their own thyroid but also to a compensator)' function of the thyroid of the fetus. The reason why symptoms of hypothyroidism become noticeable only after a certain period of time after birth and not at once, is still a debated one. Some think it possible that during nursing the milk of the mother contains thyroid products in sufficient quantity to supply the ones lacking in the newborn. What seems to corroborate this view is that the symptoms of hypothyroidism become noticeable at the wean- ing time. Cow's milk seems to have, although in a lesser degree, the same protective influence. On the other hand, when meat diet takes the place of milk alimentation, hypothyroidism symptoms progress very rapidly. It has been said that the thymus supplies the thyroid function during the first few months of the child's life, and then also becomes function- ally insufficient. Possibly, too, the hyperplastic thyroid of the mother has left in the body of the newborn enough active principles of the thy- roid to be sufficient for a certain period of time. Most likely, however, the best reason is that the symptoms of thyroid insufficiency are not, and cannot be recognized in their early development. Diagnosis is made only when they have acquired a certain intensity. Who can indeed say with a certainty that in a few months old child some of the manifestations of hypothyroidism, as for example myxedema and stupidity, are or are not present ? As a rule typical hypothyroidism is easily diagnosed. Some diffi- culty may be encountered in differentiating conditions which at first resemble those seen in thyroid insufficiency. For example, in certain forms of extreme chronic nephritis, of erysipelas of the face, when an edema develops slowly and may cover large areas of the body, a doubt might arise in one's mind as to their true nature, but a closer examina- tion will solve the problem. At the time of menopause a transient edema may be seen, especially in the face. It was considered by Dalche as of ovarian origin and was called by him ovarian pseudomyxedema. The same author has described a form of cutaneous infiltration of syphilitic origin and called by him syphilitic pseudomyxedema. In the familial trophedema Meige described a form of cutaneous infiltration which must be regarded as of trophic origin. Certain forms of scleroderma might, at a superficial glance, be mistaken for myxedema, but a more accurate examination and palpation of the neck will dissipate all doubts. Adipose degeneration of genital origin and the one seen in tumors of the hypophysis may sometimes be confused at first with myxedema, yet a careful examination of the genital apparatus and the feminine aspect of the individual will direct the attention toward genital hypoplasia. In tumors of the hypophysis the presence of headache, symptoms of DIFFERENTIAL DIAGNOSIS 213 compression on the brain, aided by an x-ray of the skull will clear up the diagnosis. Dercum and Henry have described areas of a diffuse general lipoma- tosis more marked in certain regions of the body, as in the arms or back. This condition is accompanied by symptoms of neuritis and is very painful to pressure. It is called adipositas dolorosa. Perspiration may be diminished or absent. Such cases may be very difficult to differentiate from myxedematous conditions, but the normal psyche, the absence of edema in the hands and feet, in short, the general aspect of the patient will prevent the mistaking these conditions for such as are due to thy- roid insufficiency. When doubt still exists, the thyroid treatment will throw some light upon the subject; adipositas dolorosa does not respond to thyroid opotherapy. All forms of dwarfism are not by any means symptomatic of hypo- thyroidism. Microsomia, for instance, a condition in which individuals, although of very small stature, are perfectly proportioned, has nothing to do with thyroid insufficiency. As Bayon says, "It is a lusus natural, a stunt of nature." Bayon divides microsomia into congenital and infan- tile. In the congenital form the child is born extremely small, whereas, in infantile microsomia, the child is normal at birth, but for some unknown reason remains of extremely small stature. In both forms the different portions of the body, although remaining very small, are still proportionate one to another. Daniels and Philipp compare one in these states to "a little man seen through the wrong end of an opera glass." The great majority of dwarfs seen in vaudeville theaters belong to the infantile microsomia. Such dwarfs continue to grow gradually for 35 to 40 years, and often so much so that after a certain period of usefulness on the stage they are discarded because they have grown "too tall." Cases of chondrodystrophia fcetalis, microsomia, or achondroplasia, have been regarded in some instances as cases of cretinism. But if chondrodystrophia foetalis were in relation to thyroid insufficiency, it certainly should be found much oftener in regions where goiter and cretinism are endemic. This is not the case. In fetal chondrodystro- phy, if the children are not born dead, a careful examination shows that in such conditions symptoms of hypothyroidism are wanting. I he skin is not infiltrated; constipation is not present; temperature is normal; tin- thyroid gland can be easily palpated, and the only deformity found is that the long bones are too short in proportion to the skeleton. In further development, the intelligence and genital apparatus of such patients prove to be normal. The whole clinical picture is due to ;i malformation of the cartilages, and not to the thyroid insufficiency. 1 he bones grow normally in thickness but not in length. 214 ATHYROIDISM AND INFANTILE HYPOTHYROIDISM In infantilism the osseous system and the soft parts of the body undergo their normal development; puberty only does not appear and the voung individual retains an infantile appearance. In recent years Brissaud, of Paris, and his pupils have described a form of infantilism characterized by a persistence of the juvenile state as to body, intellect, and sexuality. The face is round, the body plump, and the extremities small. This is the Brissaud type, but in other cases the body has a slender shape, the extremities are thin, the face delicate. That is the Lorain type. These conditions have nothing to do with thyroid insufficiency. There are some idiots who present a certain likeness to the Mon- golian race. This pathological class has been called Mongolism. The mongoloid has an inward and downward slanting of the converging pal- pebral fissures. He has some intelligence and is able to utter more or less distinctly a few words. The tongue is not thickened. In opposi- tion to the real cretin who remains sometimes for hours motionless, Mongoloids always show a certain restlessness in their manner. The abdomen is distended on account of obstinate constipation. The large fontanelle closes between the first and fifth year of life. Very often they have the saddle-nose as found in cretins. They are chicken-breasted. There is a great difference between the skeleton of the mongoloid idiot and the genuine cretin. In the first case the development of the bones is complete, while in the second they are considerably retarded. This can be easily demonstrated by an x-ray picture. The skin of the mongoloid has no myxedematous appearance. The hair and nails are normal. Pfaundler and Schlossmann say, "The intelligence, which is from the beginning only slightly developed, has a tendency to continue on a low level, but still a distinct development is present. The speech is deficient, notwithstanding that the mongoloids understand their surroundings very well. They are unclean for many years and never reach the degree of intelligence that appears in the majority of cases of myxidiocy under thyroid gland therapy. A short comparison best shows the great difference between mongoloids and myxidiots. The mongoloid has no symptoms of myxedema in later years, no dwarfish growth, no apathetic, motionless manner, and none of the cessation of bodily and mental development peculiar in the myx- idiot. He is uncommonly lively, dentition is normal, and he never shows the frightful, repulsive appearance of the myxocretin. Thyroid therapy affects them absolutely differently. The mongoloid reacts only in the beginning stage, not in psychic behavior. Teething, fontanelle closing, obesity, protrusion of the tongue are immediately and strikingly improved in the myxidiot, only partly, often not at all, in the mongoloid." According to Bayon, in microcephalia the patients have a normal DIFFEREXTIAL DIAGXOSTS 215 stature, but the cranial circumference is below 52 cms., and they pos- sess a brain whose weight is less than 1100 gms. These measurements, however, have really no great importance. More than once the brains of the most hopeless cretins have been found to have the same weight as a normal brain, whereas people with normal or even superior intelli- gence have been known to have brains quite below the normal weight. Microcephalia should not be confused with hypothyroidism, as in the first instance the cranium is small, whereas in athyroidism and cretinism the skull is abnormally large for the small stature. As a rule the micro- cephalic patients are alert and vivacious which is just the opposite to what is found in cretinism. Furthermore, no myxedema is found in microcephalia. Hydrocephalia has been confused sometimes with hypothyroidism and cretinism, yet this condition has no etiological relation whatever to thyroid insufficiency. Rickets has been mistaken, too, for cretinism, and Hertoghe declares infantile hypothyroidism and rickets to be identical pathological pro- cesses. A closer examination of these two conditions soon convinces one that such a statement is not true. In rickets the cartilage between the shaft and the epiphysis of the long bones is greatly thickened, the line of ossification very irregular, more spongy and more vascular than normal. Beneath the periosteum, which strips off easily, there is an osteoid tissue resembling decalcified bone. In cretinism the cartilages are thin, and poorly supplied with bloodvessels; the line of ossification is very regular and linear. In rickets the intelligence of the patient is intact and the thyroid is normal. As Bayon says, " Rachitism is a disease of civilized centers, while cretinism is a disease of the poor, ignorant villages scattered in the mountains and valleys." Of course both conditions might be encountered in the same individual. CHAPTER XVI. SMALL THYROID INSUFFICIENCY. Besides the glaring symptomatology due to absence or diminution of thyroid function and which, as we have seen, produces all forms of hypothyroidism and cretinism, there is a train of symptoms, more mild and less conspicuous, caused by a mild degree of thyroid insufficiency. Just as, for example, in renal disturbances, besides the big, more obvious symptoms of renal insufficiency, there are small, less apparent ones, so the same is true in hypothyroidism. Besides the big class of symptoms of thyroid insufficiency, we find another class scarcely sketched, or very atypical. To the first class belong athyroidism, hypothyroidism, and cretinism; to the second class belongs the small thyroid insufficiency . What is true for all the glands of the body as the ovary, liver, etc., is true, too, for the thyroid; it may be congenitally weak. Although suf- ficient to meet the ordinary physiological exigencies, the thyroid soon becomes insufficient when confronted with increased physiological demands such as in menstruation, pregnancy, infections, etc.; hence symptoms of hypothyroidism. In small thyroid insufficiency the symptoms are various and multiple. They are never all present at the same time. They may be found in earliest infancy, such as constipation, flatulence, and somnolence, as well as in a later period of life, as baldness, somnolence, and constipa- tion. These symptoms are sometimes, not always due to thyroid insuffi- ciency. Women are more predisposed to them than men. Heredity is also of importance, as it is not infrequent to find symptoms only mildly sketched in the mother, while they are more intensified in the children;- the reverse may be true, too. I have seen a family in which all degrees of thyroid insufficiency could be found, from the mildest degree to a well-developed infantile hypothyroidism. The symptoms of thyroid insufficiency were so mild in one member of the family that almost everyone would consider it as a joke of very bad taste to call that patient thyroidly insufficient. Yet the small symptoms of thyroid insufficiency which she complained of were very suggestive, and were relieved by thyroid opotherapy. The part played by consanguinity in the development of hypo- thyroidism has been well demonstrated by Hertoghe. Caloric disturbances such as cold extremities, sensation of chilli- ness, etc., are regarded by Hertoghe, Gauthier, Levi and Rothschild as SMALL THYROID IXSUFFICIEXCY 217 of thyroid origin. Such patients are very sensitive to cold seasons, are never warm enough in summer, do not like draft and complain of rheu- matic pains and neuralgia. Certain gastro-intestinal disturbances must be referred to insufficient thyroid function as, for instance, lack of appetite in certain children. Such young patients do not enjoy their meals, they care much more for sweets and, as a rule, do not like bread. Constipation is one of their chief complaints. Constipation due to thyroid insufficiency does not differ materially from constipation due to other causes. Its supreme test is thyroid treatment. It is found in every stage of life and in both sexes, and is characterized by a small stool, made of hard, drv fecal matter. It would be an error to claim that every constipation is due to thyroid insufficiency. When, however, every other therapeutic measure has failed, and especially if at the same time, some other small symp- toms of thyroid insufficiency are present, the thyroid treatment must be given a trial. As was demonstrated by Marbe in dogs with intestinal fistula, thyroid opotherapy increases the secretions of the intestinal canal, and hence its evidently good influence on constipation. Pos- sibly, too, the thyroid has an elective influence on the neuromuscular centers of the intestinal tract. As seen in the chapter on Physiology, the relations between the thy- roid and the sexual apparatus cannot be denied. We know that normal development of the genital organs goes more or less hand in hand with a normal condition of the thyroid. This has been abundantly demon- strated clinically and experimentally as in athyroidism and cretinism where menstruation remains absent, and pubertv is considerably retarded. On the other hand, during menstruation the thyroid becomes con- gested and enlarged. This explains why during menstruation some women complain of a choking sensation and show Basedow symptoms. On the other hand, the relations between the thyroid and pregnancy are well known and the hypertrophy of the thyroid seen in pregnant women is not only due to hyperemia, but is also caused by a true hyper- plasia. Gauthier, Parhon and Gaulstein have shown that the thyroid and ovaries seem to be antagonistic — the more active the thyroid, the less active is the ovarian function. Inasmuch as during pregnancy the ovarian function is suspended, the thyroid function is increased. Phis would explain why hypothyroidism is considerably ameliorated during preg- nancy. Of course, the thyroid of the fetus may account, too, for this amelioration. At the time of menopause the ovarian function ceases, the thyroid flares up and becomes hypertrophied, causing nervous and psychic dis- turbances to appear. However, after menopause has become a well- 218 SMALL THYROID INSUFFICIENCY established fact, the thyroid gland may undergo atrophy; hence symp- toms of hypothyroidism. In conclusion we can say that the relations between the thyroid and the sexual apparatus are very intimate. We must, consequently, expect to find conditions in the genital apparatus of women, which, although at first seemingly atypical for hypothyroidism, are nevertheless etiologi- cally related to it. Let us see if this is true. It is common to see young girls apparently normal in whom puberty is retarded. In some of these cases of retarded, momentarily suspended or even totally suppressed menstruation, this hypo-ovarism is due to hypothyroidism. Infantile uterus accompanied by hypoplasia of the ovaries and of. the entire genital apparatus might be regarded, too, as a consequence of hypothyroidism. Premature menopause followed by subinvolution of the genital apparatus, in other words, premature senility of that system, may also be regarded as a consequence of hypo- thyroidism. In some cases the disturbances are not objective, but only functional. Typical, for instance, is the case reported by Levi: a lady, aged thirty years, who since her puberty had menstruated but four or five times a year, and who complained of baldness of the masculine type. She was regarded by this author as a case of hypothyroidism and treated accordingly. Soon after treatment menstruation became regular, and remained so. In the same class is the case reported by the same author of a young girl, nineteen years old, whose menstruation was constantly retarded or absent, and which became regular after thyroid opotherapy. Menstruation, instead of being retarded or absent, may be advanced, very abundant, and may last too long a time. In such cases menstrua- tion is transformed into menorrhagia. In other cases menstruation is advanced and abundant, but its duration is not increased. Some other times there is, as in one of my cases, a constant serobloody discharge lasting for years. Dysmenorrhea, when no other cause can be found, may be regarded as a form of thyroid insufficiency. Sterility, too, may be in certain cases benefited by thyroid opotherapy. Hertoghe believes that sometimes abortions, when not due to syphilis, tuberculosis, or some other cause, may be regarded as some manifestation of hypo- thyroidism. These views are corroborated by the fact that in endemic goiter and cretinism, abortions are extremely frequent. Hertoghe also believes that retarded growth of the osseous system in rickets, heredosyphilis, etc., is directly or indirectly due to thyroid insufficiency. Infections and intoxications affect primarily the thyroid, hence their influence on the growth of the skeleton. Gauthier was the first to call attention to the fact that retarded consolidation in fractures might, in certain instances, depend upon thyroid insufficiency. Here, again, before using the medication, every other possibility, such as SMALL THYROID INSUFFICIENCY 219 interposition of muscular fibers between the fragments, syphilis, etc., which might interfere with consolidation, should be carefully investi- gated, and only when everything has failed, should thyroid medication be resorted to. Certain forms of dermatosis such as acne, herpes, eczema, psoriasis, scleroderma, etc., may in certain instances depend upon thyroid insuffi- ciency. This to a certain extent seems plausible, as we know that the thyroid has an undeniable influence over the nervous system and the metabolism in general. A number of other conditions might be regarded as the consequence of thyroid insufficiency. It would take me too far to go into more details. Those who might be interested in these questions may look them up with great benefit in Hertoghe, G. Gauthier, Levi and Rothschild. I should not like to be understood as saying that every case of retarded consolidation, even' trouble of the genital apparatus, every disturbance of the gastro-intestinal tract, or every skin disease is the consequence of thyroid insufficiency, and that thyroid treatment is the only one indicated in such conditions. I say only that, according to my knowledge along that line, and according to the wide experience of such other authors as Hertoghe, Gauthier, Levi and Rothschild, there are certain conditions which may be greatly benefited by thyroid treat- ment; this treatment, however, should be resorted to only when a care- ful differential diagnosis with other possibilities has been made, and only when other therapeutic measures have failed. In certain instances the facies of the patient, his mental development, an exaggerated adi- positas, or some other symptoms of thyroid insufficiency may point out the real cause for the pathological conditions with which one is con- fronted. But many other times no sign of hypothyroidism whatsoever is found which might put the physician on the right scent. In such cases, if every other therapeutic measure has been tested, it will do no harm, and may do a great deal of good, to try thyroid treatment. CHAPTER XVII. ETIOLOGY OF ENDEMIC GOITER AND CRETINISM. Historical. — Despite all modern investigations and researches the etiology of endemic goiter still remains one of the most obscure of medi- cal problems. The disease is probably as old as the human race and is mentioned in the literature of the earliest people. The Atharva Veda, an ancient Hindu collection of incantations dating 2000 years before Christ, contains extensive forms of exorcism for goiter. It is evident from the writings of Vitruvius and Juvenal, that goiter was known to them. Vitruvius says, "Guttur homini intumescit prae- sertim apud agricolas Italiae et medullos Alpinos." (Maurienne et Tarentaise) and Juvenal writes in a passage of his Satires, "Quis tumidum guttur miratur in Alpibus." Marco Polo relates in his travels (13th century) that goiter is prevalent in the plateau of Central Asia. Dur- ing the Renaissance the observations of the Swiss physician and alchem- ist Paracelsus (1493-1541) are especially noteworthy not only because of his excellent description of the malady in the region of Salzburg, an important focus to this day, but also because therein attention is first called to the existing relationship between goiter and cretinism, and the earliest positive information given concerning the latter disease. The literature of the 16th and 17th centuries offers little of interest on this subject. Hirsch gives a list of authors who report concerning the occur- rence of goiter and endemic goiter centers in the Alps, in the Pyrenees, in Hungary, in the Atlas Mountains, in Peru, in Guatemala, in Sumatra, in the Harz, and Riesengebirge, etc. None of such writers, however, treated the subject from a more comprehensive point of view or studied the question scientifically. It is true that in 1779 Saussure furnished us with some interesting observations in his Voyage dans les Alpes, but we are indebted to Malacarne, of Turin, for the first scientific treat- ment of the subject in the report of his observations in the Valley of Aosta, published in 1789 (Torino, 1789, Sni Gozzi e Sulla Stupidita). In 1793 appeared Fodere's basic essay on Goiter and Cretinism in the Maurienne and Aosta Valley, and in 1800 his Treatise on Goiter and Cretinism. Following closely upon this we have the work of Coindet and Maunoir at Geneva (1815-1822); of Rambuteau, Imperial Prefect in the Valais, and of Iphofen in Saxony (1810-1818). Toward the middle of the last century the importance of the ques- tion from a sociological point of view was officially recognized and in 1848 the Sardinian Government named a commission for the purpose DISTRIBUTION OF ENDEMIC GOITER AND CRETINISM 221 of investigating the causes of endemic goiter and of finding a remedy for the disease. This example was followed in 1864 by the French Government. These commissions, after several years of research, pro- duced elaborate reports which threw little new light upon the question but seemed to establish as a scientific fact the popular belief in the hydric origin of goiter. Since earlv in the 19th century there has accumulated such a wealth of goiter literature that it is impossible to enumerate all of these publi- cations. In the Index Catalogue of the Surgeon-General's Office, U. S. Army, not less than 1857 publications are enumerated under Cretinism, Goiter, and Thyroid Gland. Recently M. Scholz mentions 2486 publi- cations concerning cretinism alone. A. Hirsch, in his Study of the Historical and Geographical Relations of Goiter, has given an admirable and in many respects still unsurpassed recital of the historical develop- ment and various endemic and epidemic occurrences of the disease. In 1908 Switzerland created a goiter commission presided over by M. Schmidt, Director of the Federal Bureau of Hygiene, Berne. Italy has recently followed this example, and both commissions are supposed to work along experimental lines which cannot fail some day to throw light upon this still obscure question. Geographical Distribution of Endemic Goiter and Cretinism. — Perhaps to no other disease can the term endemic be so appropriately applied as to goiter. Entire districts are so intensely affected that a large pro- portion of the inhabitants are goiter-bearers, the disease affecting ani- mals as well as human beings. The limitations of the areas subjected to the endemic are so sharply defined that sometimes a hill, river, or even a street, may form the dividing line between the goiterous locality and immune territory. Further demonstration of the localized character of the malady can be found in the numerous examples of individuals from goiter-free dis- tricts who rapidly acquire thyroid enlargements while living in regions of goiter endemicity, and who recover on removing to immune terri- tory, or vice versa, in the numerous cases of goiter-bearers who remove from the endemic region sufficiently early in the development of the disease before colloid and cystic changes have ensued in the gland, when the tendency is for the struma to disappear. Thus, according to Guyon, emigrants from the Canton of \ alais, lost their goiters in Algiers; and Hubner reports that 16,000 emigrants from the district of Sal/burg, in general goiterous, saw this infirmity disappear after settling in Prussia. Cardinal Billiet writes, "When an infected family moves to a parish not in endemic territory, such goiters as are not too severe, disappear gradually, and in the second or third generation, this family will acquire normal thyroid glands." 222 ETIOLOGY OF ENDEMIC GOITER AND CRETINISM Endemic foci are distributed over all the inhabited portion of the earth's surface. So closely associated with goiter is the distribution of cretinism that the geographical occurrences of both forms of disease can- not be easily separated, and are most comprehensively and adequately treated together. In Europe the center of highest endemicity for goiter and cretinism is to be found in the Middle Alps, whence it radiates in diverse directions. There are numerous other foci in connection with different ranges or deep-lying river valleys as the Carpathian, Pyrenees, etc. But even within these areas, the endemic is not uniformly distributed. In Switzerland, the Canton of Valais, the valleys of the Rhone and its tributaries are centers of high endemicity. The Valley of the Reuss in the Canton of Uri, and the Valley of the Aare in the Canton of Aarau are severely affected. The endemic is most intense in the Cantons of Berne, Argovy, and Fribourg; no canton, however, is completelv immune. According to Bircher, from 22 to 50 per cent, of the school children and from 15 to 30 per cent, of the recruits are goiterous in the districts on the right bank of the river Aare. The statistics furnished by Kocher show from 80 to 90 per cent, of the school children of Berne to be goiterous. The endemic is intense in the valleys radiating from Mont Blanc into Lombardy, and from the Alps of Savoy into the neighboring depart- ments of the Basses-Alps, the Maritime Alps, the Haute-Garonne, etc., where both goiter and cretinism are prevalent. The extent of the social and economic loss due to the goiter endemic in European countries is scarcely appreciated. As we know, goiter and cretinism go hand in hand. As early an observer as Fodere remarked that "goiter is the first degree in a degenerative process of which cretinism is the last step," and since then the majority of scientific investigators have adopted the same conclusions. Fodere, MafFei, Roesch, Traxler, Morel, Lombroso, Milani, Marchant, Lourdes, Koestl, and Chabrand consider the causal factors of both diseases identical. MafFei calls goiter the "precursor of cretinism," Roesch considers it the "first link in the chain of degrees and forms of cretinism," Morel says that "goiter is the first stage on the road that leads to cretinism," and Niepce refers to goiter as the "first degree in the degenerative process of which cretinism is the final term." Other inves- tigators lay more stress upon the etiological relationship, believing that where the endemic factors are light, goiter alone is to be found, and that where they are severe, cretinism appears. Rambuteau says, "The causes of goiter and cretinism are the same, and only differ in the degree of activity," and Milani affirms that "where only goiter is to be found, we can be certain that the endemic factors are mild." We may there- DISTRIBUTION OF EXDEMIC GOITER AXD CRETLXISM 223 fore conclude that where goiter is at home, cretinism is rarely missing, and in regions of high goiter endemicity it is frequent. This is true not only of the Central European Alpine region, but also of the high plateau of Middle Asia and all other goiter regions of the earth. This local and geographical joint occurrence indicates, of course, an intimate connection between the conditions of both maladies. Griesinger writes, "Where the endemic is very severe, the entire population is affected. Besides the true cretins, the half-cretins, and goiter-bearers, there are innumerable weak-minded, miserable, and badly proportioned indi- viduals; there are many deaf-mutes, stutterers, and stammerers, and strabismus and deafness are frequent. Through the entire native-born population runs a streak of physical degeneration and mental dulness; even those individuals who pass for health}' and intelligent, are, on the whole, unlovely, narrow-minded, and sluggish, and the country teems with mean-spirited phihstines in whom the qualities of heart are insufficient to compensate for the lack of intellect." Often the influence of the cretinoid degeneration is to be observed only in symptoms to which ordinarily no significance is attached, they are considered as racial peculiarities or family characteristics, etc., but not as the sign of a pathological process which they really are. Among these symptoms must be classed, abnormally small stature with dispro- portionately long body and short legs, ugly repulsive features, mean- spiritedness, diminished mental faculties, retarded development, etc. Close observers have long ago noted that these peculiarities are not accidental, but stand in close relationship with the prevailing endemic goiter and cretinism. That deaf-mutism must be included in the cretinoid degeneration has been scientifically established by the investigations of Bircher and others. Deaf-mutism is to be found elsewhere than on endemic terri- tory, but is of rare occurrence and is not associated with idiocy. In countries exempt from goiter there occur 3 cases of deaf-mutism per 10,000 inhabitants, while in endemic centers it is far more frequent. Among civilized countries, Switzerland possesses the highest number of deaf-mutes. The statistics of 1 87 1 show a general average for the whole country of 24 per 10,000 inhabitants. Were we, however, to separate the endemic territory from the rest of the country, the relative figures would be far higher, amounting in some regions to 250 and more per 10,000 inhabitants. In Austria the regions where severe goiter endemics prevail suffer proportionated from an endemic deaf-mutism; in Salzburg there are 27.8 deaf-mutes per 10,000; in Stvria 20, and in Carmthia 44 per 10,000. The endemic is most intense in the Cannthian district ot St. \ eit and Wolfsberg and in the Salzburg district ofZell where there are more than 224 ETIOLOGY OF ENDEMIC GOITER AND CRETINISM 50 deaf-mutes per 10,000 inhabitants. This coincident and parallel movement points to a close inner relationship. These statistics as to endemic deaf-mutism have been drawn from H. Bircher's monograph on Endemic Goiter and its Relationship to Deaf-mutism and Cretinism. His conclusions are: "We must consider endemic deaf-mutism not only as an accompanying symptom of cretinism, but also as an intermediate form of the cretinoid degeneration between goiter and cretinism." He further says, "It is my belief that endemic goiter, deaf-mutism, and idiocy are only different degrees and ultimate results of one and the same degenerative process." Moreover, the endemics of these diseases are invariably concurrent, that is, the severer forms of the degeneration such as deaf-mutism and idiocy do not occur without the milder form — goiter. But where the endemic is slight, goiter may occur without deaf- mutism and cretinism. In conclusions based upon investigations made in the deaf and dumb asylums of Switzerland, Bircher states that while two-thirds of the pupils in these asylums are cases of endemic deaf- mutism and one-third sporadic, it is safe to affirm that 80 per cent, of all deaf-mutism in Switzerland must be attributed to the prevailing goiter endemic. Of the pupils in Swiss asylums for the deaf and dumb 72 per cent, are goiterous. In the Provinces of Piedmont, Lombardy, and Venice, in 1883, among a population of 9,565,038 there were 128,730 goiter-bearers and 12,882 cretins. That is, about 1 in every 67 of the inhabitants was either goiterous or cretinous. In the Tyrol the statistics, made by the Austrian Government in 1883, show 930 cretins in a population of 797,040; the number of goi- ters is not given. In Cisleithania, Austria, with a total population of 21,840,112, there were in 1883, 12,815 cretins, or 58.6 per 100,000. In the District of Murau in Styria, where the endemic is most intense, the proportion of cretins is 1045 to every 100,000 inhabitants. In France Baillarger estimated in 1873 that the total number of adult goiterous individuals over twenty years of age reached 370,043, and that of cretins about 120,000; that is, in a total population of 36,000,000 the proportion of goiter subjects was 1.04 per cent, and that of the cretins, 0.33 per cent. These figures, however, change most significantly if we consider the regions where the endemic prevails with the greatest intensity separately; we then find in the department of Savoy, for instance, 133.7 goiterous individuals per 1000, and in the valleys of the Maurienne and Tarantaise respectively, 22.7 and 14.5 cretins per 1000. According to the statements of Mayet in 1900 these conditions as given by Baillarger have not altered appreciably. McCarrison reports that in the part of the Himalayas where his researches were carried out, DISTRIBUTION OF ENDEMIC GOITER AND CRETINISM 225 goiter is so common that in some of the villages it is difficult to find man, woman or child not suffering from the deformity. He estimates that not less than 20 per cent, of the population of Gilgit suffer from goiter, and he found in a population of 70,000 over 200 cretins. In Himalavan India and Europe alone McCarnson estimates the number of sufferers from goiter at about 5,000,000. In fact it cannot be suffi- ciently emphasized that goiter exercises an eminently destructive racial influence, and that where it is endemic the capacity for physical and intellectual work must be seriously undermined. Nor must it be for- gotten that the mortality for endemic centers is considerably higher than elsewhere. In Tyrol, Carinthia, and Styria there are numerous goiter and cretin centers, the disease descending from the mountain slopes into the plains and appearing here and there along the river valleys such as the Danube, Enns, etc. Despite the very striking association of goiter with mountainous regions, it is not confined to them. St. Lager tells us that it is prevalent on the plains of Lombardy, of Piedmont, and of Alsace; that it occurs on the plains of the Danube in Upper and Lower Austria, and that it is met with on the plains of the Lena and Obi in Russia and along the St. Lawrence River in Canada; and that it is even to be found in some of the oases of the Sahara. Goiter is very rare in the North German Lowlands, in Denmark, the Netherlands and in the Scottish Highlands. In Sweden, according to Ewald, there existed in the whole country in 1867 only 628 goiter-bearers, of which 579 were to be found in the District of Falun. In France the Alpine Depart- ments, the Vosges, Cevennes, the Pyrenees, and the high central plateau are affected. The disease is so common in certain parts of England that it has been known as the "Derbyshire neck." It is especially prevalent in Derbyshire, Hampshire, and Sussex. In Spain endemic centers exist in the Pyrenees, Asturia, and Galicia. The mountains of Asia, Japan, and manv of the Asiatic Islands have numerous foci. The Himalayas, the Cordilleras, Caucasus, Ural, Atlas, and Altai Mountains all have goiter centers. Goiter occurs also upon islands like Ceylon, Madagascar, the Azores, Java, and Sumatra. Goiter is to be found in North America where Munson has observed closely circumscribed endemics among the Indians. According to Bircher who gives St. Lager as his authority), endemics accompanied by deaf-mutism prevail in the States of New r York, Ohio, Virginia, Mich- igan, Kentucky, Tennessee, Maine, Vermont, Connecticut, Massachu- setts, and New Hampshire. There are 15,000 feeble-minded in Ohio. In Wisconsin endemic goiter is common. The region of the Greal Lakes is reported by Dock, Osier, and Ad a mi to have numerous 15 22(1 ETIOLOGY OF ENDEMIC GOITER AXD CRETINISM goiter centers. Ashmead tells of an endemic center in Pennsylvania, and Holder, of centers in Montana, Dakota, Mississippi, and also in the vicinity of the Rocky Mountains. Marine finds the disease widely disseminated along the Great Lakes, not only among human beings, but also among animals. He states that the endemic is espe- cially severe among sheep. According to his investigations, 90 per cent, of the street dogs of Cleveland are goiterous. In the United States and Canada goiters, though numerous, are, as a rule, not large, and cretinism is rare. Along the shores of Lake Erie, Adami speaks of French-Canadian villages in which scarcely a family is to be found without one or more goiterous members. In South America the first explorers of New Granada were aston- ished to find the banks of the Rio Magdalena inhabited by a race of heavy and stupid savages of sluggish habit who passed their days in sleep. Among the goiterous Indians of the Peruvian plateau, cretinism had reached such a degree that it required nothing less than a papal bull from Paul III to convince the missionaries that these were indeed men with souls to be evangelized. In Brazil the river which divides the provinces of Corrientes and Entre-Rios is called the Guay-qui-raro or "thick-neck maker" by the Indians, a convincing testimony as to the existence of the endemic in these regions. In the Balkans the Struma River, along which heavy fighting has been taking place during this great world war, is called "Struma" because of the prevalence of goiter along its banks and tributaries. It has been asserted by Saussure and Demme that goiter was not to be found above an altitude of from 3000 to 3600 feet, and Demme and Maffei maintain that it does not occur under 900 feet. We know both of these theories to be untenable. McCarnson met with goiter at 10,000 feet in the Himalayas, and we have reliable information as to its existence up to an altitude of 15,000 feet (Nepal, Kemaon, Kash- mir, etc.), and at 6000 feet in Savoy as well as on the high plateaus of Bolivia and Peru. The mountainous regions of the Upper Tonking, Laos, and Yunnan, as shown by Clavel, Simon, Billet, and Jouveau-Dubreuil, may be con- sidered as one of the great boulevards of goiter just as severely affected as the Alps and Himalayas. In 1896 Billet wrote of Kao-Bang, "This affection is extremely common among the native population inhabiting the rocky amphitheaters and deep gorges of Upper Kao-Bang." MILITARY SIGNIFICANCE OF ENDEMIC GOITER 227 ECONOMICAL, SOCIAL AND MILITARY SIGNIFICANCE OF ENDEMIC GOITER AND CRETINISM. In an interesting article on goiter as an economic loss, Dr. Oswald writes, "If we allow the military statistics of Switzerland to speak for themselves, we shall see that an average of 17CO recruits, i. t the leg and occur during the night. Cramps in the arms and hands. somewhat tetamform in character, have been observed very rarely. Tendinous Reflexes. In the majority of true exophthalmic goiters it can be said that the tendinous reflexes arc rather exaggerated. 1 hey may be, however, normal, diminished, or even non-existent. CHAPTER XXV. NERVOUS AND MENTAL SYMPTOMS IN BASEDOW'S DISEASE. Broadly speaking, more or less all of the clinical symptoms seen in Graves' disease are of nervous origin, because they are the results of the involvement of the nervous system governing the vegetative life. In sens u strictiori, however, there are symptoms which are more than others directly due to some disturbances of the nervous system. These are the ones which we are going to study in this chapter. The chief nervous characteristics seen in Basedow's disease are: emotionality, irritability, restlessness, and instability. More severe cere- bral disturbances may also be observed such as obsessions, impulsions, hallucinations, and mental confusion. True insanity may even be encountered. Basedow patients are, above all, emotional. The slightest cause will throw them into a wild state of excitement which goes hand in hand with an exacerbation of their physical state. As Peter has said, "Base- dow patients can be compared in every respect to normal individuals subjected to great excitement." In both conditions anxiety, palpita- tion, tremor, secretory disturbances, such as perspiration, diarrhea, and polyuria, etc., are present. Some Basedow patients are afflicted with a pathological sensitiveness; they laugh and cry apparently without the slightest cause. Some of them have fits of religious mysticism, some others show abnormal excitation of the sexual apparatus, while others live in a state of constant fear. I recall a patient who developed a marked mania for music. Although devoid of any special musical gift, whenever she heard music she would plunge herself into a semicataleptic state, recoiling within herself, with a fixed and staring look, tense, and vibrating. One would have thought that she was enjoying a paroxysm of artistic sensations. Possibly she was, yet there was always in my mind a suspicion that a great deal of it was simply affected. This fact should not diminish at all the interest in the observation, inasmuch as simulation and deceit are among the features of certain hysterical derangements. I recall another patient who developed a sudden morbid passion for cards. In conclusion it may be said that the emotionality in Graves' disease is nearly always exaggerated and consequently pathological. Some thyrotoxic patients become exceedingly irritable. They may enter into the most paroxystic fits of rage. Trousseau has said that some XERVOUS SYMPTOMS IN BASEDOW'S DISEASE 335 Basedow patients live in a state of perpetual anger. Although possibly of quiet, nice, self-possessed disposition previous to the outbreak of the disease, these patients become difficult to handle. They quarrel with their most intimate friends, and render life miserable for the mem- bers of their families. Their love for their own relatives becomes less and less marked; they think only of themselves and become extremely and peculiarly egotistical. They require the most constant attention and even when the most devoted care is given them they complain of being neglected. Gradually their love changes into hate. This frame of mind will explain why a great number of these patients are divorced or separated women, and why some of them are simply abandoned by their husbands. Of course this is no excuse for the husband's cowardly act, but may explain it to a certain extent. Too often, I am sure, the husband does not realize that his wife's bad temper is pathological, that she should be treated as a sick woman, but rather takes it for granted that his wife has an infernal disposition, and that both will be better off separated. The mental condition in Basedow's disease is most restless and unstable; it varies with the degree of excitation or depression in which the patient finds himself. If he is undergoing a period of excitation, his intelligence is vivid and excessively mobile. The patient will spend hours in thinking and scheming, and will translate his exaggerated men- tal activity into a profuse loquacity, talking about everything in the most superficial way, and jumping from one subject to another with- out the slightest effort: if I may be allowed to use a metaphor, he is suffering from a veritable "cerebral diarrhea." Usually the memory is good. With this exaggerated mental activity there goes hand in hand an increased physical activity. The Basedow patient is exceedingly restless, constantly moving, and changing position. He is unable to remain seated very long at a time, but goes and comes, sits and rises, and makes hasty movements — many of them involuntary and without purpose. The patient shows considerable ardor in the accomplishment of the various tasks he undertakes, but as he is mentally unstable, he seldom terminates what he starts out to do. He will tackle one job after another, but will not accomplish much; in short, he shows an incoherent activity without any definite purpose. In other patients, on the contrary, we find mental depression; they cannot concentrate their attention upon any subject without the great- est fatigue. Their memories are weak and untrue. There is a marked intellectual laziness which prevents them from pursuing a train ot ideas. At the same time there exists a more or less complete physical apathy. Since their mental faculties are depressed and their physical needs are reduced in the same proportion, these patients will lie motion- less in bed, every physical effort being distasteful, even painful to them. 336 NERVOUS SYMPTOMS IN BASEDOW'S DISEASE In conclusion we may repeat what we said in the beginning of this chapter: the nervous and mental state in exophthalmic goiter is charac- terized bv emotionality, irritability, restlessness, and instability. These pathological features are subject to great variations; they improve as the thyrotoxicosis subsides and, vice versa, they become more marked as the thyrotoxic condition gets worse. In the late stage of the disease these psychic disturbances may acquire a more serious character. Not so infrequently the exophthalmic goiter will terminate by an acute delirium. This delirium resembles in every respect the one seen after intoxication with iodoform and in postoperative hyperthyroidism. In all three conditions the patient shows an extreme agitation and is delirious; he does not recognize his attendants any longer, nor the members of his family; he wants to get rid of his covers, his dressings, to get out of bed, and almost invariably, he "wants to go home." Some- times it takes several nurses to hold him in bed. He talks constantly in a more or less incoherent manner about those things which are familiar to him, especially those of his occupation or profession. If he is a farmer, he may talk about pitching hay; if he is a lawyer, he may talk about defending a suit; if the patient is a housekeeper, about some feature of housekeeping. This delirium, however, is not systematized. It is usually accompanied by hallucinations. Then the patient speaks to people whom he sees in his delirium dreams; they may stand beside him or on his bed; they may be at the threshold of the room, or perhaps climbing over the window. Not infrequently one will gather from what the patient says that the people whom he sees want to do him harm, that they want to kill him. This form of delirium may last for days and weeks, and usually terminates in death. That this form of delirium is in direct etiological relation to thyrotoxicosis there can be no doubt. As said before, it resembles so closely the one seen in certain forms of postoperative hyperthyroidism that its etiology must be the same. That hysteria may be found in combination with Graves' disease cannot be denied. It is a complication seen more often in young women than in men, and it may develop later as a complication of Graves' disease. As a rule, however, when hysteria is present, it has existed before Basedow's disease underwent its development. That hysteria is an entity by itself is shown by the fact that it does not follow the course of Graves' disease, improving when the latter improves, and getting worse when the other undergoes exacerbations. The hysterical symp- toms may follow their course, getting worse while the thyrotoxic symptoms gradually disappear. It would be a mistake, however, to believe that the majority of Basedow patients are hysterical; this is not so. In my own experience, XERVOUS SYMPTOMS IN BASEDOW'S DISEASE 337 I would say that the majority of patients do not show the characteristic mental accompaniments of hysteria. As Thomson says, "They look their physician straight in the face, and show no response to suggestions. They deny the symptoms which they do not have, and remain consis- tent in their description of the symptoms which they have, with no variation in their story for months, while they are always ready to acknowledge any improvement in their symptoms when thev occur." Neurasthenia sometimes occurs as a complication of Graves' disease; it is more frequent in men than in women. Like hysteria, it is not in direct relation to thyrotoxicosis, but seems to be a nervous disturbance per se. There are, however, a number of psychoses which occur in conjunc- tion with Graves' disease whose etiological relation is still an open question for discussion. I have in mind those transitory obsessions and impulsions which are sometimes seen in Basedow's disease. In 1871 Solbrig reported the case of a woman, who, although deeply loving her children, wanted to kill them. I have seen a similar case. It was that of a woman who felt at times an irresistible impulse to kill her child. A patient of Raymond and Seneux was afraid to cross a large public square because she thought that she was bound to be run over by a wagon. Another patient thought that she was going to die, that her heart was going to burst, or that something was going to fall upon her and crush her. Some patients have a tendency to suicide, and a patient of Plaignard constantly saw herself hanging to a window. All these obsessions, impulsions, and phobia have the peculiarity of being irre- sistible, or at least, of being filled with the utmost anxiety. The obses- sion is sometimes so intense that on the spur of it the patient will occa- sionally do the most extravagant things, and the most cruel thing of all is that he knows that his impulses are wrong, so that for a long time he will fight against them; hence the great moral and mental suffering which terminates only when the impulsive act, no matter how extrava- gant or immoral, has been accomplished. Although he knows that he acted wrongly, nevertheless, he feels a sense of relief and satisfaction, temporary at least, when the act has terminated the crisis. Exophthalmic goiter may occur as a complication in a variety of psychoses such as in pseudosystematized delirium of degenerates, in mania, in melancholia, in maniacal states, in depressive melancholia, in delirium acutum, in paranoia, etc. Vice versa, psychoses may follow after Graves' disease has long been fully developed. Psychoses may occur at any period of the development of Graves' disease. Sometimes only after the thyrotoxic complex has subsided entirely do we see the development of psychoses. On the other hand, the goiter may appear years after the patient has had psychic disturbances and which have long since subsided. 22 338 NERVOUS SYMPTOMS IN BASEDOW'S DISEASE We have, consequently, the right to ask ourselves the following question: Is there a true thyrotoxic insanity, or are the psychoses found in conjunction with Graves' disease purely accidental? From all the well-authenticated cases reported in the literature which I have been able to lay my hand upon, it seems to me that we cannot consider these psychoses as of thyrotoxic origin. They are only associated nervous disturbances, grafted upon a predisposed terrain. Here, too, we find the same ladened heredity, and the same psychic as well as physical stigmata found in the same psychoses complicated with Basedow's dis- ease. That, however, Graves' disease supervening in such predisposed and unstable terrain is bound to favor the eclosion of psychoses is a fact which every one will readily admit. The reverse is true, too; thyro- toxicosis will evolve more easily and more fully in individuals whose nervous system is already in an unstable equilibrium. When I see certain young, nervous, irritable and unstable individuals, I cannot help but look upon them as future candidates for Graves' disease. Chorea and choreiform conditions are sometimes seen in conjunction with Graves' disease. I, myself, have met with that combination two or three times. It occurs nearly always in young girls and children. There is no definite relation between the two conditions as to their onset; chorea may develop first, and then the exophthalmic goiter, or vice versa, or the two conditions may develop at the same time, or one of them may regress while the other remains progressive. As a rule, however, the improvement of one involves the betterment of the other. Although their association is purely accidental, there appears to be in certain instances an etiological relation. Heredity of Graves' Disease. — That Graves' disease may be heredi- tary is shown by a number of examples. Osterreicher reported the case of an hysterical woman who had ten children, six girls and four boys. Eight of these children developed Graves' disease. One of the daughters married and had four children; three of her daughters developed exoph- thalmic goiter and the fourth was hysterical. Cantilena reported the case of an hysterical woman having two children, one son and one daugh- ter; both had exophthalmic goiter. The daughter herself had three girls, two of whom developed exophthalmic goiter. Cheadle saw four cases of exophthalmic goiter in the same family. Thyssen reported a case of a mother and daughter having exophthalmic goiter. Solbng and Kronthal also reported a case of mother and child having exophthalmic goiter. Dejenne saw a family in which exophthalmic goiter was heredi- tary during four generations. I have seen three sisters afflicted with exophthalmic goiter; in another instance a mother and her daughter both had exophthalmic goiter. Similar cases are not so rare. It is not so infrequent to see Graves' disease develop in patients whose nervous heredity is heavy. CHAPTER XXVI. DIGESTIVE DISTURBANCES. Digestive disturbances are very frequent in Graves' disease, and their importance is not to be belittled, because they will often so inter- fere with nutrition that life is endangered. None of the symptoms seen in Graves' disease seems to tell upon the general condition of the patient so much and so quickly as gastro-intestinal disturbances. In a very short time the patient will melt away, and in a few weeks may be dead. We have all seen these fulminating forms of thyrotoxic troubles which in less than six or ten weeks have brought a Basedow patient, whose general condition at the onset was otherwise good, to his death. The first fact to note is, that these symptoms develop usually when the disease is in its incipiency. A number of times they will be found in the history of the patient so long before any of the thyrotoxic symptoms have been clearly established, that we may say that they are often the forerunner of the disease. This is especially true for diarrhea; hence the necessity of always bearing in mind the possibility of Basedow in cases where diarrhea sets in without apparent cause, remains persistent for a while and then subsides. The other fact is that digestive disturbances are distinctly specific, and manifestly unlike any other affections of the gastro-intestinal tract. In their mode of appearance, in their pathological manifestations, and in their way of subsiding they are always the same. They usually occur without any apparent cause and subside the same way. They sometimes appear to follow a cycle. With their paroxysmal character and with their peculiar way of appearing and subsiding, they remind one of tabetic crises. Never at any stage of their development, may it be at the beginning or the end, do they present the inflammatory, exudative, or ulcerative characters seen in other pathological conditions of the gastro-intestinal tract. Finally, they are most uncontrollable and stubbornly resist any form of medical treatment, no matter at what stage of their development it may be instituted. That there is a close relation between the disturb- ances of the gastro-intestinal tract and the other thyrotoxic symptoms is shown by the fact that the course of the latter goes hand m hand with the improvement or exacerbation of the former. One thing is certain: no improvement in the disease can be expected so long as the gastro- 340 DIGESTIVE DISTURBANCES intestinal symptoms have not subsided. On the other hand, when once they have retroceded entirely, it is remarkable to see how quickly a patient will rally and put on flesh, even when his condition was such as to appear hopeless. Another distinctive feature of these gastro-intestinal disturbances is the acetone breath which one will so often notice while near the patient, or even upon entering the room. It is due to acidosis. Let us take these gastro-intestinal symptoms separately and study them. Appetite. — Loss of appetite is very common and one of the early symptoms. It may be so marked as to lead the patient into a state of complete anorexia. I have seen fatal cases which for weeks showed an absolute repulsion toward food of any sort. In these cases if anorexia is complicated with gastric intolerance, if one succeeds in getting some food into the patient's stomach, that nourishment comes up again as quickly as it went down. In some instances loss of appetite alternates with spells of hunger. In other conditions the patient may suffer from bulimia; the appetite is then ravenous and never satisfied no matter how much food the patient takes. Bulimia often becomes intense dur- ing the night. It may even exist despite the most intense vomiting, diarrhea, and loss of flesh. Nausea. — A very common thyrotoxic disturbance is nausea. It is a very persistent and very annoying symptom which may last for weeks, months, or even years, with or without periods of remission. It is usually more marked after eating, but may have no relation whatsoever to food, occurring as often with empty stomach as it does after meals. Nausea is always worse in the morning; it rarely leads to vomiting. Gastric Flatulence. — This is another symptom which often goes with the gastro-intestinal disturbances in Graves' disease; it has a most per- sistent character. The patients attempt to relieve themselves by fre- quent eructations which have none of the acid or acrid characteristics seen in other gastric disturbances. It seems to be mostly air which they eructate. This would lead to the belief that some of the patients are aerophages or air-suckers. Vomiting. — In more serious gastric disturbances vomiting is always present. It may be so marked as to endanger the life of the patient. It occurs with empty stomach as well as after taking food. When not too severe, it may take place only four or five times a day, while in severe conditions it may occur as often as ten to fifteen times a day. The vom- itus may be watery, slimy, or colored with bile; blood is very seldom found, but if it is, it is only under the form of some bloody streaks due very likely to injury of the mucous membrane of the stomach or esoph- agus through the efforts made in vomiting. As shown by repeated fluoro- DIARRHEA 341 scopic examinations, the stomach is in a state of more or less constant spasticity. Nothing definite is known about the gastric chemistry in hyper- thyroidism and especially during the gastro-intestinal disturbances. As a rule there seems to be either anachlorhydna and apepsia, or hypo- chlorhydria and hypopepsia. In some instances, however, there is undoubtedly hyperchlorhydria. Diarrhea. — Diarrhea is among the most important digestive disturb- ances in Graves' disease. Its running down effect upon the patient is possibly more marked than that of vomiting. Apparently without any precise cause and usually in no relation to the taking of food, the patient will have a number of stools which may vary from 4 to 30 in twenty- four hours. These stools are watery, yellowish or gray in color, and often contain bile products. It is interesting to note that in certain cases the stools contain a great quantity of undigested fat. As a rule the discharges are not offensive and do not contain blood, mucus, or pus. They are neither preceded nor followed by pain, although the patient may complain of a diffuse distress throughout the abdomen and of some flatulence. Like vomiting they show morning exacerbations. No medical treatment seems to have any hold upon them. Diarrhea may alternate with spells of constipation. Often, however, as soon as diarrhea has subsided, the intestinal tract resumes its normal function, just as if nothing had ever happened. If diarrhea is moderate and unaccom- panied by vomiting, and if the appetite remains fair, its effect upon the patient will soon pass unnoticed. If, however, diarrhea becomes severe and is at the same time complicated with vomiting, the resistance of the patient will be put to a severe test. In a few cases of very severe thyrotoxicosis, icterus may be observed. This icterus is rare, although it is not uncommon to observe a yellowish tint of the sclerotica in severe thyrotoxic gastro-intestinal disturbances. The prognosis of this icterus is always bad. This icterus is not due to any obstacle in the bile ducts, but is of toxic origin. I think we are within our rights when we say that these gastro- intestinal symptoms are of vagal and sympathetic origin, secondary to some toxic influence of the thyroid secretion upon the s\ mpathetico- vagal system. CHAPTER XXVII. GENITAL DISTURBANCES. Menstrual disturbances are quite frequently seen in conjunction with Basedow's disease. Although once in a while one may meet with a case in which menstruation is prolonged and profuse, as a rule, how- ever, the opposite is true in the great majority of cases. In these men- struation becomes irregular, scant, and often stops altogether for periods which may last months or even years. In some instances menstruation ceases abruptly long before any true symptoms of the disease show up. There is then a premature menopause which may remain permanent, no matter if it does occur a number of years before the natural time for menopause has come. I have seen thyrotoxic cases in which premature menopause occurred at twenty-eight, twenty-nine, or thirty years of age, and which remained permanent after that. More frequently, however, menstrual disturbances develop gradually and in direct proportion to the severity of the disease. As soon, however, as the thyrotoxic condition begins to improve, menstruation gradually returns to its normal condition. The most hopeful sign in Graves' disease is the return of menstruation. With the menstrual disturbances, there ceases, or at least, diminishes to a great extent, the sexual appetite; the entire genital apparatus undergoes atrophy and sclerosis; the uterus, tubes, and ovaries become small. If the patient is a man, the testicles undergo atrophy. In conclusion we may say that in Graves' disease the entire genital apparatus is in a state of hypofunction. Gynecological lesions, such as inflammations, tumors, and mal- position of the genital organs, are sometimes found in conjunction with Graves' disease. In some instances the surgical treatment of these gynecological lesions resulted in the absolute cure of the thyrotoxic symptoms. CHAPTER XXVIII. RESPIRATORY DISTURBANCES. In Graves' disease respiration certainly does not follow the same rhythm seen in normal individuals. It is rapid, superficial, and irregular in character; it alternates with periods of rest which, in turn are irregu- larly interrupted by one or two deep respirations which have more the .character of a sigh: there exists a true respiratory arrhythmia. The number of respirations may attain the double. of the normal number. Hofbauer, of Vienna, has shown that the respiratory curves in Graves' disease have a decided type of their own. The amplitude of their excur- sion is shorter than those seen in normal, and other pathological condi- tions; furthermore, inspiration and expiration are exactly equal in length; finally, these respiratory curves are irregular. Hofbauer claims that this type of curve is characteristic for Graves' disease, and that it is seen, not only in patients complaining of shortness of breath, but in the ones who apparently are not conscious of any respiratory trouble. Naturally, since short and superficial respiration will have as a corollary a diminished amplitude of the thoracic excursions, and since inspiration and expiration are of equal length, it follows that the excursions of the thorax during inspiration and expiration will be reduced in the same proportion. This can be easily demonstrated with a special apparatus for thoracic measurements, as was shown by Louise Fiske Bryson in 1889. This symptom has since then been known as the Bryson symptom. Shortness of Breath. — Shortness of breath is often complained of by Basedow patients. It may be constant or may come on by spells. It may be present with or without physical exercise, but always becomes more marked when the patient does some exertion or undergoes some psychic excitement. This shortness of breath in the great majority of cases is not in relation at all to the volume of the thyroid. This might have been foreseen, as we all know that mechanical disturbances of the trachea do not cause a rapid and superficial respiration, but on the contrary, that under such conditions respiration is slower and deeper. Might not this shortness of breath be of cardiac ongm : It is true, indeed, that in certain advanced cases of hyperthyroidism we have marked cardiac disturbances due to vascular and valvular insufficiency. Under such conditions we shall have to admit that shortness of breath will be mostly due to cardiac troubles, but there again the respiratory 344 RESPIRATORY DISTURBANCES disturbances have a decided character of their own with which every one is familiar. Since shortness of breath is observed from the early beginning of the disease at the time when the cardiac muscle is still strong and its valves are still continent, we shall have to find something else than the heart to explain it. As we have seen, the cause of this shortness of breath is the disturbed rhythm of the respiratory apparatus itself. Respiration is superficial; the amplitude of the thorax is dim- inished materially, and consequently, the intake of air is ipso facto reduced. These disturbances will naturally lead to insufficient oxygen- ation of the blood and will contribute toward increasing the already disturbed metabolism. But the true primary cause is most certainly in the direct influence of the thyrotoxin upon the respiratory centers. In advanced cases degeneration of the respiratory musculature, especially of the diaphragm, as has been shown by Askanazy, might be considered as an adjuvant factor. Coughing. — A symptom which when present is persistent and annoying is coughing. The thyrotoxic cough is dry and not accompanied by expectoration; no pulmonary lesions are at the bottom of it. It is often exaggerated by the recumbent position, and becomes consequently annoying to the patient because it prevents him from sleeping. In the great majority of cases this coughing is not caused at all by the pressure of the goiter upon the trachea, but according to Sattler, it is caused by an exaggerated sensibility of the mucous membrane of the entire respira- tory apparatus. Under such conditions the irritant which in ordinary conditions would pass unnoticed is sufficient to produce a reflex cough. It must not be forgotten that many of these coughing spells are of hysterical origin. Hoarseness. — Hoarseness, without any definite pathological reason, is seldom seen. Weakness of the voice, however, is much more frequent, and may sometimes lead to aphonia. The latter symptom is not in relation to the size or to the position of the goiter. Patients often complain at the same time of a sense of constriction in the throat, and sometimes accompanied by pain. These manifestations are nearly always of hysterical origin. CHAPTER XXIX. SENSORY DISTURBANCES AND INSOMNIA. A sense of throbbing and tinnitus in the ears is sometimes com- plained of by Basedow patients. Rarely there is a disturbance in the sense of smell. As said previously, patients complain of pain in the eyes, of flashes of light, and of dark and bright-colored spectra. Pains. — Pains are among the most common complaints of Basedow patients. These pains are exceedingly variable as to their seat and nature. They may implicate such various parts of the body as the tips of the fingers or toes, the heels, the palms of the hands, the upper and lower extremities, and the joints, such as the knees, wrists, and ankles. Often these pains are purely muscular. The most common site is in the muscles of the neck, especially the sternocleidomastoid muscles. These pains differ from rheumatic pains since they are extremely shifting in charac- ter. The\' are not painful to firm palpation, do not show anv swelling and are not materially affected by changes in the weather. The)' may be distinguished, too, from peripheral neuritis by their transient character. Headaches. — Headaches are among the most frequent sensory disturb- ances observed in Graves' disease. Intermittent in character, they may be in some patients of almost daily occurrence. The)' are of the migrainous type. Sometimes the)' are periodical, occurring, for instance, at the menstrual periods. In the majority of cases they are characterized by the patient as "dull" headaches; sometimes they take the form of violent headaches. They are mostly localized in the occipital, the fron- tal, or the temporal regions, and are most frequently complained of in the morning. They are seldom accompanied by nausea or vomiting, and differ from typical attacks of migrain in not coming on in severe paroxysms, and in not leading to vomiting. It is self-evident that all patients suffering from headaches are not thyrotoxic patients. Since headaches occur with predilection in neuro- pathic individuals, it is fair to admit that Graves' disease will only exaggerate this neuropathic tendency, and, consequently will increase the chances for headache; hence the frequency of the symptom. We might even go further and admit in certain conditions the existence of a true thyrotoxic headache, dull in nature, mostly localized in the occipital region, and subject to morning exacerbations. Often, too, headache is only a symptom of acidosis which frequently accompanies thyrotoxicosis. 346 SENSORY DISTURBANCES AND INSOMNIA Vertigo. — Occasionally vertigo is complained of by the patients. It is often associated with aural disturbances and is more pronounced in patients complaining of throbbing and tinnitus of the ears. Tingling and Numbness. — Tingling and numbness of the upper and lower extremities is sometimes another complaint; it is more frequently observed in the lower limbs. INSOMNIA. Another of the frequent complaints of Basedow's disease is insomnia. From a light sleep often interrupted by periods of wakefulness, up to a more or less complete insomnia, all degrees are seen. The patient may enjoy a few hours sleep in the early part of the night, but after mid- night insomnia becomes stubborn. Very often sleep is disturbed by dreams, more or less unpleasant, and which sometimes take the form of frightful nightmares. CHAPTER XXX. CUTANEOUS SYMPTOMS. Sensation of Heat. — Vasomotor)' disturbances are quite frequent in Graves' disease; the)' manifest themselves commonly by an exaggerated sensation of heat. Basedow patients are always warm, in fact, too warm, although their bodily temperature is normal. When other people feel comfortably cool or, in fact, even cold, Basedow patients will still complain of being too warm; they seek drafts. During the coldest weather the)' feel comfortable only if the windows and doors are open. They wear only thin clothing, far too thin for a normal individual to be comfortable in. The winter is their best season, while in summer they always feel prostrated. Basedow patients often complain of hot flashes; the)' flush easily and have red cheeks; the least physical or psychical excitation is suffi- cient to cause a marked congestion of the face and sometimes of the entire body. Dermographism. — Dermographism is often found in Graves' disease. It takes its origin, too, in a disturbed vasomotor)' function. It may be obtained by scratching the skin once with a pencil or the finger. Two or three seconds after the scratching has been done, a red line, more or less intense, appears following the direction of the scratching, and which lasts quite a long time and then fades away. Not so infrequently instead of being red, the line is white; it becomes red only a little while after. In other instances the white line is surrounded on either side by a streak of redness. Hyperhydrosis. — As a rule Basedow patients suffer a great deal from hyperhydrosis. They sweat continuously and profusely, with or without any physical exercise, and very often at night as well as in the daytime. These sweatings, like the other thyrotoxic symptoms, are subject to great variations, being more marked at times than at others. As a rule the sweat is odorless; however, in rare cases, a very offensive odor has been observed. On account of the constant moisture of the skin it will be easily understood, as \ igouroux has shown, why the skin of Basedow patients offers less resistance to the electrical current than the skin of normal individuals. Itching of the Skin. Not very frequent, but when present an annoying symptom, is itching of the skin. It may be accompanied by some skin 348 CUTANEOUS SYMPTOMS eruption, but may be present, too, without any visible involvement of the skin. It may be exceedingly intense, may last night and day, and usually follows the up-and-down curves of the disease, improving when Graves' disease subsides, and getting worse when the disease undergoes exacerbations. This, however, is not always true. I have had recently under observation a patient whose thyrotoxic symptoms have almost entirely subsided, except exophthalmos and itching. Scratching neither relieves nor aggravates this itching. Urticaria. — Basedow patients are apt to have skin eruptions. The most frequently seen is urticaria, which in some cases may be remarkably transient in character. I remember a case in which urticaria was so fuga- cious that it would disappear entirely in the time necessary for the patient to go from home to the doctor's office. This, however, is not frequent, and although very changeable in character, it may nevertheless last for long periods of time. Falling of the Hair. — The hair becomes dry, brittle, and falls out. The same is true of the nails of the fingers and toes. This occurs in the early beginning of the disease and retrocedes as soon as the condition of the patient improves. It may involve not only the hair of the head, but also that of the beard, and that over the different parts of the body such as the arms, the thorax, and the axillary space; the eyebrows and eyelashes may even fall out. In all respects this falling resembles the loss of hair after prolonged fevers such as typhoid, and as they do, likewise recognizes a toxic origin. Brown Pigmentation of the Skin, which may sometimes take the bronzing tint seen in Addison's disease is not so seldom observed in Graves' disease. It may involve the entire body, but is more marked in the exposed regions such as the face, the neck, the thorax and arms. Sometimes, instead of being diffusely distributed, it is localized in patches, and in that case is more marked in the bend of the elbows, of the wrist, knees, etc. When present, it is always more marked and appears first around the eyelids, as has been shown in the chapter on Ocular Symptoms. Circumscribed edema is sometimes observed; its site of predilection is in the eyelids; this edema sometimes has a very transient character. It is, too, of nervous origin. CHAPTER XXXI. BLOOD CHANGES IN BASEDOW'S DISEASE. Although Micsowicz and Ciuffini, in 1904, found a lymphocytosis in the blood of Basedow patients, and Caro, in 1907, reported similar findings in one case, it was Kocher, however, who, in 1908, gave these findings their true significance, and considered them as the result of the disease. Since then a number of authors have published the results of their investigations upholding these conclusions. Important information can be gotten by the methodical examination of the blood in Graves' disease. These examinations should always be made with the patient's stomach empty in order to avoid the alimentary leukocytosis. The best time is in the morning before breakfast. The chief characteristics of the blood in Graves' disease are, leukopenia, hyperlymphocytosis, and hypopolynucleosis. We consider as normal, blood which contains about 5,000,000 red corpuscles for men, and about 4,500,000 for women; 7000 to 8000 leuko- cytes; 70 to 75 per cent, polynuclears; 20 to 25 per cent, small and large lymphocytes; 3 to 5 per cent, mononuclears; 1 to 3 percent, eosino- philes; and 0.5 per cent, mast cells. W 7 e shall consequently speak of leukocytosis when the number of leukocytes goes above 8000, and of leukopenia when the number goes below 7000; of hyperpolynucleosis when the number of polynuclears goes above 75 per cent., and of hypo- polynucleosis when the number goes below 75 per cent.; of hyperlympho- cytosis when the number of lymphocytes goes above 25 per cent., and of hypolymphocytosis when this number goes below 20 per cent. This being agreed upon, let us see what are the characteristic changes found in the blood of Graves' patients. The number of red blood cells is usually normal. Not infrequently, especially in young women, this number is higher than normal, running between 5,000,000 and 6,000,000 per cubic centimeter. The hemoglobin content is usually normal. There may, however, be a slight degree of anemia in advanced cases of thyrotoxicosis. The anemia seems not to be dependent upon the thyrotoxicosis itself, but must be regarded as a secondary complication due to the disturbed nutrition. The most important changes in the blood formula are found in tin- number and relative proportion of the white cells. As said beforej the 350 BLOOD CHANGES IN BASEDOW'S DISEASE total number of leukocytes, as a rule, is diminished; leukopenia is present. The lowest rate I have found was 3000; Kocher found it as low as 2000; at the same time the number of lymphocytes and mono- nuclears is increased materially. We have, consequently, a hyper- lymphocytosis: the highest rate I have found was 75 per cent. On the other hand, the polynuclears are always found diminished in a more or less degree; their lowest rate seen was 28 per cent.; we have, conse- quently, a hypopolynucleosis. It is apparent that the increase in the number of lymphocytes takes place at the cost of the number of poly- nuclears. If divergences are still found among authors concerning these blood findings, it is due principally to the fact that it is not yet clear to everybody how to classify the mononuclears which in certain cases show great variations. The eosinophiles are sometimes found increased in Basedow's disease, but this is not a constant finding, and has no special clinical diagnostic value. Mast cells and transitional forms are not materially affected. The behavior of the platelets in thyrotoxicosis is a chapter which still remains to be investigated. In the fruste forms of thyrotoxicosis, the same changes appear, but on a smaller scale. In simple goiter unaccompanied by hyper- or hypo- thyroidism symptoms, the blood formula remains normal. These laboratory findings are of good diagnostic and prognostic value. In doubtful cases where the diagnosis of thyrotoxicosis is not yet certain, a slight degree of leukopenia, of hyperlymphocytosis, and of hypopolynucleosis, will be of great help in deciding whether we have to deal with a thyrotoxic condition or not; the same is true for the prog- nosis. A marked leukopenia, a high lymphocytosis, a marked hypo- polynucleosis, will show that the case is a serious one. A high percent- age of lymphocytes without, or with only a moderate, leukopenia is of good prognostic value, whereas a marked leukopenia with a low per- centage of lymphocytes must be regarded as of bad prognosis. Hyper- lymphocytosis seems to be more or less dependent upon the severity of the disease, being moderate in the early stage, increasing with the inten- sity of the thyrotoxicosis, and diminishing gradually when the condi- tion is getting better. The change in the blood may be followed beau- tifully in operative cases. The same day of the operation the lympho- cytes diminish materially while the polynuclears increase; on the fol- lowing days, however, the blood formula returns to its previous normal pathological condition and only then improves gradually in direct proportion with the disease and usually becomes normal in the fully cured cases. If, in the apparently cured cases, the blood formula still remains abnormal, it is either because there is still some degree of thyro- toxicosis, or because the hyperthyroidism is gradually passing into one of hypothyroidism. Coagulability of the blood will then be the decisive argument which will tell which one of the two conditions we have to BLOOD CHANGES IN BASEDOW'S DISEASE 351 deal with. The return to normal of the blood formula is one of the best signs of cure. This picture of the blood in Basedow's disease, according to Kocher, is the direct result of thyrotoxicosis, either because the thyroid throws directly into the blood stream an increased number of lymphocytes, or because the thyroid secretion stimulates the function of the lymphatic system. These views seem to be upheld by Potrowsky, who found that after total removal of the thyroid in dogs, the small lymphocytes entirely disappeared from the blood. These views are corroborated, too, by the fact that thyroid feeding and the intravenous injection of thyroid extract are always accompanied by a hyperlymphocytosis and a hypopolv- nucleosis; finally, the changes in the blood formula and its return to normal after operation, are the strongest indication that Basedow's formula is dependent upon the thyroid pathology. Were this all, every- thing so far would be lovely in all these explanations. But we must not overlook the fact that we find the same blood changes in thyroid insufficiency. There the thyrotoxicosis can no longer be incriminated. What is the explanation ? Nescio. Lately some authors are inclined to believe that hyperlymphocy- tosis, hypopolynucleosis, and leukopenia are not altogether dependent upon the thyroid changes, but may be the result of alterations of the thymus. Klose maintains that these blood changes are due altogether to thymic hyperplasia. Against such views I could cite two of my fatal cases, in which the blood formula was normal although both patients had very great thymic hyperplasia, as was shown by post- mortem. It is true that these two cases were not suffering from thyro- toxicosis, but only from the mechanical symptoms caused by the large goiter. As we know that in patients with simple colloid or cystic goi- ters, unaccompanied by thyrotoxic symptoms, the blood formula remains normal, possibly, the same might be true for thymic hyperplasia. We may have cases in which thymic hyperplasia causes only mechanical disturbances, and other cases in which it causes thymotoxic disturbances; these cases only would then show changes in the blood formula. These views will have to be corroborated by further researches. One fact, however, is certain: the changes in the blood formula do not always go hand in hand with the amelioration of the disease. There are thyrotoxic cases which can be considered as clinically cured, and which still show even years after, the characteristic changes of the blood picture. Hence the conclusion of a number of authors that these changes in the blood are dependent upon thymic hyperplasia. Furthermore, as in myxedema, the blood picture is similar to the one seen in hyperthyroidism, and since in myxedema the thymus is nearly always hyperplastic, Klose considers this as another proof that the blood changes are due to th\ mic hyperplasia, and that they are not caused by the thyroid pathology. 352 BLOOD CHANGES IN BASEDOW'S DISEASE In conclusion we may say that the question is still an open one. It would be a mistake to think that lymphocytosis is pathognomonic for a thyroid or thymic condition only. Lymphocytosis has been found a number of times in connection with diseases of other glandular organs such as the liver, kidneys, pancreas, parotids, etc., consequently, before giving any diagnostic value to lymphocytosis, we should carefully elimi- nate all other possibilities which might cause that condition. On the other hand, the absence of lymphocytosis does not necessarily mean that we must exclude thyrotoxicosis, because sometimes changes in the blood formula do not occur even in typical thyrotoxic cases. Although exceedingly important, and almost pathognomonic, these blood changes must be, however, carefully interpreted and their true origin and real value established in every given case. Anyone who has had a great deal to do with Graves' disease must have encountered once in awhile a more or less severe case in which an intercurrent disease of moderate severity has, however, proved fatal to the patient. Not very long ago I saw a case in which a moderate degree of tonsillitis terminated fatally without there being any apparent cause or complication to explain such a death. The reason must be found, very likely, in the diminished number of polynuclears. We know that these polynuclears are the defenders upon which our organism counts when it is invaded by infectious agents. They respond at once by millions to the call; they contain antitoxic, peptic, and oxydative fer- ments, and have marked chemotactic properties. In Graves' disease the polynuclears being greatly diminished in number, and possibly inhibited by the thyrotoxin, the means of defense of the organism are reduced. This will explain why thyrotoxic patients are so vulnerable to acute infections, which in ordinary conditions, would be warded off easily. It is true that in the majority of such thyrotoxic conditions, whenever an acute infection takes place, the number of lymphocytes diminishes in order to allow the polynuclears to increase. As soon, however, as the acute process is past, the blood formula returns to its previous conditions, namely, hyperlymphocytosis takes the upper hand, and the polynuclears again becoming reduced in number. In a few cases, however, leukocytosis and hyperpolynucleosis do not take place, or occur in such a small degree that the organism is unable successfully to meet the invaders; it offers to them no, or very little resistance; the battle is really lost before being fought. Coagulability of the Blood. — Kottmann, Lidsky and Kostlivy found that in Graves' disease the blood shows a diminished coagulability, whereas, in hypothyroidism the power of coagulation of the blood is materially increased. This fact will perhaps explain why operations for Graves' disease are so bloody. This difference in the coagulating power of the blood is due, according to Kottmann, to the fact that blood in A DREXA LI X EMI. 1 353 hypothyroidism contains a diminished amount of antithrombin, hence its increased coagulability, whereas in Basedow the antithrombin con- tent is increased, hence its diminished coagulability. According to Doyon, antithrombin is given off by the liver. Kottmann claims that in Basedow's disease the viscosity of the blood is increased. This dif- ference in the coagulability of the blood in hyperthyroidism and hypo- thyroidism, according to Kocher, is a constant one, and an excellent differential diagnostic symptom which should be resorted to in the doubtful cases. Indeed, since the blood changes which used to be con- sidered as pathognomonic for Graves' disease such as leukopenia, hyperlymphocytosis, hypopolynucleosis, are equally found in hypo- thyroidism, the changes in the blood formula lose their diagnostic value. In doubtful cases only the coagulability of the blood will be the deciding element. It must be said, however, that Julius Bauer who repeated the same experiments as Kottmann, did not obtain the same results. Adrenaline mi a. — It is more or less universally conceded today that the suprarenal bodies produce epinephrin, and that this adrenalin reaches the blood and is used to maintain the tonicity of the vascular system. Experimentally it has been found that the blood coming from the suprarenal veins contains epinephrin, and the conclusion has been drawn that the blood contains more or less adrenalin, and that this substance varies with the pathological condition. Epinephrin has strong mydriatic properties and very likely exerts its action by influencing directly the muscular cells of the dilatator muscles of the ins, and possibly by direct action upon the sympathetic nerve. The action of the epinephrin may be considered as analogous to the electrical excitation of the sympathetic nerve. Adrenalin mydri- asis is found in all the conditions in which the sympathetic system is excited. It is found further in pathological conditions of the pancreas, hyperthyroidism, diabetes mellitus; it is furthermore found in many pathological conditions of the stomach, intestines, in lesions of the central nervous system, and of the meningeal membranes. In such conditions mydriasis is very likely due to an irritation of the sympathetic system by the pathological condition. The methods of determining the adrenalin content of the blood are numerous, but none are so very reliable. The test method which I have adopted is the Ehrmann method. This method consists in enucleating the eye of a frog, if possible, the rana esculenta y and plunging this eye into the blood serum of the patient. The time which elapses from the moment in which the eye has been put into the serum to the moment when the pupil reaches the maximal dilatation is carefully noted, and as a scale has been previously made of different solutions of epinephrin showing the length of time it takes a given solution of epinephrin to 23 354 BLOOD CHANGES IN BASEDOW'S DISEASE dilate the pupil to its maximum, it is therefore easy to find out the quantity of epinephrin contained in the blood serum. This method, of course, is not an accurate one. Another objection which may be raised is that it is not at all certain that the dilatation of the pupil is due to the epinephrin; it may be due to the other sympatheticotonic substances which belong to the same class as adrenalin, such as the pituitary and thymus extracts, and which, according to Biedl, Zandler, and Ranze, give also the Meltzer-Ehrmann reaction. It was, however, the best method I had at my disposal at the time. From investigations made in a great many cases with the method, I am unable to draw any practical information, because in many of the severe cases of Graves' disease, the epinephrin content of the blood was increased, but in other cases just as severe, it was only light or negative. It has been asserted that hyperlymphocytosis combined with absence of epinephrin in the blood is of bad prognosis. In my own experience I have been unable to convince myself that this is true. Hyperglycemia. — Tachaus has shown that the blood of normal indi- viduals contains an average of 0.086 per cent, of sugar. If these normal individuals are fed with 100 grains of sugar, no increase in the sugar content of the blood takes place. In Basedow patients, on the contrary, as soon as they are fed with sugar, the sugar content of the blood increases to double or more of its normal rate. This hyperglycemia is consequently not a primary one, but must be regarded as an alimentary hypergly- cemia; it is very likely of thyroid origin, as it can be produced more or less at will by ingestion of thyroid extract. It gradually diminishes as the thyrotoxic condition improves. Flesch claims that there is an antagonism between hyperglycemia and lymphocytosis: the stronger the hyperglycemia, the less the lymphocytosis, and vice versa. Antitrypsin Content of the Blood. — Walli found that antitrypsin in the blood of normal individuals is very rarely present. In Basedow patients, however, it seems to be constant. The clinical picture of hyper- thyroidism need not be fully developed in order to have a positive finding of antitrypsin, since the reaction is present in the early incipient cases. The antitrypsin content is in direct relation to the gravity of the disease. If this test should prove correct, it would be of excellent diagnostic value when the diagnosis is doubtful. Complement-fixation. — Papazoula has shown that the blood serum of Basedow patients was able to fixate the complement when mixed with antigen extracted from thyrotoxic goiters. According to this author the thyroid gland in that case acts as an antigen, thus causing the formation of antibodies. Hence the conclusion that in Graves' disease the thyroid secretion is not only quantitatively but also quali- tatively affected, which is an argument in favor of dysthyroidism. CHAPTER XXXII. DISTURBANCES IN METABOLISM. Loss of Flesh. — Loss of flesh is one of the most constant and most important symptoms in Graves' disease. It goes hand in hand with muscular weakness. This loss of flesh may be either a very rapid or a very gradual one, and it is, as a rule, one of the earliest symptoms of the disease. If gastro-intestinal disturbances such as vomiting, diar- rhea, etc., are present, the loss of flesh will of course be far more pro- nounced, but in a number of conditions there is no apparent cause for the loss of flesh. It may even occur despite a good appetite and a very liberal diet. Fr. Miiller has shown that this loss of flesh is due to the fact that the nitrogen losses are increased far above the normal. Not only the metab- olism of albumin is increased, but the consumption of fat and carbo- hydrates is also considerably exaggerated. Steyrer proved that in Graves' disease there is an increased production of calories due to the metabolism of albumin and fat. This hyperproduction of calories is independent of diet since it occurs even when the patient remains fasting; spells of nervousness, however, increase it very materially. Magnus-Levy has shown that in Graves' disease the gaseous exchanges are increased, namely, that C0 2 excretion is materially increased. While the quantity of sodium chloride remains about normal, the amount of phosphates existing in the urine of Basedow patients is greatly increased. We may say that in Graves' disease the metabolism is profoundly disturbed, and that the various oxydating processes are constantly and always materially increased. The patient is "burning the candle at both ends." He keeps up the fire by consuming the albumin, fats, and carbohydrates of the body. If the patient is able to offset the losses by a good diet, all well and good: the equilibrium between the intake and exchanges will remain more or less undisturbed; if not, loss of flesh will follow. If loss of flesh nevertheless occurs despite a free diet, it will be due to an impaired resorption and assimilation of the gastro-intestinal tract. This increase in all the oxydating processes is most likely of toxic origin, either because it stimulates the centers of heat, or because it influences the nervous system controlling metabolism. Temperature. With the increase of all the oxydating processes, we might then expect an increase of the bodily tempt ratine. And so it 356 DISTURBANCES IN METABOLISM happens. Rise in temperature is frequently seen in Basedow patients. It is most inconstant and most irregular; it goes and comes, may last over a few days and then become normal again. There seems to be no apparent cause for this. Temperature, however, seems to follow the periods of exacerbation of the disease. It is, as a rule, not high, evoluting around ioo, seldom goes above 101, and does so only when the case is a very severe one. Although the increase in the oxydating processes may be fully incriminated, this rise in temperature is most likely due to some thyrotoxic influence upon the nervous centers regulating the bodily temperature. GLYCOSURIA AND DIABETES IN GRAVES' DISEASE. As a general fact sugar may be found in the urine of any individual after a certain amount of sugar has been consumed. We know that the coefficient of absorption for sugar varies with each normal individ- ual; as soon as this coefficient is overstepped, then sugar appears in the urine. This is what we call alimentary glycosuria. In diabetes, on the other hand, sugar is found in the urine despite the fact that sugar and carbohydrates are withheld from the patient. It is not enough, how- ever, once in awhile to find sugar in the urine of a patient in order to diagnose diabetes, since we might erroneously consider as diabetes a transient form of alimentary glycosuria. Glycosuria must last for a long time and be independent of food, before it can be considered as true dia- betes; furthermore, diabetes is, as a rule, accompanied by polyuria and thirst. In Graves' disease alimentary glycosuria is far more frequent than diabetes: Hirschl found it in 30 per cent, and Schulze in 25 per cent, of their respective cases. These figures may not represent the true percent- ages for all cases known but the fact remains that alimentary glycosuria is comparatively frequent in Graves' disease. Far more frequent than the alimentary glycosuria is that one which appears after small doses of adrenalin are given to a Basedow patient who has just ingested 100 grams of sugar. According to Schulze, this alimentary glycosuria of adrenal origin appears in 80 per cent, of the patients. True diabetes, on the other hand, is more rare and, according to reliable statistics, is not found in more than 3 per cent, of the cases. It usually occurs after Graves' disease is far advanced. The quantity of sugar found in the urine is, as a rule, moderate; in severe cases, however, it may be very large. The presence of diabetes in Graves' disease must be always regarded as a serious complication and of bad prognosis. Ordinarily as soon as GLYCOSURIA AXD DIABETES IN GRAVES' DISEASE 357 diabetes occurs, the patient begins to lose flesh and complains of an intense muscular weakness. Despite the fact that diabetes is far more frequent in men, the combination of Basedow and diabetes is more frequently seen in women. To claim that all cases of diabetes and alimentary glycosuria compli- cating Graves' disease are of thyroid origin would be folly. A number of them supervene as an independent complication and have no relation to thyrotoxicosis. This, however, is not true for all cases. A number of clinical as well as experimental observations seem to prove that there is an intimate relation between the thyroid and glycosuria. Beclere reports the case of a male, thirty-two years old, who was suffering from myxedema. In the course of n days this patient absorbed 93 fresh thyroid glands of sheep; palpitation, tremor, dyspnea, profuse perspira- tion, insomnia, and polyuria became very marked. Urine analysis showed albumin and sugar. Nothaft reports the observation of a man, forty-three years old, who in order to get thinner took a thousand tablets of thyroid extract of 5 grains each in five weeks. After three weeks the patient began to develop marked exophthalmic symptoms; the urine contained 1 per cent, of sugar. F. Miiller saw a patient who had a light form of Graves' disease, and who was fed with thyroid extract tablets; symptoms of hyperthyroidism became extremely marked. Severe diabetes developed and death ensued. In a myxedematous patient fed with thyroid extract, Ewald found 4 per cent, of sugar. This sugar could be made to appear and disappear at will by regulating the thyroid feeding. Von Noorden reports 17 cases of obesity treated with thyroid extract; in 5 of them sugar was found during the treatment. A number of other clinical as well as experimental cases can be cited in which thyroid feeding had caused glycosuria. In the presence of all these facts it is difficult not to admit that there is a relation between the thyroid and glycosuria, and that in Graves' disease the presence of sugar in the urine must be referred to the hyperfunction of the thyroid, combined with an exaggerated excitation of the sympathetic nerve and a pancreatic insufficiency. We have then to deal with a thyreogene glycosuria. Thyreogene glycosuria is characterized by the fact that it develops with Graves' disease and disappears with its improvement. Thyreo- gene glycosuria seems to be more frequent in traumatic Basedow and is often combined with other disturbances in the resorption of fat. That the thyroid intervenes in the production of glycosuria is so much more plausible since glycosuria may be caused by other glands than the thyroid, as for instance, the hypophysis, suprarenal bodies, liver, etc. Polyuria. Polyuria is often seen in Graves' disease; it is sometimes an early symptom and occurs without any apparent pathological condi- tion of the kidneys. It is very likely a symptom of nervous origin. 358 DISTURBANCES IN METABOLISM Polydipsia. — Knowing how much Basedow patients perspire and often suffer from diarrhea, vomiting, and polyuria, in short, knowing that they are losing fluids in many ways, no one will wonder that they often complain of thirst, and that they drink water abundantly. How- ever, the etiology of polydipsia is not quite so simple, and must be regarded, too, as a symptom of nervous origin, probably due to the irritation of some buboprotuberential centers. Albuminuria. — Traces of albumin are sometimes found in Graves' disease; they are not connected, as a rule, with any disease of the kid- neys, as no cylinders and no epithelial cells are present in the urine. It is most likely of toxic origin, and disappears as soon as the condition subsides. THYROTOXICOSIS IS A CHRONIC DISEASE. Now that we have studied all the symptoms and followed their development, although at first the whole symptom-complex seemed stormy and erratic, we cannot but be impressed by one fact, namely, that the disease is essentially chronic. No matter how various and changing the symptoms are, no matter if a given case apparently changes its physiognomy hundreds of times during its course, and no matter if at times some symptoms become acute and subside again, nevertheless the general tendency of the entire process is to be a chronic one. The disease follows a cycle, which grossly speaking can be said to be identical with itself. It usually begins insidiously, reaches gradually its full de- velopment, shows periods of betterment, alternating with spells of exacerbation, lasts years and then finally either takes a decisive turn for the best, or terminates by death. No matter how various its manifes- tations are, the main symptoms are always constant in their character. Thus tachycardia, for instance, will remain identical with itself throughout the entire course of the disease so as to resemble no other form of tachycardia. The same is true for tremor. Vomiting and diarrhea may last weeks and months, may come and go without changing in their nature, and without leading into a gastritis or an enteritis. And so on for the other symptoms. FULMINATING FORMS OF GRAVES' DISEASE. That, however, one will meet once in a while with rapidly evolving cases of Graves' disease there is no doubt: the condition begins, evoluates, and terminates by death in a very short time, within a few weeks or months. From its inception the disease takes on a malignant form; tachycardia and nervousness are intensely marked, and the gastro- intestinal symptoms are especially alarming; vomiting and diarrhea are ALL THYROTOXIC SYMPTOMS ARE WORSE IN THE MORXIXG 359 continuous and become uncontrollable. The patient is profoundly thyrotoxic, and since little or no food is retained, the patient sinks rapidly, and death follows after a few weeks, with marked symptoms of acidosis. In all the fulminating forms of Graves' disease which I have seen, the gastro-intestinal symptoms were always the leading ones. ALL THE THYROTOXIC SYMPTOMS ARE WORSE IN THE MORNING. I believe anyone who has had wide experience with Graves' disease will agree with W. H. Thomson when he says, " If it be asked what are the most peculiar or most characteristic features of Graves' disease, I would answer that next to its specific tachycardia is the morning exacerbation of its symptoms." No careful observer can fail to be impressed by this singular phenomenon. I have looked for that symptom in all cases of goiter which have come under my observation, and I must say that in the great majority of cases, no matter if they were true cases of Graves' disease or simple goiters complicated with some thyrotoxic symptoms, this symptom was nearly always present. Without any hesitation the patients admitted that they were decidedly worse in the morning and would get better toward evening. When they rose they felt more tired than when they went to bed; they complained of an intense general depression; they were "good for nothing." All their thyrotoxic symptoms seemed to be more exaggerated, and tremor became more marked, so as to prevent the patient from doing any work in the morning, whereas in the afternoon such work was possible. Palpitations and nervousness became more intense but subsided toward evening. Headaches, too, were more accentuated in the morning, and the patients complained of heavy weights upon their spirits, and of a beclouding of the mind so as to preclude the possibility of mental work, or of concentration of the mind until late in the afternoon. If gastro-intestinal symptoms were present, vomiting and diarrhea underwent marked exacerbations toward morn- ing and subsided toward evening. In short, the entire chain of thyro- toxic symptoms became aggravated in the morning. This symptom is very peculiar to, and almost characteristic of, Graves' disease. Hys- teria has nothing to do with its production; it is very likely due to some disturbance in the biological chemistry of the organism, more marked at that time of the day. But what this disturbance really is and why it takes place, is still an open question. CHAPTER XXXIII. FRUSTE FORMS OF HYPERTHYROIDISM OR SMALL HYPERTHYROIDISM. It is not usual to find all the thyrotoxic symptoms ordinarily seen in Graves' disease equally developed in the same case; as a rule some of them are more prominently developed than others, while frequently, quite a few even fail to be present. In these cases, however, the diag- nosis does not offer great difficulties because one or more of the cardinal symptoms will clear at once the diagnosis. Even if one's judgment has been side-tracked, as a rule, the general physiognomy of the case, its course of development and its behavior will soon betray its true nature. There are cases, however, which require a great deal of experience, sagacity and judgment before one dares to venture the diagnosis of thyrotoxicosis. There none of the cardinal symptoms are present, or at least they are so insufficiently developed that a diagnosis of thyro- toxicosis is scarcely warranted; yet, in the last analysis these cases are of thyrotoxic origin. They are incomplete forms of thyrotoxicosis; they are called fruste, or incomplete forms of hyperthyroidism. They consti- tute what I call small hyperthyroidism. As we have the great and small hypothyroidism, so we have the great and small hyperthyroidism. These fruste cases in which the majority of the classical symptoms are absent are very apt to be overlooked, either because of lack of experi- ence, or because these cases are so atypical that it is difficult at first to trace them back to their true origin. On the other hand, there is no doubt, however, that these fruste forms of hyperthyroidism are far more frequent than is. generally suspected. If they were all recognized, it would be found that they constitute a substantial percentage of the total of patients seeking medical relief. An incomplete form of thyrotoxicosis frequently seen is that one where the heart-rate is above normal, where the patient complains of a general throbbing of the arteries, or of palpitation. At the same time there is a marked instability of the nervous system, yet, physical exami- nation of the nervous, cardiac, urinary, and other systems fails to reveal anything pathological. No apparent cause can be found to explain that condition. Such cases are often only fruste forms of hyperthyroidism. If, perchance, one is able to detect some other concomitant thyrotoxic symptoms such as possibly a small thyroid hypertrophy, some tremor, etc., then doubt is no longer permissible; this is a fruste form of hyper- thyroidism. HYPERTHYROIDISM OR SMALL HYPERTHYROIDISM 361 There are numbers of young women who, at the time of puberty complain of palpitation, tachycardia, fatigue, loss of energy, and of some swelling of the feet. As a rule the)' are regarded as chlorotic, yet laboratory findings generally show that the blood is normal. If at the same time such patients happen to have occasional rises in tempera- ture, and if they also complain of sweating, they are very apt to be considered as tuberculous and treated accordingly. However, should a careful examination be made, some nervousness, possibly even some psychic disturbances might be found — all facts showing that such patients are suffering from fruste forms of hyperthyroidism secondary to the maturation- of their genital systems. As soon as the genital pro- cess is settled and the organism has found its equilibrium, the thyro- toxic syndrome ordinarily subsides and then these patients again regain their health. The same is true for women at the menopause. The}' com- monly complain at that time of hot flashes, palpitation, nervousness, tremor, sweating, of occasional gastro-intestinal disturbances, etc. Examination reveals a moderate degree of tachycardia, little or no apparent enlargement of the thyroid, and no ocular symptoms. Ovarian extracts remain without effect. Such cases are regarded as nervous patients, and treated with all the tonics, sedatives, cardiac stimulants, etc., imaginable. Little or no results are obtained because the real cause is to be found in the hyperfunction of the thyroid. These cases are, too, fruste forms of hyperthyroidism. Not infrequently we see patients who apparently have a simple non-toxic goiter and who intermittently may complain of cardiovascular and nervous symptoms. Once in awhile they may have an occasional diarrhea alternating with constipation. This condition may go on for years, off and on, periods of complete welfare alternating with periods of thyrotoxicosis. These cases, too, are fruste- forms of hyperthyroidism. In other cases there is apparently no thyroid enlargement. The thyro- toxic symptoms are more or less of vague nature, characterized by some nervousness, and some tremor, by periods of muscular asthenia, by occasional palpitation, and occasionally by some tachycardia especially connected with physical effort, by headaches, and at times by indiges- tion or hyperacidity, and by some occasional menstrual disturbances. All these symptoms experience periods of exacerbation and improve- ment. They come and go; the syndrome is of protean type. I hese patients, as a rule, do not stand easily acute infections, they do not recover as quickly as others. Any psychic shock, even of moderate degree, will leave on them traces for weeks and months, while a normal individual would not be feazed by it. Such patients arc- treated either for gastro-intestinal troubles, or for menstrual disturbances, or for nervousness, etc. No or very little improvement is ganu-d by such 362 HYPERTHYROIDISM OR SMALL HYPERTHYROIDISM therapeutics; they may even be made worse. If, however, the correct diagnosis is made, and the case regarded as a fruste form of hyper- thyroidism, and the correct treatment is instituted, these patients may be greatly benefited. Every medical means being exhausted in vain, I have operated a few of them and cured them entirely. There are fruste forms of hyperthyroidism due to gastro-intestinal ptosis causing an auto-intoxication which in turn results in the produc- tion of a group of thyrotoxic symptoms. These symptoms may be of severe nature, and are especially characterized by nervousness, palpi- tation, tremor, loss of flesh, and intense asthenic symptoms. They may resist every medical treatment. One of my most grateful patients is a young woman who had a marked gastro-intestinal ptosis, causing spells of weakness, muscular asthenia, nervousness, loss of flesh, inter- mittent thyroid hyperplasia, palpitation and tachycardia, etc., which would incapacitate her for months at a time. A ventrofixation of the stomach and transverse colon performed some years ago cured her per- manently. That, too, was a fruste form of hyperthyroidism, secondary to gastro-intestinal auto-intoxication. There are fruste forms of hyperthyroidism in which besides some insignificant secondary thyrotoxic symptoms the only marking feature is possibly a glycosuria or fatty stools. As shown by Falta, such cases may be, too, obscure forms of hyperthyroidism because indirect inter- vention upon the thyroid by operation or .x-rays has brought about cures. Fruste forms of hyperthyroidism are observed, too, in conjunction with pelvic diseases. There, too, a timely operation upon the diseased pelvic organs may restore the patient to health. In conclusion we may say that these fruste forms of hyperthyroidism may have the most protean character. In some of them we find only thyroid enlargement, in some others, tachycardia, in some others tremor, in some others the staring and glaring look, in others nervous insta- bility, hot flashes, loss of flesh, gastro-intestinal disturbances, psychic troubles, etc. A great many of these cases are secondary to some defi- nite pathological condition. For a great many others there seems to be no apparent cause. I should not want to be accused of chauvinism, of seeing thyro- toxicosis everywhere. Discretion, judgment, clinical sense must be our guide. We must remember that "too little," just as well as "too much" always spoils everything, or as the French say: " Le trop et le trop peu gdtent tous les jeux." CHAPTER XXXIV. HYPERTHYROIDISM AND HYPOTHYROIDISM. It seems at first nonsensical to claim that symptoms of thyroid insuffi- ciency may coexist with those of Graves' disease, in short, that we may have at the same time hypothyroidism and hyperthyroidism; yet that there can be such a thing there is no doubt. The thing seems at first unacceptable because we think only of the fully developed form of hypo- thyroidism. We forget that until the condition has reached its full development there are numbers of intermediary stages, in short, that we have fruste forms of hypothyroidism as well as of hyperthyroidism. No one, I am sure, will deny that a given case of Graves' disease may ultimately turn into a myxedematous condition. We have stated more than once before that a Basedow patient, provided he lives long enough and the thyrotoxic process keeps up, is logically destined to become a myxedematous case. A number of authenticated cases could be cited to support that statement, so that there can be no doubt about it. For instance, Joffroy and Achard reported the case of a young woman, twenty-three years old, who had a typical Basedow and who finally developed a typical cachexia thyreopriva. The autopsy showed a sar- coma of the pleural cavity and a more or less complete destruction of the thyroid at which place connective tissue only was to be found. How shall we explain the combination of these two conditions in Graves' disease ? Because there the gland keeps up burning at a fast pace. This obviously cannot last forever. There comes a time when the gland is exhausted; the epithelial elements become ''stale," undergo degeneration, and are gradually replaced by connective tissue, thus naturally leading into hypofunction, and consequently into hypothy- roidism. Tachycardia, nervousness, tremor, loss of flesh, etc., gradually subside; and little by little the patient sees his thyrotoxic condition improve. Everybody thinks the cure is near. But, alas, this does not last long; it is only a transitory stage. The patient's spirits soon become curbed, his eyes lose their brilliancy and become dull; nervousness gradually fades away into quiet and rest, the intelligence becomes weak and lazy, tachycardia gradually subsides, and a suspicious adipose tis- sue of yellowish tint takes the place of the previous extreme thinness of the skin. The patient falls into a state of marasmus. Me got rid of his hyperthyroidism only to fall into a state which is just as bad, hypothy- 364 HYPERTHYROIDISM AND HYPOTHYROIDISM roidism. He saved himself from Charybdis only to fall into Scylla. Until, however, hypothyroidism is fully developed, symptoms belong- ing to both conditions remain mixed together. Even when cachexia strumipriva is fully developed, there still remain some thyrotoxic symp- toms which will show that both conditions may exist at the same time in the same patient. The case is an odd mixture of the wreckage of Graves' disease and thyroid insufficiency (Fig. 69). As a rule the symptoms of hyperthyroidism still remain the pre- dominant ones; only a few isolated symptoms may point toward hypo- thyroidism. For instance, the patient may put on an excessive amount of fat, while at the same time his skin becomes dry and scaly. In some other instances his mental activity be- comes dull, the memory loses its reliability, the patient is quiet, the movements are slow; in short, the patient develops a new condition in direct contrast to the pre- vious one in which he was constantly nervous and agitated. Yet the other thyrotoxic symptoms remain the same. The whole condition may show periods of improvement and exacerbation. The reverse may be true. Some thyro- toxic symptoms may occur during the course of the cachexia strumipriva; this, however, is rare, but has been observed by men of note, as Kocher, for instance. The possibility of the coexistence of hypothyroidism and hyperthyroidism will become more plausible and intelligible if we remember that a gland such as the thyroid has not only one function, but many ot them. It contains a number of lipoids, each one of them having a definite action on the metabolism. We have already stated that Isco- vesco isolated from the thyroid several lipoids, each one affected with different properties. One of them, for instance, injected into animals causes myxedema; another, exophthalmic goiter, another had a marked influence upon the ovaries, and so on. If this should be true, and should be further corroborated, the explanation for the existence of hypothy- roidism and hyperthyroidism would then be a simple one. A priori at least, according to all that we know of the glands of internal secretion, these findings of Iscovesco's seem rational. We know that adrenalin in small doses, for instance, causes vasodilatation, and in large doses, vasoconstriction. Fig. 69. — "Burned out" thyroid. Symptoms of hyper- and hypothy- roidism combined. CHAPTER XXXV. INFANTILE AND JUVENILE HYPERTHYROIDISM. As we have an infantile, a juvenile, an adolescent and an adult hypothyroidism, so we have also an infantile, a juvenile, an adolescent, and an adult hyperthyroidism. The term infantile hyperthyroidism is intended to embrace only those cases of exophthalmic goiter occurring in children before ten years of age, since during that period of development the genital system is still in its expectancy. Juvenile hyperthyroidism is that form of thyrotoxi- cosis occurring from 10 to 15 years of age, during which period the geni- tal system undergoes its development. We shall call adolescent hyper- thyroidism the cases of thyrotoxicosis which occur from fifteen to twenty-five years of age, during which period the genital apparatus reaches its maturity, and we finally reserve the term adult hyper- thyroidism, to the cases occurring after twenty-five years of age. Infantile hyperthyroidism is comparatively rare, whereas the juvenile form is more frequent. W. H. Lewis, quoting Mayo's statistics, found one case of infantile hyperthyroidism for 300 adult cases operated for thyrotoxicosis. The youngest of his cases was four years old when it came under his observation, and the disease had already existed eighteen months. Infantile and juvenile hyperthyroidism follow, as a rule, a milder and shorter course than that of adult hyperthyroidism. Left alone, the condition gives, according to Sattler, a mortality of 4.5 per cent. The symptoms most commonly observed in infantile hyperthyroid- ism are irritability, nervousness, and tachycardia. The little patients seldom are conscious of palpitation; exophthalmos is rarely marked, and the ocular symptoms are usually absent. Tremor as well as vasomotor)' disturbances of the skin are present in moderate degree. Gastro- intestinal disturbances are usually quite marked. As a rule these young patients especially those of infantile type, do not experience the profound muscular asthenia which is so often observed in adolescent and adult hyperthyroidism. They are able to participate in the activities of their young companions without undue fatigue. Sometimes, however, they get out of breath more easily. Thyroid hyperplasia is of moderate degree and is subject to variations. Vascular symptoms are present. 366 INFANTILE AND JUVENILE HYPERTHYROIDISM In the juvenile and adolescent forms of hyperthyroidism psychic dis- turbances and chorea may occur as complications. Glycosuria is seldom observed. In overactive children when restlessness, irritability, egotism, sel- fishness develop, the possibility of hyperthyroidism should always be considered. So far as treatment is concerned, usually ligation of both superior poles proves of itself curative. If the case is already quite markedly advanced, thyroidectomy may become necessary. CHAPTER XXXVI. EXOPHTHALMIC GOITER IN PREGNANCY. That a woman afflicted with Graves' disease may become pregnant, or that thyrotoxicosis may develop either during or at least in connec- tion with pregnancy, is a well-known fact. The point of interest does not he therein. What we want to know is, how do these two conditions influence each other, and what shall be our attitude in these given cases ? The coincidence of pregnancy with Basedow is not frequent. Out of 15,000 women seen in the Maternity of Edinburgh by Halliday-Croom, only 1 case of exophthalmic goiter in pregnancy was seen. The other 12 cases which he reported were taken from his private practice, hence his conclusion that pregnane)* and Graves' disease are oftener found among the rich classes than among the poor ones. Bonnaire came to the same conclusion, because out of 30,000 pregnant women he saw only 2 cases of exophthalmic goiter. Seitz has collected 112 cases of exophthalmic goiter complicated with pregnane}* from his own material, from literature, and from circu- lar letters. He has carefully tabulated the menstrual history, the appear- ance of the first symptoms, the history of previous pregnancies, the therapy employed, and the results as far as mother and child were con- cerned. He found that hyperthyroidism was not affected one way or the other in 40 per cent, of the cases. A very small number even improved during pregnancy. On the other hand, 67 out of 112 cases, namely, 60 per cent, of the total, were made distinctly worse by gesta- tion. In one-fourth of these 67 patients a serious menace as to health and life was the consequence of thyrotoxicosis; 7 patients died; in 5 cases therapeutic abortion, and in 1 1 cases, premature labor occurred. Three miscarriages, and 3 macerated fetuses were observed. In 7 cases thyroidectomy was performed during pregnancy. Bernard von Beck in 260 cases of Graves' disease and pregnancy said that he felt compelled to perform thyroidectomy in 5 cases, and in no case did he find it neces- sary to interrupt the pregnancy. As Gellhorn says, this is indeed a remarkable record and may be explained by the fact that these thyro- toxic conditions were secondary to previous existing goiters, since in the region where von Beck is working, goiter is endemic. Theilhabei found that the majority of coincident cases of pregnancy and Graves' disease were made distinctly worse by the disease and that only the minority 368 EXOPHTHALMIC GOITER IN PREGNANCY were improved by it. Kleinwachter and Hirst came to the same conclu- sion that Graves' disease is unfavorably influenced by pregnancy, and that it often has its origin in gestation. It predisposes the patients to uterine hemorrhages and may result in the death of the fetus. Such cases are often complicated with albuminuria. Whitridge Williams con- siders that pregnancy exerts a deleterious influence on Graves' disease; he found that tachycardia was greatly increased during gestation and lessened soon after labor. It has been, too, my experience in the cases of thyrotoxic pregnant women I have seen. We can consequently conclude that the majority of Graves' patients are made worse by pregnancy. Pregnancy must be regarded as a serious complication in thyrotoxicosis. This is so true that Theilhaber has said when speaking of thyrotoxic patients: "Girls, no marriage; women, no pregnancy; mothers, no nursing." Treatment. — So far as Graves' disease is concerned, medical treat- ment should be given the greatest care and attention as soon as preg- nancy is detected. Every form of treatment can be given a trial. Opo- therapy with hypophysis, or with thymus may be attempted; opother- apy with thyroid should be handled with extreme care. Any one of these treatments will sometimes give good results, more often none, or it will make the condition of the patient worse. Up to date the best treatment known is a dietetic, hygienic regime. The majority of cases so treated will be kept in fairly good condition and may be brought along to the full term of their pregnancy without too serious disturbances. At any rate, during the early period of pregnancy the treatment must be a watchful, waiting one. If later, however, the condition of the patient grows worse, surgical intervention then becomes necessary. Surgically, two questions arise: Shall we perform a thyroidectomy or shall we resort to an obstetrical operation ? So far the trend of opin- ion seems to be in favor of the second alternative. If the fetus is viable, a premature Cesarean section may save its life, which very likely would be lost if allowed to go on to full term. If, on the other hand, the fetus is not viable and the condition of the mother is such as to necessitate a surgical intervention, the life of the child should be sacrificed without hesitation, since at any rate it is bound to be lost. In such cases the mother's life only should be taken into consideration. I believe, however, that we should not wait until these thyrotoxic symptoms complicated with pregnancy have become so serious as to endanger the life of both the mother and the child. A timely thyroid- ectomy as I have performed twice seems to be the ideal procedure, as it not only wonderfully benefits the thyrotoxic condition, but also allows the pregnancy to go to full term, and thus saves the life of the child without undue risks for the mother. TREATMENT 369 Basedow patients should be guarded against marriage, and espe- cially against pregnane)'. At any rate, before entering married life they should have thyroidectomy performed in order to safeguard them against any future exacerbations and to protect their future offspring. It is true that in severe forms of Graves' disease the chances for pregnancy are considerably reduced, because the sexual apparatus is in a state of hypofunction. This, however, is not always the case and pregnancies may occur even in very severe cases of thyrotoxicosis. When this is the case "sterilization" of the women should be performed after pregnancy is over. 24 CHAPTER XXXVII. ETIOLOGY OF GRAVES' DISEASE. The fact that Filehnes, Walburton, Tedeschi, Dourdoufi, and Bienfait by sectioning the restiform bodies were able to produce tachy- cardia, exophthalmos, hyperemia of the thyroid, etc., has given rise to a theory claiming that Basedow's disease is of bulbar origin. It must be said, however — and this is a very important point to remember — that the thyrotoxic, clinical picture did not take place, if previously or at the same time, thyroidectomy had been performed. The French school, especially Charcot, Trousseau, etc., and the German school, represented by Gerhardt, Buscham, Wickfield, Sattler, etc., have considered Base- dow's disease as a neurosis of the entire vegetative nervous system. Notkine and Blum defended the view that Basedow's disease was due to an insufficient "depoisoning" of the organism by the thyroid on account of functional insufficiency. Friedreich considered Basedow's disease as due to an abnormal enlargement of the coronary arteries of the heart, thus causing an increased blood supply to the cardiac muscle which in turn would cause an increased excitability of the nervous system. Gabriel Gauthier considered the thyrotoxic syndrome as of thyroid origin. Mannheim considered it as of central origin. Moebius claimed that Basedow was caused by poisoning of the blood by the thyroid products, and considered the forms frustes as well as the primary and secondary forms of exophthalmic goiter as all produced by the same cause, namely, the hyperfunction of the thyroid. Crile believes that it is a "philo- genic" disease, caused by a disturbance of the entire motor mechanism in which the nervous system is primarily involved and in which the thy- roid acts as an activator. Hart and Bircher believe that Basedow's dis- ease is primarily of thymic origin. Klose, Lampe, and Liesegang believe that the disease is due to dysthyroidism. Thus, as one can see, the theories concerning the etiology of Graves' disease are numerous, and I have not cited them all by any means. The theory which up to date has rallied the greatest number of parti- sans is the theory of hypersecretion of Moebius, called thyrotoxicosis by Kocher, and hyperthyroidism by Mayo. According to these authors, Basedow's disease is caused by a surplus of thyroid secretion poisoning the entire organism. This surplus may be caused either by an increased function of the thyroid or by thyroid feeding. This theory is indeed the ETIOLOGY OF GRAVES' DISEASE 371 one which tallies best with our present knowledge, and which seems to be best supported by the facts. It is simple and clear, but I am afraid that just because of this simplicity and clearness, it is insufficient. The more one studies this question, the more one becomes convinced that the problem is a complicated one; the more one tries to penetrate the secrets of Nature, the more one sees how intricate her wars are. As v. Hansemann says, "Nature does not know a cause, but causes." Indeed, if we consider an event in its simplest form, even though the determining factor seems to be obvious, how many other "preparatory" conditions are not necessary to allow the so-called primary cause to exert its effect ? And so it is in medicine. Almost everyone will say, for instance, that tubercle bacilli are the cause of tuberculosis, yet, if truly they were the only cause, every living man would be tuberculous because it has been shown beyond doubt that everybody's organism contains tubercle bacilli. Fortunately, in order to allow tubercle bacilli to thrive, other "preparatory conditions" are just as necessary as the presence of the tubercle bacilli themselves, and only when all these conditions happen to be assembled, does tuberculosis develop. It is consequently wrong to say that tubercle bacilli are solely the cause of tuberculosis. One should say "tubercle bacilli are one among others of the conditions necessary for the development of tuberculosis." If one of these "con- ditions" is absent, there will be no tuberculosis. Take, for example, Addison's disease. If tubercle bacilli were the only necessary require- ment, again, almost everybody would have Addison's disease. This disease is too fairly frequent to be considered as the result of the mere accidental settling of tubercles in the suprarenal bodies; furthermore, the fact that the tuberculous involvement is bilateral, speaks, too, against such an explanation. The truth of the matter is that other conditions, secondary indeed, but just as necessary and important as the tubercle bacilli, must intervene before the invading tubercle bacilli can thrive in the suprarenal bodies. Exceedingly forceful in demonstrating this very thing is the hypothetical example mentioned by Sahli, that of a child who has been slapped in the face once by its teacher, and who develops soon after a tubercular meningitis. At once the family concludes that the slap in the face was the cause of the tubercular meningitis, hence a lawsuit for damages. "This lawsuit," says the defendant, "is ridicu- lous. Everybody knows that without tubercle bacilli, there is no tuberculosis, that if a tubercular meningitis develops, the child must have had tubercle bacilli in his organism previous to the slap in the face, that slaps in the face are given every day without there occurring a tubercular meningitis, that finally there is no more relation between a slap m the face and tubercular meningitis than then- is between a belly-ache and tin- moon." "All this may be very well," says the plain- 372 ETIOLOGY OF GRAVES' DISEASE tiff, "but the fact remains that the child was well before, that he got sick soon after the slap in the face, consequently had he not been slapped in the face, he would not have developed a tubercular meningitis." And no one will be able to convince the plaintiff to the contrary. He sees one cause: this cause suffices to explain the whole thing. He does not see, or does not want to see, that besides this apparent cause there are many others, in fact, more important, without which a tubercular meningitis would never have developed, and that in this particular case the slap in the face was merely a coincidence. And so it is for the etiology of Graves' disease. Of course the thy- roid lesions still play the predominating role in the development of the disease. But this is not all; other conditions intervene; other factors play their part too, such as the nervous system, and the organs of internal secretion. It is for this reason that I shall say that Graves' disease is a thyroneuropoly glandular disease. Let us proceed to try to demonstrate successively and separately the three members of that proposition: A, The thyroid origin. B, The nervous origin. C, The polyglandular origin. A. Thyrogenetic Origin of Graves' Disease. — Arguments in favor of the thyrogenetic origin of Graves' disease are among the most numerous; they are derived from clinical observation, from pathology, from experi- mentation, and from the results of surgical treatment. i. It was because he was struck by the antithesis which existed between the clinical symptoms observed in thyroid insufficiency and those seen in Graves' disease that Moebius concluded that the latter condition was due to a hyperfunction of the thyroid. Indeed, one cannot but be impressed in the same way after glancing over the masterful synopsis made by Kocher in 1902. It takes the two opposite conditions at their worst, and reads as follows: Hypothyroidism. Hyperthyroidism. Absence or atrophy of the thyroid gland. Diffuse hyperplasia of the thyroid. Hypervasculanzation. Slow, regular pulse of small volume. Rapid pulse, rather increased pressure, sometimes irregular. Absence of hot flashes, se nsation of cold. Marked vasomotory disturbances. Patient is always too warm. Indifferent, expressionless and lifeless Very anxious, exceedingly mobile look look. with a rapidly changing expression. Small palpebral fissure, small eyes. Wide palpebral fissure and exophthalmos. Bad appetite, slow digestion, constipation. Often increased appetite, vomiting, diar- rh ea. THYROGEXETIC ORIGIN OF GRAVES' DISEASE 373 Hypothyroidism. Reduced metabolism. Thick, cold, dry, scaling skin. Short, thick fingers with thickened ter- minal phalanges. Great tendency to sleep. Reduced sensibilitv and diminished sen- sory impressions. Diminished mental and intellectual power. Awkwardness and slow actions. Stiffness of the extremities. Short, thick, often deformed skeleton. Slow, deep, respiration. Increase in weight. Old appearance of the patient, even though young in years. Hyperthyroidism. Increased metabolism. Thin, warm, soft, moist skin, no scaling. Long, thin fingers with pointed phalanges. Insomnia and disturbed sleep. Increased sensibility and increased sen- sory impressions. Increased mental and intellectual activity, great psychic excitement, hallucina- tions, mama, and melancholia. Restlessness and haste in movements. Tremor but marked agility in movements. I hin, slender skeleton. Superficial, rapid, and slightly irregular respiration. Loss of weight. Rather youthful appearance, especially in the early stage of the disease. Furthermore, Kocher found that phosphates are beneficial to hyper- thyroidism, but are harmful to hypothyroidism; that a sojourn in high, cold climates is beneficial to hyperthyroidism, but harmful to hypo- thyroidism; that a sojourn at the sea is harmful to hyperthyroidism, but helpful to hypothyroidism. Certainly the antithesis between all these symptoms is forceful and speaks strikingly not only in favor of the thyrogenetic origin of the disease, but also in favor of the hyperthyroidism theory. 2. The fact that thyroid feeding is most injurious to the great majority of cases of Graves' disease, and produces, as a rule, only exacerbation of all the symptoms, must be interpreted as another proof of the thyro- genetic origin of Graves' disease, and of the hyperthyroidism theory. Since in hypothyroidism the feeding of thyroid extract is curative, it is logical to consider the bad results obtained from thyroid feeding in Graves' disease as directly due to the increased amount of thyroid secre- tion in an already saturated organism. 3. In cases where thyroidectomy has been performed in view of remedying the thyrotoxic condition, if a relapse of symptoms occurs, there is, too, a relapse of the goiter, and vice versa; hence another proof in favor of the intimate relation of the goiter with the clinical symptoms of the disease. 4. Another powerful argument is derived from the clinical observa- tion that in many cases of secondary thyrotoxic goiters one can follow a gradual transition in the intensity of the symptoms going from the slightest form of thyrotoxicosis to the most fully developed picture of Graves' disease. Anyone who has had experience with goiters knows 374 ETIOLOGY OF GRAVES' DISEASE that this sliding of the scale is quite frequent. As Wolfler says, "It is easy to go progressively from a simple goiter to a well-marked case of Graves' disease, as for instance, goiter with tachycardia; goiter with tachycardia and tremor; goiter with tachycardia, tremor, and exoph- thalmos; goiter with tachycardia, tremor, exophthalmos, and digestive disturbances, etc., until we get the complete clinical picture of Basedow's disease." These cases, no matter if they are fully developed, or consti- tute only the fruste forms of Graves' disease, all recognize the same etiology; they are all dependent upon the thyroid intoxication. 5. Another proof in favor of the hyperfunction of the thyroid is the fact that exophthalmic goiter seldom occurs in regions where goiter is endemic, namely, where the thyroid is permanently and endemically in a state of hypofunction. Even when such endemic goiters become overactive, the worst they can do is to give birth to mitigated forms of hyperthyroidism such as thyrotoxic goiter-heart, nervousness, etc. They seldom reach the fully developed thyrotoxic clinical picture. As soon, however, as we consider regions where goiter is not endemic or mildly so, where consequently the thyroid gland has retained its full functional capacity, there Basedow disease becomes very frequent and severe in its forms. 6. If in order to obtain shrinkage of the gland, the thyroid is attached to the integuments by the operative measure known as exothyropexy, it is found that the thyrotoxic goiters show a far greater secretion than the simple goiter, hence the conclusion that the thyrotoxic goiter func- tionates more than the simple one is obvious. 7. The fact, on the one hand, that a sudden hemorrhage occurring in an already existing colloid or cystic goiter will cause marked thyro- toxic symptoms, such as palpitation, great nervousness, tremor, gastro- intestinal disturbances, insomnia, and even sometimes a moderate exoph- thalmos; and, on the other hand, the fact that all these symptoms will subside, as resorption of the hemorrhage goes on, and will finally dis- appear when the goiter has returned to its quiescent state again, or on the contrary, will increase progressively into a true case of Basedow's disease when the thyroid does not quiet down, all go to show that there is a relation from cause to effect between the pathology of the thyroid and Graves' disease. 8. The fact that Basedow's disease is found with an acute thyroiditis is another proof of the thyrogenetic origin of Graves' disease. This question will be discussed later in considering the relation between thyroiditis and Graves' disease. 9. The coexistence of thyrotoxic symptoms with malignant goiter has long since been known. Already in 1871 Tillaux mistook a sarcoma of the thyroid for an exophthalmic goiter. Carrel, out of 83 malignant PATHOLOGICAL ARGUMENTS 375 goiters found 26 showing unmistakable thyrotoxic symptoms. Poncet and Bouveret saw a malignant goiter with a complete clinical picture of Basedow's disease, exophthalmos included. Delore and Alamartine, Kocher, and myself have seen similar cases. The thyrotoxic symptoms occur either after metastases have taken place or before. If they occur only after the tumor has metastasized, since we know that malignant metastases of thyroid tissue always retain their physiological secreting power, then it is logical to conclude that the symptoms of hyperthyroidism are due to the increased functionating surface due to the malignant tumor plus its metastases. If thyrotoxic symptoms occur before metastases have taken place, the hyperfunction may be due to the fact that the malignant portions of the tumor irritate the remaining normal glandular tissues and incite it to hyperplasia in the same way that intraglandular hemorrhage does: hence symptoms of hyperthyroidism as we see them sometimes after hemorrhage in simple non-toxic, cystic, or colloid goiters. Pathological Arguments. — It is not enough to support our conclusions with clinical data. No matter how strong these clinical proofs may be, they alone would not carry conviction as well as the}" would if they were supported by convincing pathological evidence. Let us see what pathology teaches us. We have seen in the Chapter dedicated to Basedow Struma that hyper- plasia of the thyroid is one of the most constant findings in thyrotoxi- cosis, so constant that Kocher has said, ''No goiter, no Graves' disease." It is indeed true that in the great majority of cases an enlargement of the thyroid is present. As a rule it is obvious. It would be a mistake, however, to believe that thyrotoxicosis necessarily means that thyroid hypertrophy is always clinically detectable. There are cases of thyro- toxicosis, even very severe ones, with only a slight hyperplasia or none at all. In a great many cases, this hyperplasia, which is clinically "apparently" absent, is nevertheless present. This is proved time and time again because at the time of the operation the gland is found to be larger than normally. Furthermore, it must not be forgotten that hyperplasia of the thyroid in Basedow fluctuates with the stage of the disease itself, that the time when the patient comes for examination may be very well the period in which hyperplasia is in its incipient stage, or in which the thyroid has returned to its quiescent state, or is undergoing atrophy: hence the impression then that there is no enlargement ot the thyroid. If, however, a careful history is taken, one will almost always learn that at one time or another there was some enlargement. So far, so good. But there is better. We have seen that the microscopic changes in the gland are characteristic of Graves' disease; and that hypertrophy and hyperplasia of the cellular elements, thinning ot the 371) ETIOLOGY OF GRAVES' DISEASE colloid, more or less marked desquamation and cytolysis, and the pres- ence of foci of lymphoid tissue throughout the parenchyma are its chief characteristics. These changes have been found by such a great number of authors that they certainly cannot be considered as merely accidental; they must bear a direct relation to the clinical syndrome of Graves' disease. Before we have the right, however, to consider these histological changes as specific for Graves' disease, we should prove that these changes occur: (i) constantly in that condition; (2) that they occur in no other condition but Graves' disease. So far as the first condition is concerned, we have concluded with L. B. Wilson (loc. cit.) : "By assuming that the symptoms of the true exophthalmic goiter are the results of an excre- tion from the thyroid, and by attempting to determine the amount of such excretion from the pathological data, one is able to estimate in a large series of cases the clinical stage of the disease with about 80 per cent, of accuracy, and the clinical severity of the disease with about 75 per cent, of accuracy. It would therefore appear that the relationship of primary hypertrophy and hyperplasia of the parenchyma of the thyroid to true exophthalmic goiter is as direct and constant as is primary inflammation of the kidney to the symptoms of Blight's disease. Any considerable finding to the contrary I believe to indicate either inaccurate or incomplete observations on the part of the pathologist or clinician, or both." We have further seen that even if there is no appreciable macroscopic hypertrophy of the gland, these typical histological changes just spoken of could be found either diffusely distributed throughout the parenchyma or in the isolated areas, provided one takes the trouble to make seriated slides. The few rare cases of thyrotoxicosis where no histological changes are present, must most likely depend upon the disturbance of some other organs of internal secretion, as the thymus, for instance. So far as the second proposition is concerned, we must admit, too, that similar histological changes may once in a while be met outside of thyrotoxicosis in the form of adenomatous formations. But we must not forget that similar does not mean identical, and that it is by no means certain that the function of such adenomatous formations as are some- times seen in non-toxic conditions is identical with that one of the hyperplastic epithelium seen in thyrotoxicosis. Even suppose that it were, then it very likely constitutes only one of the many "preparatory conditions" without which the disease cannot develop, as it requires more than the mere presence of the tubercle bacilli to cause tuberculosis. On the whole, we can consequently admit that these anatomical changes in the thyroid are specific of the disease. Experimental Arguments. — Experimentation, too, has furnished its contingency of proofs in favor of the thyrogenetic origin of Graves' EXPERIMENTAL ARGUMENTS 377 disease. Although a number of attempts to reproduce experimentally in animals the clinical syndrome of Graves' disease have proved failures, nevertheless, a great many other investigators, whose authority and scientific honesty cannot be questioned, have succeeded where others have failed. The doubt as to the feasibility is no longer permissible. Injected subcutaneously or given by mouth, thyroid extracts have more or less the same influence on thyroidectomized animals: trophic disturbances gradually disappear, myxedema becomes less marked, the skeleton grows again, metabolism increases, the blood formula reverts to its normal type, and in short, the animal gradually becomes normal. This thyroid opotherapy is not only beneficial, but is also necessary because if it is not kept up, the animal sinks again into its previous myxedematous condition. On the other hand, fed to normal animals in overdoses or for too long a period of time, the thyroid extract becomes harmful. Tachycardia, tremor, dyspnea, extreme agitation, brilliancy of the eyes, fever, polyuria, and in many instances, exophthalmos are the results. Why such a difference ? Because to the first series of animals we have given them something they had not, something they needed. To the second, we have added a surplus of thyroid product when they already had plenty of it; we have saturated their organism with it, and it is that surplus which has become injurious. Experiments proving such contention are numerous. Not only can we reproduce the whole clinical syndrome, but also the characteristic changes in the blood, such as leukopenia, hyperlymphocytosis, hyperpolynucleosis, diminished viscosity and coagulability of the blood, etc. Ballet and Enriquez have obtained the thyrotoxic syndrome accompanied by exophthalmos, after daily intravenous injection of thyroid products into animals. Krauss and Friedenthal, injecting intravenously into rabbits the thyroid products dissolved in salt solution, observed the thyrotoxic symptoms characterized by rapid pulse, nervousness, tremor, exophthalmos, widening of the palpebral fissure, and dilatation of the pupils. Tedeschi obtained in dogs the complete clinical picture of Basedow's disease, namely, tachycardia, exophthalmos, and goiter by the same process. Cunningham and Hoennicke, experimenting upon rabbits, and Edmunds, upon a monkey and dogs, have, too, reproduced the clinical syndrome of Graves' disease with exophthalmos. Baruch, in 191 2, used for his experiments non-toxic parenchymatous and colloid goiters. Soon after removal these goiters were ground finely so that they could be injected subcutaneously or into the peritoneal cavity. With this method he repro- duced experimentally in dogs, rabbits, rats, a typical Basedow's disease characterized by nervousness, emaciation, loss of hair, diarrhea, tachy- cardia, glycosuria, typical blood changes, and in a tew instances marked exophthalmos. Three of such dogs with exophthalmos were shown by 378 ETIOLOGY OF GRAVES' DISEASE him before the Breslau Surgical Society. One of these dogs as the result of lagophthalmos developed an ulcer of the cornea. Luthi and Verebeli, after producing artificially a congestion of the thyroid gland, were able to observe in the thyroid the typical histological changes which are so characteristic of Graves' disease. They observed at the same time tachycardia and an increased excretion of nitrogen and phosphorus. But the experiments carrying with them the greatest conviction were undertaken by Klose in 1909. Convinced that the unsuccessful attempts made by others to obtain the fully developed clinical symptoms of Graves' disease were due to the fact that dried and powdered gland had been used, which had most probably lost many of its properties, he used the thyrotoxic goiters in their fresh state as soon as they were removed surgically from patients. These glands were submitted to a squeezing process and the juice so obtained, called Press-saft or " Pressed juice" was then injected into the jugular vein of dogs and without anesthetic. Klose found that the best results were obtained whenever he used "highly nervous fox terriers." Soon after the intravenous injection the blood- pressure sank from 100 to 85 millimeters of mercury. The tachycardia became exceedingly marked, pulse was at times scarcely countable, respiration became irregular, tremor, sweating, gastro-intestinal disturb- ances were very pronounced, fever rose high, and exophthalmos in many instances became very apparent. Albumin and sugar were found. The typical blood changes were present. This condition lasted for a few days, then subsided and the dogs became normal again. These experiments undertaken on a large number of dogs always showed the same constant results. The intensity of the symptoms observed was dependent upon the toxicity of the Press-saft as shown by the clinical symptoms: the most intense toxic symptoms were produced by the Press-saft from primary thyrotoxic goiters. The secondary forms or Basedowified goiters were less toxic. The toxicity of this Press-saft gradually diminished after standing, and after a period of five or six days became powerless. Mechanical shaking, drying of the gland, heating of the juice, destroyed very quickly its toxicity. If to a normal thyroid or goiter which proved itself non-toxic, a solution of iodide of potash was added, the toxicity of the Press-saft at once became apparent, lasted for a few days and then disappeared. In injecting enormous doses of Press-saft from non-toxic goiters or from other organs such as the liver, etc., Klose was unable to obtain the Basedow symptoms. Efforts, although few, have been made in order to demonstrate in the blood the existence of some toxic substances which would exist only in Graves' disease and in no other condition, and which might be regarded as of thyroid origin. Most of these tentatives have been fruitless; not THYROID OPOTHERAPY IN HUMAN BEIXGS 379 all of them, however. There is no doubt that more investigation should be made in that direction, and that with appropriate laboratory methods, we shall be able to isolate many of these substances some day. That there exists in the blood serum of Basedow patients a substance which produces a marked cardiac depression is certain. Glev, in 191 1, observed that each time a serum of Basedow patients was injected into animals, there was at once a marked depression in the blood-pressure, lasting, it is true, only for a short time, but nevertheless constant. He showed, too, that a first injection of potent exophthalmic serum conferred a tolerance of such nature that subsequent injections of the same serum produced little or no effect. Blackford and Sanford have repeated Gley's experiments and have obtained the same results. Hence the conclusion that the blood serum of Basedow patients contains a powerful depressor substance. This depressor substance is not only present in the serum of Basedow patients but is also present in the thyroid gland itself, and its depressive power is in direct proportion to the severity of the disease. In simple non-toxic goiters this substance is not present at all. The acetonetrile test of Reid Hunt was applied to the serum of Basedow's disease. It is known that with this method, mice which have been fed with thyroid extract become at least ten times more resistant to acetonetrile than the controls, hence the conclusion that blood serum, if it truly contains thyroid products in excess, should render mice treated with it more resistant to acetonetrile than normal mice. This experiment has been performed and the results show that the surmise was correct; indeed the blood serum injected into guinea-pigs rendered them also much more resistant to acetonetrile than the control. Hence the warranted conclusion that blood serum of Basedow patients contains an excess of thyroid products. Finally, Arno Ed. Lampe, experimenting with the Abderhalden method upon the blood of twenty-five Basedow patients, came to the conclusion that this blood contains thyroid, thymic, and even ovarian principles which do not exist in normal individuals. Arguments Derived from Thyroid Opotherapy in Human Beings. But besides all these experiments in animals, there is a whole series of clinical observations in human beings which have the full value of experiments, and which show, too, that there is a direct relation between the thyroid and Graves' disease. These results arc- seen when a prolonged and injudicious opotherapy is resorted to. In a myxedematous patient who had ingested ()i grams of thyroid extract, Beclere noticed a marked tachycardia, tremor, exophthalmos, rise in temperature, increased perspiration, etc. Boynet reported the case of a student who during a period of eight days absorbed 6 to 8 thyroids of sheep daily, lie soon developed swelling of the thyroid, 380 ETIOLOGY OF GRAVES' DISEASE palpitation, tremor, and extremely advanced nervous condition which subsided only after the medication was stopped. Combe reported the case of Gagnebin who, while a medical student, absorbed daily one lobe of sheep's thyroid for a period of about two weeks. At the end of that time, palpitation had become violent, fever and abundant sweating were present, tremor was so intense that he could not rise nor carry his food to his mouth, and exophthalmos had become very marked; the experi- ment was interrupted and the symptoms gradually subsided. Nothaft reports a very demonstrative case of a man who was in good health and who undertook, on his own initiative, to take in a few weeks a thousand thyroid tablets of five grains each in order to reduce his obesity. He developed the typical Basedow with goiter, exophthalmos, tremor, sweating, loss of flesh, and glycosuria; the medication was stopped and ten months later the patient was normal again. Ferrarini saw the case of a woman who had taken thyroid as an antifat cure; she had taken 6 to 8 tablets of thyroid daily for two months. After that time she lost 8 kilos, complained of vertigo, palpitations, and insomnia. She never- theless increased the quantity of thyroid and then became very nervous, pulse 150, diarrhea alternating with constipation, psychic disturbances, hallucinations, etc. Kocher saw that the return to normal of the blood of a myxedematous patient followed directly the improvement of the patient's condition. When the patient was clinically cured, the blood formula was normal. If overdoses of iodothyrin were given, the typical changes of the blood would recur, accompanied this time by diminished coagulability of the blood and by thyrotoxic symptoms such as tachy- cardia, nervousness, tremor, etc. Is it possible to give a more striking proof that myxedema is due to hypothyroidism, and Graves' disease presumably to hyperthyroidism ? A greater number of cases could be cited to prove the same conten- tion, and every surgeon who has had dealings with the goiter question, has, more than once, seen patients who on account of a prolonged and injudicious use of thyroid extract or iodin, had converted a simple non- toxic goiter into a thyrotoxic one. French undertook to study the comparative toxicity of different tissues in animals susceptible to thyroid feeding, the object being to dis- cover whether the effects of commercial thyroid extracts when admin- istered, are specific or whether similar effects could be produced by other animal tissues prepared and administered in the same way; "Whether the toxicity is due to products of decomposition, or whether it is due simply to the great amount of proteid matter ingested by an animal unaccustomed to such a diet." His conclusions were as follows: 1. Thyroid in the forms used, fresh, stale, and desiccated, either commercial or laboratory prepared — contains a substance that is decidedly toxic for some animals. SURGICAL ARGUMENT 381 2. The other animal tissues used, brain, liver, spleen, kidney, and skeletal muscle, give no evidence of toxicity when prepared and fed in the same way in equal or even larger quantities. 3. While the study does not indicate the nature of the toxic substance, it would seem to show conclusively that it is not due to protein in the food. This seems to prove conclusively that the toxic symptoms found are peculiar to the thyroid and to no other organs. Massage of a non-toxic goiter, as shown by Bneger; radiotherapy, as shown by Chvostek, De Castello and Schmidt; electrical treatment, as seen by myself, have at times, by stimulating the thyroid gland, pro- duced an exophthalmic goiter. It cannot be denied that all these experiments carry with them great weight which, added to that afforded by the clinical and pathological data, becomes singularly powerful. Surgical Argument. — The best of all the arguments in favor of the thyrogenetic origin of Graves' disease is given by the results of surgical treatment. The number of cases treated by this method now reaches well into the thousands; we have consequently plenty of material to draw our conclusion from. As seen in studying the results of surgical treat- ment, this latter method produces 50 to 85 per cent, of the cures in fully developed cases of Graves' disease and nearly 100 per cent, in the ones taken in their development. Now, no matter how little value one attaches to statistics, he cannot but be impressed by these figures. We have seen, too, that x-rays, radium, injection of boiling water, etc., in short, anv method intended to directly attack the thyroid gland in itself, with the purpose of reducing its size, and hence of reducing its function, produces good results, although temporary, as a rule. Why should it be so if there were no direct relation between Graves' disease and the thyroid, and why should it be so if the relation were not an intimate one ? This is so true that Riedl has said, "We would cure all Basedow cases if we could be allowed to remove the entire thyroid gland." How often have we surgeons marvelled at the magic effect of a simple ligation or a thyroidectomy upon numbers of cases of Graves' disease which had resisted every medical treatment. I know very well that unfortunately it is not so for every case, because the etiology of Graves' disease is a most complex one, as we shall see later. But the fact nevertheless remains that in the great majority of cases the thyroid must be the main guilty factor, because by removing a part of it we not only put a stop to the progress of the disease, but also cause its regression. In the early stages the effect is rapid and sure. In the later stages the result will depend upon the damage clone to the nervous system, to the glands ot internal secretion, to the heart, kidneys, liver, etc. We cannot expect, <>t course, to restore to normal a permanently diseased organ. And yet even in 382 ETIOLOGY OF GRAVES' DISEASE advanced cases the surgical treatment is beneficial; rarely does it remain without effect. It has been said that the good results due to the surgical treatment are of psychic order. It may be partially so in a few cases of Graves' disease complicated with hysteria, but this is certainly not the rule. The results we attain are in direct proportion to the quantity of thyroid gland put out of function. Why should it be so strikingly constant if our results were due to psychic interference ? As Crile says very properly, "If psychic influences can cure the disease, then the surgeon alone pos- sesses this influence because all surgical cases have been unsuccessfully treated by internists first. This compliment to the superior psychic power of the surgeon, unhappily we cannot conscientiously accept, because the surgeon is unable to favorably influence his patient except at the time of his contact with the patient on the operating table, and at that time his patient is unconscious." It has been said, too, that the good results obtained by surgical treatment were due to the forced "rest in bed." How many patients do we not operate who have been taking in vain the "rest-cure" for months and years under the direction of possibly the best internists ? Why should we accomplish in two or three weeks what internists failed to obtain in months and years of the same "medicine." The argument is poor indeed. If we consider all the evidence gained from the clinical pathological, experimental and therapeutic data with a fair and unprejudiced mind, we are bound to recognize that the first member of our proposition made in the beginning of the chapter, namely, that Graves' disease is a thyro- genic disease is abundantly demonstrated. Although I am willing to admit that the "irrefutable, peremptory argument" is not yet at hand, and that the one which might be considered as such, as the experiments of Klose, should be confirmed, nevertheless the weight of "circumstantial evidence" is so strong that I am sure that there is no jury in the world which would let a criminal go free on the evidence of charges similar in strength. Coupled with the excellent results which we obtain with surgical treatment, this evidence will still lead us to proceed in the same line of treatment until we get something better, and no matter what the adversaries of the thyrogenetic theory say, we will repeat with Galileo, "E pur si muove." B. Nervous Origin. — Let us discuss the second member of our proposi- tion, that as to the nervous origin. As we know, there are some authors who consider the central nervous system as the cause of exophthalmic goiter, and others who regard that disease as a neurosis similar to the one seen m hysteria and epilepsy; while some authors believe that its origin is primarily due to a disturbance of the sympathetic system, and again, XERVOUS ORIGIX 383 some others, to such of the vagus system. Then, too, others consider it only as a reflex due to some irritating influence taking its origin in the uterus, intestines, etc. That the glands of internal secretion in general are directly influenced by the central nervous system is abundantly proved. For example, the puncture of the fourth ventricle causes diabetes, and the irritation of the subthalmic region causes an increased function of the adrenals, as shown by Ascher. The section of the restiform bodies, according to Filehne and Warburton, causes hyperemia of the thyroid gland, exophthalmos, tachycardia, etc. In certain psychoses, in neuroses, in catatonia as shown by Roenfeld, Kaufmann, Paganim, the metabolism is greatly disturbed, the nitrogen excretion is greatly diminished, and the phosphorus and calcareous elimination greatly increased. The same is true in Graves' disease. We must therefore recognize that the nervous system plays a very important part in exophthalmic goiter; whether this influence is primary or secondary is, however, another matter. To be sure, in Graves' disease the nervous system is unstable. There is a certain train of nervous symptoms such as emotionality, irritability, restlessness, instability, which forms an integral part of the clinical syn- drome of that condition and which is just as typical of the disease as tachycardia, tremor, exophthalmos, etc. These nervous symptoms are sometimes the dominant feature in the whole syndrome. To consider them, a priori, and always as the primary cause of the disease seems to me, however, quite premature. We have nothing at hand to substantiate this conclusion; we have very much against it. Moreover, experiments show that the nervous symptoms follow administrations of thyroid extract and not precede it. I know too well, and I have admitted it previously, that an unstable nervous system is a "predisposed terrain" on which thyrotoxicosis might easily graft itself. \\ hen I see certain young, nervous, irritable, and unstable, individuals, I cannot help but look upon them as future candidates for Graves' disease. Possibly you will say that this is the best proof that the disturbed nervous systems of such individuals is primarily the cause of their thyrotoxicosis. " Post hoc, ergo propter hoc." Possibly so; I am willing to admit that it can be so sometimes, but in many other instances, might it not be that a number of these cases of irritable and unstable nervous equilibrium are only latent forms <>t hyperthyroidism which go unrecognized, and which may never go any further or which may some day explode into a typical Graves' disease? In fact I know that in some cases it is so, as I have operated on some such cases with the most gratifying results. In studying the nervous symptoms in connection with Graves disease we came to the conclusion that the Other forms of nervous clis- 384 ETIOLOGY OF GRAVES' DISEASE turbances as melancholia, psychoses are purely accidental. They must be considered as associated complications grafted upon a predisposed terrain; heredity, psychic as well as physical stigmata, are found in the psychoses non-complicated with Graves' disease just as well as in thyro- toxicosis complicated with mental disturbances and psychoses. We have seen, too, that Graves' disease supervening in such predisposed terrain is bound to favor the eclosion of psychoses, and vice versa; thyrotoxicosis will evolve more easily in individuals whose nervous system is already unbalanced. There is no need to insist further. Great stress is laid by the partisans of the nervous theory of Graves' disease upon the element of fear, psychic shock, fright, etc., in order to prove the nervous origin of Basedow's disease. It is true that there are cases of Basedow's disease whose incipiency has been very sudden. Trousseau, for instance, reports the case of a woman whose father died, and who from sorrow developed in the space of a night, a true case of Graves' disease with exophthalmos, vascular goiter, etc. Dieulafoy saw a woman who, after violent emotion, developed very rapidly an exophthalmic goiter. In such cases there seem to be no doubt that the nervous system is the primary cause of the trouble. These lightning forms, however, are rare. They nevertheless, carry great evidential weight with them as they show that there exists an intimate relation between the thyroid and the nervous system, and that Graves' disease may take its origin in a primarily disturbed nervous system. There is another class of cases, however, where the starting-point of the disease is referred to a psychic shock due to a runaway horse, an automobile accident, railroad wreck, etc., but there thyrotoxicosis has become noticeable only weeks or months after the occurrence. For these cases the nervous origin of Graves' disease is more doubtful, because the time elapsed from the accident to the development of the disease is quite long. It must not be forgotten that if one goes into the history of these cases carefully, one will usually find that long before the accident occurred there was a latent period during which a few Basedow symptoms were already present. They may have been only barely sketched; that is enough: the nervous system of these patients had already lost its normal equilibrium, hence the ease with which the shock of psychic order affected it. Indeed, one cannot but be impressed by the fact that often the psychic shock to which the origin of the disease is ascribed is truly insignificant; at any rate would be insufficient to upset a normal nervous system. Why is it so? Either because at the time of the accident the disease was already in a period of incubation, so that the psychic shock shaped it into its definite form and intervened as the "puller of the trigger," or because this nervous system was in ordinary conditions unstable and barely able to hold its equilibrium, and only VEGETATIVE XERVOUS SYSTEM 3S5 required an insignificant cause to tip it over the border-line. This latter possibility appears that much the more plausible since Klose, in order to obtain the best results in reproducing experimentally the clinical picture of Graves' disease, resorted to highly nervous fox terriers. It is further corroborated by the fact that the same shock will affect one, and not another. For instance, did all the survivors of the Titanic disaster develop Graves' disease ? Not by any means, vet they all underwent the same ordeal. Aside from a few exceptions, it must be further positively proclaimed that in the great majority of cases of Graves' disease psychic shock cannot be accused of being the causative factor simply because it was not present. Surely no one is going to claim, for instance, that all the secondary or Basedowified goiters are of psychic origin, that a runaway accident, or a railroad wreck, is at the bottom of all the primary forms of Basedow's disease, or that a scare by a burglar, or a rape by a negro, is responsible for the cases of Graves' disease following acute infections, acute thyroiditis, and furthermore, that disappointed love must be looked for in all the cases of Graves' disease occurring at the time of puberty and menopause. In the great majority of all these cases there is no apparent cause at all for the development of the disease. To claim that these cases are primarily of nervous origin is simply to make a statement founded upon no proof. Vegetative Nervous System. — The vegetative life is under the control of two great nervous systems, the sympathetic and the autonomous; the latter comprises chiefly the oculomotors, vagi, and the pelvic nerves. In normal conditions these two systems are antagonistic; what one accelerates, the other moderates, and vice versa; for instance, the cardiac action is accelerated by the sympathetic and diminished by the vagus system; intestinal peristalsis is paralyzed by the sympathetic and accelerated by the vagus system. The welfare of the organisms depends upon the harmony and intelligent working of the two systems; as soon as one of them becomes aggressive and overdoes, then the equilib- rium is broken and disturbances follow. The same system, be it sympathetic or vagus, contains acceleratory and moderatorv fibers. For example, besides cardiac acceleratory fibers, the sympathetic contains cardiac moderatorv fibers, and besides modera- tor)' fibers, the vagus contains also acceleratory fibers. It is true that the acceleratory fibers found in the vagus and the moderatory fibers contained in the sympathetic are far less numerous than then antagonists, yet they exist, and must come into play in some way or another. 1 his shows that the same system can be acceleratory and moderatorv at the same time, a fact very important to remember, as it shows that the duality of function of an organ is possible. This dual function most 25 386 ETIOLOGY OF GRAVES' DISEASE likely occurs through the influence of hormones acting electively and exclusively upon each set of fibers. This notion of "duality of function" of the same organ is an exceed- ingly important one to remember. It must be safe to say that the nervous system cannot be the only one to have this peculiarity, but that other organs must certainly share the same property. This must be especially true for the organs of internal secretion. And so it is. As shown by Eliot, small doses of adrenalin produce a vasodilatation of the blood- vessels, whereas in higher doses it produces a vasoconstriction. Pituitrin increases the contractions of the gravid uterus of a rabbit, whereas it paralyzes the non-gravid. Iscovesco isolated from the glands of internal secretion various lipoids, each one possessing a definite property, although coming from the same gland; in that case the function instead of being dual ma} r be manifold. This principle being accepted, at once the horizon widens and facts which at first seemed to contradict themselves, as for instance the simultaneous presence of hypothyroidism and hyper- thyroidism symptoms become intelligible. Excitation of the sympathetic nerve causes tachycardia, exophthalmos, alimentary glycosuria, enlargement of the palpebral fissure, and increased metabolism. On the other hand, excitation of the vagus causes sweating, vomiting, diarrhea, lymphocytosis. Adrenalin produces the same effect as does the excitation of the sympathetic, namely, an excitatory action whenever the sympathetic fibers are excitatory, or paralyzing whenever they are inhibitory. On the other hand, small doses of pilocarpine or muscarine stimulate the vagus system; at the same time they stimulate the sympathetic fibers which supply the sudoriparous glands. Atropin paralyzes the vagus system and the sympathetic fibers supplying the sudoriparous glands. Since by feeding animals or human beings with thyroid extracts, we obtain results which resemble very much the ones seen after the adminis- tration of pilocarpine or muscarine, such as vomiting, diarrhea, lympho- cytosis, eosinophiha, sweating, respiratory disturbances, etc., it is logical to conclude that there exists in the thyroid, substances, or better, hormones, whose effects are similar to that of pilocarpine, and which act electively upon the vagus system. Furthermore, since a number of other symptoms seen in Graves' disease are exactly similar to the ones obtained by irrita- tion of the sympathetic, such as tachycardia, alimentary glycosuria, enlargement of the palpebral fissure, exophthalmos, increased metab- olism, etc., and since the ingestion of thyroid extract produces the same troubles, it is rational to conclude that either the thyroid contains one or more hormones acting electively upon the sympathetic system, or that the thyroid hormones act upon other organs such as the suprarenal bodies, whose adrenalin then influences the sympathetic system. VEGETATIVE XERVOUS S VST EM 387 But there is something more. Small doses of pilocarpine which in normal individuals will have little or no effect, may produce intense symptoms in other individuals, hence the conclusion that the vagus system of the latter subjects is normally in a state of hypertonics because an excitant, which normally would remain without effect is sufficient to cause in them marked symptoms. Hesse and Eppinger say that these individuals whose vagus system is in a state of constant hypertonus are vagotonic, and call vagotrope the substances which act upon the vagus svstem. These vagotonic individuals are normally sensitized to vago- tropic substances; at the same time they remain more or less refractory to substances which ordinarily act upon the sympathetic system. The same is true for the sympathetic. Substances which in normal individuals will cause little or no effect upon their sympathetic system, will prove very active in certain other individuals. Again, according to Hesse and Eppinger, the sympathetic system of the latter individuals is in a state of constant hypertonus; these individuals are sympatheti- cotonic, and the substances which act upon the sympatheticotonic individuals are sensitized to sympatheticotrope substances. At the same time in such individuals the vagotrope substances given in large doses remain without effect; they, too, seem to be inhibited. The vagotonus is determined by the excess secretion of the vagotrope hormones accom- panied at the same time by a diminished secretion of the sympathetico- trope hormones. The sympatheticotonus is caused by an excess secretion of the sympatheticotrope hormones accompanied at the same time by a diminished secretion of the vagotrope hormones. The thyroid consequently contains sympatheticotrope and vago- trope hormones. In Basedow's disease both varieties of hormones are increased and both act electively upon the sympathetic and vagus systems, hence the mixed symptoms taking their origin in the sym- pathetic as well as the vagus disturbances. The fact, being admitted with Eppinger and Hesse, that there are patients who are normally vagotonic or sympatheticotonic, it will naturally follow that in such individuals some of the thyroid hormones will center their effects mostly upon the already sensitized system: if the vagus, for instance, happens to be the one which is in constant hypertonus, vagal symptoms will be more marked than the sympathetic ones, hence we will have marked vomiting, diarrhea, sweating, etc., whereas, on the other hand, it the sympathetic is the one already sensitized, the poisonous hormones of the thyroid will center their effect mostly upon that system, hence the predominance of tachycardia, exophthalmos, glycosuria, etc. Purely vagotonic or m mpatheticotonic cases are rare; as a rule they are mixed. Consequently the degree of vagotonicity or sympatheticotonicity ol the organs will to a certain extent determine the nature of the thyrotoxic syndrome and 388 ETIOLOGY OF GRAVES' DISEASE its intensity, hence the explanation why thyrotoxic cases are not all alike, and why the entire symptom-complex of Graves' disease is not always met in one case. Thus it will be understood that it is not neces- sary to have a large goiter in order to have a severe Basedow, if one happens to be normally vagotonic or sympatheticotonic or both. Thus it will be understood too, that it is not necessary that the whole gland be hyperplastic, but that isolated areas of localized hyperplasia will suffice to cause the thyrotoxic syndrome, because these areas will send what Kocher in the forethought of his genius called, " Basedow impulses," and which are nothing else than lipoids acting electively upon already sensitized organs. Thus this will finally, to a certain extent at least, as other factors intervene, afford a reasonable explanation for the fruste forms of Graves' disease. Let us conclude: The nervous system takes in the production of Graves' disease a very active and important part. Although the nervous system may in a few cases be primarily affected, in the remainder of the cases it is only secondarily involved. C. Polyglandular Origin. — This is the third member of our proposi- tion. If one takes a bird's-eye view of the symptoms due to disturbances of each one of the organs of internal secretion separately and compares them with each other, besides the typical and characteristic symptoms due to the pathology of the gland itself, there is a train of secondary symptoms which occurs in almost every disturbance of these organs. Example : Suppose we deprive a young woman of her ovaries : besides the complete amenorrhea and loss of sexual appetite, we shall observe hot flashes, sweating, palpitation, moderate tachycardia, nausea, glycosuria, vomiting, nervousness, cutaneous eruptions, depressive states, and sometimes temporary insanity. And again, take Addison's disease, for instance; there, too, besides profound myasthenic symptoms characterized by an intense feeling of excessive fatigue, going sometimes into a state of complete adynamy, and besides melanodermy, there is a group of more general symptoms present, such as complete loss of appetite, vomiting, diarrhea, alternating sometimes with constipation, polyuria, and poly- dipsia, headache, loss of sleep, nervousness, states of depression, low blood-pressure, flabby heart, irregularity of menstrual function, and sometimes complete amenorrhea. And so on. The same is true in a general way for the pathological conditions of the other organs of internal secretion. It we compare these clinical symptoms with the ones seen in Graves' disease, we are forced to admit that a number of them found in the latter condition seem to be common to diseases of other organs of internal secretion, although in every instance the organ primarily involved is an entirely different one. This must mean consequently that there is POLYGLANDULAR ORIGIN 389 between all these organs a functional interrelation. And so it is, as shown by the pathology and by experimentation. No one organ is inde- pendent of the other organs. There is no one organ driving the other organs exclusively, but rather do the organs drive each other reciprocally. There is here no solar system around which everything else gravitates. Our organism is not an autocracy but a democracy. To be sure, some organs are more important than others, but they are nevertheless dependent upon the less important and vice versa. Whenever one becomes pathologically involved, its derangement repercusses upon the function of the others. There is, in other words, a functional solidarity among them all. This solidarity is not only functional, but is compen- sator)*, too. For example, if one of the hemispheres of the brain is removed, there is a compensatory hyperideation in the other hemisphere. When a large bloodvessel becomes obstructed for some reason or another, and incapable of carrying the blood through the normal channel, a collat- eral circulation takes place in order to relieve the flood; and of this no better example can be given than that of the caput medusae resulting from obstruction of the portal vein. If one kidney is removed, the other one compensates its loss by hypertrophy and increased function. And so on. The thyroid does not make an exception to these laws. Let us see if we can base our views upon something tangible. Thyroid and Hypophysis. — Boise and Biedl found a marked hyper- trophy of the hypophysis in two cases of myxedema and in one of sporadic cretinism. Schonemann and Comte found an hypertrophy of the hypo- physis whenever the thyroid was degenerated or atrophied. Rogowitsch found a constant hypertrophy of the hypophysis after complete thyroidec- tomy had been performed. Guerrmi and Dehlle, after treating various animals with thyroid extract found that there was more or less constantly an hypertrophy of the hypophysis. Hyperemia of the hypophysis has- been found in connection with Graves' disease. It is logical to admit that the hypophysis participates functionally in the production of the thyrotoxic syndrome because vasomotor)' disturbances, variations of temperature, increased sensation of thirst, and polyuria arc commonly seen in diseases of the hypophysis. The disturbed metabolism of fat and the cutaneous eruptions seen in Graves' disease are likely due to disturb- ances of the hypophysis. Alquier and Hallion, alter feeding rabbits with hypophysis extract, found vasoconstriction of the thyroid gland and finally shrinkage of the whole gland. As seen by our pathological and experimental data, there is on the whole little doubt of the existence of some sort of specific relation between the thyroid and the hypophysis. Thyroid and the Genital System. That there is a relation between the thyroid and the genital apparatus, is shown bv the fact that the great majority of Basedow patients are women, and that the djseast in 390 ETIOLOGY OF GRAVES' DISEASE influenced materially by menstruation, pregnancy, and menopause. The constitutional difference between man and woman is due solely to the genital apparatus. More than men, women are all their lives under the constant influence of their genital system. This influence begins at the time of puberty, keeps up with each menstruation, and only stops at the menopause. During all these periods not only the nervous system is jeopardized, but the entire organism is in a state of constantly changing equilibrium, hence the tendency for women to develop Graves' disease more frequently than men. As we have seen in studying the disturbances of the genital system, in Graves' disease menstruation is often irregular, and not infrequently totally absent. This total amenorrhea may remain permanent and may then give rise to a premature menopause. Hand in hand with these genital disturbances there often goes hypoplasia of the genital system. This atrophy is found, too, in hypothyroidism. When myxedema occurs in adults it is not infrequent to see a complete reversion to sexual infantilism marked by atrophy and impotence. For instance, Lanz reported the case of a man who had become myxedematous ten years after thyroidectomy; the testicles became markedly atrophic. Ceni noted a marked diminution in the production of eggs in thyroidectomized hens. Parhon and Goldstein consider the thyroid and ovaries as antago- nistic, whereas Charrin and Jardry claim that they are synergetic. Thyroid; Pancreas; Adrenals. — There is no doubt that there is between the thyroid and the pancreas an intimate relation. The disturbances in the metabolism of carbohydrates so often seen in Basedow's disease must be attributed to a disturbed function of the pancreas. The same is true for the disturbed resorption of fat which gives rise to fatty stools. Chvostek was among the first in determining these facts by showing that certain cases of Basedow were caused by disturbances of the pan- creas, and that the symptoms would retrocede after pancreas opotherapy. Kohn and Peiser confirmed Chvostek's conclusions, basing their state- ment upon postmortems of thyrotoxic patients in which undoubted pancreatic lesions were found. Eppinger, Falta, Rudinger, Grey and De Sautelle have noted that glycosuria could be produced experimentally in dogs by giving them large doses of adrenalin; and that glycosuria does not take place at all if thyroidectomy has been performed. This will explain why myxedematous patients can stand very large doses of sugar without showing alimentary glycosuria. Falta has reported one case in which after thyroidectomy marked hypertrophy of the islands of Langerhans was found. Lately Rudinger, Falta, and Eppinger have shown that the thyroid, the pancreas, and the adrenals were intimately related and exerted a reciprocal action one upon the other (Fig. 70). According to them the POLYGLANDULAR ORIGIN 391 pancreas inhibits the thyroid and the chromaffin system, the adrenals inhibit the pancreas and stimulate the thyroid, while the thyroid also inhibits the pancreas and stimulates the adrenals (Fig. 70). Conse- quent!)', the thyroid and the pancreas on the one hand, and the chro- maffin system and the pancreas on the other hand, are antagonistic, whereas the thyroid and the chromaffin system are synergetic. From this it follows that the hyperfunction of one will have as a consequence the hyper- or hypofunction of the others as the case may be. Hyper- thyroidism, consequently, must produce an insufficiency of the pancreas and a hyperfunction of the adrenals. This will explain why in pancreasec- tomized animals the excitability of the dilatator muscles of the iris is greatly increased, and this is most likely on account of the increased output of adrenalin. The same is true for animals overfed with thyroid extract, and the same is likewise true for Basedow patients, who often react by widening of the pupils after the instillation of a few drops of Thyroid Pancreas Fig. 70 adrenalin. In athyroidism and hypothyroidism, the function of the thyroid being diminished, its inhibiting power on the pancreas is ipso facto diminished also; hence the increased function of the pancreas which in turn results only in an increase of the inhibitory power of the pancreas upon the thyroid, thus forming a vicious circle in which the pancreas take more and more the upper hand. At the same time, as the exciting power upon the chromaffin system by the diminished thyroid is reduced, too, and as the inhibitory power of the pancreas upon the chromaffin system is increased, we must likewise have a diminution of adrenal function. Since normally the pancreas peptonizes the proteins through its trypsin, saccharifies the amylaceous substances through its amylopsin, and saponifies the fat through its steapsin, and as on the other hand, these various functions in hyperthyroidism are inhibited, so we must expect to find that the metabolism of carbohydrates is greatly diminished, and we must consequently expect to find loss of peptones, glycosuria, and fat 392 ETIOLOGY OF GRAVES' DISEASE in the stools. And so it happens quite frequently. On the other hand, the opposite must be true in hypothyroidism: indeed, it is a known fact that in that condition the tolerance for carbohydrates is greatly increased. Krauss and Fnedenthal have shown that normal human blood serum has no effect upon the frog's eye; if, however, thyroid extract is injected, a marked mydriatic power of the serum is found. This reaction is very likely due to an increase in the adrenalin content of the blood, or at least, to an abnormal amount of sympatheticotomc substances of some sort. Cam confirmed these statements. In using the Meltzer-Ehrmann test, many authors and myself often found an increased adrenalin content of the blood of Basedow patients; in many instances, however, this increase is not present. Kostlivy, treating per os rabbits with thyroid substances, noted a marked increased mydriatic power of the serum proportionate to the dosage. At the autopsy the adrenals of these rabbits showed marked hypertrophy. In hypothyroidism no changes in the adrenals are found. Thyroid and Thymus. — The evidence that there is an intimate relation between the thyroid and the thymus in Basedow's disease is mostly clinical. It is becoming more and more an undoubted fact that in the great majority of cases of Graves' disease there is at the same time a thymic hyperplasia. This thymic hyperplasia is mostly constituted by a proliferation of the medullary portion of the thymic lobule at the cost of the cortical portion. In severe cases the entire thymus consists mostly of the medullary substance. At the same time there is an intense prolif- eration of Hassal's corpuscles and a marked increase of eosinophiles. The entire gland is soft and exudes a milky juice. Thymic hyperplasia does not occur in conjunction with Basedow's disease only, but is often found in simple goiter. R. G. Hoskms found that the offspring of female guinea-pigs treated with thyroid substances often had hypertrophied thymuses. This fact would tend to indicate that the thyroid stimulates the thymus. Jeandehze, Lucien, and Pansot have recently shown that thyroidectomy in young rabbits causes, in every instance, a diminution of the thymus as compared with that of the control animal of equal size. Wornes and Pigache have shown the same results, a fact which tends to prove that the thyroid and thymus are synergetic. Thyroid and Parathyroids. — According to Tage Iversen, no parathyroid lesions are found in Graves' disease. On the other hand, Alquier and Hallion, after feeding animals with parathyroid extract, observed marked histological changes in the thyroid, resembling the ones seen in Basedow's disease, whereas, feeding with hypophysis seemed to produce exactly the opposite picture. Conclusions. — Although it is still difficult to gain a clear insight into this complicated mechanism of the organs of internal secretion, there cannot be any doubt as to the functional interrelation of all these organs. IODIX -BASEDOW 393 The thyroid forms one very important ring of the polyglandular chain. Its pathology repercusses upon the other organs of internal secretion which in turn react upon the thyroid, hence a vicious circle. Summing up, we are forced to conclude that, although the thyroid gland plays the most important part in the production of Graves' disease, we must nevertheless concede that other factors intervene at the same time, such as the nervous and the polyglandular systems. Hence my conclusion: Thyrotoxicosis is a thy roneuropoly glandular disease. Let us see now if we can gain some information as to how the thyroid changes take place and what the intimate working of the process is. Let us stud)- first the iodin-Basedow and then see what relation exists between Basedow's disease and thyroiditis. IODIN BASEDOW. The use of any form of iodin preparation may cause a group of symp- toms known as iodism; this condition is mostly characterized by sneezing, running of the nose, sensation of constriction of the throat, bronchitis, stomach and intestinal catarrh, conjunctivitis, with abundant lachrymal secretion, headaches, and skin eruptions. In the beginning the tongue, mouth and pharynx are dry; later, however, abundant salivation takes place. These symptoms are due to the fact that iodin is eliminated through the mucous membrane and skin, and that some patients are more sensitive than others to its influences, or that they may have some sort of idiosyncrasy for iodin. This form of iodism is benign and mostly harmless; very exceptionally it may lead to acute edema of the glottis. Ordinarily it subsides as soon as the iodin treatment is discarded, and no ill effects are felt from it afterward. As seen this has nothing in common with the clinical picture known as hyperthyroidism. An entirely different proposition, although less widely known, is that of a certain form of iodin intoxication which occurs once in a while in connection with iodin treatment of goiter and which closely resembles the clinical syndrome seen in thyrotoxicosis. It is characterized by nervousness, tachycardia, tremor, palpitation, insomnia, gastro-intestinal disturbances, depressive conditions, marked loss of flesh, and a profound asthenic condition. In many instances, exophthalmos occurs. Rilhct, of Geneva, was the first, in 1895, whose attention was called to that form of intoxication and regarded it as a sort of idiosyncrasy. He called it constitutional iodism. Since then similar observations have been made frequently and the condition has become well-known to the clinicians. Breuer called it iodin- Basedow, and that denomination has been adopted by everyone. Iodin-Basedow occurs with predilection in people of middle age, 394 ETIOLOGY OF GRAVES' DISEASE between thirty and forty; in young individuals the course of the condi- tion is much more severe. Something very peculiar is the fact that some patients developing lodin-Basedow may have used iodin prepara- tions several times previously and during more or less long periods without ill effects; then some day, for no apparent reason, the use of possibly only very small doses of iodin has been enough to cause the iodin-Basedow. Women are more often affected with it than men. The condition, as a rule, starts two or three weeks after beginning the iodin treatment, grows worse as long as the medication is kept up, and usually disappears gradually after the 10dm medication has been dis- carded. It takes, as a rule, several months before the patient's condition becomes normal again, sometimes years. Even then there sometimes remains a tendency to palpitation, nervousness, etc. In other instances, instead of regressing, the condition progresses gradually and develops into a severe case of Graves' disease; a fact which I have observed more than once. A fact worthy of notice is that hand in hand with the appearance of the iodin-Basedow goes a reduction in the size of the thyroid gland. Later, however, if the iodin-Basedow should grow into a true Basedow the thyroid gland will enlarge again. Is there any Relation between Iodin-Basedow and the Quantity of Iodin Absorbed? — In a great many cases the smallest doses of iodin are sufficient to produce iodin-Basedow; cases are known where the mere use of tincture of iodin applied once or possibly twice to the skin or gums was sufficient to cause the condition. On the other hand, it is known, too, that some individuals may stand the most prolonged and large doses of iodin without the slightest ill effect except possibly some lodism. We are consequently forced to conclude that the quantity of 10dm is in itself irrelevant. The time which elapses from the beginning of the intake of iodin to the time when the symptoms of iodin-Basedow develop is variable; ordinarily iodin-Basedow occurs ten to fifteen days after the beginning of the iodin medication; in some instances, however, it may begin only weeks after the iodin medication has been stopped. It has been observed that m countries where goiter is endemic, iodin treatment is very apt to cause an iodin-Basedow. Fleishmann has shown that susceptibility to iodin varies not only with each individual but also with regions: for instance, persons living in Geneva, or Vienna are more susceptible than others living in other cities; 68 per cent, of the patients seen in Basel, 23 per cent, in Berne, and 3.7 per cent, in Berlin when treated with iodin showed symptoms of iodin-Basedow. Why such a difference ? Nobody knows. Iodin-Basedow resembles so clearly the ordinary Basedow that we are forced to admit that both conditions are alike, and are due to the IODIN -BASEDOW 395 same cause, namely, to hyperthyroidism. There is between them only a difference of degree. The iodin-Basedow which might be called alimentary hyperthyroidism bears to the ordinary Basedow the same relation that alimentary glycosuria does to diabetes. The first form is transitory; the second is permanent, but both forms apparently recog- nize the same cause, no matter by what mechanism the)' occur. There can be no doubt that iodin-Basedow is due to the disturbed metabolism of iodin. We have said before that whenever an iodin- Basedow begins to develop, there is at the same time a concomitant reduction in the size of the thyroid gland. It is true, however, that after a while the thyroid returns to its previous size and often exceeds it. What does this mean ? It can signify but one thing, namely, that the thyroid gland is reducing its size by throwing off into the blood circulation a certain amount of its content. What can this content be if it is not the ''colloid" itself, and where can the gland throw it, if not into the general circulation ? In other words, iodin stimulates resorption so that the organism finds itself rapidly flooded with thyroid products. As the process goes on, however, the thyroid increases its secreting power by redupli- cation of the functionating parenchyma: hence, again, increase in volume of the thyroid. We know, on the other hand, that the "colloid secretion of the thyroid gland is formed mostly by "thyreoglobulin" which has a great affinity for iodin; as soon as it has fixed the radical "iodin" it becomes then "iod-thyreoglobulin." The higher the iodin content of the iod-thyreoglobulin, the higher its activity. These are the facts. How shall we bring them together and set forth a suitable explanation for the origin of iodin-Basedow? One fact seems impossible to deny, namely, that the whole problem seems to hinge upon a defective metabolism of iodin. This is proved by the occurrence of iodin-Basedow after iodin medication, by the fact that Basedow glands contain a lesser amount of iodin than any other form of goiter or normal thyroid. It is further corroborated by the fact that thyroid products are toxic in direct proportion to their iodin content. That much is certain. Another thing, too, seems to be more than probable: it is the fact that anorganic iodin as such is more or less inert; in order to be utilized by the organism, and in order to become useful or harmful it must be combined with some albuminous substances. In the thyroid the anor- ganic iodin unites to thyreoglobulin and thus becomes an organic iodized preparation which only then becomes capable of exerting its influence upon the metabolism. This will explain why anorganic iodin alone is inactive in hypo- and especially in athyroulism; in order to become therapeutic iodin must be combined with tin- thyroid products whose activity increases in direct proportion to their iodin content. It would 396 ETIOLOGY OF GRAVES' DISEASE seem that in ordinary conditions where a surplus of iodin is present in the body, the organism should not be worse off for it, as the thyroid and the other organs presiding over the metabolism of 10dm ought to dispose of it very quickly. In some instances, however, for some reasons still unknown to us, matters go differently. Is it because of "special disposi- tion," "idiosyncrasy," be it temporary or permanent, of the individual toward iodin, or because the great oxydating power of the iodin directly activates the epithelial elements and drives them to overfunction, or is it not because iodin causes a toxic thyroiditis ? We know that in iodin- Basedow the histological changes are the same as the ones seen in any other form of toxic or bacterial thyroiditis. Hyperemia of the gland takes place; cellular hypertrophy and hyperplasia occur; the thick colloid, rich in iodin, undergoes liquefaction and is quickly absorbed and thrown into the circulation under the form of an iodized albuminous substance mostly iod-thyreoglobulin. Inasmuch as undoubtedly the thyroid has lost its power to metabolize iodin in the right way, it works at top speed in order to eliminate it, or to convert it into an ab- sorbable product, hence hyperplasia, increased function, and thyroid diarrhea, as Kocher so graphically pictures it. Very likely the iodin goes through and irritates the thyroid just as undigested food goes through and irritates the intestines. On the other hand, as shown by Oswald, the iod-thyreoglobulin even in very small doses increases markedly, and for a long time, the excitability of the vegetative nervous system, be it sympathetic or vagus; consequently this increased amount of iod-thyreoglobulin, being constantly poured into the blood circulation, lowers the threshold of the nervous system, thus increasing its suscepti- bility and excitability. If it so happens that the nervous system has already been sensitized to these iodized thyroid products, at once the reaction will be intense: the thyroid products will markedly influence the nervous system which in turn will "fire back" by influencing the thyroid gland. Thus, a vicious circle becomes established; the thyroid drives the nervous system and the nervous system drives the thyroid. This will go on until one of the two gives out, or until one of the two connecting links is broken, as by thyroidectomy, for instance. We feel consequently warranted in considering the true lodin-Basedow as a toxic thyroiditis causing toxic neurosis due to the influence of the iod-thyreoglobulin upon the cerebrospinal and visceral nervous systems. The primary lesion, however, is found in the thyroid. THE RELATION BETWEEN BASEDOW'S DISEASE AND THYROIDITIS. The relation between infectious diseases and thyrotoxicosis is more than merely accidental. It is a relation of cause to effect. Indeed, a BASEDOW'S DISEASE AXD THYROIDITIS 397 number of instances may be cited to show that there is a direct relation between the infectious process and the development of Graves' disease. Almost everv infectious disease, as typhoid, articular rheumatism, scarlet fever, influenza, syphilis, tuberculosis, etc., is known to have been followed some time after by the thyrotoxic syndrome. Gilbert and Castaigne reported a case of a young girl, aged fifteen years, who during the course of Uphold fever developed a moderate thyroiditis, and a month later showed the classical symptoms of Graves' disease. Reinhold saw a patient who during an attack of influenza developed an acute thyroiditis, one lobe being more involved than the other. Three months after the patient developed a classical Basedow's disease. Curiously enough hypertrophy of the thyroid gland was most marked on the same side on which thyroiditis had taken place. De Quervain saw a patient who during repeated attacks of articular rheumatism developed a moderate degree of thyroiditis accompanied by unmistak- able symptoms of Graves' disease. The case of Breuer's is classical. His patient w T as taken suddenly sick with an acute thyroiditis developed in the left lobe of the thyroid. However, four or five days after, every- thing subsided; a few weeks after the patient began to show symptoms of exophthalmic goiter which rapidly became so severe that seven months later he died from the consequence of his thyrotoxicosis. Postmortem showed in the left lobe of the thyroid a small encapsulated abscess which proved to be of staphylococcus origin. D. D. GletnefF reported 9 cases of acute strumitis and thyroiditis followed by Basedow disease. One of them was a child, aged eleven years. Another one was a young woman, aged twenty-four years, who, after typhoid fever, developed a severe exophthalmic goiter which caused her death a few months after. I have seen a young physician, who one summer evening while in perspiration, sat on his porch and got chilled. During the night he complained of intense pain in the neck. When I saw him the following morning he was in a state of complete physical collapse, utterly unable to stand or to walk, had a marked tremor, palpitation, tachycardia. The whole thyroid was acutely inflamed, the right lobe being manifestly larger than the rest of the gland. The gland was very hard and exceed- ingly painful to pressure, temperature was 101 F. During the following five or six days the condition grew worse, palpitation, tachycardia, tremor, and gastro-intestinal disturbances being exceedingly trouble- some. The left lobe and isthmus reached about three times, and the right lobe, about four times their normal size; the whole gland remained exceedingly painful and hard; faint vascular symptoms developed in it. Graefe, Dallrymple symptoms and a moderate (hunt of exophthalmos became apparent. I he patient during all this time 398 ETIOLOGY OF GRAVES' DISEASE remained exceedingly nervous and could not sleep. After awhile, however, the symptoms gradually subsided, and after several months the patient regained his health. The author saw a young woman who after a massage treatment for a colloid goiter of the right lobe, and after a sore throat, developed an acute strumitis. Besides the thyroid symptoms such as swelling,extreme pain on pressure, hard consistency, and with a temperature of 102 ° F., she also had marked thyrotoxic symptoms characterized by palpitation, tachycardia, extreme nervousness, tremor, insomnia, unquestionable Dallrymple symptom, and a moderate exophthalmos, etc. After a week everything subsided, the thyrotoxic symptoms included. I have had under observation a young nurse who has always been in good health, although rather nervous and having a moderate-sized goiter. While nursing in the hospital, she was taken sick with an acute tonsillitis which lasted two weeks. During that short time the thyroid increased materially in size, and the thyrotoxic symptoms became very marked. After tonsillitis had subsided entirely the patient was a nervous wreck; pulse was 150 to 165, tremor intense and generalized to the whole body, nervousness very marked, exophthalmos was very apparent, Dallrymple, Graefe, Kocher symptoms were positive, muscular asthenia was intense. After several weeks of medical treatment the patient improved enough so as to be able to go through operation, which proved very successful. A great many other cases could be cited in order to prove this conten- tion, namely, that there is a direct relation between the infectious process and the development of thyrotoxicosis. It shows, furthermore, that the organ primarily affected in all these cases is the thyroid. This is of the utmost importance so far as the etiology is concerned. In cases similar to the ones just cited, where postmortems and histo- logical examination of the gland could be performed, the microscopic -hanges found resembled very much those seen in thyrotoxicosis, namely, hyperemia, cellular hyperplasia, thinning of the colloid, leukocyte infil- tration, etc., the only difference being that of degree. Furthermore, in the chapter devoted to thyroiditis, we have seen that chemical poisons such as phosphorus, nitrate of silver, iodin, turpentine, pilocarpine, may cause a toxic thyroiditis characterized by hyperplasia, degeneration, desquamation of the epithelial elements, thinning or absence of colloid, more or less marked hyperemia. The same is true in toxic thyroiditis caused by bacterial toxins. As we have seen elsewhere, Roger and Gamier, Crispino, Torri, De Quervain, and others found that the intro- duction of bacterial toxins into the thyroid circulation exerted upon the thyroid gland about the same influence as the chemical poisons; namely, hyperemia, proliferation and desquamation of the epithelium, diminu- GRAVES' DISEASE IS A TOXIC THYROIDITIS 399 tion or absence of the colloid, etc. The same pathological findings are found to a certain extent in thyroid glands during acute infectious pro- cesses. The lesions may not be such as to be macroscopically detectable; the microscope, however, shows that these typical lesions are present. For instance, Roger and Gamier, examining 40 thyroid glands taken from patients who had died of scarlet fever, diphtheria, acute gastro- enteritis, difFuse cerebrospinal meningitis, peritonitis, rabies, and small- pox, found in nearly every case marked histological changes in the thyroid. In some instances the epithelium had proliferated to such an extent as to form papillary formations projecting into the alveolar lumen. At the same time cellular desquamation was present, colloid was thin or absent, interstitial connective tissue showed little or no pathological changes except in the thyroids of patients who died from tuberculosis; there a diffuse sclerosis was found. Cnspino, Sarbach, Serrafini, \ ltry and Giraud came to the same conclusions. De Quervain, investigating the condition of the thyroid in 45 cases where the cause of death was tuberculosis, cancer, cardiac, liver and kidney diseases, peritonitis, puerperal infections, diabetes, scarlet fever, smallpox, measles, diph- theria, typhoid, pneumonia, found marked changes in the epithelium characterized by a proliferation, desquamation, fatty degeneration of the desquamated cells, thinning, diminution, or absence of the colloid, and hyperemia of the whole gland. In certain cases he found mter- alveolar leukocytic infiltration. In patients w T ho died from cancerous cachexia, diabetes, nephritis, Addison's disease and uremia, no patho- logical changes in the thyroid were found. Finally, Gregor, in 26 thyroids of children who died from scarlet fever, found the same pathological changes reported bv all the other authors. GRAVES' DISEASE IS A TOXIC THYROIDITIS. How shall we interpret all these facts? It we throw them all together, the first conclusion we come to is that the thyroid reacts in the same way to the most various and most diverse processes. For instance, in thyroiditis, be it bacterial or toxic, we find hyper- emia, cellular hyperplasia, increased absorption of colloid, leukocyte infiltration, thyrotoxic symptoms. In iodin-Basedow where 10dm seems to be the provocative agent, causing very likely a toxic thyroiditis, we find, too, hyperemia, cellular hyperplasia, diminution and thinning of the colloid, leukocytic infiltration, thyrotoxic symp- toms. In acute infectious processes of the organism such as typhoid, etc., the gland shows in a lesser degree, it is true, but nevertheless unmis- takably, the same pathological and clinical signs. Although the causes 400 ETIOLOGY OF GRAVES' DISEASE vary, the results are the same. In iodin-Basedow as in toxic and bacterial thyroiditis, as in the ordinary Basedow, the nature of the histological changes and, to a certain extent, of the clinical symptoms, is the same. There is only a difference of degree. We are consequently warranted in concluding that in thyrotoxicosis the mechanism of the development of the disease is similar to the one which occurs in iodin-Basedow, and in thyroiditis, be it toxic or bacterial. In the latter conditions the process is acute, whereas, in Basedow it is chronic. Furthermore, as in iodin- Basedow and acute thyroiditis, the thyroid gland is involved first and the symptoms occur only after, had we here only that proof in favor of our contention, it would still be logical to conclude that in the great majority of cases of Basedow's disease, the starting-point takes place in the thyroid. Hence we disagree with Mickuhcz who claimed that the thyroid acted as a "multiphcator;" with Crile, who thinks that it plays the part of an "activator" inaugurated directly or indirectly by the nervous system. If we carry our line of reasoning a little further, as in iodin-Basedow, in bacterial, toxic, or chemical thyroiditis, the true nature of the process is a toxic one, we shall naturally have to admit as a consequence of it that in the true Basedow disease we have to deal with a similar toxic process, too. In the last analysis the whole question resolves itself into a matter of a toxico-infectious process, in other words, Graves' disease is a toxic thyroiditis. So understood, this theory will explain the pain to pressure so often seen in true thyrotoxic goiters; it will explain the adhesions so often found around the goiter at the time of the operation, even when no external treatment, as iodin or x-rays, has been used; it will explain why in exoph- thalmic goiter the cervical lymph nodes are hyperplastic, why there is a leukocytic infiltration throughout the thyroid parenchyma; and it will explain, partly at least, the slight rise in temperature sometimes seen in Graves' disease. It is not necessary to look for a specific thyrotoxic microbe in order to explain all these clinical findings; they may be caused by all the microbes; their toxins; the products of auto-intoxi- cation; or any toxic chemical agent. Under the spur of their irritation the thyroid works at top speed; in order to increase its efficiency and in order to suffice for its tasks, be it to neutralize or to eliminate these poisons, or whatever it may be, it increases its blood supply; it undergoes hyperplasia. This theory consequently leads us to consider the histological changes seen in the thyrotoxic thyroid as the result of hyperj 'unction. Hence the theory of hyperthyroidism. Everything tends to prove it, especially the increased blood supply. Furthermore, Askanazy, Muller, and Farmer found that the lymphatic veins and connective tissue in Basedow's disease GRAVES' DISEASE IS A TOXIC THYROIDITIS 401 were filled with colloid, whence they concluded that this disease was caused by an exaggerated amount of colloid reaching the blood. As a result of the increased function of the thyroid there is constantly in the blood an increased amount of iod-thy reoglobulin which, as we know, acts electively upon the central and vegetative nervous systems. Thus a constant and abnormal stimulation is being kept upon the thyroid bv the nervous system which in turn stimulates the thyroid. Hence the establishment of a vicious circle: as we have said before, the thyroid drives the nervous system and the nervous system drives the thyroid. This increased, and possibly modified, thyroid secretion through its lipoids acts electively upon predisposed organs already sensitized by sympatheticotrope, vagotrope, cardiotrope, ovariotrope, etc., sub- stances. Sensitization may not necessarily have been done previously by the thyroid: the polyglandular, the nervous system, etc., may have done it. This theory seems to me to answer most satisfactorily many ques- tions. Thus, the protean origin of Graves' disease is no more a puzzle; the remote causes of it are indeed numerous and diverse, as infectious diseases, disturbed polyglandular function, chemical agents, etc., but the immediate cause is always the same: the hyperf unction of the thyroid. Thus, we shall understand better why Graves' disease is more prevalent at the time of puberty and menopause. Indeed, besides the disturbed nervous equilibrium, and possibly just because of it, besides the part which the organs of internal secretion play, toxic products due to the disturbed metabolism circulate in the blood and become injurious to the thyroid, hence toxic thyroiditis and hyperfunction. Even in cases where the primary lesion lies in the nervous system, as in cases of shock, fright, etc., the theory still holds good. Indeed, in such cases it is reasonable to admit that besides the direct influence from the nervous system upon the thyroid, products of refuse due to a suddenly increased and disturbed metabolism as shown by sweating, diarrhea, vomiting, disturbed renal function, etc., which accompany shock are driven into the circulation and may prove injurious to the thyroid and incite it to overfunction. At least these injurious stimuli may be sufficient to start a vicious circle between the thyroid and the nervous system; when once started there is no reason for stopping. Both links, however, namely, the thyroid and the nervous system, are necessary for the production of the disease: let us not forget that the section of the restiform bodies causes exophthalmic goiter as long as the thyroid is present; it it has been removed previously, the syndrome does not rake place. Dysthyroidism. There is a great deal of evidence showing thai the secretion of the thyroid is not affected quantitatively and qualitatively: in other words, besides hyperthyroidism we have dysthyroidism. I lus con- 26 402 ETIOLOGY OF GRAVES' DISEASE elusion is based upon Mannesco's experiment. He demonstrated that the antigen from a Basedow struma, when mixed with serum taken from thyrotoxic patients, prevents hemolysis on account of the formation of antibodies. If, however, the antigen has been taken from a normal thyroid gland then hemolysis takes place: hence the conclusion that the colloidal nature of the thyroid secretion is changed qualitatively. Klose is an enthusiastic believer in the dysthyroidism theory. According to him, in ordinary conditions the iodin is fixed by the thyroid to some albuminous substance in order to form the thyreoglobulin. In patho- logical conditions, however, the metabolism of iodin does not take place properly. Klose admits then the existence of a hypothetical substance which he calls, " Basedow-iodin," very toxic, closely resem- bling the anorganic iodin, and exerting vagotrope, sympatheticotrope, cardiotrope, ovariotrope, influences, thus determining the thyrotoxic syndrome. That theory would, of course, help us to understand why it is not necessary to have a great deal of hypersecretion of the thyroid if that secretion is vitiated. That would explain the cases where little or no histological thyroid changes are present, as the latter are mostly evidenc- ing hyperfunction. Of course, what part the hyperthyroidism and the dysthyroidism play in the production of the thyrotoxic syndrome is an open question. It is self-evident that the theory of dysthyroidism, as well as the one of hyperthyroidism, although to a lesser extent, still lacks the "irref- utable argument." They both, however, answer the facts very well. The atomical theory is still to be demonstrated, yet chemistry fares very well seemingly under its flag. Needless to say that in the meantime let us hope that the future will bring forth the solution of the problem. Part of the Thyrotoxic Symptoms May be of Anaphylactic Origin. — It is more than probable that part of the thyrotoxic symptoms observed are phenomena of "anaphylaxis" due to the absorption into the circu- lation of abnormal albuminous thyroid products. The intense itching of the skin without eruptions resembles closely the itching observed in anaphylaxis. Indeed, the thyrotoxic thyroid albuminous substances may very well be enough modified so as to act as a foreign albumin, thus "anaphylactizing" the organism and producing toxins centering their effects upon the nervous system. This view is based upon Schittenhelm's researches which show that the substances resulting from the splitting of albumins into secondary products produce an intoxication similar to the one obtained with peptones and characterized by fall of blood- pressure, on account of peripheral dilatation, leukopenia, acceleration of the lymphatic current, increased glandular secretion, etc. In short > GRAVES' DISEASE LS A TOXIC THYROIDITIS 403 according to Biedl and Krauss, this toxic syndrome resembles closelv the one of anaphylaxis and of Basedow's disease. These views are further strengthened by J. W. Jobling and \V. Petersen who showed that iodin incubated with blood serum lowers markedly its antiferment property; the serum of these patients treated with iodin becomes toxic because of autolysis of the glandular components; a similar process (absorption of the antiferment by agar, kaolin, bacteria, etc.) being the basis of the toxicity of the so-called anaphylatoxin. Why is it that Some People Have Exophthalmic Goiter and Others Do Not? — Why is it that some people will stand large amounts of iodin while others cannot ? Why is it that acute infectious processes will cause the thyrotoxic syndrome in some patients and not in others ? Why is that a shock, a fright which will not feaze this one, will cause Graves' disease in that one: In answer to these questions, I will sav: Why is it that between two men falling into a river, one will get pneumonia and the other articular rheumatism ? Why is it that the liver, and the pancreas of certain individuals are able to take care of enormous quantities of carbo- hydrates without giving rise to glycosuria, whereas in others they are unable to do so? Why is it that mercury will cause an acute nephritis in some individuals and an acute enteritis in others, and no symptoms in a great number of others? Most likely because the injury settles in the locus minoris resistentice. The same is true for the thyroid. There must be conditions unknown to us, but nevertheless existing, which must render certain thyroids more susceptible to injurious stimuli than others, just as certain special conditions must intervene to inhibit the hepatic and pancreatic function in the metabolism of carbohydrates, or to render certain kidneys and intestines susceptible to mercury, just as certain requirements have to be met to allow the tubercle bacilli to produce tuberculosis. Congenital weakness, heredity, abnormal disposition, abnormal susceptibility, disturbed nervous equilibrium, unsettled poly- glandular system, all play their contributing part. When the truth is known, then very likely some reduced factor of safety, some chemico- biological disturbances or congenital predisposition, will appear as the cause or the determining causes. As we have already said, "Nature does not know a cause but causes." Summary of Conclusions Concerning the Etiology of Graves' Disease. — Graves' disease is a thyro-neuro-polyglandular disease. The thyroid is almost always primarily affected; however, very much less frequently the nervous system can be the primary cause, too. There exists between them a mutual interaction; the thyroid drives the nervous system and the nervous system drives the thyroid: this constitutes ;i vicious circle which can be broken by medical or surgical treatment. From a patho- logical and cluneal stand-point, Graves' disease resembles in every respect 404 ETIOLOGY OF GRAVES 1 DISEASE what we see in acute thyroiditis, be it toxic or bacterial, and what we see in Iodin-Basedow which is, too, a toxic thyroiditis. Hence we feel warranted in concluding that Graves' disease is a form of toxic thyroiditis. It is caused by any infectious disease, by any toxic condition arising from a disturbed polyglandular function, by a disturbed nervous equilib- rium, by a disturbed metabolism, etc. Under such conditions the thyroid secretion is quantitatively and qualitatively affected, and becomes the cause of the pathological syndrome. The symptoms observed in Graves' disease are due to hyperthyroidism, dysthyroidism, disturbances of the nervous and polyglandular systems, and probably some are due to anaphylaxis. CHAPTER XXXVIII. THE TREATMENT OF GRAVES' DISEASE. We have now reached the crucial part of our work. The most elaborate researches, the most beautiful theories, the greatest effort and expenditure of energy will fall short if they do not directly or indiretly resolve themselves into some advancement of the therapeutic end, the final test of every scientific effort. From the conception one makes of the nature and etiology of this disease will derive the line of treatment. Internists who regard Graves' disease as a neurosis or as a disturbance of central origin, or as a peculiar and enigmatic trouble of some sort, no matter where it has its seat, provided it is not in the thyroid gland, still work in the dark, hence the great, motley mixture of what is called ''medical treatment." Surgeons, on the other hand, who consider the thyroid as the "guilty factor," will experience no hesitancy; their road is open; "Heraus mit dem," Out with it! A radical and not the ideal means most assuredly, but the best we have at hand so far, and the most fertile in results. We all admit that it would, of course, be more elegant, more artistic, to be able to resort to some "specific agent" which, injected subcutaneously, intravenously, or taken by mouth, would bring about a sure cure. It would be an art of the highest type to be able to say to the patient as Christ said to the lame man, "Arise, take up thy bed, and walk." Unfortunately, we are only men and not gods, we think and act according to our own little intelligence and limitations. As yet the truly "specific agent" has not been found. That it will some day there is no doubt in my mind. To find it will be the glorious task of biological chemistry. Quite a marked step forward in this direction has been taken just recently. By delicate, chemical manipulations, Iscovesco was able to isolate from the various organs of internal secretion, lipoids, main of them possessing decided physiological properties. Lipoids are contained in all the organs of the body. Some of them have an antagonistic, others a synergetic action. A given organ contains numerous lipoids. In the thyroid, for instance, there are several lipoids, each one possessing seem- ingly entirely different properties. One of the lipoids injected into voimg animals produces myxedematous s\ mptoms; another produces thyro- toxic symptoms, another causes a congestion and hypertrophy of the gland itself. I lu- ovary contains a lipoid influencing the ovary itself, another 406 TREATMENT OF GRAVES' DISEASE influencing the uterus and its appendages, and another influencing the thyroid. The lipoids which influence other organs are called hetero- stimulants; the lipoids which influence organs from which they are derived are called homo stimulants or self -activating. These facts, if confirmed, will not only solve many obscure problems, but will also widen consider- ably our field of therapeutic action. The isolation of these different substances and their appropriate use will be of tremendous value to the future physician. For the time being, however, we must content our- selves with what we have at hand, "medical" and "surgical," and try to make the best of it. If the shades of Flajani, Graves or Basedow could come back into the world, they would certainly be greatly shocked to see that the disease which bears their names has slipped out of the bosom of internal medicine into that of surgery. Very likely they would turn and with inquisitive and reproaching tone interview the internist, and as in the "Parable of the Talents," they would say, "What have you done with our legacy?" It is certainly not through mere fancy that the surgeon has become entranced with the thyroid question in Graves' disease. For long years it looked as if Basedow's disease would remain forever a medical disease. So long as the nervous symptoms, tachycardia, and exophthalmos were given the most prominence in the clinical syndrome, and so long as the goiter was considered only as a secondary and unimportant factor, the disease seemed to remain forever the appanage of the internist, and "a noli me tangere" for the surgeon. As years went by, however, with no progress made in curbing the disease, and with no new conceptions of its etiology, the disease was languishing in the painful marasmus of the "rest cure;" furthermore, although internal medicine had seemingly disinterested itself in this question, two great men, internists themselves, Gauthier de Charolles and Moebius, came along and with a new theory gave a powerful impetus to the question. It is true that previous to them a few operations had been performed for exophthalmic goiter by Kocher and others. These operations were intended, however, to remove Basedowified goiters causing mechanical symptoms. Great had been the surprise of everyone to see that at the same time the functional disturbances were relieved also. Hence suspic- ion became aroused, new but still undecided etiological conceptions, which, as just said, were soon shaped into a definite form by Gauthier and Moebius. In their judgment the disease no longer took its origin in some nervous, circulatory, or other problematic disturbances. It was no longer a neurosis. In their judgment the goiter, which for so long had been considered as unimportant, was now the responsible factor; in fact, it was the primary cause of all the trouble. That day Graves' disease became at once a surgical disease; from the sanitaria and rest-cure T RE ATM EXT OF GRAVES' DISEASE 407 places it jumped into the operating rooms. From that time on it ceased to live in the marasmus in which it had been before. It became a burning question taken up at once all over the world. Since surgerv has adopted as one of its own, this abandoned child of internal medicine it is only just to say that so far as pathology and treatment are con- cerned, great progress has been made. It is to surgery that we owe most of what we know today of Graves' disease, just as it is to surgery that we owe most of what we know of appendicitis, gastric and duodenal ulcer, gall-bladder diseases, etc. Is There Truly a Medical Treatment for Graves' Disease? — If by that we mean a well-defined, classical, efficient, specific, therapeutic line of conduct to be followed in such cases, then there is none. Indeed, there can be no doubt of that. If, on the other hand, by "medical treatment," we mean anything which is not surgical, we must concede that there is such a thing. With this form of treatment everyone feels at liberty to "experiment" with whatever he sees fit, hence the multi- tude of medical means employed, as for instance 10dm, arsenic, iodides of all kinds, bromides, digitalis, belladonna, atropin, ergotin, ether, veratrum, strophanthus, quinine, nux vomica, phosphate of soda, con- vallaria majalis, etc.; faradization, galvanization, currents of high frequency, hydrotherapy of all sorts; sojourn at the sea, or in high altitudes; gymnastics with Zander's apparatus; mountain climbing, etc.; all imaginable diets, etc., some authors advising forced feeding, others, the hunger cure; some advising forced drinking, others the thirst cure; as mineral waters of all sorts, and kephir, milk, zoulac; as serum, blood or milk of thyroidectomized animals, thyrotoxic serums; as finally, extracts of the glands of internal secretion, as adrenals, pancreas, hypophysis, ovarian extracts, thymus, testicles, etc. Everyone will admit that this medical therapeutic gamut is most variant, and everyone according to his taste can make his choice. Bur please do not think for one moment that I am trying to ridicule the medical treatment. I know too well that each one of these means employed has to its credit some improvements and some cures, and as everyone knows, too, that some patients get well without any treatment, and as was said by Mayo, some get well in spite of any treat- ment. Too often we hear adversaries of surgical treatment boast that they have cured thyrotoxic patients with the rest cure, with milk diet, with Forcheimer treatment, and what not. We all can pick out of our series, medical as well as surgical, some brilliant results m order to support our contention. That is not the point. We know thai this is true. Hut the pomt is: Of the total number of Basedow patients treated medically or surgically, what number improve or gel well, and what is the death-rate: lh;it can be best answered by statistics. Vs Riedl has 408 TREATMENT OF GRAVES' DISEASE said, " Medicine, like theology, has its dogmata." When once established, it is difficult to eradicate them even when wrong. The danger of surgical treatment in Basedow's disease is one of these dogmata; its inefficacy is another. Let us see what we can gather from statistics. Results of Medical Treatment. — Williams, out of 1569 surgical cases showed a mortality of 4 per cent., a cure of 72 per cent., while 300 medical cases treated with the antiserum gave 20 per cent, cure, 60 per cent, improvement, 10 per cent, no effect, and 10 per cent, death. Baruch, comparing the results obtained by operation and medical treatment, found for the cases treated medically: o per cent, of cure, 5.2 per cent, were able to resume their full work, 26.3 per cent, were only partially able to resume their work, 68 per cent, were unable to work at all, whereas the surgical treatment allowed 17.9 per cent, to resume their full work, 51 per cent, to resume their partial work. He furthermore found that with medical treatment cardiac hypertrophy never diminished, whereas it disappeared in 70 per cent, of the operated cases. In non- operated cases he found further, that exophthalmos remained unaffected in 7.6 per cent., was improved in 69.2 per cent., and got worse in 23 per cent., while in cases treated surgically, exophthalmos disappeared in 39.6 per cent., was improved in 54.5 per cent., and remained unaffected in only 3.2 per cent. He reported, too, that tremor disappeared in JJ per cent, of the operated cases and never in the ones treated medically. White found that in 108 cases treated medically by him, 21 died, 61 were cured, 21 improved, and 5 remained unaffected. The mortality with medical treatment is high; 10 per cent, for Cheadle and Thompson, 12 per cent, for Von Graefe, Von Dusch and Buschan. These figures are based upon 900 cases. Charcot, Williamson, and Stern's death-rate is 25 per cent. Ord and Mackenzie, out of 55 cases, obtained 10 complete cures, 24 improvements, 4 negative results, and 14 deaths. Murray had 7 deaths out of 40 cases. Vetlesen, out of 34 cases, had 7 cures, 20 improvements, and 7 deaths. Frankl-Hochwart out of 60 cases found 25 fruste forms which remained unaffected by treatment; out of the other 35 cases of true Basedow, 9 cures, 11 negatives, and 15 deaths. Lichty had 3 deaths out of 74 cases. Sainton was able to collect 219 cases treated by serotherapy; 10 per cent, were cured, 80 per cent, improved, 8 per cent, were failures, and 2 per cent, exacerbations. Rogers and Beebe, in 1909, out of 480 cases gave 15 per cent, of cure objectively, 10 per cent, cured subjectively, 15 per cent, ameliorated, and 17 per cent, failures. In 191 5 Beebe, without furnishing any statistics, estimated roughly that he had treated 3000 patients with antiserum with 50 per cent, cure, 30 per cent, improvement, and 20 per cent, failure. We must not forget, however, that this author in a general way seems to be very sanguine in his conclusions, as shown by his recent "cancer cure." In RESULTS OF MEDICAL TREATMENT 40!) 1910 Kocher reported 1000 cases treated surgically and 100 cases treated medicallv. The mortality of the operated thyrotoxic cases amounted to 4.83 per cent., while the cures gave 80 per cent. From the 100 cases treated medically, 22 had to be operated because of the failure of the medical treatment to bring about a cure, or at least, encour- aging improvement. From the remaining cases, 18 per cent, were cured, 27 per cent, improved, 33 per cent, remained unaffected, and 22 per cent. died. Syllaba reports 51 cases of Graves' disease treated medically; 9 died, 4 were failures, 27 ameliorated, improved, or cured. The balance of the other cases is not given. W. H. Becker went over all the cases admitted into the clinic of Prof. Dr. Voit in Giessen from 1890 to 1912. During that period of time 40,941 patients were admitted. Among them were 70 cases of Basedow's disease. As some of these patients were readmitted at various intervals the true total number of patients amounted to 61. Out of these 61 cases the records of the clinic show that only 1 patient was discharged cured. From the remaining 60 cases, 36 were discharged as improved (60 per cent.), 21 were unimproved (35 per cent.), 1 case was sent over to the surgical clinic, and operated, then returned to the medical clinic for further treatment with galvaniza- tion of the sympathetic and thymic opotherapy, and only then dismissed as improved. From the 2 remaining cases nothing could be ascer- tained, as no history was to be found. The treatment used from 1890 to 1903 was a purely symptomatic one: arsenic, bromides, rest in bed, ice-cap for the heart, while occasionally iron and baldnan, and galvanization of the sympathetic were employed. In 1903 for the hist time the antithyroidine of Moebius was used five times with 4 improvements and 1 negative result. Rhodagen was used twice with 1 improvement and in the other case with only a slight improvement. In 1906 x-rays were employed in 1 case which had been treated without success with antithyroidine of Moebius. In 1907 a meat-free diet was tried on ^ patients; 4 were improved, 1 showed only very slight temporary improvement, 1 remained negative. lour times Voit used phosphate of soda and phytin treatment; 3 were negative, 1 improved, and 1 markedly improved. Becker went to the trouble to look up what had become of these last 10 cases since 1907. I le succeeded in getting in touch with only 7 of them. In all the improvement had remained tin- same. They were more or less materially improved but not cured. As reported by A. Stenzel, in 191 2, 54 eases of Basedow's disease were observed in Stintzing's clinic at Jena. Otto says 10 of these mn severe cases, 30 moderately severe, ami 14 were of the milder type. Of these 70 per cent, wen women and 30 per cent. men. I hese cases were treated medically, according to the newer procedures, for at least six 410 TREATMENT OF GRAVES' DISEASE weeks. If at the end of this time the patients did not show improvement, they were transferred for surgical treatment. Eight of these cases, or about 15 per cent., were able to resume their work after treatment for an average period of two months. Of these 8 cases, 7 were mild and 1 moderately severe. In all, however, there was a typical Basedow com- plex, the cardinal symptoms all being frankly present. Twenty-one cases or about 39 per cent, were improved — 2 of these being mild forms, 15 moderately severe, and 4 severe. Nineteen cases, about one-third of the whole number, resisted all medical treatment. Among these were 3 mild cases, 12 moderately severe cases, and 4 of the severe type. Medical Cases. Name. Williams . Baruch White Cheadle . Thompson Von Graefe Von Dusch Buschan . Charcot and Williamson Ord and Mackenzie Murray Vetlesen . Frankl-Hochwart remaining Lichty Sainton Rogers Beebe No. of cases. 3OO IO8 not given not given not given not given not given 56 40 34 60 35 74 119 Kocher 100 78 Syllaba 51 Voit-Becker . 61 remaining . 60 Otto . . . 54 Williams . 23 Cure, per cent. 56 25.O fruste forms unaffected 25-71 150 objective 10. o subjective 1.65 150 Improvement, per cent. 60.O 3i-5 5-2 able to work 26.3 partially able 19.4 Rate per cent. Negative results, Death, per cent. 42.89 58.5 -41 . 66 80.0 15.0 27 52 94 60 39 3i 8 10. o 68.0 714 31-42 8.0 17.0 22.0 330 7.84 35-0 35-° per cent. IO. O 19.4 IO.O 10.0 12.0 12.0 I2.0 25.0 25.O 20.58 42.85 4.O o o 22.0 17.64 25.0 RESULTS OF MEDICAL TREAT M EXT 411 In general, this material showed that not only cases of lighter grade, but also of severer types, were not amenable to medical treatment. In the cases in which antithyroids (Moebius) was used, no good results were observed. This was true also of the x-rays, where used. In a large number of those cases in which medical treatment had failed, the symptoms disappeared after operation. Conclusions. — How eloquent all these figures are! Do thev not show that one thing must strike us forcibly, namely, that medical statistics are utterly insufficient: It is true that once in a while internists will report one or two cases treated successfully with medical means, but large statistics describing in extenso their cases, their immediate and remote results, are rare. Let us hope that internists will in the future strive to set forth more and better data. The little there is of these, however, does not well stand comparison with surgical statistics. From them it appears that medical treatment is far less efficient, far less rapid in results, far less fertile in cures and improvements, and far more dan- gerous quoad vitam. As the time goes by the surgical death-rate is being constantly reduced. So long, however, as we shall have to revert to surgical means to cure thyrotoxicosis, so long as we cannot disregard the heart of the patient, his nervous system, his thymus, his chromaffin system, his liver, his kidneys, there will always be an "unavoidable death-rate." It is remarkable to see how operative success improves with the increased experience of the surgeon. For instance: Kocher's Cases. Y<:ir i i 1902 59 1906 167 1910 376 1911 167 191 2 130 1916 300 Mayo's C\ses. 1^04 40 150 1 907 no 8.0 [QOQ 405 l 5 1 1 ) 1 1 1 000 3 . 7 1912 o Death-rate, per cent. 6 •5 5 .0 4 .0 2 ■ 3 1 ■5 I .0 412 TREATMENT OF GRAVES' DISEASE On i-i OJ 4-J 1 en O 00 rO co 00 c rt- CO — - 1-1 o c bt) r. £ C O T5 o c CO 3 a c 3 c ^ co — rt o in o a "3 CO OJ a. g a • r^ rv. 00 ■* ui "-. • oo .in in <+ o en N in O in <) • • O • • • 03 3 ^ r^ r^ • in o w in in • M -*■ On in in m en £ "(2 N N -<*■ M 1-1 a) , 03 b. .; c On oo . 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O oo a O ON a ON On On On ON ON MEDIC A L TREA TM EX T 425 i > -£ j_i X) > 'f • ■- ^ ; rs *-• — — i» C- j£ ~B E- ■ /: ~b i g-g'^.2 1 ~ z - ~ - ~ ~ - — ~ <-.'•' U " - r - ~ - — ;■ ^ < j= 'J Z S < < u '- :£ < < ZZ:£ ,5 Jai'^i. < ^ I- U-13C "H cn C 09 9 ; 1 2 O C u z - > C/3 < < a HH v. -, "« - IE - 2 ^ 'C ri 4^ iv u kri V. -*. - ~ U -7- — — ^ zl. zl 3 C^ to" to % P^ 'S. « ca • • 7Z • w n ■ u • > • >. >■, >. LO ^O CI fO N tn ex a £_ o 12 — T3 E E B - U — u — t/3 — _ Efl bo t/i :/: u E b E o = c !/l mg into the description of the operation itself let ns go over the anatomical and pathological conditions in which an operation takes place-; let us decide what is anatomically important and what can be left out; let us discuss, too, these different requirements which give to the technic its present characteristics. Before going any further lei us ;isk: \\ hat are these desiderata : \\ c w ant : i. To have constantly present in our minds a few particular anatomi- cal tacts from which will derive certain important technical procedures. 440 TECH NIC OF OPERATIONS UPON THE THYROID GLAND 2. To leave the parathyroids and the inferior laryngeal nerve uninjured. 3. To leave enough thyroid tissue so as to protect the patient against future hypothyroidism. 4. To protect the patient against future relapses. 5. As fine and as nearly invisible a scar as is possible. 6. To shape the neck so as to render it esthetic. Anatomical Facts. — Surgery of the thyroid became simple the day the surgeons learned to utilize the normal and pathological intra- as well as perithyroidal planes of cleavage. Let us suppose that we make a transverse incision in the thyroid region of the neck, and retract the upper and lower cutaneous flaps in their respective directions, we shall then find: 1. The sternocleidomastoid muscles and the prethyroidal muscles which are the sternohyoid, omohyoid, and underneath, the sterno- thyroid muscles. These muscles are covered by the superficial cervical fascia. Starting from the ligamentum nuchae this fascia forms a sheath for the trapezius muscle, passes over the entire posterior triangle of the neck until it reaches the posterior border of the sternocleidomastoid muscles. There it forms a sheath for this muscle, passes over the anterior triangle of the neck, and finally meets in the middle line the superficial cervical fascia from the other side. 2. Extending from one omohyoid muscle to the other, and from the hyoid bone to the manubrium sterni and to the middle of the clavicles, the middle cervical fascia forms a sheath for the three thyroidal muscles, goes toward the middle line and there fuses with the one of the other side and the superficial cervical fascia, thus forming the cervical linea alba. 3. The middle cervical fascia and the prevertebral fascia give origin to a loose connective-tissue capsule which surrounds the thyroid gland and is easily detachable. Let us call that capsule the surgical capsule of the thyroid. (Plate IX, Fig. 1.) 4. The thyroid parenchyma is surrounded by a capsule which is the equivalent of the one seen in other glandular organs such as the capsule of Glisson for the liver, the albuginea for the testicle, the renal capsule for the kidneys, etc. It is in close relation with the parenchyma and sends inwardly septa dividing the parenchyma into lobi and lobuli and finally surrounds each alveoli with a very thin layer of connective tissue, the glandular capsule. (Plate IX, Fig. 1.) 5. Between the sternocleidomastoid muscles and the prethyroid muscles there is a normal plane of cleavage. De Quervain calls it the sternomastoid space. (Plate IX, Fig. 1.) 6. Between the prethyroid muscles and the surgical capsule there is another plane of cleavage, the musculocapsular space. (Plate IX, Fig. 1.) -■^i^totx/f " s istind Cross-section of the Neck with its Various Organs, Showing the Relation of the Thyroid to the Neighboring Tissues and the Various Spaces Described in the Text. Danger Zone. The relation of the carotid sheath, inferior laryngeal nerve, inferior thyroid artery, middle vein, parathyroids, and of the posterior surface of the thyroid gland to each othei. The dotted curved line shows where resection should take place in order to avoid injury to these various organs. ANATOMICAL FACTS 441 7. Finally, between the glandular capsule and the surgical capsule there is another plane of cleavage formed of loose connective tissue and containing numerous arteries and veins, the intercapsular or surgical space. (Plate IX, Fig. 1.) It surrounds the thyroid gland entirely and extends from one side of the trachea and the esophagus to the other side. The relations between the glandular capsule and the surgical capsule are, as a rule, very loose. It is only on the postero-internal surface of the thyroid that they come into a more intimate contact; between them a great number of arterial and venous branches are found going in and out through the glandular capsule. Inwardly, since the thyroid is inti- mately adherent to the trachea, no plane of cleavage may be expected to be found there. In the posterior portion of this perithyroid cellular space we find the parathyroids and the inferior laryngeal nerves. Conse- quently we must regard the posterior portion of this perithyroid cellular space as the danger zone which the surgeon must carefully avoid during operation. (Plate IX, Fig. 2.) Fig. 71. — Showing proper plane of cleavage which must be entered into before attempting resection of the thyroid. Showing, too, how much thyroid tissue should be left in contact with the danger /one in order to avoid accidents. I he intercapsular space is the same as the surgical space. Such are the anatomical facts grossly described. It is obvious that the musculocapsular and the surgical spaces are the most important so far as the surgical technic is concerned. The surgical space is the "good plane of cleavage" Fig. 71 ) which must be- looked for if the surgeon wishes to make an easy and brilliant thyroidectomy. Die surgical capsule must have been opened and the surgical space found before attempting to dislocate the goiter. On the other hand, its postero-internal region must be absolutely avoided unless one wishes to expose tin- patient to 442 TECH NIC OF OPERATIONS UPON THE THYROID GLAND tetany by injuring the parathyroids, or to vocal disturbances by injur- ing the inferior laryngeal nerves. For the same reasons, it follows, too, that when resection of the thyroid is being performed, one should pur- posely avoid retracting the surgical capsule over its entire course: such retraction should take place only just enough to allow manipulations on the thyroid to take place easily. It follows, furthermore, that in order to avoid injury to the parathyroids and inferior laryngeal nerves, the danger zone must be left undisturbed. (Plate IX, Fig. 2.) This is best obtained by leaving a layer of glandular tissue in contact with it while resection is being made. The following fact is interesting: the carotid sheath is entirely inde- pendent of the spaces above described, for it possesses a space of its own: the carotid space. This was demonstrated by De Quervain by injecting the sheath of the vascular cord at the angle of the jaw with gelatin. The gelatin followed the vascular cord over its entire course, filled it up, but did not fuse in any way with the one of the ether planes above mentioned. The inferior thyroid artery passes behind the car- otid space but does not penetrate into it. This is of great importance for the ligation of the inferior thyroid artery, as the carotid sheath can be strongly retracted without exposing the inferior thyroid artery to injury. Pathological Planes of Cleavage. — So much for the normal planes of cleavage. The pathological ones are very important, too, and should be known. They are found mostly in nodular goiters, cystic or colloid, and must be always taken into consideration when one wishes to per- form an enucleation. In nodular goiters the pathological plane of cleavage is intraglandular and lies all around the nodule. It is formed by the thickened enveloping membrane of the nodule itself, and by a connective-tissue formation all around it due to the chronic pressure of the nodule on the parenchyma. Between these two layers of tissue lies the proper plane of cleavage. (Figs. 72 and 75.) As soon as it is found enucleation takes place easily. If the nodule lies at the periphery of the lobe and comes in contact with the glandular capsule, the latter capsule may fuse together with the nodule so as to destroy entirely at that point the plane of cleavage. This plane, however, can be easily found by making an incision in the neighboring parenchyma and going through it until the nodule is reached. Blood Supply of the Thyroid. — It had been thought for a long time that the thyroid arteries were terminal. These conclusions were based mostly on the researches of Hyrtl, Anna Begoune, Jaeger-Luroth, etc. Other anatomists, however, as Sappey, Cruveilhier, Thane, etc., objected to these conclusions. From a practical stand-point it was important to settle this question one way or another: indeed, if the thyroid arteries BLOOD SUPPLY OF THE THYROID 443 were terminal, ligation of one of them would expose the territory of the gland supplied by this artery to necrosis. On the other hand, if thev anastomose freely, ligation of one of them would not have any material effect upon the intraglandular circulation; this is especially important in exophthalmic goiter work. Lately, Landstrom, Delore, and Alamartine, have reviewed this question. The writer has done some research work in that line by injecting through one or more of the thyroid arteries a 20 per cent, benzin solution of vermilion and controlling the results with .\--rays. The following conclusions may be drawn: the superior and inferior thyroid arteries anastomose freely by an intricate mingling of their terminal branches and by several longitudinal anastomoses: the most constant and most important one of them follows its course in the tracheo-esophageal angle. (Plate X, Fig. 1.) Bilateral transverse anastomoses exist, too, between each lobe. Thev are less numerous and van' greatly in volume, and they connect mostly the two superior thy- roid arterial systems. The most important of them is the cricothyroid branch which lies just above the upper border of the isthmus and con- nects the anterior branches of the superior thyroid artery. This com- municating branch is the one which is severed when performing the cricothyroid tracheotomy. \ ery often there is another transverse anastomosis a little higher up, crossing transversely in front of the crico- thyroid membrane and connecting the two superior thyroid systems. Besides these two important bilateral anastomoses there are many smaller ones connecting the branches of the two superior arteries, of the posterior longitudinal anastomosis and of the cricothyroid arteries: they form a very intricate and most variable arterial plexus. r. t-The two inferior thyroid arteries communicate with each other, as a rule, through anastomoses connecting the longitudinal anastomosis of each side. However numerous these anastomoses are, it would be an error to believe that they would be able to take up, off-hand, the blood supply of the territory whose feeding artery has been severed. To a certain extent this is true for the arteries of the same side, for the superior artery supplies very rapidly and abundantly the territory of the inferior thyroid when the latter one has been ligated, and vice versa y intraglandular anastomoses being very abundant and verj effective. It is no longer quite so true for the interlobar anastomosis: these are less abundant and less effective. I here really exists between the two lobes a certain vascular independence, although not complete. l)e (Jucrvam very judiciously remarks that we already knew clinically what these researches brought to us. Indeed, it alter ligation of the superior and interior thyroid arteries of one side, resection of the lobe is undertaken, one can see plainly that the arterial hemorrhage is still going on, though much diminished. 1 think even surgeon can vouch for that. 444 TECH NIC OF OPERATIONS UPON THE THYROID GLAND Besides its own vascularization the thyroid gland possesses another vascular supply coming from the neighboring tissues, especially the trachea and esophagus. Landstrom, Delore, and Alamartine finally found a diffuse system of anastomoses connecting the superior arteries with the prethyroid muscles and subcutaneous tissues. This entire col- lateral supply is quite important and is sufficient to prevent necrosis of the thyroid after ligation of the four thyroid arteries. In conclusion we may say that the thyroid arteries are not terminal. One, two, three, even all four thyroid arteries can be ligated without exposing the gland to necrosis: sufficient vascular supply takes place through the collateral anastomosis from the neighboring organs, even if the ima artery should not be present. Which one of the thyroid arteries is the more important, the superior or the inferior? The opinions are divided. Von Eiselsberg and the majority of German authors consider the inferior thyroid as the main one, the superior being only a secondary artery. De Quervain regards the inferior thyroid artery as the one which is the more important. The same does Halstead. He believes that the inferior thyroid is usually larger than the superior vessel which is subject to greater changes because of the inconstant position of the superior pole. Delore and Alamartine do not share the same view. They believe that the superior thyroid artery is the more important. In the superior vertebrates it is the one most constantly found, whereas the inferior thyroid is not. The superior thyroid is more constant in its caliber, in its mode of division, and in its course. Its branches of division cap the superior pole. The superior thyroid artery follows the upper pole in all its changes, be it changes in form or posi- tion: where the upper pole is, there the superior thyroid will also be found. The upper pole is the best landmark for the position of the superior thyroid, and the upper pole is always easily found. The inferior thyroid, on the other hand, is much more variable in its position and volume. It does not cap the inferior pole as does the superior thyroid for the upper pole, but passing behind the vascular cord, approaches the gland laterally at the junction of the lower with the two upper thirds, goes, more or less, far behind the posterior surface and only then pene- trates the thyroid gland. (Plate X, Fig. 2.) Like the superior thyroid, it follows, too, the thyroid gland in its changes of form and position. If the inferior pole becomes greatly enlarged, the inferior thyroid artery becomes somewhat displaced, but never to such an extent as to become intrathoracic, for instance. Furthermore, the inferior thyroid artery divides into several branches, sometimes very far from its point of entrance into the thyroid gland, so that it is not uncommon to see a surgeon ligate one of these branches, thinking that he is dealing with w ^ . Intracapsular Resection. Showing the thin capsule which remains after decortication of the thyroid, also how easy it would be to injure the parathyroids and infeiior laryngeal nerve. These organs are seen by transparence through the thin capsular veil. Note, too, the longitudinal anastomosis between the superior and inferior thyroid arteries. FIG. 2 -f>y »t/ia//i,fi'r yi behind the inferior thyroid artery. On the left side it arises in front of the arch of the aorta and winds from before backward around the aorta at the point where the impervious ductus arteriosus is attached and then ascends to the side of the trachea. I he nerve on each side ascends in the groove between the esophagus and the trachea, passes either anteri- orly or posteriorly, or more often, between the branches <>t division of the inferior thyroid artery (Plate IX, Fig. 2), enters the larynx behind the articulation of the inferior horn of the thyroid cartilage with the cricoid, being distributed to all the muscles of the larynx except the cricothyroid. 448 TECH NIC OF OPERATIONS UPON THE THYROID GLAND These anatomical considerations show that the inferior laryngeal nerve, too, lies in the "danger zone," namely, the postero-internal portion of the thyroid gland. Conclusions Drawn from Anatomical Facts. — I. The postero-internal surface of the thyroid gland must be considered as the danger zone; there are found the parathyroids and the inferior laryngeal nerves (Fig. 71). 2. The surgical capsule should be detached and retracted just enough to allow the different steps of the operation to be performed easily, and especially the luxation of the goiter. This capsule should be left in situ and in its relations with the thyroid in the entire postero-internal region of the gland, and the luxation of the goiter should not be pushed too far (Plate XXI), so as not to disturb the collateral circulation between the parathyroid glandules and the neighboring tissues, and further not to run the risk of injuring the inferior laryngeal nerve. 3. Ligation of the inferior thyroid artery should be done far from its point of entrance into the thyroid gland (Plate XXI). The "ultra- ligation" of Halstead is a dangerous method. It should be remembered that not so infrequently the parathyroids are situated between the branches of bifurcation of this artery, consequently if ligation takes place near the glandular capsule the parathyroids are exposed to injury. The same is true for the recurrent laryngeal nerve. 4. Total unilateral intracapsular excision of the thyroid should be discarded because of the danger of injuring the parathyroids and inferior laryngeal nerves (Plate X, Fig. 1). Resection is the method of choice, as it leaves a more or less thick sheath of glandular tissue in connection with the danger zone. A well-managed enucleation does not expose to injury the parathyroids. 5. The collateral circulation with the neighboring tissues is so well developed for the thyroid and for the parathyroids that ligation of the four arteries can be performed without running any risks of tetany, provided that the "danger zone" is left undisturbed. EXCISION, RESECTION, OR ENUCLEATION? As in any other surgical field, the surgeon doing thyroid surgery must have at his disposal several technical methods in order to be able to meet all emergencies successfully. He must adapt his technic to the case and not suit his case to his technic. As De Quervain says, "It is no longer enough to know what should be done in a general way, but what should be done in each particular case." In doing thyroid surgery to what method shall we resort ? Shall we adopt excision, resection, enucleation, as the method of choice, or shall we use a combination of these methods ? In going over the medical literature one cannot but EXCISIOX, RESECTIOX, OR ENUCLEATION 449 be impressed by the confusion which exists in the denominations of the different surgical procedures. Nearly always the terms, excision, enuclea- tion, resection, thyroidectomy, lobectomy, extirpation of the thyroid, are used indiscriminate!)". Fig. 72. — Intracapsular excision. Excision. — Excision was used by Kocher to demonstrate the complete removal of one lobe without leaving anything of the posterior portion of the gland (Fig. 72). Excision can be unilateral or bilateral; total excision can take place only in malignant goiters. Figs. 73 :uu\ 74. Transglandular resection. Resection (Mikulicz) means the partial extirpation of the thyroid, a portion of the glandular tissue being left in situ. Resection, too, may be unilateral or bilateral I Figs. 7^ and 74). 29 450 TECH NIC OF OPERATIONS UPON THE THYROID GLAND Enucleation (Porta and Socin) means the peeling off, the decortica- tion of one or several intraglandular nodules (Figs. 75 and 76). The other denominations as thyroidectomy, lobectomy, hemithy- roidectomy, have only a general meaning. They do not convey in any way the idea of how the removal of the goiter is being done, namely, if excision, resection, or enucleation has taken place. Consequently I shall use them when speaking in a general way of the fact that an opera- tion has been performed on the thyroid without trying to indicate pre- cisely the mode in which this operation has been performed. Figs. 75 and 76. — Enucleoresection. Inasmuch as excision exposes too easily to injury the inferior laryn- geal nerves and parathyroids, this method has been more or less aban- doned as such. Kocher still advocates it and practises it, but leaves a small portion of glandular tissue in contact with the danger zone, conse- quently, properly speaking, this surgical procedure is no longer a true excision, but becomes a resection. The intracapsular or subcapsular excision which is performed by some of our American surgeons, and which may be compared to a total decortication of the lobe is, too, for the same reasons to be discarded. (Plate X, Fig. 1.) Not very long ago saw one of our foremost surgeons, when performing this intracapsular excision, come in contact with a parathyroid, crush it with a hemostat, EXCISIOX, RESECTIOX, OR EXUCLEATIOX 451 and become aware of it only when his attention was called to it bv one of his assistants. Iversen reports a case operated bv Rowsing in which both I [GS. 77 and jH.- Cuneiform resection. parathyroids were accidentally removed with the- excised lobe, although intracapsular excision was undertaken with tin- special view of safe- guarding the parathyroids and inferior laryngeal nerves. Halstead in 40 452 TECH NIC OF OPERATIONS UPON THE THYROID GLAND subcapsular excisions removed one or two parathyroids with the excised lobe only J times ! These accidents, of course, would never have occurred if resection had been performed. There may have been an error in technic; they should have remained intracapsularly. Theoretically this may be true; practically, however, it is not so easy, as the glandular capsule is thin and breaks easily. A thick layer of glandular tissue should have been allowed to remain in contact with the danger zone. Not only does it protect the patient against injury of the inferior laryngeal nerve and parathyroids, and save the surgeon great annoyance, but it has also a great cosmetic value; furthermore, if later, another operation on the other lobe should become necessary, the chances for hypothyroidism will be greatly lessened. Resection is the method of choice as it fulfils better than any other method all the requirements. This resection may be either cuneiform ox frontal. The cuneiform resection (Figs. JJ and 78) advocated in 1898 by Zoege von Manteuffel is made in the following manner: After the pre- liminary ligation of the superior or inferior thyroid arteries, or both together, the goiter is luxated; the imae vessels are carefully tied, then an oval incision extending from the upper to the inferior pole is made into the glandular capsule and the parenchyma. The resection is then made by "wedging" out the interior of the gland. The amount of tissue removed by this "melon-slice" (Plate XI) method is suited to the necessity of the case. Great care should be taken not to come too near the parathyroids and the inferior laryngeal nerves. The main bleeding vessels of the cut surface are caught and tied, then a continuous mattress suture of plain catgut through the glandular capsule including a portion of the parenchyma is made. (Plate XII.) If the cup-shaped hole is quite deep, two rows of sutures may have to be made, one intraparen- chymatous, and the other capsuloparenchymatous, which catches the edge of the capsule and rolls the two edges of the capsule into some semblance of a normal lobe. (Plate XII.) Sutures should not be made too snug, as otherwise necrosis of the sutured portion might follow, especially if both main thyroid arteries have been tied. This method has the great advantage of leaving no exposed rough glandular surface afterward. Care should be taken to ligate every vein of the glandular capsule in order to avoid air embolism, and postoperative oozing. If the trans frontal resection is resorted to (Fig. 73), and this will be the method used in the majority of cases, it is done in the following manner: After having ligated the upper poles and starting at the upper pole, hemostats are placed all the way along the external border of the gland and then the parenchyma is cut. Next the operator proceeds from outward inwardly on a frontal plane, aiming to reach the lateral ™ a i ^ Technic of Cuneiform Resection. 11k- superior thyroid vessels have been tied, goiter luxated, and a portion of the thyroid removed. melon-slice 1 PLATE XII Technic of the Cuneiform Resection. I he gland is then sewed up by continuous suture. EXCISION, RESECTION, OR ENUCLEATION. 453 surface of the trachea, thus leaving a more or less thick glandular portion in contact with the danger zone. The rough surface which remains after resection is completed, is left untouched; no effort is made to cover it by suturing the edges of the glandular wound together (Fig. 74). Resection will be employed in even' case where a diffuse, parenchy- matous enlargement, thyrotoxic or not, exists, and in all cases of diffuse colloid degeneration. Enucleation, as such, has been discarded by the majority of surgeons, as it too often predisposes to relapses. They use this method in large, solitary, colloid and cystic goiters. In the majority of cases, however, enucleation will be combined with partial resection. In that case we shall call the operation enucleoresection. Enucleation, however, should be given the preference over the resection method in the cases where the secreting parenchyma is reduced to a minimum. In such instances it is absolutely necessary to be as economical as possible with the gland- ular tissue, hence the indication to enucleate instead of to resect. When one has to be parsimonious with the thyroid tissue, it is better not to ligate the main vessels of the gland. Enucleation finds its special indications: 1. In cases where there is a large but single cystic or colloid nodule. 2. In cases of complete colloid or cystic nodular degeneration of the entire gland. In such conditions a radical operation is not to be expected. The nodules are peeled out, one after another. There remain, of course, very small ones which cannot be enucleated, and which will be liable to relapse later on. 3. Enucleation can be employed, too, in cases of goiter which have relapsed. 4. If a nodular goiter takes its origin in the postero-internal region of the thyroid, it may, after it has reached a certain development, come in contact with the parathyroids and inferior laryngeal nerves. Enuclea- tion in such cases is not without danger for these organs. Indeed, a hemostat put on a bleeding vessel, or a ligature, may injure the recur- rent laryngeal nerves or the parathyroids. It is consequentlv better in such cases to leave a thin portion of glandular tissue in contact with the danger zone, even if that portion of the gland has undergone goiterous degeneration. Curiously enough, that portion of the goiter will revert to a normal state, and seldom will cause relapses. 5. Wlu-n we have to deal with a multiple nodular goiter, enucleo- resection is the method of choice unless there should be some special reasons to do otherwise, because if enucleation only is employed, the most of the intra-nodular thin bands of glandular tissue which are still physiologically active, are caught in the sutures and ligatures and undergo fibrosis. Consequently the purpose for doing enucleation is defeated, hence it is better to combine it with resection. 454 TECH NIC OF OPERATIONS UPON THE THYROID GLAND The technic for enucleation is extremely simple. An incision is made over the glandular capsule and into the parenchyma, until the nodule is reached. This nodule is, as a rule, easily recognizable on account of its harder consistency, paler color, and diminished vasculari- zation. The proper plane of cleavage is then sought; when it is found the nodule is peeled off very easily. The main thing is to start decortica- tion only when one is certain to be in the proper plane of cleavage; as long as there is doubt, one can rest assured that the proper plane of cleavage has not been found. One does not need to fear the hemor- rhage which takes place all over the entire surface of the shell left after the removal of the nodule, as it is mostly a parenchymatous hemorrhage. If, however, an artery of some consequence should bleed, the pouch can be everted and the bloodvessel clamped and hgated. Then a continuous purse-string suture starting internally at the bottom of the pouch brings its walls into close contact and ipso facto removes any possibility of any further hemorrhage. Finally, a continuous suture of the glandular cap- sule terminates the operation on the thyroid itself. SHALL THE OPERATION BE UNILATERAL OR BILATERAL? Shall the operation be unilateral, or bilateral as advocated by Mikulicz and Kausch ? Of course this question applies only to the cases in which the thyroid is bilaterally affected. It would not enter into anyone's mind to advocate a bilateral operation unless there is a pathological reason for it on both sides. The question being so understood, I say, "Yes, the operation should be bilateral whenever it is necessary and whenever the condition of the patient warrants it, no matter if we deal with a simple or thyrotoxic goiter." In the beginning of my surgical activity, I, too, was a devotee of the unilateral resection as still prac- tised today by the majority of surgeons. But in following my own and other surgeons' cases, in which unilateral resection had been performed, I soon recognized the fact that this method was unsatisfactory, espe- cially from an esthetic and relapse stand-point. Consequently, I gave it up and resorted to bilateral operations. Indeed, in bilateral patholog- ical conditions of the thyroid this method is the only logical one. Take, for instance, a multiple nodular goiter developed in both lobes. There is here really no sense in removing the goiterous nodules only on one side and leaving the others in the lobes, as these nodules are bound to grow and form another goiter. Sooner or later symptoms will reappear, and with them the dissatisfaction of the patient and the disappointment of the surgeon. From the esthetic point of view nothing has been gained by the unilateral resection, as one side of the neck is still puffed up, while the side where the operation has taken place shows a depression. SHALL THE OPERATION BE UX I LATERAL OR BILATERAL 155 Let us consider a diffuse colloid degeneration of the entire gland. Here, again, why confine the surgical act to one side onlv ? Even if a concomitant resection of the isthmus takes place, there still remains a diffuse, colloid degeneration in the other lobe. Here, again, the opera- tion is insufficient; the functional as well as the mechanical disturbances have been only partly eliminated; the cure cannot be complete, relapses will occur. If such is the case why not resect bilaterally : In dealing with a diffuse, non-toxic vascular goiter, the same reasons which have been invoked for resecting other goiters bilaterally still stand good. A bilateral resection should be done instead of leaving a large vascular parenchymatous goiter on one side. But it is especially in the thyrotoxic parenchymatous goiter that bilateral resection finds its special indications. There, unless special contra-indications are present, the necessity for bilateral resection is an imperative one. In the great majority of cases one-sided lobectomy is insufficient to put a stop to hyperthyroidism. The patient is greatlv benefited, yet not cured. The reason is because there is still too much thyrotoxic secreting gland left. Even ligation of the upper pole of the lobe left untouched is insufficient. That patient belongs to the class called by Kocher "nicht fertig operiert." Why not then from the start resort to bilateral resection? Functionally the results will be far better; esthetically they will be perfect. Bilateral resection has the great advantage of affording a general view of the whole gland. This is indeed important. Despite the most careful and skilful clinical examination, who can be certain in every case before operation that a lobe is normal or not and to what extent it is damaged. Every surgeon has had, I am sure, the surprise of discov- ering at the operation only, that a lobe which he considered as normal was not so, that a retrosternal goiter was present which had been unsus- pected, etc. Furthermore, it is only after having inspected the whole gland that a surgeon can best decide how much gland can be resected on each side, and what the nature of the technic will be, whether resec- tion, enucleation, or enucleoresection must be resorted to. At first, one might thmk that relapses must be, theoretically at least, more frequent with bilateral resection than with unilateral excision. Indeed, with the latter method, the whole lobe having been removed, with the exception of a thin band of the posterior layer, relapse can hardly be expected, while, with the bilateral resection, as a thick portion of glandular tissue, normal or nor, is left /';/ situ the chances tor relapse are greater. Consequently one might naturally conclude that uni- lateral excision is to be given the preference: goiter developing in the non-operated side must not be regarded as ;i relapse, but is a new goiter whose- appearance cannot be charged to the method. 456 TECH NIC OF OPERATIONS UPON THE THYROID GLAND The argument retains, of course, its full strength whenever the lobe left untouched is normal. In that case if any goiter occurs, it must not be regarded as a relapse, but as a new growth. There cannot be any doubt about that. But in the great majority of cases things are not so: the pathological condition is not confined to one lobe only; as a rule both lobes are involved, one perhaps less markedly so than the other, nevertheless, they are both affected. Consequently that method is to blame which does not try to remedy the whole condition and which leaves purposely, knowingly, and carelessly, a goiter, no matter how small, on one side. An error of "omission" is, nevertheless, an error and should be charged with its consequence. One thing has struck me very forcibly: it is the fact that after bilat- eral resection a diffuse parenchymatous or a colloid gland, toxic or not, has little tendency to relapse. It seems that after an operation the gland readjusts itself and reverts to the normal type. Of course if the patient's condition is not good, if it is taking too great risk by resecting bilaterally, this operation must not be attempted; ligation of one, two, or three arteries should be given the preference; unilateral resection should be resorted to until the patient's condition warrants the attempt on the other side. In conclusion we can say that: i. Bilateral resection is the method of choice, whenever it is necessary and possible; 2. It affords a general view of the entire gland and does not let any goiter escape unobserved; 3. This method is much less apt to give relapse than the unilateral resection; 4. From an esthetic point of view it is ideal; 5. Technically the method is very simple. In fact, it is much simpler than the unilateral intracapsular excision and the risks of injur- ing the inferior laryngeal nerves and the parathyroids are certainly far less, provided, that a layer of thick enough glandular tissue is left in contact with the danger zone. The amount of hemorrhage is not materi- ally larger than with enucleation or unilateral excision, provided pre- liminary ligations of the main arterial trunks have been made, and provided, too, that the glandular tissue is cut only after being clamped with two hemostats. 6. When unilateral resection only is made, whenever there is a slight amount of thyrotoxicosis, or whenever bilateral resection must be deferred on account of the patient's condition, it is well to throw a ligation around the upper pole of the lobe which is left untouched. HOW MUCH THYROID TISSUE CAN SATELY BE REMOVED 457 HOW MUCH THYROID TISSUE CAN SAFELY BE REMOVED? It seems that even' surgeon has his own rule. Yon Eiselsberg leaves a portion of glandular tissue which can be compared in size to a hen's egg. Mikulicz leaves on each side a quantity amounting to the size of a walnut. Riedel is satisfied if he leaves one-tenth of the whole gland, while in bilateral goiters he leaves one-third of one lobe. Hoennicke, considering that the normal weight of the thyroid is in the neighborhood of 20 to 25 grams, makes it a point to leave in situ enough gland to equal about this weight. De Quervain leaves enough thyroid tissue so as to equal the volume of the normal thyroid gland. Kocher claims that whenever the thyroid shows a diffuse parenchymatous degenera- tion one-fourth of the total volume of the gland should be left in situ. Mayo says that an entire lobe, the isthmus and the two lower thirds of the other lobe can be safely removed. Kausch leaves one and one-half times the size of the normal thyroid. It is obvious that these more or less theoretical rules cannot be applied to even' case, as it would be erroneous to believe that a certain amount of pathological glandular tissue has the same physiological power as an equal amount of normal thyroid tissue. It is consequentlv wrong to set down a uniform rule which should be applied in every case. It is obvious, too, for instance, that if a patient with diffuse col- loid goiter shows symptoms of hypothyroidism, this thyroid insuffi- ciency is bound to become more marked after a certain portion of the gland has been removed. It would consequently be a mistake to remove in such cases as much thyroid tissue as in a case of hyperthyroidism, for instance. In the former case all that we want is to relieve the patient of his pressure symptoms, and to relieve him of his deformity, but we should have constantly in mind the necessity of leaving as much thy- roid tissue as can possibly be done, whereas in the latter case the func- tional activity of the thyroid being what we are trying to diminish, we shall feel at liberty to remove a far greater amount of thyroid tissue than in the former case. Furthermore, it should always be borne m mind that a certain amount of glandular tissue left after the operation undergoes resorption on account of the vascular disturbances and the organization of the blood clots and the connective-tissue formation due to the sutures. 1 his should be taken into consideration when deciding how much tissue should be left. One might expose himself to disap- pointment if he should count too much on the so-called "compensatory hypertrophy" of the remaining portion. Halstead seems to be presently inclined to believe that this compensatory hypertroph} is onlj a process of reaction of the thvroid to a low-grade infection. 458 TECH NIC OF OPERATIONS UPON THE THYROID GLAND We may consequently conclude: 1. In simple goiter, colloid or cystic, multinodular or not, without hypo- or hyperthyroidism symptoms, enough thyroid tissue should be left on each side so as to equal about the volume of half of a normal lobe. 2. If hypothyroidism symptoms are present, the amount of tissue left must be in proportion to the degree of hypothyroidism and may equal two or three times the size of the normal lobe on each side. 3. In hyperthyroidism to leave an amount equal to one-third to one-fifth of a normal lobe is a safe procedure. SHALL WE DISSECT THE PARATHYROIDS? Some surgeons have thought that they would avoid injury to the parathyroids by dissecting them in situ. A -priori this is rational, but the results obtained have not been encouraging. Indeed, when dissect- ing a cadaver, if we stop to think how difficult it is sometimes to iden- tify these little bodies, how little they differ from a small accessory thyroid glandule, from small lymph glands, or even from small fat nodules, it will then be easily understood why the above-mentioned method is impractical. It would necessitate a prolonged, tedious, and often an unsuccessful operation; it would expose, furthermore, to trouble- some hemorrhages by injuring the numerous veins of that region and would have too often as a result, the injury of the organs which we are trying to protect, namely the inferior laryngeal nerves, and the parathyroids. It is quite plain that these disadvantages and dangers add to those of a prolonged operation. Consequently any method whose aim would be to identify de visa these little, too often hypo- thetical organs, is bound to be unsatisfactory. It must then be dis- carded. The best way not to injure the parathyroids is to ignore them by leaving them undisturbed with the posterior capsule. LIGATIONS. The ligation of the thyroid arteries in goiter was already utilized by veterinary surgeons for goiters of horses, and was proposed as a thera- peutic measure in human surgery by von Muys in 1639 and Langhe in 1707. The first ligation in man was done by Blizzard in 181 3 when he tried to ligate the superior thyroid artery in order to cause the atrophy of a large goiter. The patient died from hemorrhage. In 1814 Walter attempted this operation again and succeeded. The ligation of the inferior thyroid was done for the first time by Porter in 1852 but it was only in 1888 that Wolfler and Rydigier applied this method systemat- ically to goiter surgery. They obtained good success especially in the vascular and parenchymatous forms. In cancerous, cystic, fibrous, and LIGATIONS 4.">! I calcareous forms the method failed, as could be expected, to give satis- faction. Later, when the technic became better worked out and the antiseptic era protected the patients against infection, these ligations were given up and replaced by thyroidectomy. Today they are used onlv as a preliminary step to thyroidectomy in Basedow's disease. The vasomotor and secretory nerves of the thyroid penetrate into the thyroid by the same route as do its bloodvessels. At the upper pole small branches of the external laryngeal nerve, which itself is a branch of the vagus, penetrate into the gland with the superior thyroid artery as well as the sympathetic branches. At the inferior pole the nervous branches reaching the thyroid gland in conjunction with the inferior thyroid artery are mostly all of sympathetic origin. Accord- ing to Bnau these branches come from the superior middle and inferior cervical sympathetic ganglions and anastomose freely with the cardiac nerve branches of the vagus. It is found that the inferior laryngeal nerve sends directly to the thyroid gland a very few small filets whose physiological action is not known. It is a very well-accepted fact today that the branches of the superior laryngeal penetrating the thyroid at its upper pole are essentially vaso- dilatatory: this has been demonstrated plainly by Frank and Halhon. More so, according to Ascher-Flack (Centralblatt fur Physiologie, June, 1910, xxiv, 211-213), the irritation of the peripheral end of this nerve produces an increased secretion of the thyroid; consequently the external superior laryngeal is not only a vasodilatator}', but is also at the same time an excitosecretory nerve. The central irritation of the depressor nerve causes an intense vascularization of the thyroid through a reflex intermediary action of the external laryngeal nerve. The action of the sympathetic branches are, according to Frank, Halhon and von Cyon, vasoconstrictory. Their division causes, according to Missiroli (./rchivio di fisiologia, 1908, vi, 582-594), a hypersecretion of the thy- roid parenchyma. If this is really so, then sympathectomy for Graves' disease is illogical; at any rate some other explanation should be given in order to explain its favorable results in that condition. In the light of the above considerations it follows that with our ligations we nor only diminish the blood supply of the thyroid gland, but also, at the same time, we deprive, to a certain extent at hast, the thyroid of its nerve supply. In fact, our ligations should be considered as true angioneurotomies. If we sum up these facts and the ones spoken of in the chapter on The Blood Supply of the Thyroid, we come to the following conclusions : 1. With our ligations we not only dimmish the blood supply and consequently the secreting power of the thyroid, but we act directly 460 TECH NIC OF OPERATIONS UPON THE THYROID GLAND upon the gland itself by determining atrophy of the territory deprived of the blood circulation. This atrophy is in direct proportion to the amount of blood supply suppressed. It causes a thickening of the cap- sule and an interstitial cirrhotic process invading the gland throughout; the epithelial elements have the tendency to revert to their normal type. 2. Since the external laryngeal nerve has a marked vasodilatatory and excitosecretory action upon the thyroid, and since the sympathetic branches penetrating the thyroid with the superior and inferior thyroid arteries seem to be less important physiologically, it follows that our efforts should be directed against the external laryngeal nerve. This can be done easily at its point of entrance into the gland, namely, at the upper pole, by performing a ligation including all the branches of divi- sion of the superior thyroid artery. In so doing all the branches of the external laryngeal nerve are bound to be caught. This is best done by the polar ligation method of Stamm and Jacobson. This ligation must be double, and in order to be most effective, the neurovascular pedicle included between the two ligatures must be severed with a knife or scissors. In that way the branches of the external laryngeal are surely divided. The ligation then becomes an angioneurotomy. 3. Whenever the condition of the patient is such as to warrant a ligation only, the ligation of the superior pole is the method of choice, because to the suppression of the vascular supply we add the suppression of the nervous supply through the external laryngeal nerve. 4. If the condition of the patient warrants a double ligation, the ligation of the superior pole and of the inferior thyroid artery on the same side is the method to be chosen. Indeed, as the anastomoses between the inferior and superior thyroids are very numerous, whereas the bilateral anastomoses are very much less developed, the maximal effect will be obtained if we obliterate the thyroid arteries of the same side instead of ligating, as is so frequently done, both superior arteries. 5. For the same reasons, if the upper pole has been previously ligated the one which will have to be hgated next will be the inferior thyroid on the same side. 6. If three ligations are performed in one or several sittings, two must be performed on the same side, and the third on the upper pole of the opposite side so that there will finally remain one thyroid, the inferior, to ligate if one chooses to do so. 7. Ligation of the four thyroid arteries in one or more sittings can be done without danger of necrosis of the thyroid gland and without danger of tetany, unless vascular anomalies should exist, and this cannot be foretold. Indications for Ligation. — One of the greatest advocates for this method of treatment of Basedow's disease is Kocher. As he said, "If we LIGA TIONS 461 ligate one arterv onlv, we obtain an amelioration of the patient's con- dition; if we ligate two arteries the amelioration is greater; if to it we add the removal of one lobe, the amelioration is still greater. If the results obtained are not sufficient, we can ligate one or two arteries on the other side, and we can perform another partial thyroidectomy on the lobe which has not been touched." These views have since been almost universally accepted by the majority of operators. In advanced cases successive and graduated operations are the method of choice. Ligation alone of two or three, or even of four arteries, will very rarely suffice to cure the patient who is seriously ill with Graves' disease. Although considerable improvement may follow, thus allowing the sur- geon to perform a more radical operation, a complete and permanent cure is hardly to be expected. Ligations must always be practised with the view of improving the patient's condition so as to allow a thyroidec- tomy to be safely performed later. These small operations have the further advantage of testing the patient's resistance to the operation; they consequently give precious indications for the future surgical pro- cedures. In light forms of Graves' disease it is better to resort to thyroidectomy at once without preliminary ligations. Ligations must be reserved for those thyrotoxic cases where thyroidectomy cannot be safely undertaken. Ligations are clearly indicated in those forms of non-toxic vascular goiters in which the essential feature is an enormously increased vascu- larization. Here the goiter resembles an angioma cavernosum with all its vascular symptoms, abnormally marked blood supply, thrill, systolic murmur, partial reductibility by compression, etc. 1 hyrotoxicosis may be totally absent. This is the struma vasculosa of Kocher. Ligations in these forms of struma can be performed in one sitting and can In- applied to the four arteries. A complete cure may be hoped for by tins simple method. Ligations art- ordinarily not indicated for the secondary forms of Graves' disease-, namely, in Basedowified goiters. In these cases their efficacy is only slight, and the same is true for the non-toxic parenchy- matous goiters. Exceptionally, however, if in certain Basedowified goiters the vascular symptoms should be very pronounced, preliminary ligations may be very beneficial, as they diminish the blood supply, and what is of utmost importance, lessen the thyrotoxic symptoms. There are cases of Basedow's disease apparently of nervous origin and characterized clinically by the absence, or almost abs< nee, of thy- roid physical symptoms. The symptom-complex stems to rake appar- ently its origin in an intense irritation of the cervical sympathetic sys- tem. In these eases ligations, and even resections, are not satisfactory. Resection of the sympathetic nerve with one or two of its ganglia seems to be, for the time being, the method <>t choice. 462 TECH NIC OF OPERATIONS UPON THE THYROID GLAND After one ligation has been made the patient should be given from two to six months rest; then, according to his condition, a second, and a third, ligation may be performed. From three to five months are then permitted to elapse in order to give the patient a chance to get the full benefit of these operations. Only then, and that is if the condition of the patient warrants it, may thyroidectomy be performed; otherwise the fourth artery should be ligated. In cases of advanced thyrotoxicosis in which the organs have undergone a secondary change, such as neph- ritis, hepatitis, myocarditis, arrhythmia, etc., the dangers of an opera- tion, whatever it might be, ligations or resection, are quite great, and the hope for cure, or of great improvement, is only slight. What is the Point of Election for Ligation? — For the superior thyroid artery there is no discussion. This ligation takes place just before its entrance into the upper pole. It is best done by the polar method of Stamm and Jacobson (Plate XIII, Fig. 3). For the inferior thyroid artery divergences of opinion still prevail. Some surgeons advocate ligation at its point of entrance into the gland- ular capsule; others advocate the ligation just inwardly of the vascular cord; while others advocate ligation at the inner border of the scalenus anticus. Ligation of the inferior thyroid artery near its point of entrance into the thyroid has many disadvantages. It necessitates first, the dislocation of the goiter. This is by no means always easy. In exophthalmic goi- ter, hemorrhage from the goiter itself occurs easily during this act, on account of the adhesions with neighboring tissues, and because of the friability of the bloodvessels. Furthermore, since the search for the artery takes place in the penthyroidal cellular space, which we know is very vascular, this search for the artery or its branches in that region is rendered difficult by the numerous veins found, whose injury increases the difficult)' of the operation. Furthermore, we must not forget that this region constitutes the danger zone (Plate IX, Fig. 2) which must be abso- lutely avoided, unless one wishes to run the risk of injuring the inferior laryngeal nerve and the parathyroids. In addition to this, at that level, the inferior thyroid artery has, as a rule, already undergone division into several branches so that one often ligates only a branch instead of the main trunk; the small parathyroid artery in that region is bound to be injured, and the parathyroids and the inferior laryngeal nerve are so interwoven with the branches of division of the inferior thyroid artery that the risk of injuring them is great (Plate IX, Fig. 2). In the light of all these considerations ligation of the artery near its point of entrance into the thyroid is not to be advocated. The same is true for the intracapsular ligation, as practised by those who perform thy- roidectomy by the decortication method. The same is true for the "ultraligation," as advocated by Halstead. PLATE XIII Fig. i. — The skin and platysma myoides have been cut. The omohyoid and sternohyoid muscles are then encountered. They are divided bluntly at their point of junction. The division of these muscles follows the same direction as their muscular fibers. Fig. 2. — The upper pole of the thyroid is then isolated. Fig. 3. — A curved thread carrier is swung around the upper pole and ligation is made so as to bite off a little of the thyroid tissue. Another ligation is placed a little above and the thyroid wsstls are then cut between the two ligatures. Figs. 1, 2 and 3. — Ligation of the Upper Pole. • LIGATIONS 463 The point of election for ligating the inferior thyroid is inwardly of the carotid sheath, soon after the artery has crossed it transversely and posteriorly (Plate IX, Figs, i, 2). In man)- instances the thyroid is so hypertrophied that its lateral border overlaps the vascular cord. Ligation of the artery at that point consequently offers, in the opinion of Delore and Alamartine, the same dangers and disadvantages as if the artery were ligated at the point of entrance into the thyroid. They, for this reason, consider the ligation of the artery at the inner border of the scalenus anticus as the method to be followed. (Plate X, Figs. 2 and 79.) These conclusions seem to me not quite correct. To be sure, sometimes the thy- roid is so enlarged as to render this ligation very difficult. I grant that in these cases the method for the ligation of the inferior thyroid is the one they propose. This, however, is not common. As a rule, even with voluminous thyroids, it is possible to retract the carotid sheath out- wardly and the thyroid inwardly so as to allow ligation to take place without too great difficulties. If luxation of the goiter can be performed, then ligation of the inferior thyroid can surely take place at the point of election. It should not be forgotten that, in undergoing enlargement the thyroid gland does not carry with it and away from their normal places, the parathyroids and the inferior laryngeal nerves. These organs remain where they are, no matter how large the goiter may become, whereas the carotid sheath is displaced laterally and posteriorly, so that in reality the ligation of the artery just inwardly of the vascular cord does not expose these organs to injury. Another advantage of ligating the inferior thyroid artery at the point of election as just men- tioned, is that at that point ligation takes place outside of the perithy- roidal cellular space. This lessens the danger of injuring the veins which are usually found in it. For all these reasons we may conclude that the point of election for the ligation of this thyroid artery is just inwardly of the vascular cord (Plate XXI). In ligating the artery at that point injury to the inferior laryngeal nerve and to the parathyroids is quite out of the question. Furthermore, the danger of injuring the veins of the perithyroidal cellular space is practically nihil. The only organ which might be injured is the sympa- thetic nerve with its middle cervical ganglion. In the light of our mod- ern views, even if such a thing should happen, the patient would not be the worse for it. 1 even think that in many instances, inasmuch as the sympathetic lies just behind the artery imbedded in areolar tissue, it is a good plan to add to the ligation the resection of the sympathetic nerve. I hat is precisely what I sometimes do. Technic of Ligations. The problem whether general or local anes- thesia should be used is one to be deeitled with each individual case. On the condition ol the patient depends, too, how main ligations should be dene 111 one sit ting. 464 TECH NIC OF OPERATIONS UPON THE THYROID GLAND The polar ligation of the superior pole is, as a rule, an easy opera- tion and quickly done. I have often performed it while the patient was still in bed, in order to reduce to a minimum the amount of fear and shock. But the ligation of the inferior thyroid is a more complicated matter because it is of more difficult access. Some authors even claim that this operation is as serious as thyroidectomy itself. In the great majority of cases, however, this assertion is certainly exaggerated. Ligation of the four thyroid arteries in one sitting should seldom be made because, if the patient's condition is such as to warrant a ligation of the four arteries at the same time, thyroidectomy should by all means be preferred to ligations. The amount of fear and shock will not be greater, and the result will be far more satisfactory and permanent. However, if one should choose to do so, either because he has to deal with a struma vasculosa, or for any other reasons, then the transverse, or low-collar incision, made in the usual way for thyroidectomy, should be given the preference. It is better to expose the gland in a similar manner just as if thyroidectomy were to be performed; the two upper poles are dissected out and ligated. The same is done for the inferior thyroid arteries on both sides. Isolated Ligation of the Superior Pole. — A transverse, or slightly oblique incision of four or five centimeters is made laterally to the thy- roid cartilage at the level of its superior border, and if possible, in a skin crease. As in the large majority of cases the superior pole is easily felt, the latter may serve as a landmark for the place where the incision must be made. The two skin flaps are retracted; a small branch of the super- ficial cervical plexus and one of the anterior jugular veins may be encoun- tered. They are retracted. The omohyoid and sternohyoid muscles are then prepared and separated bluntly in the direction of their running fibers. (Plate XIII, Fig. i.) The fibers of the sternothyroid, which he underneath, are divided longitudinally, bluntly too, and well retracted with blunt hooks. The upper pole is thus brought into view. (Plate XIII, Fig. 2.) It is prepared, doubly ligated with silk carried by a curved ligature carrier, and cut between the two ligatures. (Plate XIII, Fig. 3.) One should always have in mind that it is not by any means difficult to miss the dorsal branch of the superior thyroid artery while passing the ligature around the upper pole. This fact may sometimes account for the failure to realize an expected improvement in a patient with a toxic goiter after unilateral or bilateral ligation of the upper pole was thought to have been accomplished. No drainage; one or two separate sutures for the muscles; suture of the platysma, and intradermic suture. Technic for the Isolated Ligation of the Inferior Thyroid Artery. — Pre- cisely in the line of the transverse incision, contemplated for future thy- PLATE XIV A<& Ligation of the Inferior Thyroid Artery. I his operation is supposed to be a preliminary step before attempting thyroid- ectomy, hence the large incision made. The superficial cervical fascia has been divided just in front of the sternocleidomastoid muscle. This muscle is retracted outwardly while the prethyroid muscles and the thyroid gland are retracted inwardly. (The picture shows a portion of both anterior jugular veins missing. This is an error.) PLATE XV Ligation of the Inferior- Thyroid Artery. I he sternomastoid and the muscular capsular space have been entered. The carotid sheath is then retracted outwardly while the prethyroid muscles and the thyroid gland are retracted inwardly. The surgical space is carefully avoided. The inferior thyroid is then located and tied. LIGATIONS 465 roidectomy, and over the tendon of the omohyoid muscles, a transverse incision of 6 to 8 cms. is made. The two skin flaps are retracted upward and inward. Just along the inner border of the sternocleidomastoid muscle and parallel to it an incision is made on the fascia covering the prethyroid muscles (Plate XI\); then the finger penetrates bluntly between the sternocleidomastoid and the prethyroid muscles so as to travel through the sternocleidomuscular plane of cleavage until the carotid sheath is located. The sternocleidomastoid muscle and the vascular cord are then retracted laterally, and the thyroid gland cov- ered with its prethyroid muscles is retracted inwardly by a retractor especially designed for the purpose. (Plate XV.) Great care should be taken not to open the surgical capsule of the thyroid. A finger then goes in search of Chassaignac's tubercle or the anterior tubercle of the transverse process of the sixth cervical vertebrae. One centimeter below this tubercle, as a rule, the inferior thyroid artery is found, its pulsations facilitating the finding of it. A curved blunt thread carrier with a small radius is used to earn' the ligatures. Care should be taken in handling this artery, as it is often thin and friable, and especially so in Basedow's disease. Sometimes the artery is not found. It may be caught by the assis- tant's retractors and compressed so as to prevent its pulsations being felt, but release of this pressure will soon tell as to its presence. If at the point where the inferior thyroid is supposed to be, instead of finding an artery with a transverse direction, one with a vertical direction is found, then we have to deal with either the truncus thyreocervicalis, or with the ascending cervical artery. This is a precious indication, as it will help to find the inferior thyroid artery. If, however, these researches fail, the conclusions must be reached that very likely this artery is absent. Isolated Ligation of the Inferior Thyroid on the Inner Border of the Scalenus. Dietrich and Langenbeck, who were the first to advocate this method, used to pass between the two heads of the sternocleidomastoid muscle. Drobnik, Rudigier and \\ olfler have advocated the following method ( Fig. 79) : I wo centimeters above the- clavicle and about 0.5 cm. behind the posterior border of the sternocleidomastoid muscle, a slightly upward- curved incision ot 5 cms. is made. I he superficial cervical fascia is divided and if the external jugular vein is encountered, it is clamped and cut. In the triangle formed by the sternocleidomastoid muscle, the omo- hyoid and the clavicle, a blunt dissection takes place until tin scalenus amicus is found. On its anterior surface lies the phrenic nerve: it is retracted inwardly with the fat tissues. On the inner border of the scalenus the inferior thyroid is felt pulsating and may also be seen. It 30 466 TECH NIC OF OPERATIONS UPON THE THYROID GLAND is ligated between the two ligatures and cut. No drainage; intradermic suture. This operation has the great advantage of taking place far from the thyroid gland and its danger zone. It causes no risks of tetany, of injury to the inferior laryngeal nerve, or of hemorrhage through injury of the thyroid vessels, but it necessitates a new incision, and hence another scar. ding cjMmc. <*v£r *lxc- cciAfic. (vri/ at/. Fig. 79. — Ligation of the inferior thyroid artery. Incision is made above the clavicle in order to penetrate the triangle formed by the sternocleidomastoid, omohyoid and the clavicle. The thyrocervical axis is then located and the inferior thyroid tied. Note the close relation of the phrenic nerve to the thyrocervical trunk. Hemostasis. — Hemorrhages were for a long time a feared complica- tion of goiter operation. With our present anatomical and technical knowledge, however, this complication can now be avoided almost entirely. Of course there will always be operations in which hemor- rhages, no matter what is done, will be abundant; especially in Graves' disease where, because the bloodvessels are thin and friable, hemorrhage is sometimes quite marked despite a good technic. There will always be, too, hemorrhages due to some unexpected and unavoidable accident. These complications, however, can be reduced to a minimum. Hemorrhages may be: 1st, arterial; 2d, venous; 3d, parenchy- matous. LIGA TIOXS 467 Despite unilateral ligation of the superior and inferior arteries and veins of the thyroid, we know from our own previous studies that hemor- rhage may still occur on account of the bilateral anastomoses, and col- lateral circulation from the neighboring tissues. Parenchymatous hemor- rhage is, as a rule, of little importance. In certain very vascular goiters, however, the hemorrhage may be so diffuse and so abundant that one hardly knows where to put a hemostat. Furthermore, the parenchyma and vessels may be so friable that any attempt to place a hemostat or a ligature only results in an increase of the hemorrhage. The only, and the best, way to stop this diffuse parenchymatous oozing is to use what the French authors call the "ligature en masse." This is done by includ- ing in the ligature a certain amount of glandular tissue and bv tying the ligature just tight enough to stop the oozing, but not to break the glandular tissue. Hemorrhage can be greatly reduced if one follows the following rule: Never cut the glandular capsule and the parenchyma unless previously clamped, and then operate carefully, anatomically, and systematically. By ligating the one or two thyroid arteries prior to undertaking resection of the gland hemorrhage may be reduced to a minimum. The preliminary ligation of both the superior and inferior thyroid arteries, prior to resecting the goiter, is not considered by everyone as a necessary step to the operation. In Kocher's, De Quervain's and many other surgeons' work, ligation of both the superior and inferior thyroid arteries is a part of their technic. On the other hand, Mikulicz, Kausch, and others do not strive to do so. Kausch, for instance, ligates the superior thyroid only: he is never concerned with the inferior thyroid. I share the same views, except when I have to deal with thyrotoxic goiters in which the diminution of the blood supply of the remaining glandular portion is one of the aims of the operation. Otherwise, in ordinary simple goiters, I really do not see the necessity for ligating the inferior thyroid before removing the goiter. On the con- trary, I consider that leaving the inferior thyroid untouched is one of the best assets for the vitality of the remaining glandular portion, and especially for its functional activity. It is rare that hemorrhage- during operation is such that the only means to check it is to add to the liga- tion of the superior thyroid artery, the ligation of the inferior thyroid. Another reason for giving up the ligation of the inferior thyroid is to avoid any chance of injuring the interior laryngeal nerve and the para- thyroids, furthermore, quite often the vitality ot the remaining por- tion of the gland is already reduced, and consequently it it is further lowered by shutting off its main blood supply, it will hardly be able to take care of the ligatures' material, and especially so if the lattei is non- resorbable, hence pus and elimination of the threads. ( )n the other hand, 468 TECH NIC OF OPERATIOXS UPON THE THYROID GLAND as a routine measure, I always ligate the superior pole before starting the resection. It is scarcely necessary to state, if ligation of both superior and inferior thyroids is attempted by the surgeon as a part of his routine technic, since this ligation has for its sole object the reducing to a mini- mum of the hemorrhage during the surgical act, that it should take place before beginning the resection of the gland. This again is not viewed by everyone in the same way: I have often seen surgeons per- forming this ligation after the removal of the goiter was terminated. At that time of the operation, this ligation is, in my judgment, entirely unnecessary, as it presupposes that hemorrhage has already been mas- tered. Indeed, in the great majority of cases, as soon as the goiter has been removed, hemorrhage diminishes in a surprising manner: a few hemostats here and there and the bleeding is controlled. Once in a great while, however, the oozing is so profuse that it seems more expedi- ent to resort to the ligation of the inferior thyroid artery in order to check the bleeding. This, however, is rare. At any rate, if one believes in the necessity of ligating the inferior thyroid artery, the only logical moment to perform it is before starting the resection of the goiter itself. As said before, exception can be made for thyrotoxic goiters. In these cases, if for some reason ligation of the inferior thyroid artery has not already been done, it can then take place after the goiter is removed. Thyroidectomy. I he low -collar incision bein» performed and the two skin Baps retracted, the prethyroid musck-s an- divided in rlu- middle line. CHAPTER XLI. OPERATIVE TECHNIC FOR THYROIDECTOMY. INCISION. 1. In the greatest number of cases the incision of choice is the low- collar incision of Kocher. It is the one which certainly gives the best cosmetic results and when properly placed allows the surgeon to per- form every step of the operation without difficulty. It is slightly curved, its concavity being directed upwardly; it should be perfectly symmetrical. The incision is made one or two centimeters above the manubrium sterni. The length varies, of course, with the size of the goiter. The fault too often made by beginners is that of a small incision. In larger goiters the incision extends from the middle of one sternocleido- mastoid muscle to the other, or better said, from one external jugular vein to the other. In the average case it can be made much smaller. If local anesthesia is used, the incision must be larger than with general anesthesia so as to diminish the pain caused by the necessary pulling upon the retractors. It is better to give the preference to a slightly curved incision than to a straight transverse cut. In unusually large goiters the esthetic side may have to be disregarded; the "Winkelschnitt" of Kocher or angular incision with well-rounded angles above the cricoid cartilage will then give far better access to the tumor than any other incision. This incision, however, will seldom find employment because very large goiters are becoming more and more rare every day, and because, too, a well-arched collar incision will almost always meet every demand. Other incisions are sometimes advocated as the "H," "1," and "U" forms. They only prove that the surgeon who uses them is not very much concerned with the esthetic side of his work. I hese inci- sions will soon have only an historical interest. 2. The subcutaneous tissue and plat} sma are then retracted, the upper Hap as high as the thyroid cartilage, the lower flap to the epi- sternal notch. (Plate XVI.) The two median and oblique jugular veins are clamped and cut; the two external jugular veins are left uninjured. The upper and lower Haps are maintained retracted either by an auto- matic retractor or by an assistant. 3. A vertical incision extending from the thyroid cartilage to the episternal notch is made in the middle- line between the prethyroid 470 OPERATIVE TECH NIC FOR THYROIDECTOMY muscles. (Plate XVI.) A finger is then introduced under them and going up and down, loosens their posterior surface as far up and down as possible. (Plate XVII.) The greater amount of pressure must take place anteriorly against their posterior surface so as to avoid injury of the subjacent veins. 4. For moderately sized and non-complicated goiters the mere lat- eral retraction of the prethyroid muscle affords sufficient access to the field of operation. In a great many instances, however, it becomes necessary to cut them transversely. (Plate XVIII.) The point of elec- tion for their section is at their upper end; in that way their nerve sup- ply is not injured while the section breaks the line of scar thus prevent- ing the muscular suture from becoming adherent to the cutaneous one. These muscles are clamped transversely and cut between parallel hemo- stats, on one or both sides according to the necessity, and are retracted laterally and downward. Furthermore, these muscles are treated as one structure technically throughout the operation, and are always manipulated as one object; they are not being freed of their fascia cov- ering them. Usually, however, the omohyoid muscle does not need to be cut. The time lost in liberating, clamping, cutting, retracting, and sewing up these muscles when the operation is done is practically not worth mentioning. At any rate, it is more than sufficiently offset by the ease, rapidity and safety with which the operation can be done, and by the minimum ot traumatism inflicted upon the patient. The sternocleidomastoid muscle does not need to be incised at all. Its lateral retraction is sufficient to give plenty of access to the field of operation. It may, however, become necessary in large intrathoracic goiters to cut temporarily its sternoclavicular insertion. In that case its itwo ends must be sewed up afterward. 5. There is no need to say that, as the operation is progressing, every bleeding point is at once blinded with hemostats which are left in place or removed after immediate ligature has been made. In a most general way, but especially when dealing with the gland itself, clamping with hemostats must always be done before cutting and not afterward. 6. The surgical capsule is now open and the glandular capsule exposed. (Plate XIX.) This step of the operation is of the utmost importance as it affords the proper plane of cleavage, otherwise the surgeon will err in the wrong place and the operation will become very difficult. Two index fingers are introduced between the surgical cap- sule and the goiter itself and conducted up and down gently around the goiter so as to loosen the tumor from its connection with the surgical capsule. (Plate XX.) In so doing one often finds the middle or accessory veins of Kocher, which in large goiters are sometimes markedly devel- oped. They are doubly clamped and cut. PLATE XVII *W Thyroidectomy. he operator then goes with the index fingers into the musculocapsulai space, thus loosening the prethyroid muscles away from the gland. INCISION 471 7. Now comes one of the most important steps of the operation, a method first introduced by Kocher and called dislocation of the goiter. One or two fingers passed posteriorly between the gland and the surgi- cal capsule lift the gland forward, the isthmus forming, so to speak, a hinge upon which the lobe is swung. The surgical capsule is detached and retracted posteriorly as far as the "danger zone" (Plate IX, Fig. 2), but no farther, so as to avoid coming in contact with the parathyroids and inferior laryngeal nerve. Luxation, too, should not be pushed too far, so as to avoid the danger zone. Occasionally there may be some hemorrhage from small vessels torn when the gland is luxated. This hemorrhage can usually be easily controlled. In uncomplicated cases, with not too large a goiter, when the sur- gical capsule has not undergone any secondary inflammation and has not become adherent to the glandular capsule, luxation of the goiter is an easy matter, and of most impressive effect, especially when unsus- pected intrathoracic goiters are fished out. If, however, peristrumitis has taken place, as in some cases of Basedow's disease, strumitis, and malignancy, the surgical capsule being fused with the glandular capsula propria, it is no longer possible to separate them, the good plane of cleav- age cannot be entered into. Under such circumstances the operation becomes difficult and bloody. It is in such attempts to luxate the goiter that alarming hemorrhages are observed, sometimes so intense that one fears to have injured the internal jugular or subclavian veins. Under such conditions luxation must often be given up, and resection of the goiter, after having ligated the upper pole and possibly the inferior thyroid artery, must be undertaken in situ. The operation is more difficult but is technically feasible, as shown by surgeons who never luxate, but dissect the entire gland free from its attachments by sharp dissection with scalpel and dissecting forceps, laying bare the posterior capsule. ( Plate X, Fig. 1.) We have seen, however, that such technic is not to be recommended. 8. The upper pole is freed from all surrounding structures, and the left index finger is placed between the upper pole and the carotid sheath so as to prevent injury to the structures contained. A curved, blunt thread carrier is swung around the upper pole and ligation of the thy- roid vessels is made (Plate XXII). Usually it is easier to ligate the upper pole so as to bite off a little of the thyroid tissue. A safety hemostat is placed outside of the ligature. This is done for safety's sake so as to make doubly sure that no postoperative hemorrhage will take place. Another hemostat is placed outside of the Hist, then the upper pole is severed with scissors between the two hemostats just mentioned. The upper pole may be so thick as to necessitate several hemostats before it can be entirely severed from the body oi the gland. 472 OPERATIVE TECH NIC FOR THYROIDECTOMY 9. If one is a partisan of the systematic ligation of the inferior thy- roid artery, or if it has become evident from the nature of the goiter that this ligation must be undertaken, it is now the proper time to per- form it. On account of the reasons given in the chapter concerning ligations, it must be done far from the danger zone at the point of elec- tion, namely, just inwardly of the carotid sheath. (Plate XXI.) Fig. 80. — 1 he left lobe is then resected in a similar way as was the right. The picture, for clearness' sake, shows that the right lobe and isthmus have been separated from the body of the left lobe. In the ordinary technic of bilateral resection it is more elegant to leave the various portions of the thyroid in close relation one with another so as to remove them en bloc. 10. Starting at the upper part of the lobe and all along the external edge of the gland (Plate XXII), and progressing gradually inwardly toward the middle line, hemostats are placed first upon the glandular capsule and when this has been cut, upon the parenchyma itself and so on until the entire portion which was intended to be removed has been resected and until one has reached the isthmus. When resection reaches the lower pole, one or two small hemostats will take care of the little bundle of imae veins which are always present. No special effort is made in order to discover if a thyroid ima artery is present or not: the whole bundle of the imae vessels is clamped en bloc. PLATE XVIII Jltyty Thyroidectomy. W hen necessary the prethyroid muscles are divided at their superior ends after being clamped between two hemostats. IXCISIOX 473 This mode of removing the gland is known as the transfrontal resection. If one wishes to resort to the cuneiform resection, it is done in the way and manner described in Plates XI and XII. Whatever method is employed, great care should be taken to leave a thick enough portion of glandular tissue over the danger zone so as to protect the parathyroids, inferior laryngeal nerve (Plate XXIII) and to safeguard the patient against hypothyroidism. 11. What shall we do with the isthmus? Unless one has to be very economical with thyroid tissue, the isthmus had better be resected. If resection is undertaken, it is better to start the resection by its lower border at the junction of the isthmus and the lobe. When once the proper plane of cleavage between the isthmus and the trachea is found, the operation goes on easily. Resection may be either frontal or cuneiform. If one wishes to leave a thin strip of glandular tissue in front of the windpipe, he may do so (Plate XXIII); ordinarily, however, it is better to lay the trachea bare. 12. If the operation must be bilateral the technic just described for the removal of one lobe is applied in the same way for the other lobe which is to be removed. If the prelaryngeal muscles have not been severed before, they are then retracted, the goiter is luxated, its superior pole and if necessary the inferior thyroid artery are ligated and resec- tion is undertaken in the way just described (Fig. 80). Resection may take place either from the middle line toward the outside as shown in the figure or vice versa. I prefer to resect from outside inside. Here, too, enough gland should be left in order to protect the parathyroids, the inferior laryngeal nerve, and to form with the portion left on the other side a regular contour of the neck. 13. The pyramidal process is dissected out from below above up to its terminal point. One should always be sure to remove it all, other- wise compensator)- hypertrophy will take place later on in it, and give rise to an unpleasant deformity of the neck. 14. As a general principle the thyroid gland should not be removed piecemeal. It is far more elegant to resect it in bloc, its two lobes, isthmus and pyramidal process being still in connection one with the other so as to form a whole. 15. Fresh, sterilized towels are put all over the soiled ones and care- ful ligatures of whatever has been clamped are undertaken. I admit that it is sometimes tedious work, bur it is the only way to prevent secondary oozing. And even then one cannot always guard against that. Before removing the safety hemostat on the superior thyroid artery, another safety ligation should be performed so as to avoid a secondary arterial hemorrhage. Sometimes, indeed, the first polar liga- tion does not hold, or the knot is apt to slip, hence the necessity for another safety ligature. 474 OPERATIVE TECHNIC FOR THYROIDECTOMY 16. A careful exploration of the upper mediastinum is made for thymus hyperplasia. If such hyperplasia is found to be present, thymec- tomy is performed. Description of the technic for this operation will be found in the chapter on Thymectomy. 17. When hemostasis has been complete, and only then, 15 minims of a 1 : 1000 adrenalin solution are given subcutaneously, in order to obtain vasoconstriction of the bloodvessels and thus to diminish the chances of postoperative oozing. When there is a parenchymatous oozing difficult to control, packing of the wound for a minute or two with verv hot compresses proves to be very effective. Fig. 81. — The prethyroid muscles are then sewed together by a continuous running suture which is preferable to the interrupted one shown in the picture. 18. The prethyroid muscles are then sewed up at their upper end and in the middle line by continuous suture so as to restore the normal anatomy of the neck (Fig. 81). The necessity of sewing them is not an absolute one; probably more often than is expected the sutures do not hold; yet this seems to have no ill effect upon the cosmetic aspect of the neck. Some surgeons, Riedel for instance, do not sew them up at all. This procedure, however, is not anatomical and should not be recommended. PLATE XX W VGu Thyroidectomy. The surgical space is then fully enlarged and the surgical capsule is retracted as far back as necessary, keeping in mind that it should nor be retracted too fai into the danger zone. The glandular capsule is thus fullv e . > »s I. PLATE XXI ^^ a"? * Thyroidectomy. Showing how far back it is safe to retract the surgical capsule and where the ligation of the inferior thytoid artery should be performed m order to avoid injury of the inferior laryngeal nerve and the parathyroids. OPERATIOX FOR INTRATHORACIC GOITER 475 19. In the majority of cases drainage is not necessary. If, however, a drain is to be inserted, it must be done before entirely closing up the muscular belt in order to put the end of the drain in its proper position so as to avoid pressure on the windpipe or scratching of the raw surface of the thyroid which might cause hemorrhage. Following Kocher's example, I use exclusively a glass drain in thyroid surgery. There is no need of a special opening for that drain. Drainage through the incision as shown bv Fig. 82 gives the best results. • Fig. 82. — Intradermic suture is then performed. The picture shows where the glass drain, when used, should be inserted. 20. The platysma myoides muscle is sewed up by itself with a con- tinuous suture. (Plate XXV.) This is done in order to avoid later on the spreading of the scar due to traction of this muscle upon the edges of the wound. 21. Intradermic suture of the skin is then made (Fig. 82). OPERATION FOR INTRATHORACIC GOITER. The operation is difficult and requires much technical experience and thorough anatomical knowledge. A low-collar incision is made in the same way and position as for any operation for goiter. The p re- thyroid muscles are divided in the middle line and at both upper ends. The most important thing in such an operation is to free the cervi- cal portion of the goiter as completclv as possible from every connection with the other organs before undertaking the removal of the goiter; consequently the upper pole must be ligated and cut. The lobe to be removed must be resected as far down as possible, the hemostasis must be complete before attempting to remove the intrathoracic portion of the goiter. When once freed from its connection with 476 OPERATIVE TECH NIC FOR THYROIDECTOMY the other organs this cervical portion is used as a tractor to pull the intrathoracic portion of the goiter upward. It is oftentimes the only hold which we can have on the intrathoracic portion, consequently, every precaution should be taken to preserve such connection. At this stage of the operation, it is often possible to pass a finger or two around the lower pole of the goiter and to dislocate it upward. If it is not pos- sible to do so, then the goiter is pulled upward by its cervical portion, slowly, gradually, carefully, each vessel coming in contact with the capsule of the goiter, being clamped securely. It is safer to ligate at once the vessels in contact with the lower portion of the goiter, because otherwise, if ligation is done only after removal of the goiter, the raw surface in which the goiter was imbedded is aspirated again into the thoracic cavity, then ligation becomes extremely difficult and may give rise to tremendous hemorrhages. When the intrathoracic goiter has no cervical portion, and when there is no hold to pull, the goiter is seized with the special forceps devised by Kocher. In intrathoracic goiter surgery, the critical time of the operation is the moment when the goiter is fished out of the thorax and passes the so-called "critical space," namely, the superior opening of the thorax. At that time alarming hemorrhages and choking of the patient may occur. Blood sometimes gushes up in streams as from a deep well and may be due to injury to one of the large veins, the internal jugular, the subclavian, or the innominate. Suffocation is due to the fact that the goiter in passing the superior opening of the thorax flattens the wind- pipe. It is often necessary to replace the goiter in the thorax in order to allow the patient to breathe again. This may have to be done several times during the surgical procedure until the goiter has passed the "critical point," namely, the superior opening of the thorax. The intrathoracic goiter may be so large that it is impossible to pull it through the superior opening of the thorax. If we have to deal with a cyst the difficulty is easily turned. The cyst is punctured and its contents aspirated. If the tumor is solid then the method known as "evidement" or "morcellement" used in bone surgery or in fibroid of the uterus can be successfully applied here, too. One finger goes firmly through the tumor and shells it out piecemeal. Then when the goiter in toto has been so reduced in size as to pass the superior opening of the thorax, it is pulled out of the thoracic cavity. In intrathoracic goiter, drainage is indicated because there is a large, dead space located at the lower end of the wound, consequently this cavity is bound to fill up with blood. No packing should be left in, unless hemorrhage should be abundant and cannot be controlled. Intrathoracic goiter surgery is one of the most thrilling there is. If one is seeking surgical emotion, it is surely in that field that he will find what he is looking for. PLATE XXII A^ Thyroidectomy. Ligation of the upper pole is performed, the goiter is dislocated forward and a trans- glandular resection is being made, starring along the lateral surface of the goiter until the lower pole is reached. PLATE XXIII Thyroidectomy. The right lobe is then totally resected and so is a portion of the isthmus. The figure here shows that a little strip of the posterior portion of the isthmus has been left in situ. This, however, is not at all necessary. Usually the trachea is left bare. TECH NIC OF OPERATIONS FOR MALIGNANT GOITERS 477 TECHNIC OF OPERATIONS FOR MALIGNANT GOITERS. For this class of tumors it is impossible to set down hard-and-fast rules. The technic will vary with the development of the malignant tumor. In the great majority of cases a malignant goiter develops from a preexisting simple goiter. For a certain period of time the growth remains intraglandular, leaving the capsule entirely free. If one is fortunate enough to meet with such cases the technic will not be more difficult than in any ordinary goiter. The only thing to do is to perform a total unilateral or bilateral excision as the case may be. Postopera- tive hypothyroidism should be a secondary consideration, since we know that cachexia strumipriva occurs only once out of two or three cases of complete thyroidectomy. At any rate we have not the choice. If symptoms of hypothyroidism develop, thyroid opotherapy will remedy such complications Tetany may develop, too, but can be successfully met with our modern methods of treatment. Unfortunately, in the greatest number of instances the surgeon sees such cases only when the growth has already invaded the capsule and the neighboring tissues, as the trachea, esophagus, large bloodvessels, and the nerves. In such conditions complete removal of the tumor is impossible: operation, if at all performed, can be only palliative. CHAPTER XLII. OPERATIVE ACCIDENTS. Lesions of the Nerves. — Injuries to the inferior laryngeal nerves were extremely frequent when total thyroidectomies were performed and when the technic of goiter operation had not reached its present state of development. Billroth, for instance, in 71 extirpations of goiter had 23 partial or complete paralyses of the larynx. In 1885 Jenkowsky in 100 goiter operations observed paralysis of the vocal cords 14 times. Today these accidents are rare and with good technic should not occur. Injury to the inferior laryngeal nerve is most liable to occur: 1. When the inferior thyroid artery is ligated; hence the indication to perform the operation far from the thyroid, namely, on the inner border of the carotid sheath. 2. When resecting the gland; hence the indication to leave a thick layer of glandular tissue in connection with the posterior capsule. If these two requirements are observed there should be no direct injury to the inferior laryngeal nerves. It must be said, however, that a temporary, and even a permanent, paralysis of the vocal cords has been observed even when no direct injury whatsoever to the inferior laryngeal nerve was done. Wolfler found 12 of such cases. Paralysis in such cases is due, either to formation of connective tissue around the inferior laryngeal nerve, or is associated with a previous paretic condi- tion of the vocal cords, caused by the goiter itself. Hence the indica- tion never to forget to make a laryngoscopic examination of patients affected with goiter, as such a systematic examination will not only reveal unsuspected paretic or paralytic conditions of the cords, but will also be a protection to the surgeon since it enables him to warn the patient that a hoarseness or even temporary loss of voice may follow the operation. Bilateral injury of the inferior laryngeal nerves is not common. In 1890 Wolfler reported 6 of such cases. Four times death occurred from aspirative pneumonia. Injury to one of the inferior laryngeal nerves is of good prognosis. If the nerve has been accidentally resected or pinched in a ligature, its continuity is never reestablished, although the patient will in time recover his voice on account of the compensatory swinging over of the other cord. Phonation will in time become so improved that the patient is unaware of any change. Leischner collected 67 cases of postoperative Thyroiclee corny. \ u\v of the field of operation after bilateral resection has been performed. As stated before, a small strip of glandular tissue representin» the isthmus is usually not present. PLATE XXV 11 f^'V Thyroidectomy. The platysma myoides muscle is sewed up by itself by a continuous running suture. SUFFOCATION AND COLLAPSE OF THE TRACHEA 479 troubles of varying degree due to the injuries mentioned. In 4 cases there was paralysis of both cords; 6 cases of unilateral paralysis; 35 cases of unilateral paresis; 19 cases of slight unilateral paresis; and 3 cases of slight bilateral paresis. The final results in these cases, as to the return of the vocal function, were as follows: Of the 4 cases of bilat- eral paralysis, 2 patients regained normal voice and 2 remained very hoarse. Of the 6 cases of unilateral paralysis, 3 patients regained their voices, 2 remained hoarse and 1 was hoarse occasionally. Of the 19 cases of unilateral paresis of slight degree, 17 regained their voices and 2 remained hoarse. Of the 3 cases of bilateral paresis, the voices became normal. Of the 35 cases of unilateral paresis, 22 regained their voices, 2 remained hoarse, and 4 were hoarse occasionally. Many authors have reported cases of vocal disturbances existing before the operation which disappeared very soon after goiter had been removed. In such conditions the disturbances are caused by a simple irritation of the recurrent nerve on account of pressure. As soon as the goiter has been removed, pressure ceases, hence restitutio ad integrum of the nervous function. In other conditions the vocal disturbances are caused by a congestive condition of the larynx, caused by pressure from the goiter on the laryngotracheal tube. There, again, as soon as the goiter is removed, compression disturbances and congestion cease, while the vocal cords return to their normal condition, and consequently to their normal function. Injuries of the superior laryngeal nerve are infrequent. Injuries of the phrenic and sympathetic nerves may occur only in malignant goi- ters. Injury of the hypoglossus may accidentally occur in large goiters extending high up into the submaxillary region. Injury to the vagus nerve occurs frequently during removal of malignant goiters. Not so uncommonly the nerve must be cut away with the tumor. Usually the division or resection of the vagus is harmless. Its irritation, however, through stretching or pinching with a liemostat, is far more serious, since it may lead to diminished cardiac action, lowered blood-pressure, dyspnea, and even collapse and death. Suffocation and Collapse of the Trachea. One of the most dramatic accidents which may occur during goiter operation is suffocation. It is found mostly in connection with partially or totally intrathoracic goi- ters. It is due to occlusion of the windpipe, either because the trachea is compressed by the tumor when passing the superior opening oi the thorax, or because the displacement and compression of the windpipe arc exaggerated during the operative maneuvers. And strange as it may stem, suffocation mav occur even after the goiter has been entirely removed. At first this seems paradoxical. We have seen, however, that in long-standing goiters pressure causes atrophy <>l the tracheal 480 OPERATIVE ACCIDENTS walls; they consequently become soft and pliable. While the goiter is present it acts as a splint and supports the weakened portion of the trachea. But suppose we remove the goiter. No longer reinforced by the goiter and having lost their normal elasticity the walls of the trachea are sucked in with each inspiration. The more violent the efforts at each inspiration, the more complete will be the occlusion, because the atrophied walls are drawn into the tracheal lumen like a valve, and as mechanical obstruction of the windpipe is always accompanied by catarrh and edema of the laryngeal and tracheal mucous membrane, the lumen of the trachea available for respiration consequently becomes utterly insufficient. If the operation is performed under local anes- thesia, the patient will soon protest in such a way that the surgeon is bound to know that something is radically wrong. Even if general anesthesia is used, and if the accident happens during the operation, the surgeon will soon locate the trouble. But if the accident happens after the operation is over, if the surgeon has not noticed during operation the condition of the trachea, and if he is not aware that such an accident is possible, he will think that he is confronted with a case of cardiac collapse, of thymic hyperplasia, or will incrimi- nate the anesthetic. In the meantime the life of the patient will be fast slipping away. If suffocation takes place during the passage of the goiter through the superior opening of the thorax during the act of fishing it out of the mediastinal space, and if luxation cannot take place very quickly, as already stated, it is better to push the goiter back again into its former place in order to relieve pressure. This may have to be done several times until the goiter has been sufficiently loosened from the surrounding structures and removed. In some other instances luxation must, on the contrary, be completed very quickly, as suffocation will cease only when this luxation is complete. If suffocation is due to an aspirative collapse of the tracheal walls on account of their atrophy, the case is a little more difficult to handle. The ordinary tubes for larynx intubation are of no value because the obstruction lies lower than these tubes can reach. Catheterism of the trachea with catheters used for intratracheal insufflation are the only ones which can be useful. They may be left in situ until the walls of the trachea have become self-supporting. The best plan, however, which has proved successful with other surgeons and myself is to pass at the time of the operation one or two threads through the collapsing walls and to suture them to the muscular belt, with just enough tension to maintain the collapsing walls far apart, but not so as to tear the suture through. The head should then be immobilized so as to set the cervical muscles at rest. The threads will AIR EMBOLISM 481 hold just long enough to allow the trachea to become adherent in its new position to the neighboring tissues, and consequently to prevent any further collapse. As a means of last resort there remains tracheotomy. It is really impossible to set down hard-and-set rules for each case. The surgeon himself must decide at the time what is really best to do in each given condition. In that critical moment the decision, experi- ence and skill of the surgeon will be the best assets to guard the patient against death. Injury to the Trachea, Esophagus and Pleura. — In non-malignant goiters, accidental injury of the trachea and esophagus practically never occurs. If it does, it must be charged to an error in technic. In malig- nant goiters, however, which have grown adherent to the esophagus and trachea, partial resection of the latter organs may have to be deliber- ately undertaken. In strumitis such a resection is not warranted. Injun' to the pleural membrane is very rare and occurs in conjunc- tion with removal of intrathoracic goiters. Tracheotomy. While starting out to operate a goiter a surgeon may be called upon to perform a tracheotomy in patients choking on account of pressure from goiter. In order to be successful the operation must be methodical, and at the same time very rapidly done. It is not always an easy matter to open the trachea while a patient is choking to death, while there is an intense congestion of the entire cervical region, while a large goiter prevents getting at the windpipe quickly, and while the trachea is so displaced and compressed that the anatomical landmarks are completely disturbed. And indeed it is not enough to open the wind- pipe, but the cannula introduced into the trachea must be long enough to pass the stenosis. This is not always the case, as compression may take place low down in the thorax. Our ordinary cannulas in such cases are not always long enough to reach the stenotic point, hence the necessity of always having longer cannulas provided for emergencies. Such have been devised by several authors especially Verneuil, K6mg, Poncet, etc. Air Embolism. One of the greatest dangers connected with injury of the venous trunks in goiter operations is air embolism. In ordinary condi- tions the thinness of the walls of the veins and their natural tendency to collapse makes air embolism quite unlikely. However, in goiters complicated with strumitis or malignant degeneration, air embolism is very apt to occur, because the veins being adherent cannot collapse. The only time that I have met with such an accident was while removing a malignant goiter. Here the subclavian was adherent to the tumor and was inadvertently injured. Before I succeeded in locating tht- bleeding vessel and clamping it, enough air had been aspirated into the circulatory system so that death followed two days after without the patient having regained consciousness. 31 CHAPTER XLIII SYMPATHECTOMY. Thinking that Graves' disease was due to a neurosis of the sympa- thetic system, Jaboulay sought to cure it by performing sympathec- tomy. The first operation was done by him on February 8, 1896. Jonnesco and Abadie at once adopted the same method of treat- ment and two years later, Jonnesco was able to report 10 cases of sympa- thectomy with 6 complete cures, 4 improvements, and no deaths. From that time on the operation was performed by a great number of surgeons until 1900 when it gradually fell into disrepute. In 1899 Garre per- formed a bilateral resection of the sympathetic nerve in a patient who had already undergone thyroidectomy. In this case the exophthalmos was so marked that ulceration of the cornea followed, the resection of the sympathetic remained without any effect. In 1902 Ballacescu and Jonnesco advocated a complete resection of the cervical sympathetic nerve including the superior, middle and inferior ganglia. In 1908 Kocher had intervened only three times on the cervical sympathetic with 1 success, 1 failure and 1 death. Landstrom combined in one case thyroidectomy with sympathectomy and obtained a complete cure. In England and America the same disregard for the operation is observed. Curtis performed it 7 times and gave it up as a dangerous operation because he had 3 deaths out of the 7 cases. In 1910 Jonnesco reported 30 operations for Basedow's disease without death. Twice he performed a resection of the superior and middle ganglia and 16 times a cervicothoracic sympathectomy, thus resecting entirely the cervical trunk including the superior, middle, and inferior ganglia. For the time being, only two surgeons, Jaboulay and Jonnesco, have remained true to that method of operation. The most complete statistics we have on that subject are those given by A. Charlier; they refer to the material taken from the clinic of Jaboulay from 1896 to 1910. Jaboulay performed sympathectomy in 31 cases, 23 women and 8 men. In 1 case bilateral elongation only of the nerve was performed. In 9 cases the mere division of the nerve, namely, sympatheticotomy was performed, twice unilaterally and 7 times bilater- ally. In the remaining 21 cases, resection, namely, partial sympathectomy including the resection of the superior ganglion was performed; 4 times the operation was unilateral and 17 times bilateral; twice only the removal of the middle ganglion was added to it. Four of these cases had already undergone thyroidectomy without results; 3 of these sym- IMMEDIATE RESULTS OF THE OPERATION 483 pathectomized cases had to undergo a subsequent thyroidectomy on account of failure of the sympathectomy to bring about relief. Out of the 31 cases of Jaboulay's 6 died, thus giving a death-rate of 19.35 per cent. One patient died from thymus hyperplasia. The immediate post- operative course, according to Charlier, was, as a rule, very benign — some fever, some dysphagia, were about all. There was often, however, a complication which seemed to threaten the life of the patient, namely, bronchopneumonia. Four out of the 6 cases of Jaboulay's statistics died on account ot pulmonary complications. A very severe hyper- thyroidism may follow the operation, as in Duret's experience. Pathology. — The morphological nature of the sympathetic is exceed- ingly variable; it is consequently difficult to know what is pathological or what is not. In some instances the ganglia, as observed by Herbert, Eulenberg, Guttman, Reith, Moore, especially the superior, are materi- ally increased in size, congested and red. Jaboulav noticed very fre- quently an increased vascularization of the whole sympathetic. The microscopic examination, made by various authors, of the sympa- thetic ganglia and cord taken on the whole does not reveal any micro- scopic changes. On the other hand, L. B. Wilson found definite histological changes in the cells of the cervical sympathetic ganglia in exophthalmic goiter. These histological changes consisted of various stages of degeneration, namely, (1) hyperchromatization, (2) hyperpig- mentation, (3) chromatolvsis, and (4) atrophy, or (5) granular degenera- tion of the nerve cells. So far as could be determined from the small number of observa- tions, the pathological changes in the cervical sympathetic ganglia were parallel to the stage and intensity of the symptoms of hyperthyroidism and to the hyperplastic and regressive changes in the thyroid. The fact that the exophthalmos retrocedes so quickly has been interpreted as due to the vasoconstriction of the vessels of the orbit. I his, however, cannot be the case because we know that sec- tion of the sympathetic causes a vasodilatation, as is shown by the con- gestion of the veins of the conjunctiva and the retina, caused by the vasodilatation of the retrobulbar vessels. Consequently, if the inter- pretation given were correct, instead of a diminished, we should have an increased exophthalmos. Immediate Results of the Operation. One of the most constant and most noticeable results is the diminution or disappearance of exoph- thalmos. I his feature is sometimes noticeable on the operating table. It is very likely due to the paralysis of the unstriped musculature of the orbit, especially Landstrom's muscle. At the same time there is a marked diminution of the widening of the palpebral fissure- due to the paralysis of Midler's muscle; the pupils become more contracted. An exaggerated secretion of the lachrymal glands lasting only a few 484 5 ] MPA THECTOM V days is sometimes seen. Jaboulay has observed that a sympathectomy has a peculiar and remarkable influence on certain cases of near-sighted- ness. It causes a remarkable improvement of vision, the distant vision especially showing such benefit. Jaboulay believes that this is due to the fact that the eyes sink back into the orbital cavity and become smaller as the result of sympathectomy. He bases his contention upon the fact that the more one is near-sighted, the larger and more protruding are the eyes. Everyone seems to agree that when sympathectomy is successful the subjective symptoms of the patient show a considerable improvement. He becomes more quiet, less impressionable, less agitated, tremor dimin- ishes; tachycardia, however, is little influenced or not at all, and the same is true for the goiter. In conclusion it may be said that the results obtained from sympa- thectomy when present are very immediate. The ocular symptoms are the ones most happily influenced by the operation; the others such as nervousness, tachycardia, and goiter, are problematical. Remote Results. — In going over the cases operated bv Jaboulav as far back as twelve and fourteen years, A. Charlier was able to find that a number of his patients had been cured completely. He was able to retrace 1 8 out of the 31 cases operated by Jaboulay from four to fourteen years be- fore. Three of them were completely cured, 9 of them were so ameliorated that the subjective cure was a complete one, the objective cure, how- ever, being incomplete; the 6 remaining cases were doubtful. All these patients experienced considerable benefit to their nervous symptoms; in all exophthalmos had either disappeared or subsided; vision was improved and no trophic disturbances of any sort followed as the result of sympathectomy. The cardiac disturbances and goiter were the symp- toms less influenced and the ones in which the improvement showed less. The impression one gains in going over the literature on this subject is that failures and relapses seem to be quite frequent with this method. Choice of Operation. — The results observed by Jaboulav seem to be more or less the same no matter whether sympathectomy, or svmpa- theticotomy, or simple elongation of the sympathetic has been done. This is a very important point to note since it follows that extensive operations upon the sympathetic, as for instance, complete removal of its cervical portion including the superior, middle and inferior ganglia, as advocated by Jonnesco, are not only most laborious, most difficult, and most prolonged operations, but would also appear to be unneces- sary surgical risks. The simple unilateral partial sympathectomy gives sometimes about as good results as the bilateral, yet the maximum of effect is obtained solely by bilateral intervention. The age and sex of the patients seem to be of no particular importance since the results are PLATE XXVI Infernal jugular vein Superior tKyroid vesse Sympathectomy. * ■ - SURGICAL TECHXIC FOR SYMPATHECTOMY 485 the same for young or old, for men or women. The operation upon the sympathetic is especially successful in cases of Basedow's disease where exophthalmos is very marked and where little or no goiter is present. Here, too, the sooner the operation is performed, the better the results will be. Surgical Technic for Sympathectomy. — The preparatory treatment of the patient for operation is absolutely the same as for any other thyroid operation. When once it is admitted that an extensive operation involv- ing the entire cervicothoracic trunk of the sympathetic does not give better results than simple partial resection, then this latter operation must be considered as the method of choice. The location of the incision will depend upon the following condi- tions: if sympathectomy is going to be the only surgical act, and is not to be combined at the time of the operation or later with thyroidectomy, then the incision is better made parallel to the anterior border of the sternocleidomastoid muscle, the middle of the incision being located at about the level of the upper border of the thyroid cartilage. (Plate XXVI.) If, however, sympathectomy must be combined either at the time of the operation with thyroidectomy or thymectomy, then the incision had better be the usual transverse or low-collar one, adopted for thyroidectomy. Through the latter incision it is possible, not only to remove the thyroid and the thymus, but also to ligate the inferior thyroid artery and to remove the sympathetic which lies, as a rule, just behind the inferior thyroid. If the lateral incision is made, ligation of the upper pole (Plate XXVI) can be made at the same time as shown by Mayo. The sternocleidomastoid muscle is reclined laterally. The same is done with the carotid sheath after, however, having located the vagus nerve. The thyroid gland and the thyroid cartilage are reclined inwardly. (Plate XXVI.) When trying to locate the sympathetic it is well to remember that it lies just behind the carotid sheath on the prevertebral fascia covering the rectus capitis anticus major and the longus colli muscles about one-halt centimeter inwardly of the transverse processus of the cervical vertebrae. Chassaignac's tubercle, or transverse process of the sixth cervical vertebra, is a good landmark when locating the sympathetic and its middle ganglion in the region of the inferior thyroid. The carotid sheath does not fuse intimately with the cellular atmosphere sin rounding the sympathetic, hence the possibility of reclining the carotid sheath laterally, thus leaving the sympathetic exposed and in inti- mate contact with the prevertebral fascia. It sometimes happens that the sympathetic trunk is not found. In that case it is well to release the carotid sheath from the retractor, as it sometimes happens that in Helm- ing the vascular sheath the sympathetic follows. I his is not frequent, 486 SYMPATHECTOMY however. The operation is sometimes made more difficult by the pres- ence of hyperplastic lymph nodes more or less adherent to the carotid sheath; in that case the lymph nodes must be removed before access can be had to the sympathetic. Superioi- cervicaL Kiddle cervicci! ganglion Inferior cervical ganglion In\ev\ov "fWoid. arter-y_ Fig. 83. — Relation of the sympathetic to the surrounding structures. Note the inferior thyroid artery passing between some of the sympathetic fillets. Note, too, the position of the middle cervical ganglion. As a rule the sympathetic lies directly behind and slightly inward from the vagus nerve (Fig. 83). It must be, as already said, an absolute rule never to resect the sympathetic without first having exposed, or at least located, the vagus nerve. When once located, the sympathetic is followed as far up and down as possible, and then resected. If the superior and middle ganglion, or one of them only, can be resected at the same time, that should be done. The removal of the inferior sympathetic ganglion is a delicate opera- tion, inasmuch as it lies in the upper part of the mediastinal space, is of very difficult access, and is surrounded by a number of very important organs. CHAPTER XLIV. CANTHORRAPHY. In some patients despite thyroidectomy and sympathectomy, exoph- thalmos remains unaffected and becomes a source of trouble and great annoyance to the patient. Such patients are sometimes greatly bene- fited by a canthorraphy. This consists in scalping the edge of both lids from a quarter to a third of an inch at the outer canthus and sewing the denuded marginal portions of the lids. CHAPTER XLV. BOILING-WATER INJECTIONS. Boiling-water injections into the thyroid gland for hyperthyroidism have been devised lately by M. F. Porter. This method is based upon the old principle which is at the base of any injection method, namely, to destroy a portion of the parenchyma. We have seen in the chapter devoted to injection methods for simple goiter, that almost any medica- ment has been used. M. F. Porter uses boiling water, which is less irritative and just as effective as any other means for bringing about degeneration of the parenchyma and the formation of connective tissue instead. It has the same advantages and disadvantages of all the injec- tion methods. It is of simple application and reduces the surgical shock to a minimum, yet Babcock had I death from acute hyperthyroidism, and Mavo, 2 deaths. The method is not devoid of danger because injec- tion may be made erroneously intravenous. As sloughing and subsequent infection have occasionally been the results of injection methods, it is reasonable to assume that this may be the same for the boiling-water method, although accidents have not yet happened in Porter's experi- ence. It is difficult to judge how much parenchyma is being destroyed, and the method has furthermore the disadvantage of converting tin- thyroid into a more or less great mass of connective tissue, thus exposing the patient later on to respiratory disturbances on account of compres- sion of the trachea. I can recall a case of parenchymatous goiter which had been treated by medicamentous injections, and in winch just such a complication occurred. The patient finally had to be operated in order to relieve the pressure symptoms. The method, however, lias its clear indications and ma\ be oi gnat 488 BOILING-WATER INJECTIONS value in preparing for subsequent operations, patients who, for the time being, are too bad surgical risks. Personally, however, I have never used it. In Porter's and Babcock's judgments, this simple opera- tion can very well be compared to ligation so far as its efficacy is concerned. The technic of the operation as given by Porter is as follows. Technic. — "An all-glass syringe of 10 c.c. to 20 c.c. capacity is best. The greater the capacity of the syringe the longer the heat of the water is retained. The needle should be long, flexible, and rather fine. The syringe is boiled with the water over a gas or alcohol flame by the side of the table or bed on which the patient is lying. After proper cleansing the areas to be injected are infiltrated with 1 per cent, novocain. The filled syringe is removed from the water, which is actually boiling, and the injection quickly made. From 5 to 20 c.c. are injected, according to the size of the lobe. By partially withdrawing the needle and reinserting it, contiguous areas may be injected through one puncture. Dr. Babcock has made injections in his office, but thinks, as I do, that this is not to be commended. I prefer to have the patients remain quiet for one-half or one hour after the injection is made. The needle punctures are covered with gauze wrung out of alcohol for a couple of hours. Sloughing has never occurred, and the small eschars on the skin produced by the needle are not permanent. The needle should penetrate the skin as nearly as possible at right angles in order to reduce the burning to a minimum. I have been in the habit of hand- ling the syringe with the aid of forceps and gauze, but in the future I shall use Babcock's method which is better. He wears three pairs of gloves: first, a pair of rubber gloves covered with thick cotton gloves, and over all a pair of rubber gloves. Most patients complain immedi- ately after the injection of a feeling of fulness in the goiter and some pain in the occiput, but the discomfort is really trifling. The injections are to be repeated until the desired effect is attained. If one is using the treatment preparatory to thyroidectomy then it is well to repeat the injections every two or three days, that is, if more than one is neces- sary; but if one has decided to try to effect a cure by this means, it will be better to wait a week to ten days before repeating the injections, as indicated above. While the improvement is usually marked within the first forty-eight hours, it does not reach the maximum for ten days to two weeks. It is better, especially in the large goiters, to inject two, three or more areas at one seance than to make the injections at intervals. Indeed, I may say that the tendency is, as experience grows, to make large and multiple injections at a single seance, rather than to make smaller and single injections and to repeat the seances. In some cases with small, ill-defined glands, it is better to make an injection through a small incision in the midline, done under local anesthesia, which will enable the operator to do the work under the guidance of the eve." CHAPTER XL VI. PREOPERATIVE TREATMENT OF THE PATIENT. When the patient is once in the hospital he is to be kept in bed and given rest. Unless there should be vital indication to do otherwise, not only is it an error, but it is criminal to operate a goiter patient without a treatment preparatory to operation. This preliminary treatment may last only a few days, or several weeks, just as the case mav be. The room must be well ventilated, the surroundings must be quiet and pleasant, everything must be done to gain the confidence of the patient and his cooperation. He must be induced to "make himself at home." Two or three hours a day he will be allowed to sit up in order to break the monotony of the rest cure. A few congenial visitors mav be admitted. I pon entering the hospital, if the bowels have not been regular, a mild laxative can be given. Subsequently cathartics must be given only if absolutely necessary. The traditional "cleaning of the bowels" the day before operation must be discarded. Ten to fifteen drops of Digalen Cloetta and 10 to 15 drops of tincture of strophanthus are given daily. In the majority of cases thev have a remarkable toni-cardiac effect. If not well tolerated thev should be discarded. If bromides, veronal, tnonal, baldrian are deemed necessary, they must be given. The last two days before operation the patient, especially if thvro- toxic, is given 150 grams of glucose and 5 to 10 grams of bicarbonate of soda as a preventative of postoperative acidosis. (See chapter on Acidosis.) The patient must be kept in absolute ignorance of the day and time when the operation is to take place. When he asks, "Doctor, when am I going to be operated upon":" he must be told jokingly, "That's none of your business." He is then told why. Menstruation is a contra-indication to operation, as the nervous sys- tem of these patients, especially the thyrotoxic ones, is often very much disturbed during the menstrual cycle. It is better to wait until that process is over. In thyrotoxic patients no surgical preparation ol the held <>t opera- twin is made until the patient is on tin- operating table. In simple, non- complicated goiters, three or tour hours prior to operation, tin field of operation may In- washed with soap and water, cleansed with ether and 490 PREOPERATIVE TREATMENT OF THE PATIENT alcohol and then protected with an aseptic dressing. This, however, is not necessary. Of late I do not resort any more to the preliminary surgical preparation. I found that simple preparation with iodin on the operat- ing table is just as satisfactory as when combined with preliminary washing with soap, water, ether and alcohol a few hours previously. The surplus of iodin is washed off with alcohol. When using iodin we must not forget that its disinfecting and penetrating power is far greater when used on dry skin than when used on a skin which has just been washed and cleansed. Hence the necessity of performing the preliminary washing with soap, water, alcohol and ether several hours before the operation, when one wants to resort to that method at all. Forty-five minutes before operation the patient is given f grain of pantopon and ytw grain scopalamin. (See chapter on Pantopon.) CHAPTER XL VI I. OPERATING ROOM TECHNIC. On the table the patient is put in the recumbent position with a hard, triangular pillow under his shoulders so as to overextend the head. The purpose of this is to make the neck as prominent as pos- sible and to put the thorax in a dependent position. It is advisable, if the operating table permits, to elevate the upper part of the trunk slightly and to lower the foot so as to obtain an oblique elevated posi- tion. This lessens the venous congestion of the upper part of the body and produces a certain degree of cerebral anemia, thus facilitating anesthesia and reducing the amount of anesthetic used. The field of operation is painted with iodin, and then washed with absolute alcohol. In thyrotoxic goiters, where one wants to avoid iodin intoxication, McDonald's solution answers the purpose very well. I have used it with entire satisfaction. Here is the author's formula: Acetone (commercial) 40 parts Denatured alcohol 60 " Pyxol 2 " The operative field is then isolated from surrounding parts with sterilized sheets. The Kocher screen for protecting the field of opera- tion from the mouth is absolutely necessary; no one can be morally certain of his asepsis without it. The hands of the operator, assistant and nurses are washed with hot water and soap for two or three minutes, dried, then immersed in iodin and washed with alcohol. There should be no need to say that according to modern views on asepsis, no surgeon who is really anxious to be thoroughly aseptic will approach the oper- ating table without having his arms protected up to the wrist with sterilized gowns, his hands fitted with sterilized gloves, and the mouth and head covered with some sterilized device. The same is true for his assistants and nurses. Only now after the above preparation shall the anesthesia be started. Inasmuch as I consider the anesthetic one of the greatest dangers in goiter surgery, I aim to reduce that danger to a minimum. 1 hat is the reason why I give the anesthesia at the last moment only, and cease it before the operation is terminated. In the greatest number of cases the element of excitement and fear during the ten to fifteen minutes during which the surgical preparation is being made prior to the anesthetic is 492 OPERATING ROOM TECH NIC negligible. That is, at least, my experience. If properly explained that it is done for his own benefit and safety, the patient readily consents to being anesthetized in the operating room. Moreover, the presence of the surgeon while the anesthetic is given is always a source of comfort to the patient, as usually he has implicit confidence in him, while he may not have the same amount in the anesthetist whom he does not know. As a general principle general anesthesia must be always light in goiter surgery. Since I adopted that mode of doing, after having tried everything else, my postoperative complications such as hyper- thyroidism, acidosis, etc., and my death-rate have been reduced con- siderably. The more severe the thyrotoxic case is, the stronger, in my judgment, is the indication to reduce the period and amount of anes- thesia to a minimum, or even to resort to local anesthesia. Before the present great war broke out, I used systematically, as advocated by Crile, the subcutaneous infiltration with novocain. Since, however, novocain remained for a long time unavailable, I have been compelled to do without it. To my great satisfaction, I have not noticed any effect for the worse in the postoperative welfare of my patients. In fact, I do not see any difference. Consequently I have given up the use of novocain infiltration in conjunction with general anesthesia. The suture material used is silk for ligation of the upper poles, and inferior thyroid arteries, and iodin catgut for ligatures and sutures. Silk is used on account of its non-resorbability. CHAPTER XLVIII. POSTOPERATIVE TREATMENT. As soon as the patient is brought back from the operating room a proctoclysis, 20 to 2^ drops a minute, is started. I use the following formula : Sodium chloride 6.0 Calcium chloride 1.0 Potassium chloride 0.3 Bicarbonate of soda 100. o Glucose i5°o Alcohol 20.0 Aq. dest iooo.o This proctoclysis is kept up for one or two hours and then stopped. A few hours after it may be repeated again. It is an excellent means to combat thirst, and furthermore has the great advantage of increasing the blood-pressure. Vomiting is present in a small percentage of cases, but is rarely so persistent as to require washing out of the stomach. Transient vomit- ing is rather an advantage since it clears not only the stomach, but also the tracheo-broncho-pulmonary apparatus. As soon as the patient wants it he may have cracked ice and water and just as often as he wants it, even if vomiting persists, since it will act as a stomach lavage. If, however, vomiting should remain too persistent fluids may then be withheld for a time. If the cardiac action is very rapid, ice-bag on the heart may be very beneficial. If the cardiac action becomes weak, if the blood-pressure falls, strophanthus, digalen, adrenalin, are given hypodermically. If symptoms of shock appear, the usual treatment for such a condition is instituted. Blood transfusion may even become necessary. If the patient is very restless, nervous, and suffers pain, then pantopon, codein, bromides, are used. If one fears hyperthyroidism or acidosis, then bicarbonate of soda, and glucose are resorted to, and the patient must be fed with fluid food as soon as possible even the same day of the operation. Twenty-four hours after, the drain, if any has been used, is removed. If, however, the blood is still fluid, it is better to leave the drain twenty- four hours longer. Forty-eight hours after the operation ;i cathartic is used, such as castor oil, salts, or citrate of magnesia. As soon as the bowels are well open, the patient is given solid food. The thread for intradermic suture is removed eight days after. CHAPTER XLIX ANESTHESIA. The ideal means of anesthesia for human surgery has not yet been found. In canine surgery, however, we can say that a sufficient amount of morphin injected subcutaneously is the ideal means to put the dogs under complete anesthesia. A few minutes after the subcutaneous injection has been made, a reflex vomiting usually takes place; then the dog quietly goes to sleep, and about one-half to one hour after, when the dose has been sufficient, the dog is so completely anesthetized and insensibility lasts so long, that any major operation can be performed without the slightest indication of pain or struggle. Even hours after the operation has been terminated, the influence of the narcotic may still be active. Then gradually and slowly the dog emerges from his artificial sleep. Only exceptionally we shall find dogs which seem refractory to the influence of morphin. No ill effects remain afterward. The dose of morphin required, varies of course with the weight of the dog, and its nervous temperament, but with a little experience, one can easily tell the amount of morphin which should be used. As a rule one to two grains is all that is necessary. Even very much larger doses of the drug are not fatal to dogs. The experience of Dr. Bromley of the Veterinary Department of the Ohio State University at Columbus, Ohio, proves this. Wishing to kill a dog, he administered to it a sub- cutaneous dose of several grains of morphin. When he left, the dog looked as if dead. Great was his surprise on the following morning when he came back, to find the dog gay and brisk. That day a new method for anesthetizing canines was discovered. The advantages of this method are too obvious: no need of an anesthetist, no fear of these alarming and spectacular respiratory or cardiac collapses which still too often occur with other means of anesthesia. During the entire artificial sleep the animal breathes regularly, and superficially, while the pulse remains good and strong all the way through. It is a delight. But unfortunately this method so well suited to the canine species cannot be applied to human beings. To be sure, once in a while I have met with patients so sensitive to pantopon-scopolamin anesthesia that a moderately large dose was absolutely sufficient to put them under complete and perfect general anesthesia, allowing me, for instance, to perform from start to finish the complete removal of an intrathoracic goiter without necessitating the help of any other drug. All that I can AXESTHESIA 495 say about it is that I have never operated under better conditions than in these cases. Unfortunately in the great majority of cases this method is insufficient. The amount of narcotic required to produce insensi- bility is so near the borderline of the fatal dose that to use it would jeopardize the life of the patient. Let us hope in the meantime that we may some day find a means to anesthetize our patients in a similar way with a drug just as effective as morphin, pantopon, etc., but deprived of their disadvantages and dangers. The ideal would be to find a means to induce general anesthesia with a safe, harmless medicament injected hypodermically. For the time being the two choice methods of anesthesia which we have at hand are: local anesthesia with novocain, and general anesthesia with chloroform, ether, and nitrous oxide. Which one of these methods should be given the preference in goiter surgery and especially in Base- dow's disease ? Should we use local anesthesia only or the general one ? And if we decide to use general anesthesia, to what drug should we give the preference, to chloroform, ether, or to nitrous oxide ? All these questions are by no means settled since the most prominent surgeons in this field are divided in their opinions. Kocher, Riedel, Mikulicz, Berg, Ackermann and others are of the opinion that general anesthesia is dangerous on account of its liability to cause asphyxia, bronchitis, pneumonia, cardiac collapse, etc. Indeed, they say how often during general anesthesia do we not see alarming states closely resembling death: suddenly respiration and heart action stop, the face becomes pale, livid or cyanotic, pupils become dilated, and for a few seconds, sometimes a minute, despite artificial respira- tion, traction of the tongue, rhythmic pressure over the thorax, etc., the function of the pulmonary and cardiac mechanism remains suspended. To be sure, life comes back but it does it slowly, and the patient's con- dition remains precarious throughout the operation. There can be no doubt that postoperative deaths in many instances would have been avoided if such cardiopulmonary accidents had not occurred. In Basedow's disease the majority of postoperative accidents arc- attrib- uted by these authors to general anesthesia. Riedel does not hesitate to charge general anesthesia with the majority of sudden deaths. Kocher attributes his low mortality to the use of local anesthesia. For these authors the superiority of local over general anesthesia is out of the question, not only so far as the mortality is concerned, bur also so far as postoperative complications are concerned. On the other hand, \Ia\o, Ilalstead, Curtis, (laiir, Ochsner, Crile and others believe that a well-conducted and well-handled general anesthesia is less apt to !><• followed In severe consequences than a local anesthesia. In fact, during the latter form of anesthesia, the ps\ chic 496 ANESTHESIA emotions and shock may be just as marked as with general anesthesia and their consequences just as disastrous. Certainly, real harm may be done to a patient by the mental strain and physical suffering while undergoing an operation without being unconscious. With local anes- thesia the operation must be done very slowly, much time must be lost in encouraging the patient, hence a prolonged operation and increased chances for surgical shock; in addition during operation, on account of the movements for defense made by the patient in order to escape pain, there is an increased venous hemorrhage. Furthermore, the veils, cries, and sometimes the insults which the patient pours out on the surgeon who is endeavoring to do his best, are very trying to the nervous system of the operator. For these reasons it will be easily understood why many surgeons prefer the use of general anes- thesia. There is therefore a matter of personal cohesion and there is certainly a great deal of truth in what Ochsner says, "The patient's con- fidence must be gained before the administration of local anesthesia, otherwise the patient will imagine he is suffering and this will be almost as much harm to him as actual pain. This is very largely a personal matter. Many surgeons have the full confidence of all their patients and for them it is not difficult to employ this method." Before drawing our own conclusions let us studv a little more fully the dangers connected with general anesthesia. When the fumes of ether or chloroform are impure, or when they are inhaled too abruptly, especially if the patient is a very nervous subject, reflex accidents may occur which may prove very alarming, sometimes fatal. They may occur even with the first inhalations of the drug. They are due to an abnormally intense reflex starting in the naso-pharyngo- laryngeal mucous membrane, even before the fumes have reached the pulmonary alveoli. We know experimentally that irritation of the nasal and laryngeal mucous membrane may cause a more or less marked diminution of the number of respirations and cardiac beats; it may even produce respiratory or cardiac collapses. The centripetal routes taken by these reflexes are the branches of the trigeminus and vagus nerves. The cardiac collapse is due to a centripetal reflex from the vagus nerve which, we know, is a moderator of the cardiac apparatus. This inhibition, however, would be only a temporal)' one if the bulbar moderator)' centers would not soon come into play and render the col- lapse permanent. The respirator)' collapse is due to a centripetal reflex from the trigeminus, resulting finally in an inhibition of the respiratory centers. When inhalation of the anesthetic takes place too rapidly there is at first an increased heart action which may reach I 50 to 200 beats, then the heart action diminishes and finally a cardiac collapse of bulbar AX EST H ESI A 497 origin may take place. When too much anesthetic is given paralysis of the respiratory centers takes place. Besides these alarming symptoms there are others of less importance but nevertheless very annoying to the patient, such as coughing, increased amount of saliva due to centrifugal reflexes through the chorda tym- pani and the lingual nerves, etc. All these reflexes, of course, take place mostly during the early period of anesthesia, because at that time the reflex power of the nervous centers is increased; at a later period they become greatly diminished or suppressed. General anesthesia with ether, chloroform, or nitrous oxide has other disadvantages. It is accompanied by a period of excitation which is very unpleasant for the patient and for the surgeon. Furthermore, it is followed either during or after the narcosis by vomiting. To sum up, the dangers connected with general anesthesia are more than one; to a great extent they can be eliminated if certain rules are followed. In order to avoid respiratory and cardiac collapses, the anes- thethic should be very pure: it should be given with extreme care, slowly, allowing plenty of air to be inhaled with the anesthetic agent. The excita- bility of the patient should be diminished by a preliminary dose of morphin, or better, pantopon, and scopolamin. Theoretically, a sufficient dose of atropin would be ideal, as this drug suppresses the physiological function of the cardiac moderator)' apparatus, and consequently sup- presses at the same time the risks of cardiac collapse. Unfortunately, this drug is too toxic and in order to be effective, the doses would have to be too large. But to return, a respirator)' collapse can be avoided with a careful watching of the course of the anesthesia and the patient. If it does happen, artificial respiration made in time will remedy the accident. The great advantage of general anesthesia, with volatile narcotics such as chloroform, ether, nitrous oxide, is that in case of necessity it can be stopped at will at any time. The patient himself is his best protection as he eliminates the poison with each respiration, whereas if the anesthetic drug is used hypodermically the drug injected cannot be withdrawn, the detoxication lasts a long time, and takes place only through the kidneys, intestines, etc. From all that has been said, it follows that it is impossible to sit down hard-and-rigid rules as to just what should be done m regard to anesthesia in goiter surgery. It would be ridiculous to proclaim ex cathedra that general anesthesia should be used, that local anesthesia should or should not be used, and vice versa. Here as well as in ;m\ other medical question there is a just milieu, a happy medium. On the other hand, there is no question, tor instance, that in patients with goiters of long standing and large size, with tracheal deformations, 32 498 ANESTHESIA spells of suffocation, chronic congestion of the entire respiratory appa- ratus, myocarditis, arrhythmia, marked dyspnea, general anesthesia is contra-indicated, as it would mean enormous risks for the patient. Con- sequently the surgeon and the patient should get together and consent, the one to perform the operation under increased difficulties, and the other to undergo the operation with a little more discomfort and pain. But fortunately the majority of patients with simple goiter are in good general health, their hearts are strong, their resistance as yet has not been impaired, and the goiter has not had time to do very much harm. Under such conditions it is really more satisfactory for everybody con- cerned to use general anesthesia rather than a local one. In Basedow patients profoundly thyrotoxic with a functionally insuf- ficient myocardium, kidneys, and liver, there is no doubt, too, that general anesthesia must be regarded as a great danger. Local anesthesia is the method of choice. It must be remembered that in such cases any surgical intervention, however small it may be, and no matter what form and nature of anesthesia, is dangerous; consequently, how to pro- ceed is a matter of surgical tact, experience, sound judgment, and per- haps to a certain extent, of personal preference. I firmly believe, how- ever, that a well-managed local anesthesia is better suited to these patients. In the other class of Basedow patients which are still safely surgical, a well-conducted general anesthesia carefully given and carefully watched, is the method to be chosen. In doubtful cases especially when local anesthesia cannot be employed on account of the extreme nervous condition of the patient, a mixed anesthesia can be used to great advan- tage in the following manner: a reasonable dose of pantopon-scopolamin is given one and one-half hours and repeated again one-half hour before operation; then the patient is brought into the operating room and prepared for operation. Only then general anesthesia is started, just enough to "slumber away" the patient. In the meantime the field is thoroughly infiltrated with 0.5 per cent, solution of novocain, a con- siderable quantity being used. The general anesthesia is stopped off and on; if necessary a few drops of ether are given. The patient is all the time half-awake but unconscious of pain. I think it is the safest way of handling these cases. Here, too, the great secret of success is to know how to proportion the surgical act to the condition of the patient. Too often, indeed, failures and misfortunes are charged to the anesthetic, when they recognize as the sole cause a lack of judgment and of experience on the part of the surgeon and an injudiciously per- formed operation, either because "the right thing has been done at the wrong time, or the wrong thing at the right time." Chloroform, Ether, or Nitrous Oxide? — If we resort to general anes- thesia, what drug shall we use? CHLOROFORM, ETHER, OR XITROUS OXIDE 499 It is now universally conceded that chloroform is a dangerous anesthetic agent. The statistics of Prof. C. Andrew, made in 1880 and based on 200,893 anesthesias, gives 1 death for 2723 anesthesias with chloroform. The record of Roger Williams, of Bartholomew's Hos- pital, London, gives 10 deaths out of 12,368 anesthesias with chloroform. Gurlt, out of 201,224 anesthesias found 88 cases of death. The average of these figures gives the round proportion of 1 death per 2000 anes- thesias with chloroform. Very likely this average is low, as probably a great many accidents were never reported. Chloroform is toxic for the blood, as it destroys a certain number of red cells and diminishes the activity of the white cells. It is very toxic, too, for the kidneys and liver: a temporary nephritis and hepatitis not infrequently are the sequelae of chloroform anesthesia; even a fulminating icterus in abso- lutely normal patients has been observed after chloroform anesthesia. Furthermore, it is profoundly toxic for the heart, and is an intense depressor of the blood-pressure. For all these reasons chloroform must be discarded in goiter surgery. For the time being the most popular drug, not only for thyroid surgery, but for any kind of surgery, is ether. It is the one used by such prominent surgeons as Mayo and Ochsner in America, and in Europe by Garre, Berard, and by Kocher when obliged to, in fact, by the great majority of American and European surgeons. It is the one to which I give preference. It is superior to all others in safety and range of application, its record for mortality being about 1 to 10,000. Nitrons oxide anesthesia is not practical enough to be safe. While in the hands of Crile it has so far given excellent results, its pre- paration and administration are so delicate that it has not entered into every-day use in surgery. We might even say, and I know that the same view is held by Crile, that unless very chemically pure and care- fully administered by an expert anesthetist, this means of anesthesia is a dangerous one. ''Enthusiastic writers," says Freeman Allen (he. cit.) y "cite the statistics of Teter, of Cleveland, and the tabulations of Crile" (Surgery, Gynecology and Obstetrics, 191 1, xiii, 170): 17,714 administrations by Teter of nitrous oxide without death show: 12,886 administrations lasted less than . 5 minutes 3.36s It 5 to 15 " 865 << 15 to 30 " 346 it 30 to 60 " 228 it i to 2 hours 22 «< 2 to 3 " 2 << 3 to 4 " 17.714 500 ANESTHESIA It is therefore evident that the majority of these administrations were for dentistry or other minor surgical procedures requiring brief inhala- tions, and not for major surgery. According to Freeman Allen, Thomas L. Bennet, of New York, is still of the opinion that (loc. cit.) "while he had no deaths, alarming states have several times appeared with such rapidity and so little warning that it seems probable that the general adoption of this form of anesthesia would lead to a mortality more nearly approximating if not exceeding that of chloroform and ether." Freeman Allen has, too, met with alarming states similar to those mentioned by Bennet {loc. cit.). "They occurred suddenly without any warning. The patient suddenly becomes livid, respiration fails, the pupils dilate, corneal reflexes become faint or absent." In the light of the above, Allen concludes "that gas and oxygen anesthesia is not the safest anesthetic method in major surgery and it would seem desir- able that exploiters of this method in citing statistics designed to show its safety should carefully separate the brief administrations required for dentistry and other minor surgery from the prolonged administra- tions for major surgery; otherwise no correct estimation as to its safety in the latter can be obtained." Undoubtedly, nitrous oxide has given entire satisfaction to Cnle so far. Nevertheless, so far the number of anesthesias for major surgery is not large enough to warrant definite judgment of the method. "The shortcomings of nitrous oxide anesthesia," says Crile (loc. cit.), are: "It is the most difficult anesthetic to administer; its effects are fleeting; there is an imperfect relaxation of the abdominal muscles; it is more expensive than ether, and there is more venous congestion. The anes- thetist must be an individual of the keenest perception of the precise condition of the patient at every moment, i. e., the anesthetist must be a delicate human recording apparatus." Charles K. Teter (Jour. Am. Med. Assn., Nov. 23, 1912, lix) says: "That nitrous oxide is contra-indicated in children under five years of age, in old people in whom arteriosclerosis is present. Nitrous oxide as an anesthetic is not ideal for major surgery in patients possessing a strong, vigorous constitution, or extremely nervous temperaments, or in those addicted to drug habits or the excessive use of tobacco. In other words, any patient who requires a large amount of general anes- thesia is not a good gas-oxygen subject for control, owing to the lighter form of anesthesia induced by nitrous oxide. The ideal patients for nitrous oxide and oxygen anesthesia are the very ill, the anemic, the debilitated, those possessing a low vitality from any cause, in short, all cases except those requiring a powerful anesthetic agent." In the light of the above we can conclude that nitrous oxide anes- thesia is not yet a practical method. We can even say that except in LOCAL ANESTHESIA 501 the hands of a very few as Cnle, Bloodgood, for instance, the method is dangerous. It is impossible for me to overlook the fact that in the practice of one of my colleagues, 3 cases of sudden death occurred under nitrous oxide anesthesia; yet the anesthetic was given by an expert anesthetist and for simple operations as appendicitis, hernia, etc. If we stop to think that these deaths occurred in a series of about 150 anes- thesias with nitrous oxide, we find the percentage of death to be about 2 per cent. Of course I am ready to admit that this might be only a coincidence. I am not trying in any way to discredit the method, but I am trying to remain objective. LOCAL ANESTHESIA. Cocain is still the most powerful among the local anesthetics, but its toxicity forbids its being used too freely. The drug of choice for local anesthesia for the time being is novocain. It possesses a far more superior anesthetizing power than stovain, tropocain, and about an equal power with cocain. On the other hand, novocain is twice less toxic than cocain. The injection of 0.5 per cent, solution hypodermicallv is slightly pain- ful if novocain is dissolved in simple water, but becomes absolutely painless if dissolved in normal salt solution. Anesthesia with novocain is complete eight to ten minutes after the injection has been made and is nearly always perfect in the injected area. It lasts about half an hour. The period of anesthesia may be prolonged by adding adrenalin to the novocain solution. The following formula is the one which gives the best results: Salt solution ... 100. o gms. Novocain .... 0.5 " Adrenalin 1:1000 25 drops. It a 2-c.c. syringe is used for injection, each syringe contains 0.01 gm. of novocain and one-half drop of solution of adrenalin 1 : 1000. This mixture of novocain-adrenalm possesses a powerful anesthetizing capacity which is about equal to that of cocain; its effects last about an hour. It is absolutely painless and while novocain alone has no effect upon the bloodvessels, the mixture, novocain-adrenalm, causes a pro- nounced vasoconstriction lasting several hours. The adjunction of adre- nalin does not increase the toxicity of the drug, consequently large doses of the solution can be used in the same patient. Chaput, using it for the removal of a cancer of the breast, went so far as to use 140 c.c. of 0.5 per cent, solution. No ill effects wen- observed. It must be always remembered that the mixture novocain-adrenalin, does not keep very long. // must he freshly prepared each time before using it. Inasmuch as a solution of novocain, just as that of adrenalin. 502 ANESTHESIA kept separately keeps perfectly for a long time, it is better to have both at hand always separately prepared and to mix them only just before the operation. The novocain solution can be sterilized at the autoclave without injuring its anesthetizing properties. So far as adrenalin is concerned, we have the choice between the adrenalin itself, which is extracted from the suprarenal bodies, and the one synthetically obtained and called suprarenin. Theoretically, supraremn offers greater advan- tages than adrenalin. Being synthetically prepared, it is always iden- tical with itself, consequently its properties are constant. Furthermore, it can be sterilized with impunity at the autoclave, whereas adrenalin is readily oxidized and when sterilized loses a great part of its proper- ties. The oxidation and consequently the deterioration of the solution are recognized by the fact that the solution becomes pink, then red and finally brown in color. Adrenalin chloride, however, which is an addi- tional product formed by the action of dilute hydrochloric acid upon adrenalin seems to be a quite stable product. When in ampoules, according to Rowe, it may be heated to the temperature of boiling water, and can be sterilized several times in succession without loss of activity. When exposed to the air, it may be sterilized twice without loss of activity. There are on the market small tablets of novocain and adrenalin already mixed in the desired proportions. These tablets, of course, are of the greatest convenience, but according to Piquand, they are far from- having the same anesthetizing power that is possessed by a mixture prepared on the spot just before the operation. Local anesthesia should never be employed unless the patient is lying down. If the injection is made in the sitting posture, collapse is liable to take place. This is not at all to be wondered at when we know that the injected solution of novocain-adrenahn does not exert its action locally only, but that to a certain extent, its influence extends to the entire organism. As adrenalin is one of the most powerful vasocon- strictive drugs, vasoconstriction takes place in the brain, producing cere- bral anemia, and hence collapse. If the patient is in the dorsal decubi- tus, the chances for collapse are less marked since the lying posture favors congestion of the brain. Before using local anesthesia it is pru- dent whenever it is possible to give a dose of pantopon and scopolamin half an hour before. Scopolamin, being a vasodilatator, is especially indicated in local anesthesia, as it more or less counter-balances the general effects of adrenalin. Technic of Local Anesthesia. — Although apparently simple, this technic requires skill and experience. When once the course of the future incision is decided upon, one of its ends, the nearest to the surgeon, is seized between the thumb and index finger of the left hand so as LOCAL ANESTHESIA 503 to form a thin, cutaneous fold which is then lifted. The fine needle of a syringe loaded with 0.5 per cent, solution of novocain-adrenalin is inserted into the derm of the skin and not in the subcutaneous tissue. A small quantity of the anesthetic is then forced into it. At once it forms a white bleb 1 cm. in diameter, which is the best proof that the injection is really intradermic. The needle is then pushed forward and while pushing, a continuous pressure upon the piston of the syringe forces continuously some of the anesthetic solution into the tissues, thus rendering the injection painless. Fig. 84. — Local anesthesia. I he picture shows a row of intradermic blehs along the line of future low-collar incision. The picture shows, furthermore, where the injection will have to be made in the prethyroid muscles after the two skin flaps have been retracted before undertaking their division. A well-managed local anesthesia should cause only at one time a little pain, and that is when the needle goes through the skin for the first time. Then the patient should be warned that he is going to teel a 504 ANESTHESIA pricking pain. In the subsequent injections, as the needle goes through the anesthetized area, no pain should be felt. These intradermic injec- Fig. 85. — Local anesthesia. Local anesthetic is injected into the whole field of operation in order to render anesthesia as perfect as possible. w/ Fig. 86. — 3 and 5 are made not only subcutaneously but also deeply behind the sterno- cleidomastoid muscle so as to reach the bulk of the superficial cervical plexus. tions are repeated until the entire line of the future incision forms a continuous row of blebs from one to two centimeters in width (Fig. 84). LOCAL AXESTHESIA 505 When once the site of the future incision has been thoroughly anes- thetized, subcutaneous injections of novocain-adrenalin are made along the same course. Then the anesthetizing solution is forced into the entire subcutaneous region above and below the incision, not only where the upper and lower flap will be dissected but also in the entire region neighboring on the field of operation (Figs. 85 and 86), as the sterno- cleidomastoid region, the thyroid cartilage region, etc. The more per- fect the infiltration of the cervical region with the anesthetizing solution, the less will be felt the pain during operative manipulations. FlG. 87. — Local anesthesia. Showing how and where to inject the local anesthetic in order to fully anesthetize the deep tissues. Eight or ten minutes should elapse before cutting is done. Only then the incision and the preparation of the upper and lower flaps can be made without pain. The Upper and lower Maps being retracted, the cervical fascia and its underlying muscles are then infiltrated with novocain-adrenalin solution, especially at the point where the incision will take place (Fig. S4). As the thyroid is not sensitive it will not be necessary to inject any anesthetic into it. The two regions where some pain is felt are the upper and lower poles. They are consequently thoroughly anes- thetized with the mixture. Before luxating the goiter, as this part of 506 AN EST H EI I A the operation is very painful, it is well to inject some novocain-adrenalin solution into the surgical capsule. The same must be done, too, around the trachea and esophagus, and on the posterior surface of the thyroid (Fig. 87), bearing, however, in mind the danger zone. When dealing with the isthmus, novocain-adrenalin solution must be injected above and below the isthmus and between the latter organ and the trachea (Fig 87). If one follows carefully the three following rules, local anesthesia will give in a great many instances very satisfactory results. 1. One should wait eight to ten minutes after infiltration is com- pleted before beginning the operation. 2. The surgeon should always keep within the limits traced by the injection. As soon as he steps outside of these limits pain is sure to follow. 3. Operation should be done carefully, methodically, with gentle- ness. Roughness does not agree with local anesthesia. In this respect the assistants with their retractors, if not intelligently controlled, can do a great deal of harm. Intratracheal Insufflation Anesthesia in Thyroid Surgery seemed at first to be full of promise. I have, however, found it disappointing. Just in the cases where it was expected to be the most useful, namely, in goiters with pressure symptoms it failed to fulfil its expectations. 1. As is known, before the intratracheal insufflation can be used the patient must be put to sleep in the usual way. It is only when the patient is anesthetized that the catheter is passed into the trachea. Now then, in goiter causing pressure symptoms, suffocation, as a rule, occurs with the first inhalations of ether, so that one has no time to resort to the intratracheal insufflation method; the operation must be very quickly done in order to relieve pressure upon the trachea, or tracheotomy must be performed a tout prix — at all costs — otherwise the patient will be dead; consequently the object of intratracheal insufflation is defeated. 2. Since in order to pass the catheter into the trachea the head must be excessively extended, if the pressure symptoms are already marked, suffocation is bound to be made much worse by the hyperextension of the head, hence the necessity to pass quickly the catheter into the larynx. This is not always easy. I confess that in some of these distressing moments I have failed. Mucus is so abundant and congestion is so marked that the process is not an easy matter by any means. Add to it all that the time you have at your disposal is so short that you are confronted with the dilemma: either to pass the tube or to let the patient die. Each second lost in the attempt means that much less time left to reach the windpipe by the cervical route through an incision, if the catheter cannot be passed into the trachea. Knowing that after thyroidectomy a thymic dyspnea is liable LOCAL AXESTHESIA 507 to occur most unexpectedly, I always have the intratracheal insufflation apparatus in the room of the patient read)' for an emergency. In 3 cases where I had such accidents I failed to pass the tube into the trachea. 3. If the trachea is displaced and compressed, the catheter often cannot be made to pass the point of compression. 4. Robinson collected 1400 cases of intratracheal anesthesias with 7 deaths, 1 from lung rupture and 1 from emphysema. Pantopon-scopolamin. — Nowadays anesthesia, be it general or local, is obtained through a mixed narcosis: a preliminary dose of an hypnotic of some sort is given hvpodermicallv before; and the effect of this adds to that of the subsequent drug used for general anesthesia. Up to now morphin has had the priority; lately, however, pantopon seems to take its place very advantageously. Pantopon is superior to morphin for manv reasons. It contains the totality of the useful alkaloids of opium soluble in water, and it can be injected hvpodermicallv just as well as morphin. No doubt morphin possesses the analgesic and hypnotic properties of opium; but opium owing to the presence of its various alkaloids possesses other secondary actions which morphin has not. For instance, it has a sedative action over the nervous system, a tonic influence over the cardiac system, and an antinauseous effect which morphin certainly has not. Pantopon may be regarded as a purified opium. All the harmful alkaloids have been eliminated, and the useful retained. Roughly speaking, pantopon contains 50 per cent, of morphin, 20 per cent, of narcotin, 2 per cent, of codein and papaverin, and 1 per cent, of thebain and narcein. This drug has been advocated by Sahli, of Berne, in collaboration with Scharges. In equivalent doses, morphin may be slightly- more analgesic and probably has a more rapid action, but the digestive tolerance of panto- pon is far superior. Vomiting after the use of pantopon is less frequent than after the use of morphin. The tonic influence over the cardiac system is manifest with pantopon. The paralytic influence of morphin is well-known; according to Wertheimer, Lowy, and Bergien, the paralytic influence of pantopon on the respiratory centers is far less accentuated. After pantopon has been given hvpodermicallv, in association with scopolamin, the patient falls into a dozing sleep — the " Dammerschlaf" of the Germans. The active movements cease; the sensation of pain is diminished to a great extent; consciousness although still present is con- siderably reduced; the patient sleeps, but may be awakened by call, light, or sound. In some instances the patient is so thoroughly anes- thetized that a complete operation may be performed without his knowl- edge. Naturally, such results vary with the doses employed and the individual's sensibility. I have seen, although not frequentlj , patients who did not respond to the action of pantopon and to whom morphin 508 ANESTHESIA had to be given instead. They were nervous, mostly thyrotoxic patients, in whom the cerebrospinal system was greatly excited. However, this lack of response happens with morphin, too. As a rule women react more readily than men, consequently smaller doses of pantopon may be given to them. Pantopon may be given to children as well, without any danger. To sum up, pantopon-scopolamin in surgical work seems to have great superiority over the morphin-scopolamin combination. It dimin- ishes the vomiting to a great extent during and after the operation. It reduces materially the quantity of the drug used to induce general anesthesia and diminishes the preanesthetic excitation period. It has not the same constipating effect on the intestines as morphin. The average dose is from 2 to 4 cgms. of pantopon and from 0.0003 to 0.0005 cgm. of scopolamin. As a general rule we can say that the dose of pantopon which must be employed is about double the one of morphin; consequently in cases where 1 cgm. of morphin would be given, 2 cgms. of pantopon will be necessary to obtain the corresponding effect. One must be careful in the handling of scopolamin. It is best to have the solution freshly prepared each time before using. Pantopon and scopolamin may be given simultaneously or separately. However, the majority of authors claim that it is better to give them separately and at intervals of one-half hour. In goiter surgery pantopon-scopolamin is used to the best advan- tage in the following manner: 1 grain of pantopon and j^ grain of scopolamin are given one-half hour before operation. If a patient shows an idiosyncrasy to the drug, the operation must be postponed a day or two in order to permit elimination. I have been using pantopon-scopolamin for five years now and have not met with such a necessity. No medicament is ideal and the pantopon-scopolamin combination has its weak points, too. As said before, in alcoholic and Basedow patients, instead of producing a sedative effect on the nervous system it may, on the contrary, cause an excitement of it; this is rare, however, and also happens with morphin. After the use of pantopon-scopolamin the patient often complains of dry mouth and thirst. This sensation is not due to pantopon but to the scopolamin, since we know that the latter drug influences the terminal ends of the secretory nerves. This action is purposely counted upon in giving ether anesthetic, as it prevents the troublesome formation of mucus in the bronchotracheal tract. The really greatest danger of pantopon-scopolamin is its liability of causing a paralysis of the respiratory centers. As said before, this liability is less marked for pantopon than for morphin. Large doses should not be used in weak people, in old patients, and in those with disturbances of the respiratory apparatus. CHAPTER L. POSTOPERATIVE COMPLICATIONS. Shock. — The phenomenon known as shock was a condition recog- nized as early as 1568 by Clowes, and by Weismann in 1719, who spoke of it as a condition probably caused by the presence of a foreign bodk- in the wound or blood. The word "shock" was first used clinically in the eighteenth century and was meant to express the notion of grave organic disturbances unaccompanied by demonstrable organic changes. It is difficult, not to say impossible, to give a clear, concise and correct definition of shock. The word does not represent a definite symptom, but a symptom-complex dependent upon more than one causative fac- tor. The best definition of shock which I know of is the one given by the elder Gross when he said, "Shock is the rude unhinging of the entire machinery of life." Clinically, we call shock a condition characterized by a low blood-pressure, a soft, rapid, and thready pulse, a marked pallor oi the mucous membrane and integuments, a rapid and superficial, and often irregular respiration, air hunger, subnormal temperature, cold and moist extremities and finally a more or less marked degree of stupor, with diminished or suppressed sensibility to painful stimuli; sometimes there is mental anxiety without outcry. It is an error to make a differ- ence between shock and collapse: they are the same thing. In the last few decades explanations and theories have succeeded one after the other, each one trying to locate the "unhinging" at the door of some organ or function, but everyone of these theories has failed to solve the problem. The most important theories regarding shock are: 1. \ asomotor exhaustion and paralysis. 2. Cardiac spasm and eventual failure. 3. Inhibition of the function of all the organs. 4. Deficiency of carbon dioxide in the blood 01 acapnia. 5. Morphological changes in the ganglion cells. 6. Loss of vasomotor control due to inhibition from afferent sensory influences. 7. Primary suprarenal exhaustion. 1. Vasomotor Exhaustion and Paralysis. Nearly half a century ago Keen, Mitchell, Moorehouse and Fischer advanced the theory of vaso- motor exhaustion with flooding of the splanchnic veins and contraction of the peripheral vascular system. This theory was. for a time, rejuve- nated by (Vile. lie argued, "that the essential phenomenon of shock 510 POSTOPERATIVE COMPLICATIONS was low blood-pressure, that since there was no demonstrable lesion in fatal cases and no later effects in those who recover, we must assume exhaustion rather than structural lesions to be the cause of this fall." This exhaustion is not located in the heart. The accelerated heart action must be taken as evidence of the effort of the regulating centers to recover the lost blood-pressure. The splendid action of the heart under these conditions after infusion of the salt solution proves it to be well capable of further action. This exhaustion is located neither in the cardio-inhibitory nor in the cardio-acceleratory centers, as shock may occur even when the cardiac nerve supply, namely, the vagi and sympathetic branches have been severed. The peripheral nerve vascu- lar mechanism cannot be incriminated, as it responds to stimulants always. Finally, the vasomotor centers are not exhausted either because these centers respond to electric stimulation even when the organism is in a state of profound shock. Porter and Quimby showed that the central end of the sciatic nerve can be stimulated for hours without causing any fall of pressure. On purely empirical grounds Malcolm, of England, claimed that the vasomotor centers not only were not exhausted, but were overactive throughout shock, and that the peripheral vascular system instead of being relaxed was contracted. He based his conclu- sions on the fact that in shock the surface of the body is cold, the skin pale, the pulse small, the mucous membrane blanched, and the bleeding from the wound surface scant. Sheen very judicously remarked that in shock an unduly large proportion of blood was in the abdomen. Accord- ing to Janeway and Ewing, it is "as though the branches of the mesen- teric arteries emptied into a large reservoir with perfectly flaccid walls, into which they bled to death. The aptness of the comparison of the splanchnic area to a flaccid rubber bag is made more apparent by pressure on the abdomen: the blood-pressure can be raised "at will by this procedure." This will explain why the peripheral vessels are small. Henderson claimed that "in shock the vasomotor center does its full duty almost to the last; the fall in blood-pressure is due to the diminu- tion of the volume by transudation of its fluid constituents out of the vessels into the tissues. In his experiments on dogs, he noticed that they died of "respiratory failure long before pressure had become very low." This, I have experienced clinically, too, in one of my patients who died in a state of profound shock after thyroidectomy performed under local anesthesia. In that case respiration had stopped a long time before cardiac action had ceased. Seelig and Lyon very elegantly demonstrated that in normal animals stimulation of the central end of the vagus nerve when divided causes a rise in blood-pressure and that this rise occurs even when the animals are in the most profound degree of shock, thus showing that the vasomotor centers are still capable of MORPHOLOGICAL CHAXGES IX THE GAXGLIOX CELLS 511 activity. We must consequently admit that low blood-pressure is an important accompanying symptom of shock, but that it is not the primary cause of it. 2. Cardiac Spasm and Eventual Failure. — Boise attempted to prove that, on account of peripheral trauma, the heart is overstimulated and thrown into spasm, hence an increased systole, and decreased diastole, a lessened output of blood from the heart, and consequently a lowered pressure. As Seelig says, Boise fails to explain why the work of numerous investi- gators who have thoroughly isolated the heart from its afferent paths have still been able to produce shock. 3. Inhibition of the Function of all Organs. — Meltzer, reviewing all the more recent theories of the nature of shock, ventures the assumption "that various injuries which are capable of bringing on shock do so by the inhibition of all the functions of the body." Differing from Crile, he quite justly questions the legitimacy of distinguishing etiologically between shock and collapse. He fails, however, to give satisfactory proof of his theory of shock. 4. Deficiency of Carbon Dioxide in the Blood or Acapnia. — Henderson thought that shock was due to a deficiency of carbon dioxide in the blood on account of the rapid and deep breathing induced by traumatism, so causing an undue ventilation of the lungs resulting in a condition of overoxygenation of the blood with diminished carbon dioxide or acapnia. Carbon dioxide is not merely a poisonous excretion, but is an important regulator)' hormone upon whose presence depends the activity of the respiratory centers. According to Henderson the tonicity of the walls of the bloodvessels is in direct proportion to the carbon dioxide content of the blood. This doctrine of acapnia is clinically untenable, as in the great major- it)' of cases of shock excessive ventilation of the lungs cannot be regarded as a causative factor. Howell demonstrated that the heart still beats in complete acapnia, and Seelig found that by introducing directly carbon dioxide into the blood current, he could not influence the course of shock. 5. Morphological Changes in the Ganglion Cells. G. W. Crile explains shock by the exhaustion theory. According to him, the brain is a great storage batten in the kinetic system, driving the suprarenal, the muscles, and through its action on the suprarenal, the other important viscera. In his judgment all forms of shock are caused by overstimulation of the nervous system, and finally by exhaustion. Basing his theory upon stud) - of the phylogenetic history of the whole motor mechanism, he claimed that when there is no response to nervous stimulation, the energy is expended in the cortical cells. The brain cells then show physical changes which vary with the stage of shock in which they are 512 POSTOPERATIVE COMPLICATIONS examined. He found in the brain cells hyperchromatic stages followed by hypochromatic ones. In his judgment these demonstrable, constant morphological alterations of the brain cells are the primary cause of shock. This, he thinks, he has been able to demonstrate by an enormous amount of experimental work done in the numerous and various states and con- ditions. The brain cells studied were almost entirely those of the cere- bellum (Purkinje cells). As Seelig says, "the essence of his doctrine lies in the belief that the cells are composed of labile compounds capable, when adequately stimulated, of converting their potential energy into kinetic. If this power to convert is unduly excited, phenomena of exhaustion with all their consequences occur." Gray and Parson, two English authors who have worked along the same line as Crile, most definitely and emphatically state that the most careful histological examination of the brains and spinal cords of shocked animals fails to reveal any changes in the ganglion cells as described by Crile and Dolly. In the spinal cords they found no cytolytic changes whatever. The spinal cortex showed very little change and the Purkinje cells showed no striking alterations. They concluded that in shock the exhaustion theory cannot be proved histologically. Mann claims that it is impossible to reduce the anesthetized animal to a state of shock by any degree of sensory stimulation, provided all hemorrhage is prevented and its abdomen not opened. Since the same pathological changes as the ones described by Crile are found in other conditions than shock, as overwork, anemia, infection, poisoning, Graves' disease, etc., these changes are not in the least con- sidered by many as specific of any etiological factor, nor are they specific for shock. Seelig says, "The theory of ganglion-cell excitation as the primary cause of shock stands as the type of sohdistic pathology. Virchow has characterized all sohdistic theories in pathology (as con- trasted with humoral theories) as metaphysical and speculative; and in this statement resides the crux of the problem. Crile may encounter no difficulty in showing that the condition of shock has definite morpho- logical representation in the ganglion cells of the cerebellum, but he frequently approaches dangerously near the borderline of speculative metaphysical reasoning in his attempt to prove that these same morpho- logical changes are the primary cause of shock." 6. Loss of Vasomotor Control. — Janeway and Ewing claim that shock is due to loss of vasomotor control caused by inhibition from afferent sensory impulses. To prove their contention they have undertaken a series of very interesting experiments. But through what mechanism this condition is brought about is not explained by them. 7. Primary Suprarenal Exhaustion. — Finally, the last theory of shock up to date is the one of Corbett: primary suprarenal exhaustion PRIMARY SUPRA REX A L EXHAUSTION 513 is a shock factor. Corbett says: (he. cit.) "The amount of epinephrin in the blood of a normal individual is very slight, somewhere between one part in two hundred millions, as determined by Hoskins, and one part in ten millions as determined by Waterman and Smith. Further than this, the epinephrin output per minute per kilogram of dog cannot be above 0.2 c.c. of a 1 : 1,000,000 solution of epinephrin. The smallest amount of epinephrin that will have anv effect upon the blood-pressure ol a normal dog is 0.42 c.c. of the same solution. This amount produces not a rise, but a fall in the blood-pressure, and the amount necessary to produce a rise is several times as much. These facts indicate that in the normal individual just enough epinephrin is in circulation to maintain the tone of the 'myo- neural junction,' as the pegs of a violin maintain the tension of the strings. Therefore we have no right to say that the normal blood- pressure is maintained by epinephrin in the blood, but rather that epinephrin sensitizes unstriped muscles of the vasomotor system to the sympathetic.' 1 '' Furthermore, the splanchnic nerves must also be intact in order to have function of the suprarenal glands, as shown by Cannon, Dreyer and Elliot. Peritoneal traumatism, stimulation of the sciatic as shown by Elliot, reduce not only the epinephrin output, but also actually reduces the epinephrin content of the glands. After a number of experi- ments Corbett comes to the conclusion that symptoms of shock fully develop onlv after the supplv of epinephrin is greatly depleted. Epi- nephrin exhaustion is a shock factor. Such are the theories. Everyone of them sees a part of the truth, but none of them explains the problem of shock full)*. Shock is a com- posite of various factors. It seems to me, however, that Crile is on the right track, when he requires for the production of shock the interven- tion of the nervous sytem, whatever form it may take, but takes things too much for granted when he concludes that the morphological changes in nervous cells are the primary cause of shock. How far have we the right to take the cells' morphology as an index of their functional activity : Most probably in the course of future researches and when our knowledge of biological chemistry is more advanced, we may find the solution of the problem in the pathological biologicochemical interrela- tions not only of the nervous system, but also of the entire apparatus of internal secretion. What would tend to prove that my contentions are correct, is the fact that shock can be- nearly always successfully handled if a sufficient amount of new blood is transfused. I his has been elegantly shown by Janeway and Ewing. I hese authors saw dogs, so deeply shocked that the controls similarly shocked died, immediate!) resuscitated by blood transfusion. Why should it be so if the primary 33 514 POSTOPERATIVE COMPLICATIONS cause of shock is to be found in the morphological lesions of the nervous system ? So rapid a recovery precludes the idea that the disturbing factor is due to an exhaustion of the nerve centers. It is hard to con- ceive an exhausted center recovering so quickly. It seems reasonable to admit that the new blood transfusion brings "something" which is no longer, or which is insufficiently present, in the system of the shocked animal, and which when reintroduced into the organism, sets going all the machinery, just as a few drops of HC1 will set going again an exhausted electric battery. What this something can be, I know not. Perhaps as Corbett says, the epinephrin; perhaps a glandular secretion of some other sort, or one or more lipoids, or one or more biologicochemical compounds, whose chief duty is to stimulate the nervous centers, or possibly some others of the organs of internal secretion. Not enough attention so far has been paid to the organs of internal secretion, as to their possible etiological relation to shock. We know that these organs contain a great number of lipoids, each one of them possessing individual physiological properties. Certainly lipoids must not be the. only compounds which intervene in the compli- cated biological chemistry of our body; there are and must be others, and most probably it will be only when we know more of the science, still in its infancy, namely, biological chemistry, that we shall get a little nearer the solution of the problem of shock. Shock may be of psychic, traumatic, toxic, and hemorrhagic origin. It is quite certain from clinical observations that shock may follow psychic disturbances without any definite trauma, toxin, and loss of blood. This psychic shock is mostly caused by fear and anxiety. This psychic factor is a very important one, and it is often not given sufficient consideration. It vanes with the individual, with sex, with age, race, and social condition. The fear of an impending operation is sometimes considerable, and it is indeed the duty of the physician and surgeon to alleviate this fear as much as possible. Traumatic shock in accidental injuries has been known for many years. Shock connected with operation seems to recognize the same causes as the ones seen in accidental injuries. For a long time surgeons have felt that if the patient is generally anesthetized, the operative manipulations on the unconscious patient may be done with impunity. Crile has taken the opposite stand and claims that even during artificial sleep, painful impulses from the wound to the brain are taking place, are registered there just the same, but are not felt, as the entire sensitive apparatus is anesthetized. These nocuous impulses, he says, are a contributory factor of shock; they increase the probability of post- operative complications, increase the discomforts of the convalescence and prolong the period of disability, and they should consequently be TREATMENT OF SHOCK AXD HEMORRHAGE 515 eliminated as much as possible. Hence the origin of the anoci-associa- tion theory of Crile. He aims to prevent shock by sequestering the brain from the field of operation by blocking the nerves with novocain. I have expressed elsewhere my views on this subject. Toxic shock may be seen in diseases of long standing, as thvrotoxi- cosis, typhoid, acute and intestinal obstruction, jaundice, certain stages of diabetes, etc. It is seen, too, after the use of drugs for local and general anesthesia. Hemorrhagic shock is seen after severe hemorrhages either previous, during, or after operation. Man)" or all of these different factors, as a rule, are combined in order to produce shock. One factor seldom acts alone. Treatment of Shock and Hemorrhage. — Prevention is, of course, the best method of treatment. It is clear that if it is true that during gen- eral anesthesia, nocuous impulses are nevertheless transmitted to the brain in such a way as to jeopardize the life of the patient, something should be done to prevent that risk. Consequently, if one believes in Crile's theory of shock and in his anoci-association theory, to be con- sistent with himself, he will have to employ the methods which Crile advocates in order to prevent shock. I have done so for three years. But, as said before, since this present war broke out, as novocain could not be had any longer, I felt forced to give up the anoci-association method. Despite that fact I have been unable to see anv difference for the worse in my results. So, until further convincing proof, I have discarded the use of novocain. The necessity of eliminating as much as possible the factor of fear is self-evident and this can be done by the most careful cooperation on the part of the nursing and operating staff. It may be reduced to a great extent, too, by the intelligent use of morphin or pantopon. As claimed by Crile, general anesthesia should be administered very care- fully, taking care to prevent loss of body heat, and to avoid hemorrhage during operation; furthermore, the tissues should be handled carefully, without roughness, and the operation should be performed with such speed as is commensurate with the safety of the patient. It would be an error, however, to believe that because one has blocked the nerves, has eliminated the factor of fear, has used nitrous oxide, etc., in short, has applied the method of anoci-association, that he is safe in undertaking any operation on a patient, and that he may be sure that the outcome will be all right. This, indeed, is not so. The best anoci-association method I know of is a sound surgical judgment. As already said more than once, the judgment and experience <>t the surgeon will, 1 think, determine very largely the outcome of each given case. \\ c have killed a great many patients with exophthalmic and other 516 POSTOPERATIVE COMPLICATIONS forms of goiter because we have done too much, because we have used a general anesthesia when local anesthesia should have been used, because we have subjected them to an operation near or at the top of a wave of hyperthyroidism, because, in other words, we have done " the right thing at the wrong time, or the wrong thing at the right time." There is possibly no other field in surgery where it is truer than in thy- roid surgery that the surgeon must be, not only a good technician, but also a most capable physician, competent to appreciate the strength of the heart, to judge how much shock a nervous system will stand and how much it will not, to know if the case is complicated with thymus enlargement or not, and to decide if the degenerative processes of the organs have gone so far as to compromise the success of the operation, or if they will stand the strain. Even with the best medicosurgical judgment and with wide experience every surgeon will meet with mis- fortunes because the conditions found are very deceiving. A heart seems to respond beautifully to a preliminary treatment, and great is the disappointment when you expect this heart to stand by you, to find that it simply "quits." That is why I believe Crile is not doing himself justice, and is giving too much credit to his anoci-association theory, when he attributes the good results mostly to this method. Ten, five, yes, even two years ago, the technic, the indications, the conception of the operations, were not in many respects what they are today, and very likely in a few years from now they will have advanced and changed again. Our experience becomes every day larger, and with it improves our surgical judgment. Every day we learn better what to do, what not to do, how far to go, and how far not to go. How could it be otherwise? If we consider the results of the men of great authority, such as Kocher and Mayo, who do not apply the method of anoci- association as advocated by Crile, and who do not use nitrous oxide, we see that their results are not only among the best, but are also con- stantly improving. What shall we say of Kocher, who systematically uses local anesthesia in his goiter work, who does not make a point of eliminating the factor of fear, whose patients know beforehand the day and the very hour of their operation, and who even walk to the operating table? Everyone of us knows that an operation performed under local anesthesia is not as painless as one would wish it, consequently the nocuous impulses toward the brain are still extremely active and harm- ful, yet who can criticise Kocher's results, not only so far as mortality, but so far as immediate and remote results are concerned. I think Bevan is quite correct when he says: "Cnle's excellent surgical work is done not because of anoci-association, but in spite of it." When shock takes place during the operation, the anesthetic should be stopped at once, and the operation interrupted if possible. Then 6 i o 3 60 So 20 TREATMENT OF SHOCK AXD HEMORRHAGE 517 if a two-staged operation can be devised, it is far better to do so. If not, as much as possible of the operation must be done under local anesthesia. When shock is already established, it is treated in the following manner: the extremities are bandaged; the foot of the bed or operating table is elevated; heat is applied if the patient is cold; ice to the head in hot weather, or if the patient has temperature. If tachycardia is very marked an ice-bag is applied to the cardiac region. If the patient is very restless, small doses of morphin may be given with benefit. If shock is only moderate, proctoclysis by the drop method with the following solution should be started at once. Sodium chloride Calcium chloride Potassium chloride Bicarbonate of soda Glucose Alcohol Aq. dest 1000. o This should not be given in too great quantities at a time, but should be repeated at intervals, and given slowly. This solution increases the pressure in the vena cava, and since the output of the heart is in direct proportion to the pressure in the vena cava and not at all to the aortic pressure, rectal infusions at once increase the blood-pressure and the volume of the pulse. Hypodermoclysis is best made underneath the breast or in the axilla. If for any reason the thorax must be avoided, the space of Retzius can be used advantageously. If, however, one is in need of more quickly acting methods, intravenous infusion must be resorted to at once. The best solution to use is the Locke-Ringer, which is far superior to the salt solution commonly used up to date. The Locke solution has been employed for a number of years in laboratories not only as a means of keeping up artificial circulation in experimental work, but also as a medium to preserve the life and excitability of the tissues coming from the liver, intestines, urether, etc. Its composition is the following: Sodium chloride 8.0 "rams Calcium chloride (non-crystal (if crystallized) 0.4 Potassium chloride . Bicarbonate of soda I )extrose I purified) . \<|. desi < K\ gen, 1 nough to saturate. zed) o. •ram 0.2 " 0.2 " 1.0 " 1000.0 c.c. 518 POSTOPERATIVE COMPLICATIONS The Locke solution is preserved in sterile bottles and the whole sterilized anew at the autoclave. The chemical products entering into the formula must be chemically pure. The oxygen which is a necessary condition for experimental work when producing artificial circulation, is no longer necessary when used clinically for transfusion. The sodium chloride is used in order to give the liquid the osmotic property equal to the one of the blood, so that the hemoglobin will remain fixed to the red corpuscles, in other words, m order to prevent hemoly- sis. The calcium is necessary to keep up the function of the heart and the potassium is intended to regulate the function of the cardiac fibers. The bicarbonate of soda is necessary in order to confer to the liquid about the same alkalinity as the blood. Glucose is destined to be a nutritive element for the myocardium. Adrenalin may be added to the infusion or given separately hypo- dermically; 15 to 20 drops of a 1 : 1000 solution is an excellent stimu- lant. Strophantine given intravenously is sometimes very effective. It is found on the market in sterile ampules, each containing 1 c.c. of a 1 : 1000 solution. This injection may be repeated six to ten hours after, but generally not again. Small but often-repeated doses of strychnin are also of good value. Alcohol seems to have but little effect. When the acute stage of shock is over, digalen, given hypodermically or intra- venously, proves sometimes an excellent stimulant. However, the best of all methods for the treatment of shock is blood transfusion; it may be done by the direct or indirect method. The indi- rect method, however, is the one which is within the reach of everyone on account of its simplicity, and what is more, it is just as effective as the method of direct transfusion. The indirect method which I have devised can hardly be improved in its simplicity. Crotti's Technic of Indirect Transfusion. — Although thoroughly familiar with the technic of vascular surgery, I have always felt that the direct transfusion of blood by arteriovenous anastomosis is a very delicate operation and too often unsuccessful. Everyone who is familiar with that kind of work knows how difficult it is to anastomose properly the small vein of a child, for instance, with the large radial artery of a man, and even when the anastomosis has been successfully performed, there is no way of telling whether the arterial blood is running into the vein, and if it is, how much has been transfused. The operation is a long and difficult one. The same objections are true for the other methods of transfusion as, for instance, when performed with small glass tubes prepared with albohne or paraffin. Therefore I sought to find a simpler method which might be just as efficient, if not more, and become more popular on account of its simplicity. It is called indirect transfusion of blood. POSTOPERATIVE HYPERTHYROIDISM 519 With Dr. Shilling, pathologist at Grant Hospital, Columbus, Ohio, I made a series of experiments on dogs in order to determine the coagu- lation time of the blood, when withdrawn, first, in a sterile drv glass; second, in a glass boiled in normal salt solution; third, in a glass boiled in alboline. The average coagulation time was from five to eight minutes for blood withdrawn in a sterile dry glass, and from seven to twelve minutes for blood withdrawn in glass boiled in salt solution or alboline. Therefore I thought there would be plenty of time to withdraw blood with a svringe from a vein and to reinject it into another one without running any danger of coagulation. This was indeed successfully demonstrated in each of our numerous experiments. We were able, provided, that cer- tain rules were followed, to withdraw several hundred centimeters of blood from the vein of a dog and to reinject it into the vein of another without a particle of trouble. I was able also to demonstrate the efficacy of the method in human surgery more than once. Iodin preparation of the skin of the donor. Local anesthesia with novocain, I per cent. Incision of the skin three or four centi- meters long in the angle of the elbow. The cephalic vein is dissected out and cut at the upper end of the incision. The proximal end is ligated with catgut. To the distal end three small mosquito forceps are applied at an equal distance one from the other in order to maintain the lumen of the vein open. A small artery clamp applied a few T centimeters below prevents the blood from leaking. The same operation is performed on the recipient with the difference that the vein is ligated at the lower end of the incision. A blunt needle which has been adapted to the syringe is introduced into the vein of the donor in the opposite direction to the blood current; blood is aspirated into the syringe, and reinjected into the vein of the recipient, in the same direction as the blood current. The transfusion may be repeated as often as is necessary without coagulation, provided, needle and syringe are freshly washed each time with a warm normal salt solution. The best plan is to have two needles and two syringes, and to have one set washed by the assistant while the other is in use. When transfusion is terminated the veins are ligated and the skin incision closed. By this method any amount of blood may be transfused from one patient to another, and the exact amount trans- fused is known. 1 he- fact that the blood is venous seems to be without importance. 1 he technic is simplicity itself and may be used by any- one. A few bubbles of air are of no importance. If one prefers to take arterial blood from the donor, he may do so by preparing the radial artery in the same way as described above. Postoperative Hyperthyroidism. Whoever has operated many thy- rotoxic goiters must have occasionally met with this dreaded compli- 520 POSTOPERATIVE COMPLICATIONS cation. Fortunately, postoperative hyperthyroidism is very much less frequent today than it was in the early period of thyroid surgery because of our better knowledge, better technic, and better judgment, nevertheless this complication does occur, and sometimes very unex- pectedly, no matter how small the surgical traumatism has been. Generally speaking, we may say that postoperative hyperthyroidism is only an exaggeration of all the symptoms seen in Basedow's patients. It is characterized by palpitation, tachycardia, tremor, vomiting, fever, sweating, extreme agitation, hallucinations, psychosis, etc. Though often the operation is not yet terminated, the tachycardia is already intense, the pulse beating between 150 and 200. As soon as the patient comes out of the anesthetic he shows extreme agitation; jumps up in his bed; his whole body shaken by an intense tremor; perspiration is abundant, and although there is no mechanical obstruction in the trachea, the patient shows air hunger; temperature climbs up to 103 or 104 F. or more; the highest I have seen was 107 ° F. The patient becomes more and more restless, wants to get out of bed, and to go home; has hallucinations; sees people, and talks vehemently. The condition usually reaches its most acute stage toward the end of the second day. This peracute form of hyperthyroidism lasts one, two and three days and usually terminates in death. In the milder forms, however, the symptoms are less pronounced: the storm, less intense, is over sooner. The nature of this postoperative hyperthyroidism is not yet clear. Rehn, Mikulicz, Moebius and others believe that it is due to an abun- dant resorption of thyroid secretions intensely toxic. This may be true in certain number of cases but this explanation does not hold good for all cases since Curtis and Delore have observed it after sympathectomy, Pollosson after a gynecological operation in a Basedow patient, and Crile, after only "the prick of a hypodermic needle." Since it appears after simple ligation, after enucleation or resection, no matter whether one leaves a raw surface or not, it would appear that the "raw surface" and "squeezed juice" hypothesis do not adequately explain post- operative hyperthyroidism. Kocher and Riedel believe that hyperthy- roidism is due to general anesthesia. This, however, is not always true since it has been observed after the use of local anesthesia. It cannot be denied, however, that the anesthetic, no matter whether ether or nitrous oxide is employed, is -per se a potent contributing factor in the production of postoperative hyperthyroidism. Local anesthesia is far less liable to cause postoperative hyperthyroidism than general anesthesia. Crile claims that postoperative 'hyperthyroidism is due to shock. Some authors think that postoperative hyperthyroidism is related to thymic hyperplasia. Most likely this is partly true since the thymus ACIDOSIS 521 belongs to the chain of organs of internal secretion and inasmuch as that gland plays, as we shall soon see, a part in the production of post- operative hyperthyroidism. At any rate, one thing m my practice seems to corroborate these views. Since, as routine work, I combine thyroidec- tomy with thymectomy, postoperative hyperthyroidism is far less frequent in my experience than it used to be. In my judgment postoperative hyperthyroidism is nothing more nor less than a fulminating spell of the ordinary hyperthyroidism which we see even' day in thyrotoxic patients. The symptoms are the same. The only difference is a matter of degree. In postoperative hyperthy- roidism all the symptoms are greatly intensified sometimes to such an extent that the organism, unable to stand the impact, is swept away in two or three d.ays by this tremendous wave of hyperthyroidism. Just as in an ordinary case of thyrotoxicosis, shock, be it psychic or traumatic, be it light or severe, is liable to determine a very acute spell of hyper- thyroidism, so in any surgical intervention, be it ligation, resection, gynecological operation, or only the pricking of a needle as in Crile's case, the traumatic shock from the operation, the psychic shock from going through the ordeal, and the toxic shock from the use of the anes- thetic, etc., are all factors which, with others, intervene in producing the thyrotoxic explosion called postoperative hyperthyroidism. It is con- sequently logical to consider postoperative hyperthyroidism and ordi- nary hyperthyroidism as having the same cause. As we have consid- ered the latter, a thyro-neuro-polyglandular disease, so we consider the former as a. fulminating thyro-neuro-polyglandular spell. The organ- ism is suddenly flooded with an enormous amount of thyroid products, be it from overfunction of the gland or from absorption from the "raw surface" itself. The nervous system is running wild, either because driven by the toxic thyroid products or, because it has lost its "gyro- static control," if I may say so. The polyglandular system is working at random, thus mobilizing toxic products of metabolism which only further aggravate the situation. In short, the entire thyro-neuro-poly- glandular machinery is out of gear. Acidosis. Although of recent acquisition, acidosis is nevertheless of vast clinical importance. For years I have been impressed with the fre- quency with which the "acetone breath" was encountered in many of my postoperative- casts. I thought for a long time that 1 had to deal with some transitory diabetes, but repeated examinations, however, failed to show the presence of sugar in the urine. In [913 an article on the subject by two French authors, Chavain and Oeconomos enlight- ened me considerably, as they showed that the symptoms which I had observed were due to acidosis. Since then other authors, among them Crile, have but confirmed their views. 522 POSTOPERATIVE COMPLICATIONS Alkalinity is essential to life not only for animals, but for plants also. We all know that an acid soil remains non-productive until it has been alkalized with alkaline fertilizers, that plants cannot grow in acidulated waters, and that if the alkalinity of the blood in animals becomes lowered, life ceases. All the fluids of the body except the urine and gastric juices are alkaline. Acid is constantly being formed in the body as the result of many metabolic processes. Exercise, emotion, etc., increase the amount of acid in the blood which in turn activates the respiratory centers. One of the most characteristic symptoms of acid poisoning is an "acetone breath;" furthermore, the tongue is coated or perhaps abnor- mally red, the face is pale, or sometimes flushed, the surface of the body is often cold and moist, nausea or vomiting may be present. The patient is exceedingly thirsty, and shows excessive nervous irritability. Acetone and diacetic acid are present in quantities more or less great in the urine. It is a known fact that starvation is a great source of acidosis and that in a surgical case, the length of the pre- and postoperative starva- tion periods, the amount of anesthetic, and the amount of surgical traumatism, will be the deciding factors in the intensity of acidosis. From the foregoing facts it follows that we ought to be able to pre- vent, to a certain extent at least, acidosis by reducing the pre- and post- operative periods of starvation to a minimum and by reducing the amount of anesthetic. That is what I have been doing as a general principle in my surgical work, be it goiter or any other form of surgery. I do not deplete the patient any more with cathartics: when a cathartic is deemed necessary it is given several days before the operation. Nor do I restrict the diet of my patients in the least unless there should be a special contra-indication for it; on the contrary, I want them to eat plenty of food; even their last meal before operation must be a good substantial meal, rich in carbohydrates. In severe cases where I fear the operation will precipitate an impending acidosis, I have my patients take some food just an hour or two before the operation, as oatmeal, etc. As soon as the operation is over and as soon as they have recovered from the anesthetic, I want them to take plenty of water because just as the acid soil needs water, so does the acid animal body. Even if they vomit, water is still given plentifully, at least for a time, as it is a very simple and efficient means to clean out the stomach. It may seem excessive to compel patients who may be vomiting to swallow food, yet, in severe cases a few hours after operation as soon as the stomach has sufficiently quieted down, a carbohydrate food, as gruel, potato soup, etc., is given to the patient, and as soon as possible feeding is pushed to the limit. POSTOPERATIVE FEVER 523 Glucose and bicarbonate of soda are used freely before and after the operation. A day or two before the operation the patient is given 150 grams of glucose in water flavored with peppermint which renders the taste of the mixture agreeable. At the same time the patient is given 5 to 10 grams of bicarbonate of soda daily. As soon as the patient has come back from the operating room a proctoclysis, 20 to 25 drops a minute, is started. The following formula is used: Sodium chloride 6.0 grams Calcium chloride 1.0 " Potassium chloride 0.3 " Bicarbonate of soda 100. o " Glucose 150.0 " Alcohol 20.0 " Aq. dest 1000. o " If the acidosis should become threatening a pint or two ot the following solution is given intravenously : Sodium chloride 8.0 grams Calcium chloride (non-crystallized) 0.2 " (if crystallized) 0.4 " Potassium chloride 0.2 " Bicarbonate of soda 0.2 " Glucose 1 .0 " Aq. dest 1000. o c.c. At the same time bicarbonate of soda is given larga manu, that is, generously by every possible way. Postoperative Fever. — Postoperative fever may be caused by infec- tion, or may be entirely independent of it. In the preaseptic era infection was one of the most feared complica- tions. It occurred after enucleation or after resection, and too often terminated by mediastinitis, empyema, and pericarditis, and finally by death. But in these daws with conscientious and intelligent asepsis, with careful protection of the field of operation from surrounding parts, with the Kocher screen, and with carefully selected and sterilized suture material, infection is very rare; in fact, it seldom occurs. For three years consecutively I have not had a single infection. There is, however, another form of postoperative fever which is not due to infection. It occurs the same day of the operation and usually reaches its maximum on the second or third day after operation. It oscillates between 102° and 103 °, and seldom goes above 104 1*. Excep- tionally, however, it may go higher; the highest temperature I have seen was 107 I., which terminated by death. In ordinary condi- tions this temperature lasts three, four and five days and then gradu- ally disappears. It is accompanied by an increased pulse-rate, and In 524 POSTOPERATIVE COMPLICATIONS more or less marked symptoms of hyperthyroidism. This postoperative fever occurs both in simple and thyrotoxic goiter, but it is far more frequent and far more marked in the latter condition. The pathogeny of the postoperative fever is the same as that of postoperative hyperthyroidism. Postoperative Tetany. — Tetany was very frequent at the time when total thyroidectomies were performed and when the technic of goiter operations had not reached the state of development which it has today. Nowadays postoperative tetany is rare. Kocher saw it only 5 times in his last 1000 operations; Mayo, in 1200 operations, saw it once; Frazier, reporting the results of 2000 operations done by American sur- geons, found 8 cases of tetany reported, 3 of them being fatal; Boese in 410 cases, operated on by Hochenegg, found 2 cases of tetany. I have seen it twice in my surgical practice. Thyroidectomy does not need to be total in order to produce tetany. The removal of one lobe only is sometimes sufficient to cause it. The reason lies in the fact that, although only one or two parathyroids have been removed, the parathyroids of the other side are either insufficient or absent. Benjamins, who made a systematic examination of goiters removed by operation, found that in many instances one or two, or even three para- thyroids had been removed with the goiter. Another reason why tetany may appear sometimes after partial thyroidectomy is that, on account of abnormal vascular development, the small artery which supplies the little parathyroid glandules is destroyed, causing necrosis of the parathyroids, and hence the tetany. Erdheim made thorough seriated microscopic examinations of the cervical region in 3 cases which died of tetany. In the first case he found no trace of parathyroids, but found two very small accessory parathyroids imbedded in the thymus; in the second case only one parathyroid was found but it was entirely necrotic; in the third case no trace of parathyroid tissue could be found. (See chapter on Parathyroids, page 445.) Symptoms. — The symptoms of postoperative tetany usually appear in the next twenty-four hours after operation and are characterized at first by a pricking sensation and by a slight stiffness of the fingers. The symptoms usually reach their maximum on the third day and are always bilateral. Exceptionally, tetany may occur only six, eight, ten or fifteen days after the operation. Some claim that it may even happen months or years after. In the latter cases the operation cannot be held directly responsible. When fully developed the disease is characterized by tonic and inter- mittent spasmodic contractions in the flexor muscles of the upper extrem- ities. Such contractions are present, too, but in a lesser degree in the lower extremities. The interval between the contractions is at first POSTOPERATIVE TETANY 525 quite marked, but gradually they become more intense and more fre- quent. In severe cases the tonic contractions may last one or two hours; m such conditions the musculature of the back, the masseter muscles and the diaphragm may become involved. Of course all cases of tetany are not alike, and all do not show the same severity; some are of the mild type and show only "tetanoid" symptoms. Besides the muscular contractions, four other cardinal symptoms are found in tetany. The}' are: i. The Chvostek symptom. 2. The Weiss symptom. 3. The Trousseau symptom. 4. The Erb symptom. The Chvostek symptom is a sudden and fugacious contraction of the muscles of the face obtained by a slight percussion on the facial nerve at its point of emergence in the parotid region. Percussion mav be done with the percussion hammer or simply with the finger just as in the act of percussing the thorax. Percussion must be very gentle and soft. Frankl-Hochwart distinguished three different degrees of the Chvostek symptom : Chvostek I. — The entire facial musculature of the side percussed responds to a slight percussion made upon the facial nerve at its point of emergence in the parotid region. Chvostek II. — Contractions are localized only in the ala nasi. Chvostek III. — Contractions are seen only at the angle of the mouth. The Chvostek symptom has been considered for a long time as path- ognomonic of tetany, but it occurs also in conditions which are entirely foreign to parathyroid insufficiency. For instance, the Chvostek III may be found in tuberculosis, epilepsy, neurasthenia, and even in nor- mal individuals. In interpreting the Chvostek III one should be sure that it is not of muscular origin, because sometimes percussion in the outer edge of the orbicularis oris may determine some fibrillar contrac- tion in that muscle, which thus becomes a source of error of interpreta- tion. On the other hand, the Chvostek may be missing in very marked cases of true tetany. It is more often present in stomach retain of adults than in infantile tetany. I lit Weiss symptom is a sudden contraction of the muscles frontalis corrugator supercilu and orbicularis oculi, taking place when the tem- poral and zygomatic branches of the facial nerve are percussed at the outer angle of the orbita. I he Chvostek and Weiss svmptoms are caused by an exaggerated excitability of the facial nerve, often causing the entire facial musculature to assume a peculiar expression known as the "tetanic face" Fig. 88). 526 POSTOPERA TI VE COM PLICA TIOXS In that condition the angles of the mouth are drawn; the nasolabial groove is more deeply marked, and there is an anxious expression over the forehead with the eyelids remaining wide open. The Trousseau Symptom. — In 1864 Trousseau saw that by exerting a circular compression on the upper arm of patients with parathyroid insufficiency, so as to compress the nerves and bloodvessels in the bicipital groove, spasmodic contractions and flexion of the forearm and wrist took place. At the same time the hand and the fingers took a position known since as the accoucheur's hand, or the obstetrical hand (Fig. 89). The best way to produce the Trousseau symptom is to exert Fig. -Tetanic face. circular compression on the arm with a rubber band. Often, however, simple compression with the two hands in the region of the middle arm is sufficient. The Trousseau symptom may appear very quickly after circular compression has been started. In many other instances, how- ever, compression has to be exerted for quite a long time before the symptom is obtained. In some cases the symptom appears only after compression has been removed. Where the Trousseau symptom is fully developed and the accouch- eur's hand is present, the fingers are found to be moderately flexed in their phalangometacarpal joints but extended in the remaining pha- langophalangeal articulations. The thumb is in middle position between adduction and opposition and tightly closed against the fingers (Fig. 89); this compression may be so intense and may last so long that decubitus may take place at the point of contact of the thumb with the fingers. The hand, as a rule, shows some degree of palmar flexion; it may be, POSTOPERA TI I 'E TE TA N I ' 527 however, moderately extended. The forearm is moderately flexed upon the arm and in the middle position between pronation and supination; at the same time it is adducted. In the lower extremities the thighs and legs are extended; the feet show a plantar flexion of the toes and supination of the foot. The posi- tion taken by the foot is that of the "equine" or "varoequine" foot. Exceptionally, the foot may be pronated instead of supinated. The adductor muscles of the thigh being spasmodically contracted bring consequently the thigh into marked adduction. Lately, Schlesinger has described what he calls the "leg" symptom. The leg being fully extended on the thigh, if next the entire limb is flexed upon the pelvis, then, after two or three minutes, marked tetanic convulsions appear in the limb. Fig. 89. — letany. "Accoucheur's" hand. These spasmodic symptoms found in the upper and lower extremi- ties, are known as the carpopedal symptoms. The tendinous reflexes, as a rule, are normal. They may even be slightly diminished especially in the early stages. According to Falther and Kahn the patient after a severe tetanic spell complains of pain in the bones and in the joints. Spasmodic cramps of the masseter muscles, of the tongue, of the diaphragm, of the bladder and rectum, arc sometimes observed in severe cases. Spasmodic contractions of the esophagus and larynx may be present, too. Laryngospasm, however, is more frequently seen in infantile tetany than in that of postoperative. Bechterew, by com- pressing the phrenic nerve, caused at once a spasm of the diaphragm. 528 POSTOPERATIVE COMPLICATIONS Intentional cramps are not so infrequently seen in postoperative tetany. They are characterized by spasmodic contractions in the mus- culature which for a few seconds may prevent the patient from per- forming the movements which he had intended to do; for instance, if shaking hands, the hand remains for a few seconds tightly closed, as if the patient had some difficulty in releasing his grip. Similar intentional spasmodic contractions occur in the lingual and esophageal musculature. Frankl-Hochwart has shown experimentally that the Trousseau symptom is not due to the shutting off of the blood circulation in the arm, but is due to compression of the nervous trunks. After dissecting the nerves and vessels in the bicipital groove in dogs, this author was able to obtain the Trousseau symptom only when compressing the nervous trunks, and never when exerting a compression upon the arteries and veins alone. Pressure upon the nervous trunks of the thigh gives, too, the same symptoms which have been described above. According to Schlesinger, if compression is exerted upon purely motor nerves only, no Trousseau symptom occurs. It appears only in mixed nerves, namely, those containing motor and sensory fibers. The Erb Symptom.— In 1878 Erb showed that in tetany the elec- tric irritability of the motor nerves was gradually increased. This electric excitability is higher during the spasmodic contraction than during the intervals. This point is important to remember, especially in the latent forms of tetany where examination may show that during the intervals the Erb symptom is negative. As soon, however, as the Trousseau symptom has been elicited, the Erb symptom becomes positive. The hyperexcitabihty of the nervous trunks is best determined with the galvanic current. It is characterized: 1. By musculature contractions on closure of the negative pole with currents of intensity, inferior to 1 milliampere when this current is applied on the ulnar or other motor nerves. 2. By muscular contractions at the opening of the positive pole with currents inferior to 5 milliamperes. 3. By muscular contractions at the opening of the negative pole with currents inferior to 5 milliamperes. Symptoms of hyperesthesia are frequently found in connection with tetany and are especially localized in the upper extremities. They con- sist of a burning, pricking sensation, and dead feeling of the fingers. Sensory disturbances of the hearing, smelling, tasting apparatus are not so uncommon. The pricking and tingling sensations are sometimes intolerable. The length of the convulsions may be very short or may last for hours. Sometimes there is only one spasmodic spell and then every- POSTOPERATIVE TETANY 529 thing is over. Usually, however, the spells are numerous. As in tetanus, noise, touch, light, heat, cold, etc., may determine an acute spell. Dur- ing convulsions, the muscles are hard, offer great resistance to passive movements and are spontaneously painful. Adrenalin and pilocarpin exaggerate the tetanic contractions and determine an intense vaso- constriction of the entire bod}', but especially of the face, hence the reason why patients with tetany look pale, although their blood is normal. Just before and during the tetanic cramps there is tachycardia. The heart action is stronger, the sounds are more strongly marked, especially the second pulmonary and aortic sounds. Respiration is increased, too. Cyanosis and dyspnea may be present. The respiratory disturbances are partly due to spasmodic convulsions of the diaphragm, and partly to disturbances in the respiratory centers. As a rule tem- perature does not go very high. In some cases, however, it may be very marked. Even vomiting and diarrhea may be present. Tetany should not be mistaken for tetanus, because in tetanus the tendinous reflexes are markedly increased, the heart is not involved, and the ordinary symptoms of tetany are not present. How Many Parathyroids May Be Removed Before Tetany Appears? This question cannot be fully answered. As a general principle, we should aim not to remove any parathyroid tissue at all. It is true that Erdheim found that one, two, or even three parathyroids had been removed in con- junction with thyroidectomy and that no, or very little, disturbance was observed. This would consequently tend to prove that one parathyroid alone is sufficient to prevent tetany. It would be dangerous, however, to bank too much upon that fact since we know that not only the number, but also the size of the parathyroids are two important factors in the production or non-production of parathyroid insufficiency. The volume of a single parathyroid might be larger than that of three other glandules taken together, while in other cases two small parathyroids, for example, may prove insufficient to protect the patient against para- thyroid insufficiency. Consequently the aim of the surgeon should be to protect these little glandules and to safeguard them from any injury. Despite, however, profound anatomical knowledge and good technic, postoperative tetany will sometimes occur. I have observed a case of tetany in a young girl whom I operated for a nodular colloid goiter, the size of a small egg, located in the isthmus. This median goiter was simply enucleated. Both lobes were left untouched inasmuch as they were normal. No ligation of the thyroid vessels was undertaken, so that I cannot see how I might have injured the parathyroids, yet the day following the operation the patient developed a mild case of tetany which happily was cured in five or six days with parathyroid opotherapy and $4 530 POSTOPERATIVE COMPLICATIONS lactate of calcium. Tetany in this case does not necessarily mean that the parathyroids were injured, although it is still within the range of possibilities that on account of some abnormal anatomical condition a slight injury to their nervous and blood supply might have occurred, thus putting them in a state of temporary insufficiency. It is more probable, however, that for some reason or another, they had been tem- porarily inhibited in their function. Some parathyroids, like some other organs, may normally have a reduced functional capacity; they may be congenitally weak, too. In ordinary conditions, however, they are still able to meet the physiological requirements of the metabolism, since their insufficiency is only potential. But let them be confronted with some abnormal condition, then they at once become insufficient to their task. Prognosis. — The prognosis of postoperative tetany depends upon the quantity of parathyroid tissue left. The more removed, the worse the prognosis. In the first case reported by Erdheim, where no para- thyroid tissue was found, death occurred three days after accidental parathyroidectomy. In the second case, where the one parathyroid found was necrotic, and in the third case, where two tiny para- thyroids were found imbedded in the thymus, death occurred seventeen days after. Most probably, in the two latter cases, death was delayed on account of some partial function of the parathyroids present. If the two accessory parathyroids found in the thymus had been large enough and could have undergone a sufficient compensatory hypertrophy, death very likely would not have taken place. Most likely, some of the cases of chronic tetany which we sometimes observe can be explained in the same way: the normal parathyroids for some reason or another, having ceased to functionate more or less entirely, the accessory parathyroids partially supply their function but are not capable, however, of offset- ting the loss of the main parathyroids. The course of tetany in experimental pathology is the same as the one seen in human beings. The disease may become extremely acute or may take a very chronic, slow course. Exacerbations without any apparent cause are apt to be observed. In animals tetany differs materi- ally with the species of animal involved. For instance, dogs develop a markedly acute and rapidly fatal tetany after complete thyroidectomy, while monkeys show a more chronic form of the disease. In human beings, too, we observe a great variety in the form and intensity of tetany. From the most severe forms, which are rapidly fatal, to the lightest form of the disease, all stages can be found. Postoperative tetany, no matter if severe or light, must always be considered as a serious complication, since we know that even the lightest form of tetany will, for no apparent reason, suddenly show marked exacerbations which may terminate in death. Von Eiselsberg seems to think that when TREATMENT OF TETANY 531 tetany occurs late, that is, after a certain period of time after opera- tion, its prognosis is more serious than in cases of tetany occurring at an earlier period. Postoperative tetany may retrocede spontaneously in about 35 per cent, of the cases. When death takes place it is caused by spasm of the glottis, of the diaphragm, or of the bronchi. Postoperative tetany has a great tendency to become chronic. When such is the case it becomes a troublesome disease since it is hard to manage by therapeutic treatment. Treatment of Tetany. — Opotherapy with, fresh parathyroids taken from cattle or horses has proved effective in a great many instances. Para- thyroids may be given, too, in dry form either in powder or tablets. The results, no matter whether the parathyroids are taken in fresh or dried states, have not always been satisfactory. At any rate, large doses of parathyroids must be given in order to obtain good results. Having observed that in tetany, elimination of calcium is enor- mously increased, and that the treatment of such animals with calcium strontium and magnesium diminishes the excitability of the motor nerves to such an extent that the spasmodic contractions disappear, MacCallum and Voegtlm thought that tetany was due to a poisonous substance circulating in the blood and depriving the tissues of their cal- cium content. They consequently advocated the use of calcium in treating parathyroid insufficiency, the results of which have been very satisfactory. Other authors as Parrhon, Urechi, Berkeley, Beebe, Bell, Martin, Biedl, have confirmed these findings and results. They claim that calcium, strontium, and magnesium act directly upon the nervous trunks and render them incapable of transmitting the nocuous impulses causing the tetanic convulsions. Musser was able to check tetany in twenty-four hours after administering calcium lactate to one of his cases. Halstead, while treating a chronic case of postoperative tetany, replaced the parathyroid opotherapy by lactate of calcium and obtained excellent results. Arthus and Schaefermann, on the other hand, did not obtain good results with calcium treatment. Calcium is best used under the form of lactate. Lactate of calcium is given by mouth or rectum in a 10 per cent, solution, 4 grams every three hours, or subcutaneously in a 5 per cent, solution. The only inconvenience connected with this medication is that it must be given in increasingly large doses. Furthermore, the curt- is not permanent but lasts only as long as the medicament is used. If the patient still possesses some parathyroid tissue, calcium lactate may tide the patient over the danger period until the parathyroid tissue has undergone compensatory hypertrophy. Hot packs, too, are a good therapeutic measure in the treatment of tetany. 532 POSTOPERATIVE COMPLICATIONS Grafting of the Parathyroids. — Two different conditions may occur. i. During operation a parathyroid may be inadvertently removed. In that case there must be no hesitancy as to what should be done. This parathyroid must be reimplanted at once in the thyroid tissue which is to be left in situ, as shown by Halstead. The thyroid is selected on account of its rich vascular supply. The chances for success for this autotransplantation are very good. We know that experimentally it has been shown time and time again that autotransplantation could be made successfully. Christiani, for instance, showed that transplanted parathyroids could be still physiologically active five years after trans- plantation. 2. We may have to deal with a patient who, during operation has been deprived of one or more parathyroids, and in whom a marked para- thyroid insufficiency sometimes occurs later. In such cases, of course, autotransplantation is out of the question. We must resort to hetero- transplantation. We know experimentally that in the majority of these cases this method has proved to be a failure. Its effects, as a rule, are only temporary and last only during the time necessary for the grafting to become absorbed. Consequently, if one wishes to resort to this method he must be sure that there exists a parental relationship as close as possible between the donor and the recipient. The ideal would be to obtain a parathyroid from someone closely related to the patient, as father, mother, or sister. Not only such close parental or family relation is of importance, but the age, sex and the conditions of the life of the donor and recipient should be approximately alike, since it is easily understood why a parathyroid removed from an old man and transplanted into a young child will have less chance to be successful than if the donor were also a child. If all these requirements are met, the grafting may then become permanent. Such an operation becomes, more strictly speaking, a homoiotrans plantation. In order to be successful the homoiotransplantation must take place in an individual in whom parathyroid insufficiency is well defined; if that is not the case the grafting will not "take." This fact has been demonstrated experimentally by Halstead, Christiani, and others. On the other hand, Iselin has shown that if parathyroid insufficiency is very marked, the chances for the grafting to "take" are greatly diminished. All this shows that the conditions of nutrition must be of a certain kind to allow the grafting to become successful. In such cases it is better to submit the individual to be grafted to a previous treatment with lactate of calcium or to parathyroid opotherapy. The results of grafting should not be expected to become noticeable before six to ten weeks. Have we the right to parathyroidectomize an individual, even partially, PULMONARY COMPLICATIONS 533 in order to benefit another? The importance of the parathyroids is too vital to deliberately remove one or two parathyroids from one patient in order to benefit another. I do not think a surgeon should do so even with the consent of the donor, for who knows whether the parathyroid tissue left will be sufficient to meet not only the physiological purposes, but also the increased demands made upon the system, when patholog- ical conditions occur, as infectious diseases, etc.? A woman who is liable to become pregnant should never be deprived knowingly of one or more of her parathyroids, because eclampsia seems to be too closely associated with parathyroid insufficiency. At any rate, if one wants to transplant a parathyroid from one individual to another, it should be done only after having ascertained by dissection that the others are seemingly normal. Everyone who has had some experience with the dissecting of that region knows how difficult it is sometimes to find the parathyroids. At any rate, it would mean a long, tedious work which might endanger the life of the very organs one is taking so much trouble to save. Homoiotransplantation should, consequently, not be undertaken unless for some especially strong motives. The only possibility which then remains is to take, as Kocher did, the parathyroids from someone who has just died bv suicide, or as Pool did, from someone who had died from a disease which would not prove to be detrimental to the recipient. The shortest possible time should be allowed to elapse between the removal and the transplanta- tion. The best thing to do is to dissect the parathyroids as soon as possible after death of the donor and to put them in a warm Locke solution, or better, in the blood serum of the recipient himself while he is being prepared. The method known as the method en semis, spoken of when dealing with transplantation of the thyroid, may be used here, especially if the parathyroids are of good size. One or more parathy- roids may be used. The place of choice for parathyroid transplantation is the same as for thyroid transplantation. It may be done either in the abdominal walls between the muscles and the peritoneum or in the tibia. The thyroid itself and the spleen should afford good chances for success. The same rules indicated for thyroid grafting apply for parathyroid transplantation. I he- operation should be done very rapidly; the gland- ule should be handled with greatest care and gentleness; hemostasis of the cavity where the grafting is done should be absolutely perfect, and no antiseptic whatsoever should be used for the instruments, the hands, etc. Pulmonary Complications. For a long time pneumonia and broncho- pneumonia had been among the postoperative complications threat- ening most the life of the goiter patient. I Ins was due partly to the fact that at that time large goiters with their complications were fre- 534 POSTOPERATIVE COMPLICATIONS quently seen and partly to the indiscriminate and ignorant use of the anesthetic. Nowadays the operations are done to patients whose gen- eral condition is better. We understand the use of the anesthetics better, and we are more skilful in administering them. Consequently pneumonia and bronchopneumonia are certainly much rarer complica- tions than formerly. In all my cases I have had only once a case of pneumonia, and that was following tracheotomy. Postoperative Dysphagia. — After operation for simple or toxic goiter the patients often complain of dysphagia for twenty-four to forty-eight hours. This is likely due to the involvement of the esophagus in the aseptic inflammatory processes following the operation, and possibly to the injury of some of the pharyngo-esophageal plexus, during the various manipulations occasioned by the removal of the goiter. Postoperative Hematoma. — Despite the greatest care in ligating every bleeding vessel, and especially when no drainage has been used, postoperative hematoma is sometimes observed. It is an unpleasant but insignificant complication. This postoperative hematoma is better left alone. It often drains spontaneously ten to fifteen days after. If not, and if at that time the swelling is still marked, some of the blood may be aspirated with an aspirative syringe, cautiously in order to avoid a fresh hemorrhage a vacuo. Raising of the Scar. — In spite of the greatest care on the part of the surgeon, some patients will sometimes "raise" a scar and form large, thick, unsightly elevations resembling cheloids. In some cases the sur- geon is really not to blame for this since it is a pathological peculiarity ot the patient. In the majority of cases the raising of the scar, however, is due to a "bevelled" incision. Hence the necessity for using a fine, sharp knife and of holding it perpendicular to the skin while cutting. After-treatment. — I cannot do better than to quote the entire section of Ochsner's paper bearing on this subject: "By far the most important point in the surgical consideration of this condition consists in the after-treatment, because with careful after-treatment almost all of these patients may become nearly as use- ful as they were before they began to suffer from exophthalmic goiter, while in cases in which the after-treatment is not carefully carried out, practically all of these patients develop a condition as bad, if not worse, than that with which they presented themselves primarily for surgical treatment. The surgeon should bear in mind, in the first place, that practically all of these patients belong to a class of neurotics, and that this undoubtedly had much to do with the development of their goiters primarily, and that unless this condition is carefully taken into consid- eration in the after-treatment, the weakened physical condition of the patient will not be able to bear the wear and tear to which the neurotic RULES FOR GOITER PATIEXTS 535 tendencies would surely expose the patient. The same is true concern- ing the diet which is habitually chosen by the patients, which is usually exceedingly unwholesome, and it is consequently important that they be impressed with the fact that unless they will adhere to the use of a reasonable diet, their chances for permanent recover)' will be very slight. We have always given these patients printed directions which contain all of the important rules to be observed, and we have advised the patients to read these directions at regular intervals and to follow them for many years. The following is a copy of the directions which we use in these cases, and which have proved eminently satisfactory. The patient received a mild tonic and a laxative and an absolute diet list upon leaving the hospital. Rules for Goiter Patients. — I. You should avoid all excitement or irritation, like attending receptions, shopping, church work, and politics. 2. You should get an abundance of rest by going to bed early, and taking a nap after luncheon. 3. You should have an abundance of fresh air at night, consequent!)' you should sleep with wide-open windows or on a sleeping porch. 4. You should eat and drink nothing that irritates the nervous sys- tem, like tea, coffee, or alcohol. Of course you should not use tobacco in any way. 5. You should eat very little meat. If you are fond of meat, take a little beef, mutton, or breast of chicken, or fresh fish once or twice a week, or at most, three times a week. 6. You should drink a great deal of milk or eat things that are pre- pared with milk, such as milk soup, milk toast, etc.; cream and buttermilk are also especially good for you. 7. You should avoid beef soup or beef tea or any kind of meat broths. 8. You should eat an abundance of cooked fruits and cooked vege- tables or very ripe raw fruits, or drink fruit juices prepared out ol ripe fruits. 9. You may eat eggs, bread and butter, toa^t, rice, cereals. 10. You should drink an abundance of good drinking-water, or if this is not available, you should boil your drinking-water for a few minutes or drink distilled water." CHAPTER LI. THE THYMUS GLAND. ' Synonyms. — English, sweetbread; French, riz-de-veau; German, Briesel, Brosel, Kalbsmilch, Lactes. History and Etymology. — The first mention of the thymus gland in the literature was made by Polydeukes and Rufus, while Vasal and Bartholinus were the first to give descriptions and pictures of it. For some authors the word "thymus" comes from the Greek word dvfxos which means "the thyme" and was used to designate the gland on account of some resemblance in the shape of the thymus gland and the leaves of that plant. For Galen the word, "thymus" comes from the Greek dvfxds which means "courage" and was applied to the thymus on account of the intimate relation of that gland with the heart. Embryology. — The thymus gland is present in all the vertebrates; it has not yet been found in the Amphyoxus. Developed from the third branchial cleft, the thymus lies at first in very close contact with the thyroid and the parathyroids. Later on, however, in embryonic life the thymus passing in front of, very seldom behind, the left innominate vein, descends into the superior mediastinal space and spreads over the pericardium, thus becoming entirely intrathoracic. GrosschufF, in 1896, showed that the thymus did not take its origin from the third branchial cleft alone, but that in a great number of animals such as the dog, goat, sheep, etc., the thymus is developed from the fourth branchial cleft also. This close relation of the thymus with the thyroid and the para- thyroids will explain the origin of the thymic nodules which are found, not only around the lateral regions of the thyroid, but also in the midst of the parenchyma itself. These intrathyroid nodules, according to Grosser and Betke, are more or less constant in young children up to two or three years of age. They are frequently found in specimens of later life, provided, one searching for them takes the time to make seriated slides. The knowledge of the existence of such accessory thymic nodules is important since it has been shown experimentally that after complete thyroidectomy these nodules undergo a compen- satory hypertrophy. They may also play a part in the production of hyperthyroidism; finally, they may give rise to the development of tumors. In early embryonic life each lobe of the thymus has an excretory canal connecting the gland with the third branchial cleft. This is called PLATE XXVII Jibuti*? Thymus of Newborn Baby (Natural Size). Note that the thymus fills almost the entire mediastinum and extends upward as far as the thyroid gland. 1 he figure illustrates very well what is called the "cervical" and the "intrathoracic" portions of the thymus. Note, too, the vessels extending from the thyroid to the thvmus. SURGICAL AX ATOMY OF THE THYMUS 537 the thymopharyngeal duct. This canal, however, undergoes atrophy in the beginning of the third month of embryonic life. Like the thyro- glossus duct, the thymopharyngeal duct sometimes remains patent, thus causing the production of cervical fistulae whose feature it is to be always lateral, while the fistulae developed from the thyroglossus duct are always median. Thymopharyngeal fistulae begin on the lateral wall of the pharynx a little below the fossa tonsillaris; extend downward, passing above and m front of the hypoglossus nerve, then run between the carotids and reach the inner border of the sternocleidomastoid muscle, which they follow until they break through the skin, usually a little above the clavicle. In other instances the thymopharyngeal duct becomes obliterated partially, so that only portions of it remain. These portions are then liable to give rise to cystic or solid tumors. The thymopharyngeal canal, like the thyroglossus duct, is lined with ciliated epithelium, which in some instances, however, may be low or cuboidal. Histology. — Histologically, the thymus is composed of two portions, the cortical and the medullary. The medullary portion is composed of a meshwork of giant and syncytial-hke cells and of Hassal's corpuscles; lymphocytes are found here only in moderate numbers. On the other hand, the cortical portion is composed of basophile lymphocytes and eosinophiles mostly. The eosinophiles are very abundant from the seventh month of embryonic life up to a few months after birth; they then diminish very rapidly in number during the first years of life and are mostly absent after the tenth or twelfth year. No one is yet clear as to the origin and real significance of Hassal's corpuscles. By some they are regarded as of epithelial origin, while by others they are con- sidered as the remainder of the thymic ducts. The thymus must be regarded as a lympho-epithelial organ. Surgical Anatomy of the Thymus. — The thymus is formed by two lobes which are in close relation, one with the other, but entirely inde- pendent; no isthmus is present. The thymus lies in the upper and anterior portion of the mediastinal space, just behind the manubrium and corpus sterni. It covers the basis of the heart, the origin of the thoracic vessels such as the aorta, pulmonary artery, the innominate veins and arteries, and the vena cava and the trachea (Plates XXVII and XXVIII). Furthermore, the thymus comes in contact with the vagus, inferior laryngeal and phrenic nerves; laterally, it comes in contact with the pleural membrane. In cases of extreme hyperplasia, the thymus covers the entire pericardium and may reach the diaphragm. In children the upper pole oi the thymus extends, as a rule, i or 2 cms. above the episternal notch. Sometimes these poles come in contact with the lower poles oi the thyroid. In adults the thymus when hypertrophied does nor, as a rule, extend very 538 THE THYMUS GLAND far above the episternal notch. Between the upper poles of the thymus and the lower poles of the thyroid a connective-tissue ligament contain- ing thymic vessels coming from the inferior thyroid artery is more or Fig. 90. — A, thyroid; B, lungs; C, thymus; D, heart. less always present; this ligament is called the thyrothymic ligament. (Plates XXVII, XXVIII and Fig. 90.) The blood supply of the thymus comes from the inferior thyroid and the internal mammary arteries; sometimes direct branches are given INVOLUTION OF THE THYMUS 539 off from the subclavian artery. From below it receives blood from a pericardiophrenic branch. (Plate XXVIII.) Its lymphatics run into the intrathoracic lymph nodes. The nerve supply comes from the sympathetic, the vagus, and according to Marfan, from the phrenic. Involution of the Thymus. — It was formerly thought that the thymus after birth grew up to the second year, then gradually diminished and disappeared more or less entirely after the thirtieth year of life. Today it is more generally understood that the thymus is an organ belonging to the period of development. As soon as the physical development has reached its completion, the organism seems to have no more need of that organ, hence its atrophy. Consequently it must be expected that we find this gland increasing in size and weight during the period of growth, and so it is. According to Hammar this gland reaches its maximum of size between the eleventh and fifteenth years, its normal weight being about 37 grams. It then diminishes gradually until vestiges only are found in later life. The first to disappear are the cortical and next the medullary portions; in the final stage of involution Hassal's corpuscles onlv are found as the last vestiges. This is known as the physiological involution. The following table of weights of the thymus at varying ages is given by Hammar: Newborn . I to 5 years 6 to io years II to 15 years 16 to 20 years 21 to 25 years 26 to 35 years 36 to 45 years 46 to 55 years 56 to 65 years 66 to 75 years 13.26 grams 22.98 it 26. IO tt 37-52 a 25-58 u 24-75 k 19.87 it 16.27 << 12.85 a 16.08 a 6.00 M It is an interesting fact that the thymus of animals undergoes a very marked involution when the animals are starved for a certain period of time, and that both the cortical and medullary portions of the thy- mus undergo atrophy, while the connective tissue increases. At the same time fatty degeneration invades the gland. This is known as the pathological involution. The same involution takes place in pathological conditions especially in acute diseases such as pneumonia, nephritis, etc. Usually, the involution is a temporary one and when the acute process is over, the organ returns to its previous normal condition. In diseases of standing, however, this is no longer true; there the thymus under- goes a sclerosis which remains permanent. Involution is then permanent. 540 THE THYMUS GLAND Experimental Pathology of the Thymus. — After total thymectomy there is at first no change in the external habitus of the animal. Three or four weeks later, however, the animal begins to show retarded growth and diminution of weight and acquires a spongy, pasty appearance due to fatty degeneration. Here we have the stage of increased adipose tissue. Cachexia, however, soon follows that stage. The hair falls out; extreme muscular weakness takes place, and a marked tremor becomes apparent. The animal becomes apathetic and gradually enters into a state of idiocy similar to the one seen in thyroid insufficiency. This cachectic stage may last from three to twenty months, and then death takes place after the animal has been in a state of thymic coma with absolute loss of consciousness lasting several days. In cases where the removal of the thymus has not been complete, regeneration of the gland may take place, and a gradual restoration to health may follow. Skeleton. — Complete thymectomy performed in very young animals has a marked effect upon the after-development of the osseous system, as was shown by Klose, Matti, and others. The bones become soft and rachitic, showing curvatures and deformities. This osteomalacia, involv- ing especially the spinal column, affects also the pelvic bones, thorax and skull. From an histological point of view one will see that the epiphyseal line is abnormally enlarged and very irregular; that the bones show a deficiency of calcareous compounds in the cortical portion, and that, instead of 65 per cent, of calcium salts which bones normally con- tain, they have only 32 to 34 per cent, of these salts, while the trabeculae of the spongiosa are thinner and fewer. The changes occurring in the skeleton following thymectomy must be regarded as similar to those found in rickets, and are caused by a deficiency of calcareous material in the osseous system. If this insufficiency occurs in a growing skeleton, rickets with all its deformities will follow, but if this insufficiency occurs in an already fully developed bone, osteomalacia and osteoporosis only will be the results. Nervous System. — In thymectomized animals H. Vogt found swell- ing of the brain, of the ganglia and the glia cells, and he found, too, an increased amount of gray matter. The ganglia and the glia cells are not only swollen, but are also degenerated. This swelling of the nervous elements is due to an increased retention of water among the elements, most likely due to an increased acidity of the blood serum. This acid- osis may be caused by an actual increase of the acid contents of the blood, or may be due possibly to the absence of substances destined to counter- balance the acidity. This fact, too, is exceedingly interesting and of practical importance, because as we know, acidosis frequently follows an operation for exophthalmic goiter and is always a dreaded compli- cation, since it often terminates in coma and death. PLATE XXVIII TAuroid fnternal 'jugular ¥■- Common carotid Thuro-ffiym'C /lynmen, unfhifc "arc. branches In nominate Vein TAymus Phrenic Jferve Subclavian Srartcn Normal Anatomical Relations of the Thymus to the Other Organs. Newborn Baby Having "Thymic Death.' Note the enormous size of the pared with the size of the heart, intimate relation between the thymi through the thyrothvmic ligament. EjOtolnq INTERRELATION OF THYMUS TO ORGANS OF SECRETION 541 Muscular System. — After a certain period of time thymectomized animals show an extreme muscular weakness and tremor. The muscles have lost their striation; their sarcolemma and external perimysium have become thickened and swollen; the muscular fibers are atrophied; the connective tissue is very much increased and swollen; the actual content of the musculature is manifestly decreased. At first these findings seem to throw some light toward a satisfactory explanation of the muscular symptoms seen in Basedow's disease. Indeed, the muscular asthenia seen in such cases is exceedingly marked. It would therefore seem that most of these muscular symptoms seen in thyrotoxicosis are due to thymus insufficiency, yet it is a well-known fact that in Basedow's disease the thymus, instead of being atrophied, is hyperplastic. On the other hand, we know that myasthenia gravis is often accompanied by thymus hyperplasia. The musculature in such cases shows marked pathological changes such as round-cell infiltration, fatty degeneration, etc. Whatever the final explanation may be, we must admit, nevertheless, that there is some relation between the thymus and the muscular system. Interrelation of the Thymus to the Organs of Internal Secretion. — As shown by such authors as Basch, Matti, and Klose, there is an intimate relation between the thymus and the thyroid. After thymec- tomy the thyroids of animals used for experimentation become mani- festly hyperplastic; the follicles become larger, the epithelium higher, having the tendency to become cylindrical; in short, the thyroid gland shows in a general way the histological picture of the thyroid gland seen in Basedow's disease. The reverse is true, too, namely, that after thy- roidectomy the thymus undergoes hyperplasia. This fact is also of great practical importance since it will allow us to understand why after an operation for goiter we may have to deal with mechanical as well as functional disturbances due to an increased thymic hyperplasia. In 12 cases of mors thymica in newborn, Hedinger found 7 cases with enlargment of the thyroid gland. In goiterous regions, especially in Bernese regions where goiter is endemic, the thymus hypertrophy and struma in newborn is exceedingly frequent. In 1910, in the Bernese Pathological Institute, 44 postmortems of newborn were made. In 12 of these cases the thymus hyperplasia was extremely marked and the goiters were of large size. In several cases the hyperplasia of the goiter and thymus, although quite marked, was not as pronounced as in the cases just mentioned, and only in 3 cases were there concomitant goiters. In adults this combination of thymus hyperplasia and goiter is extremely frequent, as has been reported by Virchow, Gluck, Wiens, Weber, Nettel, Kaufmann, Rossle, Hair, and myself. 542 THE THYMUS GLAND The parathyroids, too, undergo a marked hyperplasia after thymectomy. It is a very interesting fact, too, that after thymectomy the supra- renal bodies undergo marked hyperplasia whereas, in cases of thymic hyperplasia the chromaffin system seems to be decidedly diminished, hence the conclusion that there is possibly an antagonism between these two systems. The same is true for the genital system, so that there seems to be a decided antagonism between these two apparatuses. After complete thymectomy the testicles become manifestly hyper- plastic. It has been generally observed that in cases of status thymo- lymphaticus the development of the genital apparatus is very much retarded, while, on the other hand, it seems that in young individuals whose genital system is prematurely developed, the involution of the thymus occurs at an earlier period. This is another point in favor of considering the genital apparatus and the thymus as two antagonistic systems. Status Thymolymphaticus. — Thymus hyperplasia is not infrequently combined with a concomitant hyperplasia of the entire lymphatic sys- tem. The tonsils and adenoids are enlarged; the lymphatic ganglions and their follicles are hyperplastic; the follicles of the basis of the tongue are markedly increased; the spleen is larger than normally; the adenoid tissue of the entire lymphatic apparatus is involved. This condition is known as the status lymphaticus of Paltauf. When there is a concomi- tant hyperplasia of the thymus the condition is then known as status thymolymphaticus . This condition is accompanied by a reduced caliber of the aorta and of the arterial system. The patients affected with status thymolymphaticus are pale, yellowish in color, although more or less well nourished. It is often said of them that they have a lymphatic habit, a condition which is more easily recognized than described. Such patients have a diminished resistance; they are more vulnerable to and stand a good deal less than others, bacterial and toxic influences. Their nervous system is impaired; their cardiac function, for some reason or other, is easily inhibited and death from cardiac paralysis in such cases is frequent. Thymic Tracheostenosis. — The most striking symptom of thymic hyperplasia is dyspnea. This may be characterized by a labored respira- tion only, or by the most intense choking spell. Between these two extremes all forms of transition are found. Dyspnea may be constant or intermittent, and with or without acute paroxysms. Between attacks respiration may be normal. There may be a constant and persistent inspiratory stridor, and in extreme dyspnea, an expiratory stridor may also be found, which, however, is less marked. The choking spell may occur without cause, or when the child cries from pain or anger. Hyper- PLATE XXX The relation of the innominate of the common carotid and aorta to the vagus and inferior laryngeal nerves. It will be easily seen how a tumor compressing and displacing these large vessels will put the inferior laryngeal nerve on the stretch, thus causing closure of the glottis and choking spell. The figure shows, too, where compression on the windpipe by the thymus will take place. PLATE XXXI Thymectomy. The two flaps obtained after the transverse incision has been made are retracted and the superficial cervical fascia is grasped between two forceps and cut in the middle line. Thymectomy. The prethyroid muscles are divided in the middle line and retracted laterally. CHROXIC FORM OF THYMIC HYPERPLASIA 543 extension of the head or dorsal decubitus exaggerates dyspnea. This would explain why dyspnea is more marked during sleep than during waking hours. The choking spells may last but a few minutes, or a few hours, or a few days, and then respiration becomes normal again. In other cases death ensues. In certain cases the child dies at the beginning of the choking spell. This dyspneic condition begins, as a rule, in the first weeks or months, diminishes during the second year of life and is seldom found after this period. This may be due to the fact that the gland normally retrocedes after the second year of life and that the superior opening of the thorax becomes larger with the growth of the child. In children the dyspneic symptoms due to thymic hyperplasia may be acute or chronic. Acute Symptoms. — Certain cases of asphyxia of newborn babies can be explained only by thymic hyperplasia. In such cases the child is born apparently dead, so that it often takes quite a long time to bring it back to life. Cyanosis is marked, breathing remains difficult and loud; in many instances the child dies after a few minutes or hours. Post- mortem examination shows compression of the windpipe by a hyper- plastic thymus (Plate XXIX). In other instances the child may have been in good health for weeks or months when a most unexpected choking spell comes up. Suddenly, without any apparent cause, or possibly after a few spells of moderate dyspnea to which little attention has been paid, the child throws his head backward and makes intense efforts to get his breath. He rolls his eyes upward and his face, especially the lips and tongue, become cyanotic and swollen. The veins of the neck are congested, and a loud stridor is present. The entire accessory respiratory musculature is called into play. A marked "tirage" of the supra- and of the infra- sternal fossae is noticed. Soon, however, everything relaxes and the pupils become widely dilated; cyanosis subsides and is soon replaced by a gray, ash-like color; the lips and tongue become livid. The child is dead. No one has had time fully to realize what was going on. We have all lived through such cases and have all remained stunned and speechless at the sudden and unexpected outcome of the drama. Chronic Form of Thymic Hyperplasia. — Fortunately, all cases do not have such a fulminating character. The choking spells are not all fatal; they subside soon and are replaced by intervals of quiet and easy breathing. Often, however, the respiration remains labored all the way through the attack. These cases are the ones in which an early recog- nition of the condition and prompt surgical treatment will save the patient's life. In children what might be termed a latent thymus hyperplasia may 544 THE THYMUS GLAND exist for a longer or a shorter period of time. Such cases, as a rule, do not come under surgical jurisdiction. They are seen by the family physician who finds that the child is in poor general condition and suffering from some vague respiratory disturbances. The physician Fig. 91. — Showing how the thymus during hyperextension of the head or coughing comes up like a wedge and is caught at the superior opening of the thorax, thus compressing the trachea. may or may not connect these symptoms with thymus hyperplasia; but even if he makes a correct diagnosis the parents will likely never consider an operation necessary until more decided dyspneic symptoms are present. But unfortunately, sudden death is sometimes the first symptom which reveals the latent form of thymus hyperplasia, and in PRESSURE AT SUPERIOR OPEXIXG OF THORAX 545 a great many cases this unsuspected condition is revealed only at the autopsv. Today, however, since we know a little more of this patholog- ical condition, I believe that this fulminating form of death without any prodromic symptoms is rare. As a rule the learned physician will find in the history of these cases a few symptoms which, if well interpreted, will arouse the suspicion, at least, of a hyperplastic thymus. As in Blight's disease, so there are in thymus hyperplasia, too, some minor symptoms which will lead the physician to a correct diag- nosis. But it is just because such symptoms have not been carefully observed that the diagnosis of thymic hyperplasia is not made; as a result the child is found dead in his bed; autopsy shows a large thymus compressing the windpipe. Explanation of the Choking Spells and of Thymic Death. — How are we to explain the pathogen)' of these choking spells ? Pressure may take place at two points: i. At the superior opening of the thorax. 2. In the thorax. Pressure at the Superior Opening of the Thorax. — We know that in young infants the anteroposterior diameter of the superior opening of the thorax is quite small and that it does not exceed 2 or 3 centi- meters. Because of the relation of the thymus with the thyroid, with which it is connected by the thyrothymic ligament, the thymus will follow the up-and-down movements of the windpipe and larynx, during the various acts of swallowing, coughing, and hyperextension of the head, etc. A finger placed behind the episternal notch feels the impact of the rising thymus. Consequently the thymus when hyperplastic comes up like a wedge between the spinal column and the manubrium sterni CFig. 91). There it is caught and constricted at the superior opening of the thorax, the so-called "critical space." Inasmuch as the bony ring which forms the superior opening of the thorax is non-elastic, the organs which it contains must necessarily undergo compression. Since the trachea lies immediately below the thymus it is the first to be compressed, hence the choking spells ( Fig. 91 ). If the superior opening of the thorax cannot increase its diameter, it can, on the other hand, diminish it, for instance, in the hyperexten- sion of the head. In such cases the vertebrae are projected forward and in SO doing diminish the anteroposterior diameter of the superior opin- ing of the thorax, hence the further cause of dyspnea (Fig. 91). 1 Ins would explain wh\ m certain cases death has followed exaggerated hyper- extension of the head. With young children flattening of the windpipe will be so much the more apt to occur since in them the cartilaginous rings of the trachea are not fully developed. 546 THE THYMUS GLAND Pressure in the Thorax. — Another place at which compression of the windpipe may take place, especially in adults, is the point situated between the innominate artery and the left common carotid (Plate XXX). This compression is not confined to one ring of the trachea alone, but extends over a certain portion of it. This is easily understood when we consider the anatomical relations of the thymus to the trachea in that region. Since the thymus presses on the anterior surface of the trachea in the space between the left common carotid and the innomi- nate artery, and since the trachea lies in front of the spinal column, then in cases of sudden enlargement the thymus, being itself com- pressed between the spinal column and the sternum, must exert a compression on the trachea. Fig. 92. — Superior opening of the thorax viewed from above in order to show the ana- tomical relations of the thymus with the other organs enclosed in "bony ring." The first form of compression which takes place at the superior opening of the thorax, is found mostly in children, while the second, or thoracic form, which takes place as above mentioned, between the innominate artery and the left common carotid, is found mostly in adults. Spasm of the Glottis. — Inasmuch as the hyperplastic thymus com- presses the large vessels, namely, the aorta and the innominate trunk, and as we know, the inferior laryngeal nerve winds around these vessels, it will be easily understood that these nerves might become stretched by the displacement of these bloodvessels from the hyperplastic thymus (Plate XXX). We have already seen that irritation or stretching of the SPASM OF THE GLOTTIS 547 inferior laryngeal nerve causes spasm of the glottis, despite the fact that dilators as well as constrictors of the glottis are supplied by the same nerve, the inferior laryngeal nerve. The reason lies in the fact that the constrictors of the glottis being stronger than the dilators, irritation of the inferior laryngeal nerve by stretching must cause a spasmodic contraction, instead of a dilatation, and consequently a spasm of the glottis. In such cases tracheotomy would save the patient. In other cases I believe that direct pressure on the base of the heart and consequently on the heart ganglia, may be the cause of death. In many instances, however, thymic hyperplasia whether accom- panied or not by status lymphaticus does not interfere mechanically with the trachea, yet death takes place sometimes most unexpectedly and suddenlv. I have in mind those cases of sudden death which take place during some intense nervous excitement such as coitus, etc., those of sudden death just before or during anesthesia, and those of sudden death following a cold bath, etc. In this respect Reckling- hausen's case is an extremely interesting one. It was that of a boy who had fallen from a boat into the river, but was rescued at once before he had had time to swallow any water, yet when he was taken out he was dead. In all these above-mentioned cases the only pathological findings were a thymic hyperplasia accompanied or not by a status lymphaticus, but compression of the windpipe was not present. What, then, is the explanation of such sudden death ? Of course here everything is still hypothesis. The fatal issue in some cases may be explained by the sudden swelling of the thymus due to some exertion such as in crying, or to some interference with circulation. Possibly, in other cases the pressure over the basis of the heart, and especially over the cardiac ganglia, may have caused a sudden inhibition of the cardiac system; possibly, too, in certain vulnerable individuals with a nervous system in constant unstable equilibrium, the shock from the peripheral origin as was experienced by falling into cold water, for instance, was such as totallv to inhibit the central nervous system. Possibly, too, the laryngo- tracheal reflex caused by the first few inhalations of the anesthetic agent was powerful enough to inhibit an already unstable cardiac system. Most likely, however, in many instances the explanation must be an entirely different one, and we shall hold the solution of the problem only when the problem of internal secretion shall have been solved. As stated before, even organ contains several lipoids, each one possessing a different physiological property; the thymus and lymphatic apparatus do not escape this rule. In all marked casts of status thymolymphaticus, it has been found that a concomitanl hypo- plasia of the chromaffin system and especially of the suprarenal bodies 54S THE THYMUS GLAND was present, hence the supposition of Wiesel that because the secretion of the suprarenal bodies is insufficient there is not enough adrenalin output to entertain a normal and constant excitation of the sympathetic system which is an excitatory system; consequently since the normal equilibrium between the sympathetic and vagus, which is an inhibitory system, is disturbed, the vagal inhibitory system takes the upper hand. These views are not all purely hypothetical inasmuch as Neusser, Eppin- ger and Hesse have shown that the thymic hormone is antagonistic to Fig. 93 adrenalin and is vagotonic. As said before, it has been shown experi- mentally that after extirpation of the thymus there is a marked hyper- plasia of the cortical portion of the suprarenal bodies. Furthermore, we know that usually such individuals with status thymolymphaticus are vagotonic; they perspire freely, their respiratory rhythm is easily affected, their blood-pressure is below normal and their arterial system is lypotonic. Diagnosis of Thymus Hyperplasia. — No matter what the accepted explanation may prove to be, all our efforts should be directed toward detecting the presence of thymus hyperplasia whether accompanied or not by status lymphaticus. In children the diagnosis is, as a rule, DIAGNOSIS OF THYMUS HYPERPLASIA 549 easy. Percussion over the manubrium sterni reveals a dulness which, in cases of marked hyperplasia, overlaps on each side the ribs and carti- lages (Fig. 93). Auscultation over that region reveals a prolonged expiration tubular in character. A finger placed above the episternal notch may not be able to feel the impact of the rising thymus during deglutition, coughing, etc. But the most certain wav to detect in 94 children thymus hyperplasia is given by the .v-ray 1 Fig. 94): the shadow, its form and location are, so to speak, pathognomonic and the diagnosis may be made with certainty. In adults, however, the diagnosis becomes more difficult. '1 he dulness may be present, bur ma\ be absent, too. The shadow of the mediastinal space may often be typical, and allow a diagnosis, yet sometimes great difficulties arc- encountered in deciding 550 THE THYMUS GLAND whether we have to deal with a thymus hyperplasia or not. One of my cases will illustrate this proposition very well. My clinical examina- tion did not reveal any symptoms pointing toward thymic hyperplasia, consequently I decided clinically that a thymus was not present, yet the .x-ray showed a shadow with some of the characteristics of thymic hyperplasia. I consequently concluded that I had been misled by my clinical findings, and that my conclusions were erroneous. However, not long after, a postmortem showed that no thymic enlargement was present. X-ray Characteristics of Thymic Hyperplasia. — Normally, on a skia- gram, the mediastinal space measures from 2.5 cms. to 3.5 cms. under the arch of the aorta; from 3 to 3.5 cms. at the arch of the aorta, and from 5 to 6 cms. at the conus arteriosus. The shadow of this region is dark, opaque, regularly distributed, and has definite limits. But in thymus hyperplasia there is a shadow which overlaps laterally this mediastinal shadow. The shadow may be found over one lobe more than over the other, or over both lobes in the same proportion. The shadow may be more or less triangular in shape, and may extend upward from the region of the auricle in a straight line or may follow to some extent the contour of the mediastinal shadow. Sometimes the region of one or both auricles may bulge out as if the auricles were overdistended, thus forming an angle between the ventricle and the auricle. In that case the base of the heart is enlarged and the enlargement is not in pro- portion to the size of the heart. The thymic shadow in some cases is superimposed on the base of the heart like a cap which fits right over the base of the heart. The character of this shadow differs extremely from the cardiac and mediastinal shadows. It is thin, transparent, soft, and regularly distributed and the edges are, as a rule, sharply limited and linear. Differential Diagnosis of Thymic Hyperplasia. — It would be a mistake to believe that thymus enlargement is the only cause which may give a congenital stridor and respiratory trouble. Such conditions may also be found with malformations of the vestibulum of the larynx, with tracheobronchial glands and with adenoids. An accurate differential diagnosis must be made between these different forms of stridor. The congenital vestibular stridor is seen after birth. It is entirely inspiratory and is not found on expiration, except in rare cases. Cyano- sis is present, too, but the stridor and dyspneic symptoms disappear with intubation of the larynx, which is not the case for thymic dyspnea in children. The laryngoscopy examination when possible and the autopsy will show that this stridor is due to a malformation of the superior opening of the larynx. The epiglottis has a gutter or beak- like form, and is folded in the middle line. The plicae aryepiglotticae RELATION OF HYPERPLASIA TO BASEDOW'S DISEASE 551 of both sides come in contact one with the other; they are pulled down over the opening of the larynx and so diminish the orifice, hence dyspnea and stridor. Stridor due to tracheobronchial glands is found mostly on expiration and with it the voice has a bitonal character. Furthermore, the thymic stridor is congenital; the tracheobronchial stridor is acquired. Percus- sion and radioscopy will reveal entirely different findings. In adenoids there may be difficult and labored breathing which is more noticeable during sleep, but in such cases diagnosis will be easv. Thymic stenosis should not be mistaken for a retrovertebral abscess or for an acute laryngitis. In laryngismus stridulus the period of apnea is short, and respira- tion soon begins again. During the intervals it is usually normal. It is always a manifestation of a spasmogene diathesis and, furthermore, is always accompanied by other spasms or other stigmata (Erb's, Chvostek's, and Trousseau's symptoms). Inasmuch as the hyperplastic thymus may come in contact with and compress the right and left auricle and ventricle, the superior vena cava, the aorta, the innominates, and the left common carotid, cyanotic symptoms, characterized by distention of the veins of the neck, bv puffi- ness of both supraclavicular spaces, and by cyanosis of the face and distention of the large fontanelle, may be present. During paroxysm these symptoms become extremely marked. The veins of the neck are much distended and the fontanelle protrudes; the face is puffed and the child is in a semicomatose condition. The heart beats violently, or in certain cases stops altogether. When the paroxysm is over these symp- toms retrocede, but in other cases death ensues. Autopsy shows that compression of the right ventricle and of the superior vena cava and aorta is very marked. In such cases the dyspneic symptoms are of secondary importance. The vascular symptoms dominate the scene and extreme repletion of the face and neck, distention of the large fon- tanelle, and the tendency to collapse will differentiate this form of cyanosis from the ones due to malformation of the heart. In blue babies the cyanotic condition of the patient is uniformly distributed and persistent. Relation of Thymic Hyperplasia to Basedow's Disease. For a long time the presence of thymic hyperplasia in connection with Basedow's disease was thought to be only a coincidence, but in late years the facts have become so numerous and so convincing that it is no longer possible to deny that there is an intimate relation between the presence of thy- mic hyperplasia and Graves' disease. Rossle reports a series of ^2 eases of hyperthyroidism with thymus hyperplasia. McCardi, in 35 cases of sudden death in hyperthyroidism, found is cases with thymic 552 THE THYMUS GLAND hyperplasia. Rehn, in 319 cases of Graves' disease treated surgically, had 42 deaths. Six patients died with extremely marked dyspneic symptoms. In the literature Matti found 183 cases of hyperthyroidism in which postmortem had been held, and in 98 cases, making 74 per cent, of the total number of cases, hyperplastic thymuses were found. Kapelle, in 59 postmortems of Basedow cases, found that thymic hyperplasia was present in 79 per cent, of the cases. These figures show that thymic hyperplasia in combination with Graves' disease, is very frequent. I have reported sev- eral cases of thymic hyperplasia and Basedow's disease corroborated by postmortem (Fig. 95). The importance of such facts is great, and whenever it is possible the probable presence of thymic hyper- plasia should be ascertained before attempting thyroidectomy or at the time of the operation. Remarkable, and somewhat disconcerting, is the fact that thymus hyperplasia is very much less apt to be found in very severe and protracted cases of Graves' disease than it is in the earlier forms. Already in 1908 Hart came to the conclusion that besides a thyroid Base- dow there could be such a thing as a thymus Basedow, the latter form being characterized by the same cardinal symptoms as those seen in thyroid Basedow. These views have been up- held by Kappelle, Bayer, Bircher, and Klose. Bircher reproduced experimen- tally in dogs a Basedow's disease by injecting thymus products into the peritoneal cavity; tachycardia, nerv- ousness, tremor, exophthalmos, were Fig. 95. — Thymic hyperplasia and T , , , „ , , ,. present. 1 have repeated these exper- rJasedow s disease, a postmortem speci- r r r men. Note that the thymus covers the iments several times, and although I heart entirely. was not able to obtain the symptoms THYMOGEXE BASEDOW 553 with the same intensity as Bircher, yet I was able to see the same cardinal symptoms moderately developed. Lately Svehla has asserted that the thymus gives off an internal secretion, and thinks that death is due to this substance acting on the heart and nervous system. By injecting a watery solution into animals, Svehla found a diminution in the blood-pressure and increased rapidity of the pulse. Repeated injections caused the death of the animals; therefore he considers the mors thymica as a consequence of hyperthy- mization resulting in a diminution of the blood-pressure. There is unquestionably a synergic action between the thyroid and the thymus; one activates the other, and vice versa. This seems to be demonstrated bv cases of Basedow's disease where surgical interference on the thyroid did not give the expected results, but where the cure was secured most rapidly and most completely by adding to it the removal of the thymus. Such cases have been shown by Garre, Kapelle and Barer. Von Haberer's case in that respect is most instructive. The patient was a man suffering with the most intense hyperthyroidism accompanied by marked choking spells. Ligation and thyroidectomy were performed br eminent surgeons, one of them none other than Kocher, ret the improvement of the patient was only slight and tem- porary, so that he soon fell back into a pitiful condition which was con- sidered hopeless. Besides the thyrotoxic symptoms the dyspnea w T as intense and the condition of the heart was so bad that death was looked for at anr time. Von Haberer decided to attempt the removal of the thrmus, but at the operation was very much disappointed to find no trace of thrmus; all that he was able to remove was a small piece of fat which, nevertheless, proved under microscopic examination to contain some thymus gland. From the time of this operation on, the improve- ment of the patient was so marvelous that he recovered rapidly and entirely. Thymogene Basedow. — We may say, consequently, that the majority of cases of Graves' disease are of thyroid origin, but that their intensity may be increased by a concomitant thymic hyperplasia. In other words, the deleterious effects of the two glands sum each other up; consequently the presence of a thymic hyperplasia in Graves' disease must always be looked for, and must always he regarded as a complication. We may, furthermore, admit that we may have some eases of Graves' disease of purely thymic origin, as we have cases of Graves' disease of purely thyroid origin. Finally, we may have both forms combined. Differential Diagnosis between Thymic and Thyroid Basedow. It all these conditions are true, it will then be necessary to ascribe to ever} case of Graves' disease its true origin. In other words, we shall have to decide if we have to deal with a thyroid, or a thymic, Basedow, or a 554 THE THYMUS GLAND mixed one. Let it be said right now that in the greatest number of cases we shall have to deal with a thyroid Basedozv. This form, however, may be combined with the thymic Basedow. The pure form of thymic Basedow is rare. How are we going to differentiate these two forms ? As was seen in the chapter on Basedow's Disease, in many cases there is a certain group of symptoms which seem to be more dependent upon the excitation of one of the two nerves of vegetative life, the vagus and the sympathetic. If the predominating symptoms are of vagus origin, the case is called vagotonic. If, on the other hand, the predominating symptoms are of sympathetic origin, the case is called sympatheticotonic. We have seen, too, that according to Eppinger and Hesse, the vagotonic symptoms are: i. A moderate degree only of tachycardia, but intensely marked subjective symptoms. 2. A marked Graefe symptom with pronounced enlargement of the eyelids, accompanied, however, by a moderate exophthalmos, but with no Moebius. The lachrymal secretion is increased. 3. Profuse perspiration. 4. Diarrhea, hyperacidity, vomiting. 5. Increased eosinophilia. 6. Alimentary glycosuria. According to the same authors the sympatheticotonic symptoms are: 1. A marked exophthalmos but no Graefe; with positive Moebius; and with suppressed lachrymal secretion. 2. Pronounced tachycardia, however, with only moderate subjective symptoms. 3. No perspiration, no diarrhea, no vomiting. 4. Marked falling of the hair. 5. No eosinophilia, no alimentary glycosuria. 6. Occasionally a slight increase in temperature. According to Eppinger and Hesse the vagotonic symptoms are pro- duced by a thymic hormone which would act as an excitant of the vagal system. It is not, however, demonstrated beyond all doubt that all the symptoms considered as vagotonic are really of such origin. The same is true for the sympatheticotonic symptoms. There will be needed further work in order to throw light upon that subject. So far the true thymogene Basedow is still difficult to diagnose beforehand. As a rule this diagnosis is made only retrospectively after the thyroid has been removed, and after it is found that the micro- scopic examination does not show the typical microscopic changes in the thyroid known as pathognomonic of the disease, and after one sees that the clinical results do not come up to the expectations; only then TREATMENT OF THYMIC HYPERPLASIA 555 the idea of a thymic Basedow dawns upon one's mind. Unfortunately, the ff-rays as a diagnostic means in adults have not proved as useful as I thought they would. In a series of several hundred goiters of all kinds, I have systematically made a Roentgen examination. In many instances I was able to demonstrate beforehand the presence of an enlarged thymus, but others in which, according to the radiograms, no thymus was present, I was very much surprised to find at the time of the operation quite an important thymic enlargement. A symptom which I think is of good diagnostic value in diagnosing thymic hyper- plasia complicating a Basedow case, is marked muscular asthenia. Furthermore, the presence of small lymph nodes in the cervical region must be regarded, in my judgment, as a strong presumption in favor of the presence of thymic hyperplasia; in fact, the)' belong to the status thymolymphaticus. Lymphocytosis has been the subject of much discussion. It was at first considered as of thyroid origin, but lately the number of research workers is constantly increasing who seem to be inclined to believe that lymphocytosis is due to thymic hyperplasia. In conclusion I believe that: Although the question is far from being settled, nevertheless a high lymphocytosis with moderate enlargement of the thyroid; a moderate tachycardia, but with intense subjective symptoms; the presence of small cervical lymph nodes; an increased area of dulness over the manubrium sterni; a prolonged expiration over this area with a character which is truly tubular; all these symptoms together with a positive .v-ray are strongly suspicious of a thymic hyperplasia. Treatment of Thymic Hyperplasia Complicating Graves' Disease. — From what has been stated, it follows that thymic hyperplasia in goiter surgery can no longer be disregarded. It is a serious complication which occurs not only in Graves' disease, but in simple goiter also. It is liable to kill the patient either by choking him, or by causing a thymic intoxi- cation leading to hyperthyroidism, hyperthymism, and possibly to acidosis. What shall we do then ? Simply remove the thymus. Sim- ply combine thymectomy with thyroidectomy. And that is just what 1 have been doing in the past few years in every goiter case that has come my way. In every case as soon as thyroidectomy is terminated, 1 explore systematically the mediastinum and whenever thymus is found, it is removed. In so doing, not only the remote results are better, but the postoperative course is also far more satisfactory. First of all, the possibility <>f a mechanical thymic death is eliminated, and this, cer- tainly, is a great relief. Always before tins, after a thyroidectomy, I felt exceedingly uneasy and anxious for twenty-four hours because at any time a choking spell was liable to occur. 1 here are no more such fears for me now. 556 THE THYMUS GLAND Furthermore, the postoperative reaction which so often follows an operation for goiter, but especially the thyrotoxic one, is unmistakably better; temperature is not so high; nervousness is not so extreme; delir- ium is far less marked; acidosis is less severe and what is more the death- rate is certainly less. All told, I consider this combined operation a great step forward in the surgical treatment of Graves' disease. Treatment of Thymic Hyperplasia in Children. — In cases of thymic hyperplasia in children, if the mechanical symptoms are alarming, I operate at once. What is the use of running the risk of losing the little patient by trying any other method of treatment when the operative treatment is still safe ? Two of my cases which had a marked thymus hyperplasia and in which the thymus compressed not only the trachea but also the esophagus, gained an ounce the same day that thymectomy was performed, and continued to do so for two weeks after; in three months the two little patients had become prosperous and healthy. Several others who had choking spells increasing constantly in intensity, so much so that when brought for operation they were between life and death, as soon as thymectomy was performed, soon breathed regularly and regained perfect health. If, however, operation cannot be performed because of impending death, intratracheal rubber tubes should be introduced, either through the larynx or through a tracheotomy opening. It is important to make sure that the tube opens at the end and not on the side. It is important, too, to extend the tube well into the trachea so as to pass the point of compression. We must remember, however, that tracheotomy ought to be resorted to as a last measure, because we know by experience that tracheotomy combined with thymectomy is usually fatal on account of postoperative bronchopneumonia, and especially mediastinitis. If the choking spells are not alarming, x-ray treatment is the method of choice. PLATE XXX II > -# Thymectomy. After the sternohyoid and the sternothyroid muscles have been separated in the middle line and reclined, a more or less round mass is often seen bulging upward with each expiration and disappearing again with each inspiration. That is the thymus. FIG. 2 Thymectomy. If the thymus is grasped between two forceps and its capsule cut, the thymic paren- chyma bulges <>ur as if under pressure, especially with each expiration. CHAPTER LI I. SURGICAL TECHNIC OF THYMECTOMY. Anesthesia. — In adults it is self-evident that almost invariably thymectomy should be performed under anesthesia. In children, espe- cially in newborn, the dyspnea may be so intense that anesthesia, no matter what form, may only increase the dyspnea, consequently in such conditions the operation may have to be performed under local anesthesia or without anesthesia at all, as in newborn for instance. In the great majority of cases, however, it is better to resort to complete anesthesia, as the crying from pain will only increase the congestion of the thymus and consequently increase the dyspnea. In small children chloroform seems to be preferable to ether. M. mylohyoideus Os Viyoideuan "Plafysma. M. sterjw-hyoideus Storna-cloido-mciAtoidei _ _M. stei'nO- Inyreoideus Fig. 96. — Anatomv of the muscles involved in performing thymectomj Surgical Technic. 1. A short transverse incision is made just above the manubrium sterni. The skin is cut and the two Maps are retractedj one upward and the other downward. 2. The superficial cervical fascia is clamped between two forceps and CUt in the middle line. (Plate \X.\1, Fig. 1.) 558 SURGICAL TECH NIC OF THYMECTOMY 3. The prethyroid muscles are separated in the middle line and retracted laterally. (Plate XXXI, Fig. 2.) 4. After the sternohyoid and the sternothyroid muscles have been separated in the middle line and retracted, one often sees a more or less round mass bulging upward with each expiration and disappearing again with each inspiration. That is the thymus. (Plate XXXII, Fig. 1.) In children, and sometimes in adults, the hyperplastic thymus reaches the lower pole of the thyroid so it is easily discovered. 5. The thymus is then clamped between two hemostats and pulled gradually upward. Great care should be taken in clamping every bit of loose tissue around the capsule of the thymus so as to catch every small vessel. In the great majority of cases resection of the thymus is better made extracapsularly, as usually the thymus is easily loosened from the sur- rounding structures. Whenever, however, there is some perithymitis and consequently there is some difficulty in getting the thymus up, it is better then to perform an intracapsular thymectomy as shown in Plate XXXII, Fig. 2. The glandular capsule of the thymus is then opened and as soon as this is done the thymic parenchyma bulges out as if under pressure, especially with each expiration. The parenchyma is then shelled out slowly, gradually, and more or less easily. As said before, however, at least in my experience, the extracapsular method is the one of choice, provided one takes a great deal of pains to clamp every par- ticle of loose connective tissue in connection with the thymus. In the numerous thymectomies which I have performed, I have never met with an unpleasant hemorrhage following this mode of operating. 6. When sufficiently isolated the thymus is then ligated snugly at its basis (Plate XXXIII, Fig. 1) in order to catch the few thymic vessels which supply the gland and it is cut far enough from the ligation to prevent the ligature from slipping. If this should happen, a hemorrhage almost impossible to check except by packing will occur. 7. After all ligations of the clamped vessels have been performed, the prethyroid muscles are sewed up again in the middle line by run- ning suture or by one or two interrupted stitches. (Plate XXXIII.) 1 he subcutaneous tissue and platysma are sewed up by continuous running suture, and intradermic suture is performed. PLATE XXXIII FIG. 1 :«# Thymectomy. When isolated, the thymus is ligated snugly at its basis in order to catch the few thymic vessels and it is cut far enough so as to prevent the ligature from slipping, thus causing a hemorrhage almost impossible to check except bv packing. FIG. 2 J* Thymectomy. 'I he prethyroid vessels art' then sewed together in the middle line, subcutaneous tissue is sutured by itself and intradermic suture is performed. INDEX Acapnia, 511 Accidents, operative, 478 Acidosis, 521 Adenocarcinoma, 67 Adenoma, fetal, 57, 64 malignant, 67 Adrenalin, chloride, 502 opotherapy, 428 Adrenalinemia, 353 Adrenals, 390 Air embolism, 481 Albuminuria, 358 Anatomical facts of thyroid, 440 conclusions from, 448 Anatomopathological relations of goiter, 1 1! Anatomy, 17 pathological, 1 15 Anesthesia, 494, 557 general, 495, 498 intratracheal insufflation, 506 local, 495, 498, 501 technic of, 502 Antithyroid chymotherapy, 426 Antitoxic action of thyroid, 53 Antitrypsin content of blood, 354 Aortic goiter, 87 Aphonia, 344 Appetite, 340 Arginine, 38 Vrsenic, 287 in thyroid, 50 Artery, ima, 20 inferior thyroid, 20, 125, 462 parathyroid, 446 superior thyroid, [9, 124, 462 Athyroidism, congenital, i<;o, 203 differential diagnosis, 210 (I iologV of, 203 opotherapy in, 2SS s\ mptoms, 207 surgical, i«>o, 196 opotherapy in, 2XS S3 mptoms of, [96 B Ham dow iodin, $93 struma, 311 Basedow thymic and thyroid, differential diagnosis of, 553 thymogene, 553 thymus, 552 thyroid, 552 Basedowified goiter, 311, 312, 434 Basedow's disease, 303. See Graves' dis- ease, relation of thymic hyperplasia to, 551. thyroiditis and, 396 Benign goiter, 58 Blood, antitrypsin content of, 354 changes, 349 coagulability of, 352 deficiency of carbon dioxide in, 511 pressure, 3 10 supply, 19. 442 Bloodvessels, relation of goiter to, 124 Bodies, postbranchial, 27 Breath, shortness of, 343 Cachexia strumipriva, 182, 189, 190 surgical, 196 symptoms of, 196 thyreopriva, 31, 183. 189, 190 Cancer, 65, 66 aneurysmal, 176 course and symptoms of. 175 diagnosis of, 178 treatment of, 179 Cancroid. 76 Canthorraphy, 487 Carbon dioxide, deficiency of, in blood. ;ii Carcinoma, 70 sarcomatodes, So Cardiac spasm, ? ' • Cardiopathic goiti r, 133 Cardiovascular symptoms, 303, 304 Chemistry, biological, 42, 405, 514 Chloroform, 1.98, 1.99 Choking spells, thj mic, 343 Chorea, }?S Ch\ ostek symptom, 525 ( 'In motherapy, antii nj roid, \-<< Circular goit< r, 122, [63 diagm isis of, 1 63 s\ mptoms of, 1 ' 1 560 INDEX Circular goiter, treatment of, 164 Cleavage, pathological planes of, 442 Coagulability of blood, 352 Collapse of trachea, 479 Colloid, 22 desquamation of, 23 goiter, 57, 61, 166 diffuse, 62 Congenital goiter, 166 symptoms of, 167 treatment of, 168 Constipation, 341 Contagion by contact theory, 265 Coughing, 344 Cretinism, 203 differential diagnosis of, 210 economical significance of, 227 endemic, 189, 190 etiology of, 204, 220 fluctuations of, 234 geographical distribution of, 221 military significance of, 227 opotherapy in, endemic, 289 social significance of, 227 sporadic, 190 symptoms of, 207 Cretinoids, 21 1 Crotti's formulae for non-toxic parenchyma tous goiter, 281 for exophthalmic goiter, 428 technic of indirect transfusion, 518 treatment for exophthalmic goiter, 428 for non-toxic parenchymatous goi- ter, 281 Cutaneous symptoms, 347 Cyst, false, 62 hydatid, 1 13 median, 83 true, 62 Cystic goiter, 166 D Dallrymple symptom, 319, 322 Danger zone, 441, 442, 448, 462, 471 Deaf- mutism, 223 Death, goiter, 162 sudden, 300 thymic, 545 Delirium, acute, 336 Dermographism, 347 Dermoids, 59, 81 Desquamation of colloid, 23 Diabetes, 356 Diagnosis of circular goiter, 163 differential, of cancer, 178 of congenital athyroidism, 210 of cretinism, 210 of intrathoracic goiter, 155 of spontaneous infantile hypothy- roidism, 210 Diagnosis, differential, of thymic hyper- plasia, 550 and thyroid Basedow, 553 of thyrotoxic tachycardia, 304 of goiter, 130 of intrathoracic goiter, 152 of malignant goiter, 178 of strumitis, 98 of thymic hyperplasia, 548 of thyroiditis, 98 Diarrhea, 341 Diet, 420 Diffuse goiter, 57, 58 Digestive disturbances, 339 Disease, Basedow's. See Graves' disease. thyro-neuro-polyglandular, 372, 393, 403 Duct, lingual, 25 thymopharyngeal, 537 thyroid, 25 Dysphagia, 127 Dyspnea, 126 Dyspneic symptoms, 313 Dysthyroidism, 370, 401 E Edema of eyelids, 325 Electrotherapy, 421 Embolism, air, 481 Embryology, 23 Emotionality, 334, 336 Endothelioma, 79 Enucleation, 448, 450, 453 Enucleoresection, 453 Epidemics, goiter, 228 Epithelial neoplasms, 65 Erb symptom, 528 Esophagus, injury to, 481 relation of goiter to, 123 Ether, 498, 499 Etiology of congenital athyroidism, 203 of cretinism, 204, 220 of exophthalmos, 326 of goiter, endemic, 220 theories regarding, 341 of Graves' disease, 370 of hypothyroidism, 198 of infantile hypothyroidism, 204 of spontaneous adult hypothyroidism, 289 of strumitis, 93 of thyroiditis, 93 Excision, 448, 449 Exhaustion, vasomotor, 509 suprarenal, 512 Exophthalmic goiter, 60, 303 Crotti's treatment for, 428 eyelid symptoms in, 322 in pregnancy, 367 treatment of, 368 IXDEX 561 Exophthalmos, 303, 319 bilateral, 320 etiology of, 326 unilateral, 319 Exothyropexy, 374 Fibrosarcoma, 77 Fibrous goiter, 63 Flatulence, 340 Ganglion cells, morphological changes in, 5 1 . 1 Genital apparatus, 105 disturbances, 342 system, 389 Glands, accessory, 27 Glottis, spasm of, 546 Glycogen-containing goiter, 72 Glycosuria, 356 Goiter, accessor}', 27, 59, 82 anatomopathological relations of, 118 and radio-active waters, 262 in animals, 236 aortic, 87 Basedowified, 311, 312, 434 benign, 58 cardiopathic, 133 in children, 169 circular, 122, 163 diagnosis of, 163 symptoms of, 163 treatment of, 164 clinical symptoms of, 126 colloid, 57, 61, 166 congenital, 166 symptoms of, 167 treatment of, 168 Crotti's treatment for, 281 cystic, 166 death, 160 diagnosis of, 130 diffuse, 57, 58 colloid, 62 nodular, 62 dislocation of, 471 endemic, economical significance of, 227 etiology of, 220 fluctuations of, 232 geographical distribution of, -21 military significance of, 287 social significance of, 227 water and, 242 epidemics, 228 exophthalmic, 60, 203 (Yoi ti's treatmeni for, 42K eyelid symptoms in, t,zz 36 Goiter, exophthalmic, in pregnancy, 367 treatment of, 368 fibrous, 63 glycogen-containing, 72 heart, mechanical, 133 thyrotoxic, 136, 307 heredity- in, 248 intrathoracic, 240 accessor}', 186 diagnosis, 152 differential, 155 operation for, 475 prognosis of, 159 relation to neighboring tissues, 142 symptoms of, 143 intratracheal, 165 lingual, 85 malignant, 58, 65 clinical aspects of, 173 course and symptoms of, 175 diagnosis of, 178 forms of, 80 relation to structures, 178 technic of operation for, 477 treatment of, 179 mechanical symptoms of, 126 median, 122 metastatic colloid, 70 nodular, 57, 58, 119 colloid, 62 relation to bloodvessels, 124 non-toxic vascular, 63 ovarian, 87 parenchymatous, 57, 60, 166, 167 diffuse, 118 pendulous, 1 19 plunging, 141, 160 postbranchial, 73 proliferating, 67 pyramidal, 122 relation to larynx and trachea, 120 to nerves, 125 to pharynx and esophagus, 123 to skin and muscles, 119 retro-esophageal, 175 retrotracheal, [65 simple, indications for operation, 295 medical treatment, 276, 277 pregnancy and, 175 t rear men t of, 171 thyrotoxic, consistency of, 312 histology of, 315 pathology of, 315 surface of, 313 \ olume of, 5 1 _ \ ascular, 58, 63, 166 ( Iraefe S3 mptom, } 10. 322 ( irafting of parai In roids, 532 of thyroid, 291 ( Iraves' disease, .unit- delirium in, 336 adrenalin in, 428 adrenalinemia in, 5 5 j 562 INDEX Graves' disease, albuminuria in, 358 antitrypsin content of blood in, 354 appetite in, 340 blood changes in, 349 brown pigmentation of skin in, 348 chorea in, 338 coagulability of blood in, 352 constipation in, 341 coughing in, 344 Crotti's treatment for, 428 cutaneous symptoms in, 347 Dallrymple symptom in, 322 dermographism, 347 diabetes in, 356 diarrhea in, 341 diet in, 420 digestive disturbances in, 339 disturbances in metabolism in, 355 edema of eyelids in, 326 electrotherapy in, 421 emotionality in, 334, 336 etiology of, 370 eyelid symptoms in, 322 falling of hair in, 348 flatulence in, 340 fulminating forms of, 358, 436 genital disturbances in, 342 giving away of knees in, 331, 333 glycosuria, 356 Graefe symptom in, 322 headache in, 345 heredity in, 338 hoarseness in, 344 hydrotherapy in, 421 hyperglycemia in, 354 hyperh) drosis in, 347 hypophysis in, 428 hysteria in, 336 indications for surgical treatment, .430 insomnia in, 345, 346 instability in, 334, 335, 336 irritability in, 344, 336 is a medicosurgical disease, 438 is a toxic thyroiditis, 399, 404 itching of skin in, 347 Kocher symptom in, 323 lachrymal secretion in, 325 leukopenia in, 349, 350 loss of flesh in, 355 medical treatment for, 407, 417 medication in, 419 mental symptom in, 334 Moebius symptom in, 324 muscular cramps in, 333 fatigue in, 332 symptoms in, 331 nausea in, 340 nervous origin of, 382 symptoms of, 334 neurasthenia in, 337 numbness in, 346 Graves' disease, ocular symptoms in, 319 pains in, 345 pancreas opotherapy, 428 parathyroid opotherapy, 428 pathological arguments, 375 polydipsia in, 358 polyglandular medication in, 427 origin of, 388 polyuria in, 357 radiotherapy in, 422 respiratory disturbances in, 343 rest cure for, 417 restlessness in, 334, 335, 336 results of medical treatment, 408 sensations of heat in, 347 sensory disturbances in, 345 serotherapy in, 426 shortness of breath in, 343 staring look in, 325 Stellwag symptom in, 324 temperature in, 355 tendinous reflexes in, 333 tingling in, 346 treatment of, 405 for each case, 434 of thymic hyperplasia compli- cating, 555 tremor in, 331 thymus opotherapy in, 328 thyrogenetic origin of, 372 thyrotoxic symptoms in, 359 urticaria in, 348 vertigo in, 346 vomiting in, 340 when cured?, 415 H Hair, falling out of, 348 Headaches, 345 Heart, mechanical goiter-, 133 test of functional capacity of, 310 thyrotoxic goiter-, 136, 307 Heat, sensations of, 347 Hematoma, postoperative, 534 Hemorrhage, treatment of, 515 Hemostasis, 466 Heredity in goiter, 248 in Graves' disease, 338 Histology of goiter, 21 of thyrotoxic goiter, 315 Hoarseness, 344 Hydrotelluric theory, 249 Hydrotherapy, 421 Hyperhydrosis, 347 Hyperlymphocytosis, 349 Hypersecretion, 370 Hyperthyroidism, 303, 363, 370, 372, 400, 434 . fruste forms of, 360, 437 infantile, 365 IXDEX 563 Hyperthyroidism, juvenile, 365 postoperative, 519 small, 360 Hypertrophy, thyroid, 303 Hypoglycemia, 354 Hypophysis, 55, 195 in opotherapy, 428 in thyroid, 389 Hypopolynucleosis, 349, 350 Hypothyroidism, 51, 182, 190, 363, 372, 417 etiology of, 198 fruste forms, 190 relationship of forms of, 187 spontaneous, 190 adult, 198 opotherapy of, 289 symptoms of, 200 infantile, 203 differential diagnosis of, 210 etiology of, 204 opotherapy of, 288 symptoms of, 207 surgical, 190 Hysteria, 336 Icterus, 341 Idiocy, 188, 189, 203 with pachydermic cachexia, 189 Incision, 469 low collar, 469 Infection theory, 272 Inflammations, 59 Ingestion method of treatment, 285 Inhibition of the function of organs, 511 Injections, boiling-water, 487 technic of boiling water, 488 treatment with, 300 Injury to trachea, esophagus, and pleura, 481 Insomnia, 345, 546 Instability, 334, 335, 336 Insufficiency, to prevent thyroid, 41 treatment of thyroid, 283 Insufflation, intratracheal, 506 Internal secretion, 55 functional interrelation of organs of, 55 Intrathoracic goiter, 140 accessory, 86 diagnosis of, 1 52 differential, 1 55 opera nun for, 475 prognosis of, 1 59 r< la t ion to neighboring tissues. 14: s\ mptoms of, 1 43 Intratracheal goiter, 165 lodin- Basedow, 593 medication, dangers of, 282 in tin roid gland, 44 in treatment of goiter, 271; Iodism, constitutional, 393 Iodothyreoglobuhn, 42, 52 Irritability, 334, 336 Isthmus, 17 Itching of skin, 347 K Katzenstein test, 310 Knees, giving way of, 331, 333 Kocher-Reverdin controversy, 182 Kocher symptom, 319, 323 Lachrymal secretion, 325 Laryngoscopic examination, 131 Larvnx, relation of goiter to, 120 Lesions of the nerves, 478 Leukopenia, 349, 350 Ligaments, suspensory, 19 thyrothymic, 538 Ligation, 458 indications for, 460 intracapsular, 462 isolated, of inferior thyroid arterv, 464. 465 of superior pole, 464 point of election for, 462 technic of, 463 Lingual duct, 25 goiter, 85 Lobes, 17 Loss of flesh, 355 Lymphatics, 23 M M m.h.n w 1 goiters, 58 clinical aspects of, 173 diagnosis of, 178 forms of, 80 mechanical symptoms of, 126 relation to surrounding tissues, [73 treat nun t of, I Ji) Median goiter, 1 22 Medicaments, 271; Medication, dangers of iodin, 282, 41 9 polyglandular, 427 Mental symptoms, 334 Metabolism, disturbances in, 555 Metastases, 65 Metastatic colloid goiter, 70 Moebtus symptom, j 19, ;:| Muscles, relation of goiter to, 1 1 9 Muscular cramp, j j j fatigue, 531, 332 s\ mptoms of, j j 1 s\ stem, ^41 564 INDEX Myxedema, 31, 32, 33, 182, 189, 192 infantile, 188, 189 operative, 182 Myxedematous, dystrophia, 189 infantilism, 189 Myxosarcoma, 79 N Nanism, 188, 203, 208 Nausea, 340 Nerve, hypoglossus, 129 phrenic, 129 spinal, 129 sympathetic, 129 Nerves, lesions of, 478 recurrent laryngeal, 447 relation of goiter to, 125 vagus, 129 Nervous symptoms, 334 system in thymectomy, 540 vegetative, 385 Neurasthenia, 337 Nitrous oxide, 498, 499 Nodular goiter, 57, 58, 119 colloid, 62 Non-toxic vascular goiter, 63 Novocain, 501 Nucleoproteid, 43 Numbness, 346 O Ocular symptoms, 319 Operating room technic, 491 Operation, bilateral, 454 contra-indications for, 299 for intrathoracic goiter, 475 indications for, 295 technic of, for malignant goiter, 477 upon thyroid gland, 439 unilateral, 454 Operative accidents, 478 Opotherapy, adrenalin, 428 Crotti's treatment, 428 dangers of thyroid, 283 in endemic cretinism, 289 hypophysis, 428 opotherapy in congenital athyroid- ism, 288 in spontaneous adult hypothyroid- ism, 289 infantile hypothyroidism, 288 in surgical athyroidism, 288 pancreas, 428 parathyroid, 428 thymus, 428 thyroid, 283 Organic theory, 263 Origin of Graves' disease, nervous, 382 Origin, polyglandular, 388 thyrogenetic, 372 arguments from thyroid opother- apy, 379 experimental arguments, 376 pathological arguments, 375 surgical arguments, 381 Osseous system, 193 Ovarian goiter, 87 Pains, 345 Palpitation, 307 Pancreas, 390 opotherapy, 428 Pantopon-scopolamin, 507 Papilloma, 74 Paralysis, 331, 509 Parastruma, 58, 72 Parathyroids, 32, 392, 445 grafting of, 532 number removed before tetany appears, 529 opotherapy, 428 shall we dissect?, 458 Parenchymatous goiter, 57, 60, 166, 167 diffuse, 118 Paresis, 331 Pathological anatomy, 115 planes of cleavage, 442 Pathology, 57 of inflammation of thyroid, 95 of strumitis, 95 of sympathetic, 483 of thyroid insufficiency, 191 of thyrotoxic goiter, 315 Pendulous goiter, 119 Perithelioma, 80 Pharynx, relation of goiter to, 123 Phosphorus in the thyroid, 50 Physiology of thyroid, 30 history of, 30 Pigmentation, brown, of skin, 348 of eyelids, 326 Pleura, injury to, 341 Plunging goiter, 141, 160 Plutonian theory, 359 Polydipsia, 358 Polyglandular medication, 427 origin of Graves' disease, 388 treatment, 290 Polyuria, 357 Portion of thyroid to leave, 41 Postbranchial bodies, 27 goiter, 73 Postoperative complications, 509 dysphagia, 534 fever, 523 hematoma, 534 hyperthyroidism, 519 IXDEX 565 Postoperative tetany, 524 prognosis of, 530 symptoms of, 524 treatment, 493 Pregnancy, exophthalmic goiter and, 367 simple goiter and, 170 Preoperative treatment, 489 Proliferating goiter, 6j Prophylaxis, 276 Pulmonary complications, 533 Pulse, thyrotoxic, 309 Pyramidal goiter, 122 process, 18 R Radiotherapy, 422 Regulating action, 55 Repin's theory, 259 Resection, 448, 449, 452, 453 bilateral, 456 cuneiform, 452, 473 enucleo-, 453 transfrontal, 452, 473 Respiratory disturbances, 343 Rest cure, 418 Restlessness, 334, 335, 336 Retroesophageal goiter, 165 Retrotracheal goiter, 165 Sarcoma, polymorphous-cell, 78 round-cell, 78 Sarcomata, 65 Scar, 534 Sensory disturbances, 345 Serotherapy, 426 thyrotoxic, 427 Sexual apparatus, 217 Shock, 509 hemorrhagic, 514, 515 psychic, 514 toxic, 514, 515 traumatic, 514 treatment of, 515 Simple goiter, indications for operation in, 295 pregnancy and, 170 treatment, 170 medical, 276, 277 Skeleton, 540 Skin, \<)i brown pigmentation of, 348 itching or, 347 relation of goiter to, 1 19 Soda, bicarbonate of, 2X7 Staring look, 325 Stellwag symptom, 319, 324 Stridor, congenital vestibular, 550 Struma, Basedow, j [ 1 Struma mediana, 122 profunda, 140 vasculosa, 461 Strumitis, 58, 90 diagnosis of, 98 etiology of, 93 pathology of, 95 prognosis of, 101 symptoms of, 95 Suffocation, 479 Sulphur in the thyroid, 50 Suprarenal exhaustion, 512 Suprarenin, 502 Surgical athyroidism, 196 cachexia strumipriva, 196 technic, 439 Sympathectomy, 482 results of, 483 surgical technic for, 485 Symptoms, Bryson, 343 cardiovascular, 303, 304 Chvostek, 525 clinical, 126 cutaneous, 347 Dallrymple, 319, 322 due to injury of inferior laryngeal nerve, 128 dyspneic, 313 Erb, 528 eyelid, 322 functional, 130 Graefe, 319, 322 Kocher, 319, 323 mechanical, of malignant goiter, 126 mental, 334 Moebius, 319, 324 muscular, 331 nervous, 334 ocular, 319 of anaphylactic origin, 402 of cachexia strumipriva, 196 of cancer, 175 of circular goiter, 163 of congenital athyroidism, 207 goiter, 167 of cretinism, 207 of infantile hypothyroidism, 207 of intrathoracic goiter, 143 of malignant goiter, 175 of postoperative tetany, 524 of spontaneous adult hypothyroidism, 207 of strumitis, 95 of surgical athyroidism, 196 of tetany, 524 of thyroiditis, 95 of vascular, of thyroid, ] 1 j Stellwag, 3 [9, 324 thyrotoxic, of Graves' disease, 3^9 I rousseau, 526 Vincent's thyroideal, 105 Weiss, 525 566 INDEX Tablets, non-toxic goiter, 281 polyglandular, 428 toxic goiter, 428 Tachycardia, differential diagnosis of thyro- toxic, 304 etiological explanation of, 306 paroxystic, 305 Temperature, 355 Tendinous reflexes, 333 Teratoma, 59, 81 Tetany in animals, 33 postoperative, 524 in animals, 35 prognosis of, 530 symptoms of, 524 treatment of, 531 Theories regarding etiology of goiter, 241 Thorax, pressure in, 546 Thymectomy, anesthesia in, 557 muscular system in, 541 nervous system in, 540 surgical technic of, 557 with thyroidectomy, 555 Thymic hyperplasia, acute symptoms of, 543 chronic form of, 543 diagnosis of, 548 differential, 550 relation of, to Basedow's disease, 551 treatment of, in children 556 complicating Graves' disease, 555 x-ray characteristics, 550 tracheostenosis, 542 Thymogene-Basedow, 553 Thymopharyngeal duct, 537 Thymus, 536 Basedow and, 552 embryology of, 536 experimental pathology of, 540 histology of, 537 hyperplasia, 474 involution of, 539 opotherapy, 428 organs of internal secretion and, 541 pressure of, 545, 546 surgical anatomy, 537 thyroid and, 392 Thyrogenetic arguments from thyroid opo- therapy, 379 experimental arguments for, 376 origin of Graves' disease, 372 pathological arguments for, 375 surgical arguments for, 381 Thyroid, action of, on blood, 38 on cardiovascular system, 37 on nervous system, 40 on nutrition, 39 on osseous system, 40 of thyroid administration, 36 Thyroid, anatomical facts of, 440 and hypophysis, 55, 195, 389 antitoxic action of, 53 aplasy, 33 arsenic in the, 50 Basedow, 552 blood supply of, 442 chemistry of, 51 congestion of, 114 contusions of, 116 duct, 25 elixir, 287 function of, 51 gangrene of, 98 genital system and, 389 grafting of, 291 hydatid cyst of, 113 hypertrophy of, 303 inflammations of, 89 insufficiency of, 191, 216 to prevent, 41 treatment of, 283 opotherapy, 283 dangers of, 283 pancreas, adrenals, 390 parathyroids and, 32, 392 phosphorus in, 50 physiology of, 30 portion safe to remove, 457 powdered desiccated, 286 pulsations of, 313 stages of, 27 sulphur in, 50 surgical technic of, 439 syphilis of, 108 thrill of, 313 thymus and, 392 traumatic lesions of, 115 tuberculosis of, 106 tumor in, 130 vascular symptoms of, 313 wounds in, 116 Thyroidectomy, 173 action of, on metabolism, 36 operative technic for, 469 results of experimental, 31 thymectomy with, 555 Thyroidism, 36, 285 Thyroiditis, 58, 90 bacterial, 90 Basedow's disease and, 396 Chagus, 1 1 1 diagnosis of, 98 dissecans, 98 etiology of, 93 Graves' disease is a toxic, 399, 404 parasitic, 1 1 1 pathology of, 95 pneumonic, 96 prognosis of, 101 puerperal, 96 symptoms of, 95 INDEX 567 Thyroiditis, toxic, 103 treatment of, 102 typhic, 96 woody, 107, 109 Thyroids, accessory, 19 Thyro-neuro-polyglandular disease, 372,393, 403 spell, 521 Thyroptosis, 140 Thyrothymic ligament, 538 Thyrotoxic goiter, consistency of, 312 histology of, 315 pathology of, 315 surface of, 313 volume of, 312 heart, 307 pulse, 309 serotherapy, 427 symptoms of anaphylactic origin, 402 tachycardia, differential diagnosis, 304 etiological explanation, 306 Thyrotoxicosis, 303, 358, 370. See Graves' disease. Tingling, 346 Trachea, collapse of, 479 injury to, 481 relation of goiter to, 120 sabre-sheathed, 143 I racheotomy, 172, 481 Transfusion, Crotti's technic of indirect, 518 Treatment, after-, of goiter patients, 534 Crotti's, for exophthalmic goiter, 428 for non-toxic parenchymatous goi- ter, 281 for simple goiter and pregnancy, 171 ingestion method of, 285 iodin, 279 medical, for Graves' disease, 405, 407, 417 results of, 408 of cancer, [79 of circular goiter, 164 of congenital goiter, 168 of exophthalmic goiter and pregnancy, 368 of ( haves' disease, 405 for each case, 434 of hemorrhage, 5 I 5 of malignant, 179 of shock, 515 of tetany, 53 I Treatment of thymic hyperplasia in chil dren, 556 with Graves' disease, 555 of thyroid insufficiency, 283 of thyroiditis, 102 polyglandular, 290 postoperative, 489 preoperative, 489 surgical, for Graves' disease, 430 with injections, 300 Tremor, 303, 331 Trousseau symptom, 526 Tumor in the thyroid, 130 nature of, 132 Tumors, benign, 59, 60 of branchial origin, 28 connective tissue, 59, 65, 77 epithelial, 59, 67 malignant, 59 of mesobranchial origin, 28 mixed, 59, 80 U Urine, modification of, 40 Urticaria, 348 Vascular goiter, 58, 63, 166 symptoms of thyroid, 313 Vasomotor control, loss of, 512 exhaustion, 509 Wins, imae, 20, 125 middle, 20 superior thyroid, 20 Vertigo, 346 Vincent's thyroidal symptom, 105 Vomiting, 340 W Water and endemic goiter, 242 boiling the, 289 radioactive, and goiter, 262 Weiss symptom, 525 When cured, 41 s 0,5 - / COLUMBIA UNIVERSITY LIBRARIES This book is due on the date indicated below, or at the expiration of a definite period after the date of borrowing, as provided by the rules of the Library or by special arrange- ment with the Librarian in charge. 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