COLUMBIA LIBRARIES OFFSjTE HEALTH SCIENCES STANDAHD HX641 20430 RC201 .T37 Syphilis by LoydTho 'Pl» n- Y^T l&tUtmtt ICtbrarg Digitized by the Internet Archive in 2010 with funding from Open Knowledge Commons http://www.archive.org/details/syphilisOOthom SYPHILIS BY LOYD THOMPSON, Ph.B., M.D. PHYSICIAN TO THE SYPHILIS CLINIC, GOVERNMENT FHEE BATH HOUSE; VISITING UROLOGIST TO ST. JOSEPH'S HOSPITAL; CONSULTING PATHOLOGIST TO THE LEO N. LEVY MEMORIAL HOSPITAL, HOT SPRINGS, ARKANSAS; FIRST LIEUTENANT, MEDICAL RESERVE CORPS, UNITED STATES ARMY; MEMBER OF THE AMERICAN UROLOGICAL ASSOCIATION, AND OF THE AMERICAN ASSOCIATION OF IMMUNOLOGISTS ILLUSTRATED WITH 77 ENGRAVINGS AND 7 PLATES LEA & FEBIGEE PHILADELPHIA AND NEW YORK 1916 Yt. Entered according to the Act of Congress, in the year 1916, by LEA & FEBIGER, in the Office of the Librarian of Congress. All rights reserved. 1^ C a \ TO THE MEMORY OF HIS FATHER THIS VOLUME IS LOVINGLY DEDICATED BY THE AUTHOR PREFACE. The advance made in our knowledge of syphilis during the last fifteen years finds no equal in the entire history of medicine. It may well be maintained that since the epoch-making work of MetchnikofJ and Roux in transmitting syphilis to lower animals more information has been gained concerning this disease than was acquired during all the preceding centuries. In preparing this volume for the profession it has been the aim of the author to present the subject of syphilis in as practical a manner as possible. For this reason a considerable portion of the work is devoted to diagnosis and treatment. The chapter on laboratory diagnosis is made especially full, as today the desir- ability, in fact the necessity, of laboratory aid is more evident for the successful treatment of syphilis than for any other disease. Matters of theoretical and historical interest, of course, are dis- cussed, but usually only when they have some bearing upon the practical handling of the subject. Syphilis, today, no longer is to be considered a genito-urinary disease, nor a dermatological disease, nor a disease belonging ex- clusively to any specialty; but is to be thought of as a disease requiring knowledge in all fields of medicine. As Osier so aptly remarks, "Know syphilis in all its manifestations and relations and all other things clinical will be added unto you." It is, however, the genito-urinary specialist upon whom the burden of responsibility should rest, for he it is who, as a rule, sees syphilis in the beginning, and if his work is well done there should be no need for that of others in the majority of cases. The author has drawn freely from the literature of syphilis at his command for his material and has added his personal views and experiences. In all instances where possible he has given credit to those authors whose work he has cited. vi PREFACE The illustrations are, to a large extent, from photographs taken by the author of cases in his own practice. A few were taken by him of cases in the practices of Doctors E. H. Martin, Charles Dake, J. B. Shelmire, and at the Leo N. Levy Memorial Hospital in the services of Doctors William H. Deaderick and M. F. Lautman. A number of photographs have been furnished by Doctors Howard Fox, Martin F. Engman, Isadore Dyer, and J. B. Shelmire. Illus- trations from other works also have been used. The author here wishes to thank the above-mentioned physicians for the courtesies extended. He also wishes to express his obligations to Doctor J. L. Greene for the use of his extensive library and for valuable suggestions. The author's most sincere gratitude is due to Doctor William H. Deaderick, who read the entire manuscript in the making and gave freely of his store of knowledge of the subject of syphilis as well as of his technical knowledge of the writer's art. To his wife is due the author's gratitude for assistance in con- sulting and indexing the literature and for ready encouragement and stimulation from the inception of the work to its completion, without which it would have been impossible. And, finally, to the publishers, Messrs. Lea & Febiger, the author wishes to express his appreciation for assistance in selecting the photographs for the illustrations and for unfailing courtesy and personal encouragement throughout the entire time from the first correspondence concerning the work to its completion. L. T. Hot Springs, Arkansas, 1916. CONTENTS. PART I. CHAPTER I. History of Syphilis. Syphilis in the Old World 17 New World Origin 21 Nomenclature . . . . ' 22 CHAPTER II. Importance of Syphilis. Geographical Distribution 25 Prevalence of Syphilis 25 Economic Importance 27 CHAPTER III. Etiology. Early Views 30 Microbiology 31 Cytoryctes Luis -. 32 Treponema Pallidum 32 Morphology 33 Location : . . . . 34 Animal Inoculation 34 Agglutination 37 Cultivation ....'..■. . 37 Modes of Transmission 40 Direct Contact 40 Intermediate Contact 41 Secondary Etiological Factors 42 Idiosyncrasy — Immunity 42 CoUes' Law 42 Age 43 Sex 43 viii CONTENTS Secondary Etiological Factors — Race 44 Climate 45 Occupation 45 Civil State 45 Social Condition 45 CHAPTER IV. Pathology. Chancre 47 Lymphatic Glands 48 Cutaneous Lesions 48 Macular Syphiloderm 50 Papular Syphiloderm 50 Vesicular Syphiloderm 52 Bullous Syphiloderm 53 Pustular Syphiloderm 53 Nodular Syphiloderm ....'■".. 53 Gummatous Syphiloderm 53 Mucous Membranes 54 CHAPTER V. Clinical History. Ricord's Stages 55 Ricord's Classification Inadequate 55 Development and Course 56 Chancre 58 Development 58 Location 59 Varieties 65 Complications 65 Lymphatic Glands 66 Cutaneous Lesions 68 Macular Syphiloderm . 68 Papular Syphiloderm 72 Vesicular Syphiloderm 82 Bullous Syphiloderm 83 Pustular Syphiloderm 83 Nodular Syphiloderm 90 Gummatous Sj^philoderm 92 Syphilis of the Appendages of the Skin . 95 Hair 95 Nails 98 CONTENTS IX Mucous Membranes 100 Macular Syphilomycoderm 100 Papular Syphilomycoderm 101 Gummatous Syphilomycoderm 103 General Symptoms 103 Malaise 103 Anorexia 103 Temperature 104 Pulse 104 Respiration . . . ' 104 Polydipsia 104 Blood-pressure 104 Blood 104 CHAPTEP. VI. Clinical Diagnosis. Chancre 108 Lymphatic Glands Ill Cutaneous Lesions 112 Syphilis of the Appendages of the Skin 118 Mucous Membranes 119 General Symptoms 121 CHAPTER VII. Laboratory Diagnosis. Demonstration of Treponema Pallidum 122 Collection of Material 122 Dark-field Illumination 123 India-ink Method 126 Collargol 126 Staining of Smears 126 Staining Sections of Tissue . . 127 Paretic Brain Tissue 129 Complement-fixation Tests 130 Principles 130 Technic — Preparation of Reagents 134 Performing Test — Wassermann's Method 146 Noguchi's Method 147 The Author's Method 149 Theory of Complement-fixation in Syphilis 154 Value of Complement-fixation Tests in Syphilis 155 Provocative Wassermann Test 157 Wassermann Reaction in Diseases other than Syphilis .... 157 The Hecht- Weinberg Reaction 158 X CONTENTS Other Serological Tests 159 Cobra Venom Test of Weil 159 Precipitin Tests . 159 Enzyme Test 160 Landau's Color Test . . 160 Luetin Reaction 160 Preparation 160 Experimentation . 161 Mode of Application 161 Reaction 161 Value of Luetin Reaction 163 Cerebrospinal Fluid . ' 164 Anatomy 164 Physiology 164 Physical and Clinical Properties 164 Rachicentesis 165 Methods of Examination 168 Estimation of Protein 168 Lange CoUoidal Gold Test 169 Cytology 174 Reduction of Fehling's Solution 175 Complement-fixation 175 CHAPTER VIII. Prognosis. The Wassermann Reaction in Prognosis 177 Chancre 177 Lymphatic Glands 178 Skin Lesions 178 Syphilis of the Appendages of the Skin 179 Mucous Membranes ' 180 General Symptoms 180 Blood 180 Syphilis and Marriage . . 180 Mortality 182 CHAPTER IX. Prophylaxis. Personal Measures 184 Public Measures .... 185 Regulation of Prostitution 185 Education 186 Legislation 187 CONTENTS XI CHAPTER X. Treatment. General Treatment 188 Hygienic • • 188 Dietetic 189 Hydro therapeutic 189 Specific Treatment . . , 194 Mercury . . . - 194 Methods of Administration .... 194 Precautions in Administering 206 Contraindications .... 206 Physiological Action 207 Untoward Effects ..... 208 Comparative Value of Methods of Administering 210 Arsenic 211 Atoxyl 212 Soamin 213 Sodium Cacodylate 213 Venarsen 214 Salvarsan 215 History 215 Physical and Chemical Properties . . . . . . 217 Methods of Administration 218 Neosalvarsan ■ 222 Physical and Chemical Properties . ... . . 222 Salvarsan Natrium 223 Dose . . . . ' 224 Technic of Injection 224 Administration by Enteroclysis 229 Advantages of Various Methods of Injection 230 Indications 230 Contraindications .231 Preparation of Patient 232 After-care of Patient 232 Action of Salvarsan 232 Untoward Effects 232 Salvarsan Natalities 238 The Fate of Salvarsan in the Body 239 Comparative Value of Mercury and Salvarsan . . . 240 lodin 246 Methods of Administering lodin 247 Therapeutic Effects 249 Untoward Effects 250 Elimination of lodin . 251 Symptomatic and Special Treatment 252 Chancre 252 Lymphatic Glands 253 Xll CONTENTS Symptomatic and Special Treatment — Cutaneous Lesions 254 Syphilis of the Appendages of the Slvin . . 255 Mucous Membranes 255 The Cure of Syphilis 255 PART II. Syphilis Heart .... Pathology Clinical History Diagnosis Prognosis Treatment Arteries and Veins Pathology Clinical History Diagnosis Prognosis Treatment CHAPTER XI. OF THE Circulatory System. 257 257 ,258 259 259 259 2^0 260 261 262 262 262 CHAPTER XII. Syphilis of the Respiratory Tract. Larynx 263 Pathology 263 Clinical History . 263 Diagnosis 263 Prognosis 264 Treatment 264 Trachea and Bronchi 264 Pathology 264 Clinical History 264 Diagnosis 265 Prognosis 265 Treatment 265 Lungs 265 Pathology 265 Clinical History 266 Diagnosis 267 Prognosis 267 Treatment 267 Pleurae 267 CONTENTS xiii CHAPTER XIII. Syphilis of the G astro-intestinal Tract. The Mouth and Pharynx 268 Pathology 268 Clinical History 268 Diagnosis 268 Prognosis . . . , 268 Treatment 269 The Esophagus 269 Pathology 269 Clinical History 269 Diagnosis 269 Prognosis 270 Treatment .270 The Stomach and Intestines 270 Pathology 270 Clinical History 271 Diagnosis 271 Prognosis 272 Treatment . 272 CHAPTER XIV. Syphilis of the Liver, Gall-bladder, Spleen, and Pancreas. The Liver 274 Pathology 274 Clinical History 274 Diagnosis 276 Prognosis 276 Treatment 277 The Gall-bladder 277 The Spleen 277 Pathology 277 Clinical History 277 Diagnosis 278 Prognosis 278 Treatment 278 The Pancreas 278 Pathology 278 Clinical History 278 Diagnosis 278 Prognosis •. 278 Treatment 278 xiv CONTENTS CHAPTER XV. Syphilis of the Breast, Thyroid, Thymus, Adrenals, and Pituitary Body. The Breast 279 Pathology 279 Chnical History 279 Diagnosis 279 Prognosis 279 Treatment 279 The Thyroid Gland 280 Pathology 280 Clinical History ■ • 280 Diagnosis 280 Prognosis 280 Treatment 280 The Thymus Gland 280 The Adrenals 281 The Pituitary Body .......' 281 CHAPTER XVI. Syphilis of the Genito-urinary Organs. The Penis 282 The Testicle 282 Pathology ... 282 Clinical History . 283 Diagnosis ... 283 Prognosis ■ 284 Treatment 284 The Prostate 284 Pathology 284 Clinical History 284 Diagnosis 284 Prognosis 284 Treatment 284 The Seminal Vesicles 285 The Vagina 285 The Cervix 285 Diagnosis 286 Treatment 287 The Uterus 287 The Fallopian Tubes . 288 The Ovaries 288 The Urethra . 289 Treatment .289 CONTENTS XV The Bladder 290 Diagnosis 290 Prognosis . 290 Treatment . 290 The Ureter 290 The Kidney 291 Pathology 291 Clinical History 291 Diagnosis 292 Prognosis 293 Treatment 293 CHAPTER XVII. Syphilis of the Bones, Joints, Bxjrs.e, Tendons, and Muscles. The Bones .294 Pathology 294 Clinical History ■ . . 295 Diagnosis 301 Prognosis 302 Treatment 302 The Joints . 303 Pathology 303 Clinical History . 305 Diagnosis 307 Prognosis 308 Treatment v 308 The Bursa} 309 The Tendons , 309 The Muscles 310 Prognosis 311 Treatment 311 CHAPTER XVIII. Syphilis of the Nervous System. History 312 Pathology 312 Meninges 313 Arteries 31^^ Brain Substance 314 Cord Substance ' 315 Nerves 317 Clinical History 317 Meninges 317 Arteries 322 Brain »Substance 323 Cord Substance 328 Nerves . . . . : 334 XVI CONTENTS Diagnosis 335 Meninges .• . 335 Arteries 335 Brain Substance 336 Cord Substance 337 Nerves .338 Prognosis 338 Meninges 338 Arteries 338 Brain Substance 339 Cord Substance ......' 339 Nerves 340 Mortality 340 Treatment 341 Standard Treatment 354 CHAPTER XIX. Syphilis of the Eye and Ear. The Eye 356 Pathology 356 Clinical History 358 Diagnosis 361 Prognosis 362 Treatment 363 The Ear 364 Pathology 364 Clinical History 365 Diagnosis 365 Prognosis 366 Treatment 366 PART III. CHAPTER XX. Congenital Syphilis. Nomenclature 367 Historical 367 Etiology 368 Secondary Etiological Factors 370 Syphilis in the Third Generation 371 CONTENTS xvii CHAPTER XXI. General Pathology and Clinical History. Placenta 372 Lymphatic Glands 374 Cutaneous Lesions 374 Macular Syphiloderm 374 Papular Syphiloderm 375 Maculopapular Syphiloderm 375 Vesicular Syphiloderm 375 Bullous Syphiloderm 376 Pustular Syphiloderm 376 Nodular Syphiloderm . 378 Gummatous Syphiloderm • . 378 Syphilis of the Appendages of the Skin 379 Mucous Membranes 379 General Symptoms 379 Temperature 379 Blood 379. CHAPTER XXII. Regional Syphilis. Syphilis of the Circulatory System 381 Heart 381 Arteries 382 Veins 382 Syphilis of the Respiratory Tract 382 Rhinitis 382 Larynx 382 Trachea and Bronchi 383 Lungs 383 Syphilis of the Gastro-intestinal Tract 383 Mouth 383 Teeth 383 Esophagus, Stomach, and Intestines 384 Liver 385 Gall-bladder 386 Spleen 386 Pancreas 386 The Thyroid Gland 386 The Thymus Gland 386 The Adrenals 387 The Genito-urinary Organs . 387 Testicles •. 387 Uterus and Ovaries 387 Kidney " 387 xviii CONTENTS The Bones 388 The Joints 390 The Bursse 390 The Tendons and Muscles .391 The Nervous System 392 The Eye . 396 The Ear 397 CHAPTER XXIII. Diagnosis. Laboratory Diagnosis 400 CHAPTER XXIV. Prognosis, Prophylaxio, and Treatment. Mortality . 401 Prophylaxis 402 Treatment 403 General Treatment . . . > 403 Specific Treatment 403 Symptomatic and Special Treatment 404 The Cure of Congenital Syphilis 405 PART I. CHAPTER I. HISTORY. For nearly four centuries the medical world has been divided upon the subject of the origin of s;v'philis. Did this now world-wide disease have its beginning in the dim recesses of antiquity to be transmitted in an uninterrupted stream to modern times, or was it born overnight, as it were, at the close of the fifteenth century? Was syphilis known to the ancients, or did Columbus' men, after their long forced continence, contract it from the native women of the island of Espahola and introduce it into Europe upon their return? These are the questions which have vexed syphilographers for four hundred years, and in spite of the weight of authority on both sides they have not yet been answered with certainty. SYPHILIS IN THE OLD WORLD. Prehistoric and Ancient. — There are two methods of approaching the problem of the origin of syphilis: The first is to examine the bones, the only tissues that remain of people of a former age, for evidence of the disease. The second method is to study the T\Titings of ancient civilizations for mention of it. Bones. — In making a study of bones for proof of the origin of lues the syphilographer must first call for the aid of geologists or archeologists to establish the approximate date of the life of the individual whose remains are being examined. If after this has been done pathologists of mature and reliable judgment agree unquali- fiedly that certain abnormal changes in the bones are due to s\'philis, then, and only then, can the syphilographer state without opposition that syphilis existed at a certain period. Buret,^ who is a very ardent supporter of the ancient origin of syphilis, gives an account of the discovery at Solutre, in 1872, of a female skeleton which, according to Broca, Parrot and others, 1 Syphilis in Ancient and Prehistoric Times, American edition, Philadelphia, 1891, p. 37. 2 18 HISTORY could be referred to the Stone Age, and in the tibiae of which are to be found unmistakable evidences of syphilis. These are in the nature of exostoses, and are particularly well marked in the right tibia. This bone shows three such lesions and, according to Buret, were examined and pronounced syphilitic by such eminent authori- ties as Broca, Oilier, Parrot, and the great Virchow himself. Buret cites many more prehistoric bones which he claims show evidence of syphilis. Edwards^ states that bones from the Stone Age found in Japan show probable evidence of syphilis. In direct contradiction of these statements, Iwan Bloch- avows that Virchow repeatedly declared that no such (syphilitic) pre- Columbian or prehistoric bone was known to him, and Bloch continues that it is quite certain that no such bone is contained in either English or German collections or museums. Writings. — That syphilis existed in the" Old World centuries before the discovery of America is the contention of Buret and others, and they cite as evidence the ancient manuscripts of many countries. Chinese. — The oldest writings quoted are those of China, and date back to the year 2637 B.C., at which time, according to the manu- scripts translated by Captain Dabry, in 1863, the Emperor Hoang-ty ordered all the then existing documents of medicine to be gathered together, and also all the medical lore and traditions to be written on parchment. Then with this data in his possession the emperor wrote the renowned medical work Hoang-ty-ni-king . In the portion dealing with venereal diseases we find, says Buret,^ that the Chinese knew the duality of the chancre, and that gonorrhea and syphilis were separate and distinct diseases. The chancre was described and was said to be followed by headache, with fever, pains in the bones, cutaneous manifestations, and lesions of the mucous mem- branes. Hereditary syphilis was known, and as treatment mercurial frictions were prescribed. Buret continues his quotations from early writings of the Japanese, the Egyptians, the Assyrians and Babylonians, the Hindoos, the Hebrews, the Greeks and the Romans, and points out that diseases and sjonptoms described therein are syphilis. Japanese. — The Japanese manuscript which furnishes the most evidence is one similar to the Chinese treatise of Hoang-ty, which was prepared for the Emperor Heizei-Tenno by his two physicians in the year a.d. 808. This work was lost or stolen soon after its ' Principles and Practice of Medicine, New York, 1909, p. 253. 2 Power and Murphy: System of Syphilis, London, 1908, i, p. 8. 3 Syphilis in Ancient and Prehistoric Times, American edition, Philadelphia, 1891, p. 61. SYPHILIS IN THE OLD WORLD 19 preparation and remained in obscurity until 1827, when it was discovered by a shopkeeper at Bungo. In this manuscript, according to Buret, it is clearly shown that the Japanese, at this early date, were fully alive to most of the lesions of syphilis. Egyptian. — In the early inscriptions and papyri of the ancient Egyptians, Buret finds evidence of syphilis, but admits that from these alone it would be impossible to draw definite conclusions. However, he states that when we remember the Hebrews dwelt for many years among the Egyptians and that the Hebrews had syphilis, no doubt remains. Hebrew. — To prove the existence of syphilis among the Hebrews, Buret quotes extensively from the Bible. The account of the journey of Abram and his beautiful wife, Sarai, to the court of Pharaoh is taken as proof of the existence of syphilis at that time. "And the Lord plagued Pharoah and his house with great plagues because of Sarai, Abram's wife."^ The story of the death of David's first son by Bath-Sheba, after seven days of life, and David's , subsequent lamentations concerning his ailments, especially the condition of his bones, is set forth by Buret to prove that the author of the Psalms contracted syphilis from the wife of Uriah. Many other passages of Scripture are cited, and while they are most convincing of the presence of venereal disease in this race, that syphilis existed is not beyond dispute. Hindoo. — From that portion of the Hindoo Vedas, the Ayurveda, which is devoted to medicine, are quoted many passages which purport to show that syphilis existed in India from remote antiquity. Certainly, some of these writings describe symptoms which can readily be assigned to lues. Such is the following passage: "The shameful diseases number forty-four: the round ulcer, the prominent pustule, the stone-like excrescence, the alterations of the nails, the pustules of the head, the bubo, the ulcerations of the feet, the alopecia, the papules of youth, the stricture of the anus ."- Others are quoted by Buret, but apparently add nothing to the evidence of the existence of syphilis. Grecian. — In passing from Asiatic and African to early European civilization we find in the writings ascribed to Hippocrates, the great Father of Medicine, several passages which can readily be taken to refer to syphilis. In the chapter of Aphorisms (Lecture III, section 21) is found the following: "In summer occur — opthalmias, pains in the ears, ulcerations of the mouth {aroiiaTojp eX/ccoo-tes), and rotting of the genitals {arjwedoves aLdoiwv)." Many other Greek writers, medical and lay, both those who lived 1 Genesis, xii, 17. - Buret: Syphilis in Ancient and Prehistoric Times, American edition, Philadel- phia, 1891, p. 119. 20 HISTORY before and those who Hved after the beginning of the Christian era, might be mentioned as furnishing evidence of the antiquity of syphilis, but after a careful perusal of those quoted by Buret the author is of the opinion that they furnish nothing additional. Roman. — Of the Latin writers one of the most celebrated physicians was Celsus, who lived in the first century before Christ. He writes "Fungo quoque simile ulcus in eadem sede (anus vel os vulvae) nasci solet.""^ Buret^ insists that the author refers to papulo- hypertropic syphilides, not vegetations, which are not ulcerated, and certainly not to cancer, as Celsus describes this malady quite well in another place, stating that it rarely is observed except in the old. The work of Galen, the great Greek physician, who practised in Rome, contains much that might refer to syphilis, but nothing absolutely convincing. Other Roman writers, Pliny, Horace and Juvenal, describe dis- eases of venereal origin which can, without any stretch of the imagination, be called syphilis. Catullus denounces the mighty Csesar as a sodomist, and accuses him and his companion, Mamm-ra, of having "contracted a disease whose marked spots have left upon their bodies stains which will not disappear."^ Medieval. — It has been pointed out in the foregoing paragraphs that there is some evidence of the existence of syphilis in the old world both in prehistoric ages and in times of which we have records. Certainly, there can be no doubt of the existence of venereal dis- eases, but there was obviously no clear-cut understanding of these disorders. From the time of the fall of the Roman Empire in a.d. 312 to about the close of the fifteenth century all knowledge was more or less curtailed. The various peoples were almost continuously at war, licentiousness and vice ran riot, while the practice of medicine advanced but little. It is true that during this period there were a number of men whose names stand out prominently, like beacons in the night, from among the vast throng of charlatans, magicians, and professional poisoners in whose hands the therapeutic practices of the times were mostly found. But these men failed to add much to medical knowledge; they merely preserved for posterity the teachings of their predecessors. While the loose morals of the age were certainly provocative of venereal disease, most of the phy- sicians failed to grasp the opportunity to study these maladies. If syphilis did exist it was not usually of the virulent type noted later. 1 An ulcer resembling a fungus growth may occur in these same parts (the anus or entrance of the vulva). 2 Buret: Ibid., p. 163. ^ Ibid., p. 181. SYPHILIS IN THE OLD WORLD 21 So when the malady broke out in virulent epidemic form during the closing years of the fifteenth century it was considered by many to be an entirely new disease. It is generally conceded that it was during the siege of Naples, in 1497, that syphilis reached the height of its intensity; but it is still a moot point whether it was endemic in Europe and only developed a greater virulence and was propagated more rapidly at that time, or whether it was absolutely a new disease to the Old World, having been introduced by Columbus' men. New World Origin., — The earliest published mention of the New World as the cradle of syphilis was by Leonard Schmaus, in 1518. According to Buref^ he was stimulated to make this state- ment by Nicholas Poll, who had written, in 1517, that guaiac, which came from the newly discovered island, was a cure for venereal disease. Buret fails to mention the writings of Diaz de Isla, a physician of Barcelona, Seville and Lisbon. His account of syphilis was written in 1510, but was not published until some years later. In this account the Spanish physician states that the "disease of the island of Espahola" was an entirely new disease in Barcelona, introduced by Columbus' men in 1493. This statement Bloch^ considers as final, and "with one blow rends the veil which has covered the origin of syphilis." Karl Sudhoff, by his brilliant researches, has thrown much light upon this vexing problem. This eminent medical historian shows that the Gotteslasterer Edict (the edict against Blasphemers), of Emperor Maximilian I, issued August 7, 1495, refers to syphilis, but does not mention it in connection with the Siege of Naples. However, he points out that, according to Guicciardini, there was no siege, but that Charles VIII marched through Naples without interference, on February 21, 1495, and did not leave Novara until October 10, over two months subsequent to the issuance of the Gotteslasterer Edict. This edict, as Sudhoff points out, proves that syphilis was well known in Germany in July and could not have been spread by Charles' men. Sudhoff further shows that, contrary to the belief of some, the physicians of the time had quite a thorough knowledge of the therapeutics of syphilis, prescribing, among other remedies, inunctions of mercury. Evidences of Prehistoric Syphilis. — Many investigators have attempted to show the existence of syphilis in America before the advent of Columbus both by archeological and philological studies. A number of writers have reported the finding of bones in America which are ascribed to a date prior to the coming of the Europeans, and are alleged to show signs of syphilis. Probably the most notable 1 Syphilis in the Middle Ages and in Modern Times, American edition, Philadel- phia, 1895, p. 157. 2 Power and Murphy: System of Syphilis, London, 1908, i, p. 12. 22 HISTORY are those discovered by Jones and reported in 1876 in the Smith- sonian Contributions. Here, as elsewhere, archeologists disagree as to the date of the graves from which the bones were taken, and pathologists of note did not agree as to the nature of the pathological processes. Phylological studies of the many Indian dialects reveal the fact that in each of these dialects there was a primitive term for syphilis, and that there was no evidence of recent coinage. Epidemic of Naples. — Whether we accept the Old World or the New World as the original home of syphilis, it is beyond dispute that following the invasion of Italy by Charles VIII there was a rapid spread of the disease over all Europe. And while it was in reality a pandemic, it has been styled the Epidemic of Naples. As has been pointed out, syphilis manifested a very exaggerated course at that time. It was, however, in all probability, compli- cated by other diseases, but notwithstanding this many physicians soon described with fair accuracy its lesions and symptoms. One of the earliest of these was Niccolo Leoniceno (1428-1524), who, in 1497, published a treatise on this disease. However, the most distinguished man of this period to lend his name to the advancement of the knowledge of syphilis was Para- celsus (1493-1541). This eminent physician was the first to assert that lues could be transmitted from parent to offspring. NOMENCLATURE. The appellations given to this disease of the ages are almost as numerous as its lesions. In the early days of the recognition of syphilis, that is, in the closing years of the fifteenth and the opening years of the sixteenth centuries, the name of the country in which it was supposed to have had its origin was applied. Also the various peoples used the name of the country of their enemies. Thus Morbus gallicus was used by the Germans, Spaniards, and Italians, while the French, wishing to shift the blame of its origin from themselves, called it Morbus neapolitanus, although at quite an early date they used the term la grosse verole. Among the Spaniards it was popularly known as hubas, and it was also known as Turkish, German and Polish pox. From its supposed American origin it was termed by Diaz de Isla the " disease of the island of Espafiola." In this connection it may be noted that of all the names applied to syphilis by the native Americans, not one crept into the nomenclature of Europe. It remained, however, for the Veronese physician, Girolamo Fracastoro (1484-1553), who was also poet, pathologist, physicist, astronomer, and geologist, to give to this disease the name by which it is known almost the whole world over. In his immortal poem. NOMENCLATURE 23 "Syphilus sive Morbus Gallicus," published in 1530, Fracastoro tells of a shepherd, Syphilus by name, who, in a fit of anger on account of a drought which destroyed many of his sheep, denounced the gods and set up altars to the king. In revenge a scourge was sent upon the people, Syphilus being the first one attacked, and "this terrible disease — known since then among us by the name of Syphilis — does not take long to spread to our entire nation, not even sparing our King himself."^ The history of syphilis from the time of Fracastoro to that of John Hunter is practically the history of medicine. There is scarcely a name with which is connected any advancement of the healing art but is found in the syphilology of these years. John Fernel (1496-1558) pointed out the necessity of an abrasion of the epidermis for the syphilitic virus to gain entrance to the body. He also showed the relationship between the chancre and the general infection. Gabrille Fallopio (1523-1562),. who was primarily an anatomist, and whose name still clings to anatomical nomenclature (Fallopian tubes), also wrote about syphilis, and believed that syphilis of the viscera and bones was due to mercury. He was therefore bitterly opposed to its use. Jean Astruc (1684-1766), in 1736, published his De morhis venereis, which was a comperidium of the understanding of syphilis of the times. Astruc was a firm believer in the American origin of of syphilis, and in this work proved it to his own satisfaction. John Hunter (1728-1793). Probably no other name in all the history of medicine stands out more prominently than that of John Hunter. Great beyond his time as a surgeon, he undoubtedly retarded the knowledge of syphilis many decades. Convinced of the unity of syphilis and gonorrhea. Hunter inoculated himself on the glans and prepuce with gonorrheal pus. When a chancre developed, followed by constitutional syphilis, he considered it proof-positive of the truth of his contentions.^ While this experiment of Hunter's and his false interpretation of it dominated syphilology until Ricord disproved it, a few men disagreed with the great surgeon and had the courage of their con- victions. Among these may be mentioned Benjamin Bell (1749- 1806), who in his work on venereal diseases maintained the duality of syphilis and gonorrhea.^ Phillippe Ricord (1800-1889). Wherever syphilis is studied will be felt the influence of the work of Phillippe Ricord, and with him it may be said began the modern knowledge of syphilis. He was described by Oliver Wendell Holmes as "the Voltaire of pelvic 1 Fracastor's Syphilis: St. Louis, 1911, p. 55. 2 Hunter: A Treatise on Venereal Disease, Philadelphia, 1859, p. 432. 3 Bell: Treatise on Gonorrhea Virulenta and lues Venerea, Edinburgh, 1793, ii. 24 HISTORY literature — a skeptic as to the morality of the race in general, who would have submitted Diana to treatment with his mineral specifics and ordered a course of blue pills for the vestal virgins." This great syphilologist, by. over 2500 inoculations, proved con- clusively the duality of syphilis and gonorrhea, although he did not consider that the latter possessed a specific virus. ^ Ricord will also long be remembered for his division of the mani- festations of syphilis into three stages. This division has been accepted and followed by most syphilographers up to the present time. According to Ricord, syphilis begins with the primary stage, which includes the chancre and the adjacent adenopathy. This is followed by the so-called secondary stage, when the disease becomes general and the various cutaneous and other lesions are manifest. During the third, or tertiary, stage the bones and deep viscera become involved. Ricord believed that only during the primary stage was syphilis inoculable, but that during the secondary stage it was transmissible to the offspring. During the tertiary stage it was neither inoculable nor transmissible. He, however, later retracted these views in part and L,dmitted that in the secondary stage syphilis was inoculable. Ricord described vaginal and uterine chancres and pointed out that in certain cases in which no chancre is discovered the lesion is probably located in the urethra.^ It would be impossible even to mention the names of all the men who have contributed to the knowledge of syphilis since Ricord showed the way. Such leaders as Virchow and Fournier lent the aid of their master minds to the elucidation of its problems. The modern renaissance of syphilis, however, may be said to have begun with the epoch-making work of Metchnikofl and Roux,^ who in 1903 succeeded in transmitting this disease to monkeys. Then followed, in rapid succession, the finding of the infecting organism by Schaudinn,* the announcement of the complement-fixation test for syphilis by Wassermann,^ the discovery of salvarsan by Ehrlich,'' the cultivation of the Treponema pallidum,'^ the use of cultures for diagnostic purposes by Noguchi,^ the intraspinal injection of salvarsanized serum in the treatment of syphilis of the nervous system by Swift and Ellis,^ and finally the demonstration of the organism of syphilis in the brains of paretics and the spinal cords of tabetics by Noguchi and Moore. ^^ ' Ricord: Traite pratique des maladies veneriennes, Paris, 1839. ^ Ricord: Letters on Syphilis, American edition, Philadelphia, 1857, p. 101. 3 Ann. de I'Inst. Pasteur, 1903, xvii, p. 809. / ■• Arb. a. d. k. Gsndhtsamte, 1905, xxii, p. 527. s Deutsch. med. Wchnschr., 1906, xxxii, p. 745. 8 Die experimentelle Terapie der Spirillosen, Berlin, 1910. ' Noguchi: Jour. Exper. Med., 1911, xiv, p. 99. * Ibid., p. 557. 9 New York Med. Jour., 1912, xcvi, p. 53. 1" Jour. Exper. Med., 1913, xvii, p. 232. CHAPTER II. IMPORTANCE OF SYPHILIS. Geographical Distribution. — One of the most striking features of syphilis is its world-wide distribution. There is scarcely a spot on the globe where human beings reside which has not harbored this ubiquitous disease. It is found in the gold camps of the Yukon and among the ivory hunters of the Congo; on the vast steppes of Siberia and the plains of Argentine. It is, however, especially a disease of dense population, whether temporary or permanent. In the great cities of the world, London, Paris, New York, Berlin, syphilitics are numbered by the thousands, and such multitudes as gather together for great fairs and expositions as Nijni-Novgorod, Chicago and St. Louis leave syphilis in their wake. It has been affirmed that Iceland is peculiarly free from this disease. If such is the case, it would seem that this is due, not to the geographical situation, but to the simple lives and morality of the inhabitants. Livingston has stated that when the nativfes of central Africa contract syphilis on the coast it disappears without treatment upon their return inland. This statement must be taken with the greatest reserve, for it is a well-known fact that apparent spontaneous cures have occurred when in reality the disease was lying dormant. It would be well-nigh impossible to name all the countries in which syphilis is found, much less trace the source of the disease for each. In Europe, Russia, with her vast hordes, is infected; Germany, France, and Italy contain her hot beds of pollution; while England, with her great cities, harbors syphilitics in immense numbers. Passing to Asia we find the disease most prevalent in China and Japan, where crowded districts are so common. In the United States the great cities New York, Chicago, Philadelphia, St. Louis, San Francisco, and the lesser ones, even dow^n to the smallest villages, contain syphilis to a greater or less extent. It is, however, a matter of common observance among physicians of certain rural districts that syphilis is rarely encountered. The author has talked to a number of them, who informed him that in the course of several years' practice they have seen but one or two cases. Prevalence of Syphilis. — It will be seen from the above that syphilis is an almost omnipresent disease, and yet from the very 26 IMPORTANCE OF SYPHILIS nature of it, it is one of the most difficult concerning which accurate statistics may be obtained. Many estimates as to the prevalence of syphilis have been made, those of Erb and Fournier probably being the best known. The former considered that of the adult population of Berlin, 12 per cent, were infected, while the latter estimated that 15 per cent, of the adult population of Paris had syphilis. In December, 1912, the Department of Health of the City of New York sent a circular letter to 7000 physicians of Greater New York,^ requesting that the number of cases of venereal disease seen by each physician during the past year be reported. Of the 7000 physicians only 2217 replied, and' they reported 13,350 cases of syphilis. The number of physicians reporting represents less than one-third of the total number of physicians to which the letter was sent, and if those who did not report had seen as many syphilitics as those who did report the total number would be approximately 40,000. Estimating the population of Greater New York at about 5,000,000, the number infected with syphilis is seen to be 0.8 per cent, of the entire population. The author considers this an exceedingly low figure, because there are many syphilitics who during any given year do not see a physician. Banks,^ after examining the records of the United States Marine Hospitals, has arrived at the interesting conclusion that 2 per cent, of the adult males of the United States are syphilitic. In our present state of advancement in municipal and State control of disease it would be impossible to make a complete survey of the population in regard to syphilis; but it is possible, with certain units of population, such as those in hospitals, eleemosynary institutions, penitentiaries, etc. Indeed, such investigations have been made, especially in hospitals, and the results have been most instructive. For example, Hammond^ applied the Wassermann reaction to the entire population of the New Jersey State Hospital, finding 6.3 per cent, positive. Lucas,^ by examining HI cases in the Children's Hospital in Boston, found 31 per cent, were syphilitic. Southard^ reported 23 per cent, of 6000 Wassermann tests performed in the Harvard Neuropathologic Testing Laboratory were positive. He stated,' however, that the cases were in many instances selected because likely to be positive, and therefore the percentage is undoubtedly much higher than it otherwise would be. 1 Monthly Bulletin, Department of Health, City of New York, June, 1913, p. 147. 2 U. S. Public Health Reports, February 26, 1915, p. 618. 3 Am. Jour. Insan., 1913, Ixx, p. 107. * Boston Med. and Surg. Jour., 1913, clxix, p. 423. 5 Ibid., 1914, clxx, No. 25. ( I V f ECONOMIC IMPORTANCE 27 The same fact applies to the author's series performed at the Arkansas State Hospital for Nervous Diseases, where 33 per cent, of 1000 tests were found to give positive reactions. The practice in this institution was to make serological investigations for syphilis only in such cases as gave a suspicious history or upon physical examination showed evidence which suggested luetic infection. Of all the social units the military services, army and navy, present possibly the best field for investigation into the prevalence of syphilis, for in these services the individuals are kept under more or less strict surveillance. In the British Army^ the admission for syphilis per 1000 of strength varied from 96.43 in 1869 to 179.37 in 1886, to 19.19 in 1908. In the United States Army the figures have never reached as high as in the British Army, nor have they gone so low. The highest number of admissions for syphilis per 1000 was in 1867, when the figures were 117, while the lowest mark was reached in 1908, when there were but 19.99 per 1000. In his report for the year 1914^ the Surgeon-General of the United States Army says, " From recent investigations it is, indeed, probable that the frequency of venereal diseases among our soldiers is less than among adult males in the cities of this country. ' This statement is based upon an extensive Wassermann survey made by Vedder.^ This investigator found that 16.77 per cent, of recruits are undoubtedly syphilitic, and estimates that fully 20 per cent, of the young men of the country of the general class from which recruits come are infected. Of the white enlisted men of the army he found 16.08 per cent, syphilitic. Of the West Point cadets, 2.57 per cent, gave very strongly positive Wassermann tests, while 2.89 gave less strongly positive tests, from which Vedder estimates that 5 per cent, of the young men of the country of the college- student class are syphilitic. Economic Importance. — While syphihs, as a rule, especially in the early periods, is not a disease to incapacitate its victim for work, it may pursue its insidious course until the vital organs are attacked, and in one way or another rob the individual of his ability to gain a livelihood. It is probable, however, that nearly every syphilitic loses some time from his accustomed vocation even in the earliest stages of the disease. In the United States Army the total number of days lost on account of syphilis during the year 1913 was 38,597, which represents a monetary value of approximately $53,000. In those conditions caused by syphilis which have been designated as parasyphilitic, 1 Power and Murphy: System of Syphilis, London, 1910, vi, p. 29. 2 Surgeon-General's Report, 1914, p. 12. 5 The Prevalence of Syphilis in the Army, Bull. No. 8, War Department, Washing- ton, 1915. 28 IMPORTANCE OF SYPHILIS of course the economic loss is much greater. Tabetics, as a rule, are unable to perform their accustomed work, while paretics not only are unable to perform their accustomed work, but very fre- quently in attempting to do so make grave financial errors and cause great loss to themselves or their employers. The old adage that ''syphilis never kills" is, of course, false, and while it is true, it is most rare nowadays to see deaths due to acquired syphilis in the acute stages; yet there are many deaths each year that are undoubtedly hastened by this disease and also many deaths which can be attributed directly to its later mani- festations. Congenital syphilis also causes many deaths of infants and kills in utero many others. Ravogli^ collected statistics from the Cincinnati City Hospital from 1888 to 1907, and found that of 100,713 patients and 9705 deaths only 168 were caused, by syphilis. In the United States Army of about 81,000 men there were 397 deaths due to all causes during the year 1913, and out of these only 5 were due to syphilis and its results.^ According to the mortality statistics of the Bureau of the Census the number of deaths from syphilis m the registration area of the United States during the year 1913 was 4589. Deaths from paresis amounted to 4371, while tabes claimed 1674, making a total of 10,734 deaths directly due to syphilis. The total for 1912 was 9582; for 1911, 8433; and for 1910, 7600. Typhoid fever killed but 11,323 in 1913, while smallpox, once the scourge of the race, destroyed only 125 persons during the same period. The regis- tration area of the United States comprises about two-thirds of the entire population, so it may readily be seen that if the registration area is representative of the whole country, and there is no reason to think to the contrary, the total number of deaths from syphilis in the United States for the years given above were as follows: 1910 ...... 10,132 1911 11,244 1912 12.776 1913 16,101 In all probability these figures are too low, as many physicians do not report deaths due to syphilis out of deference to the relatives of the deceased, and undoubtedly many deaths from syphilis occur when an error in diagnosis has been made. In the year 1913 there were 87,755 deaths reported as due to organic heart disease and certainly in a large percentage of these the heart disease was caused by syphilis. It is probable that the increase in the number of 1 Syphilis, New York, 1907, p. 147. 2 Surgeon-General's Report, 1914, pp. 221-222. ECONOMIC IMPORTANCE 29 deaths from syphilis shown from 1910 to 191 3 was due, in a measure at least, to more correct diagnosis being made. However, the fact remains that an appalling number of deaths from syphilis do occur, that the number of persons suffering from syphilis is in some localities as high as 1 per cent, of the entire population, and that the economic loss to the nation is almost beyond compute. The statement of an eminent foreign visitor to the International Congress of Hygiene and Demography in Washington in 1912, after visiting the prominent medical centres of the country, that in none of the clinics of Europe was there so much syphilis as he saw in the United States ; and that if measures were not taken for its suppres- sion it would soon cause marked deterioration of the race, certainly furnishes food for thought. Aside from the deaths caused directly by syphilis, aside from the abortions it claims, aside from the physical suffering it entails, no other disease has evoked so much mental agony, both to those who have contracted it through immoral acts and to its innocent victims, and also to those near and dear to the sufferers. This mental anguish alone undoubtedly has very materially lessened the effectiveness of the individual and not infrequently has driven its victim to a suicide's grave. CHAPTER III. ETIOLOGY. EARLY VIEWS. It is not surprising that primitive man before the dawn of civihzation laid at the door of the angered gods or evil spirits the blame for the causation of disease. But some of the beliefs concern- ing the cause of syphilis which gained credence during the year following the opening of the sixteenth century are most astounding. At this period astrologers were much in vogue, and we find that by many syphilis was ascribed to various astrological observations. For example, Steber wrote, in 1494, of a new disease caused by conjunction of planets. Carl Sudhoff^ quotes from a manuscript of Paul von Middelburg in which he prophesied concerning the con- junction of Mars, Jupiter, and Saturn in the sign of the Scorpion on November 25, 1484, and that the earth would be visited by a horrible venereal disease which would be most severe about 1492-1500. Other absurd views were held. Nicolo Leoniceno believed that syphilis could be ascribed to the heavy rains and overflow of the rivers which occurred in 1494. Fallopius thought the wells of Naples were poisoned by the Spaniards, and that they had plaster placed in the bread which acted as causes of the disease. Paracelsus con- sidered syphilis a sort of bastard offspring of leprosy and buboes, and Van Helmont wrote that it came from sodomy with a mare diseased of farcy. This Ricord considered as at least possible.^ A theory which held sway at various times, and has had numerous advocates, was that by having intercourse with a number of men a healthy woman could develop lues through a multiplicity of male elements. Btit of all the alleged causes of syphilis the most gruesome was that advanced by Fioraventi, who considered the disease to be due to eating human flesh. He further claimed to have produced it in animals by experimentation. Finally, however, with the advance of knowledge these grotesque ideas gave place to more rational views, and we find Hunter^ speaking of the syphilitic ''poison" and Ricord* writing, "this poison may at present be called by its name; that is, the syphilitic virus." 1 Aus der Friihgeschichte der Syphilis, Leipzig, 1912. 2 Ricord: Letters on Syphilis, American edition, Philadelphia, 1857, pp. 98-99. 3 A Treatise on Venereal Diseases, American edition, Philadelphia, 1859. p. 41. * Letters on Syphilis, American edition, Philadelphia, 1857, p. 99. MICROBIOLOGY 31 MICROBIOLOGY. Historical. — The Jesuit priest Athanasius Kircher (1602-1(580) was the first to state a belief in microorganisms as the cause of disease. With the crude microscope of his time he examined the blood of patients sick with plague and saw what he called "worms" in countless numbers. As pointed out by Frederick Loeffler/ these were probably rouleaux of red blood cells and not micro- organisms. Other microscopists followed Kircher, who undoubtedly saw the larger bacteria and protozoa. Notably among these was Antonj van Leuwenhoek (16.32-1723), the Dutch linen draper, who possessed some 419 lenses, most of which he ground himself. The work of these men stimulated the belief in the microbiological causes of disease; but it was left to Marcus Anton von Plinciz, Sr. (1705-1786), to express the belief, in 1762, that each disease has its special seminium verminosum. However, it was over a century later, in 1863, that a specific microorganism was proved to be the cause of disease. In this year Davine showed that the small rod-shaped bodies described by Pollender in 1855, and found in the blood and spleen of animals dead of anthrax, would produce the disease in healthy animals. Following the discovery of the anthrax bacillus a renewed and diligent search was made in all syphilitic lesions for an organism which might be ascribed to this disease. Donne, as far back as 1837, found in chancres certain minute spiral bodies which he at first thought might be the causative factor in syphilis, but later, in 1844, expressed the view that they were accidental. Many were the workers in the field and many were the organisms described. But few of them, however, created much credence in the scientific world until 1884, when Lustgarten,^ working under the guidance of Weigert, announced the discovery by a special staining technic of a small slelider bacillus in indurated chancres and gummata. This organism closely resembled the bacillus of tuber- culosis, but, unlike the latter, could not be cultivated. Many investigators attempted to confirm the work of Lustgarten, and for a time it appeared that the long-sought goal had been attained. However, soon after the publication of Lustgarten's second paper,^ in which he went more into detail concerning the morphology ahd staining characteristics of his organism, Alvarez and TaveP announced that they had been unable to find the Lust- garten bacillus in many syphilitic lesions, but had found it in some, 1 Volesungen iiber die ^eschichtliche Entwicklung der Lehre von den Bacterien, Leipzig, 1887, pp. 1, 2. 2 Wiener med. Wchnschr., 1884, No. 47. ' Lustgarten: Wien. med. Jahrbucher, 1885. * Arch, de physiol. norm, et, path., 1885, vi, p. .303. 32 ETIOLOGY as well as an organism identical in morphology and staining in the smegma of healthy individuals. In the succeeding years numerous other workers in the field of microbiology found and described organisms, which they considered the etiological factor in syphilis. Thus, Disse and Taguchi^ were convinced that the encapsulated diplococcus they had isolated from syphilitic lesions was the cause of the disease. They even went so far as to claim that their cultures developed distinctive specific lesions when inoculated into rabbits. Joseph and Piorkowsky^ attacked the problem in an entirely original manner. By the use of fresh human placenta and semen from syphilitic individuals they obtained in pure culture a bacillus which they thought had solved the problem. But when a number of healthy physicians were inoculated with these organisms with negative results they were forced to admit their error. Cytoryctes Luis. — Early in 1905 SiegeP announced the finding of a small protozoon in the exudates and blood of patients suffering with syphilis and gave to it the name Cytoryctes luis. Treponema Pallidum. — Siegel was very enthusiastic over his discovery, declaring that at last the long-looked-for germ of syphilis had been found, and to a certain extent his enthusiasm was shared by others. So much was this so, in fact, that a commission was assembled in Berlin to confirm, if possible, his findings. At the head of this work was placed Schaudinn, a zoologist, who, although a comparatively young man, already had established an enviable reputation for himself in his chosen profession. Associated with him in this work was E. Hoffmann, a thoroughly trained syphilol- ogist. These two scientists attacked the problem with unlimited energy, and it was not long until they had shown that Siegel's "cytoryctes" was not a protozoon but an organic artefact. And while by so doing they destroyed the hopes of some, they were destined to make a discovery which was to revolutionize the study of syphilis. On March 3, 1905, a young woman with syphilis of ten weeks' standing was examined. A chancre of the left labium majus and a number of papules of the vulva were found. The exudate from one of the latter being placed under the microscope, Schaudinn^ saw a considerable number of fine spirilla, and the parasite of syphilis had been discovered. The news of this epoch-making work soon spread over the 1 Deutsch. med. Wchnschr., 1885, No. 48; 1886, No. 14. Das Contagium der Syphilis, Tokio, 1887. 2 Berl. klin. Wchnschr., 1902, p. 257. 3 Sitzengsberichte der kgl. Preussischen Akademie der Wissenschaften. Physik. Mathem. Klasse, Berlin, 1905, February 25. 4 Arb. a. d. k. Gsndhtsamte, 1905, xxii, p. 527. PLATE I A. Fig. 1. — Treponema pallidum from ehanere, stained by Levaditi's method. X ISOO. Fig. 2.— Treponema pallidum from rabbit's testicle, stained by Leva- diti's method. X ISOO. Fig. 3. — Treponema pertenue from ya^v, stained by Levaditi's method. X IBOO. Fig. A. — Spiroeheta reeurrentis from blood of mouse. X lOOO. {Bulletin No. 1, Medical Department, United States Army.) MICROBIOLOGY 33 scientific world, and before long many confirmations of it were reported. The name Spirocheta pallidum was given to the organism by Schaudinn upon its discovery. Later he renamed it Treponema pallidum, and while the old name still clings to it, it would seem that the newer appellation is the more correct. McDonagh,^ in 1913, pubHshed the description of a protozoon which he considers the true causative agent of syphilis, and later, in 1916, in an exhaustive treatise, described the life history of this organism in detail, suggesting the name Leucocytozoon syphilidis. According to this worker the Treponema pallidum represents but a part of the life-cycle of the protozoon, developing from the male gametocyte and later fertilizes the female gamete. McDonagh states that Peri Rocamora and Klausner have repeated a part of his work and substantiated his discoveries. Other confirmation apparently is lacking. The place in biology of the Treponema pallidum has been a moot question almost from its discovery. While Schaudinn did not definitely classify the organism, his writings show that he was inclined to consider it of the protozoa. Some observers were from the first very insistent that the Treponema pallidum is a bacterium, while still other workers assigned to it a place midway between the bacterial spiral forms and the flagellated protozoa.^ It seems to the author that this is but an evasion of the question. The argument advanced by the adherents to the protozoal nature of the treponema are: the variations in thickness, longitudinal, rather than transverse division, the absence of cilia, the alleged presence of an undulating membrane; and, until recently, the fact that it could not be cultivated. Those who believed that the organism of syphilis is a true bacterium deny the presence of an undulating membrane, maintain that cilia are observed, that transverse division occurs, that culti- vation may be effected and that no demonstrable nucleus and blepheroplast exist. Craig,-^ who probably has done as much work with protozoa in general and the Treponema pallidum in particular as any man in America, while admitting that the question is not definitely settled, is of the opinion that this organism is a protozoon. The well-known effect of arsenic upon the protozoa and the equally well-known efi^ect of salvarsan upon the Treponema pallidum seems to the author an argument in favor of its protozoal nature. Morphology. — The Treponema pallidum is an extremely delicate organism, 4 to 14 microns long, by about \ micron wide, although 1 The Biology and Treatment of Venereal Diseases, Philadelphia and New York, 1916. 2 KoUe and Hetsch: Die cxperimentelle Bakt., Berlin, 1906. Noguchi: Personal Communication. 3 Personal communication. 3 34 ETIOLOGY occasionally longer individuals are seen, even up to 40 microns or more in length. The body is round in section, not flattened, as is the case with some spirochetes. Schaudinn^ described flagella at either end of the organism, but in view of the more recent work on the subject it is probable that such appendages do not exist. However, at the beginning of division, two very fine "cilia" are seen at one end. Schaudinn de- scribed the longitudinal division, stating that the division occurred in a very few seconds. Other investigators claim to have observed transverse division, but Noguchi^ has shown that in cultures, at least, the division is almost constantly longitudinal. He states that during division the curve may become shallow, but that after separation is complete the typical curved form is resumed. Finally, he states that the process is not rapid, but consumes about two hours for completion. The organism is actively motile, the motility being of three varieties: (1) a very rapid, smooth, spinning motion on its long axis; (2) a forward and backward motion; and (3) a lateral, bending motion. The typical curves persist whether the organism is in motion or at rest. Noguchi^ states that he has been able to isolate strains of Treponema pallidum which differ in morphology and pathogenicity, and suggests that perhaps these dift'erences may account for certain clinical variations in syphilis. Location of the Treponema. — ^As has been stated, the first syphilitic lesion to give up the secret of its etiology was a papule of the vulva. Since that time the "pale spirochete" has been found in every class of syphilitic lesion and in all organs and tissues of the body. It has been found in chancres, in syphilodermata, in gummata and condy- lomata, in the heart and bloodvessels, in the liver, spleen and pancreas, in bones, in the brain, in the blood and lymph. It has even been found in the urine* and spermatic fluid^ of men, and in the milk of women.^ Animal Inoculation. — That syphilis had been transmitted to the lower animals before the discovery of the exciting organism was pointed out in Chapter I. Metchnikoff and Roux, Neisser and others, inoculated the higher apes, and later monkeys, on the eye- brow with material obtained from the superficial lesions of syphilitics. This produced a typical lesion at the site of inoculation and in some 1 Arb. a. d. k. Gsndhtsamte, 1907, xxvi, p. 17. 2 Jour. Exper. Med., 1911, xvi, p. 90. 3 Jour. Am. Med. Assn., 1912, Iviii, p. 1164. " Dreyer and Teuvel: Brit. Med. Jour., May 12, 1906. 5 Finger and Landsteiner: SitzungsberichtQ der k. Acad. d. Wissenchafern, 1905, Abtheil, iii, p. 497. 6 Uhlenhuth and Mulzer: Deutsch. med. Wchnschr., 1912, xxxix, p. 891. MICROBIOLOGY 35 cases generalized symptoms. So, soon after the announcement of its discovery by Schaudinn, numerous investigators attempted to detect the treponema in the lesions of these animals, and almost immedi- ately several workers announced that this had been accomplished. Levaditi and Manouelian^ found the organism in the lymphatic glands of a monkey with syphilis of the eyebrow, while Zabolotny^ found it in the spleen of a syphilitic monkey. At first it was thought that only the simians were susceptible to syphilitic infection, but it was soon discovered that the rabbit also could be successfully inoculated.'^ This opened up a wide field for experimental investigation, as the rabbit, on account of the ease with which it may be handled and its inexpensiveness, makes an ideal laboratory animal. At first the anterior chamber and cornea of the eye were inoculated, but later the testicle and scrotum were found to develop typical lesions after injection with syphilitic material. After many failures Uhlenhuth and Mulzer^ succeeded in infecting young rabbits by injecting syphilitic material intracardially which developed into general infection, and after passing the virus through several animals were able to infect adult rabbits, producing multiple lesions of the skin, mucous membrane, etc. In inoculating a rabbit intratesticularly with syphilitic material from a chancre a preliminary examination is made with the dark field illuminator^ to determine the presence of the treponemata. If they are found in sufficient numbers, two or three drops of serum are taken up with a small hypodermic syringe, and after shaving the scrotum of a large rabbit and painting with iodin, the needle is thrust into the centre of the testicle and the serum injected. After about two weeks' incubation period the testicle swells gradually, and at the same time the consistency becomes increased, due to the infiltration of cells. The maximum growth is attained in from four to six weeks, at which time immense numbers of the treponemata are demonstrable. In order to transfer the infection from one rabbit to another a needle is thrust into a testicular nodule, a few drops of fluid aspirated and injected as described above. When it is desired to use a mucous patch as the source of material a small cupper is applied to the lesion until about 5 c.c. of serum are obtained which are injected into the testicle. The eye is inoculated by cocainizing the cornea, making a short slit and inserting a small piece of tissue from a chancre or other infected area. Scrotal lesions are produced by a similar technic. That the blood of syphilitics from the chancre to the terminal stages of general paralysis is infectious for rabbits has been shown 1 Compt. rend. Soc. de biol., November 25, 1905; February 10, 1906. ^ Verhandlungen der Deutschen dermatol. Gesellschaft, 1907, p. 304. 3 Bertarelli: Cent. f. Bak. Orig., 1906, p. 320; Parodi: Ibid., 1907, p. 428. ^ Deutsch. med. Wchnschr., 1911, xxxvii, p. 51. ^ See Chapter VII. 36 ETIOLOGY by a number of investigators. Hartwell^ reported 24 cases of untreated syphilis, from the blood of which he inoculated rabbits, securing ten positive results. Hartwell's technic was to draw a few cubic centimeters of blood from a superficial vein at the elbow, and after defibrination to inject slowly 2 c.c. into the testicles of rabbits. With the blood of general paretics, Graves^ has succeeded in successfully inoculating the testicles of two rabbits with syphilis. The spinal fluid of syphilitics of various stages has served as a means of inoculating animals experimentally. Hoffmann^ succeeded in producing a characteristic lesion on the eyebrow of a monkey by inoculating it with the spinal fluid of a syphilitic with papular lesions. Nichols and Hough* successfully inoculated a rabbit intra- testicularly with the spinal fluid of a patient with early involvement of the central nervous system. The author, following their technic in 3 cases of general paralysis, failed to produce any syphilitic lesions. The finding of the Treponema pallidum in the stained brain substance of paretics and in the spinal cord of a tabetic by Noguchi and Moore^ stimulated a desire on the part of numerous investi- gators to isolate the living organism from these structures. Noguchi'' succeeded in doing this in 1 out of 6 cases by emulsifying small pieces of brain tissue removed at necropsy soon after death, and injecting it intratesticularly into rabbits. Typical syphilitic nodules were formed in two rabbits, although the incubation period was long, and many treponemata were found with the dark-field illumination in one instance and by the Levanditi method of staining in the other. Nichols and Hough'^ reported a similar apparently successful inoculation with brain substance of a paretic removed at necropsy one hour after death. In their experiments, however, while there developed fairly characteristic lesions, they were unable to demonstrate treponemata either by dark-field illumina- tion or by the Levaditi method of staining. Wile^ was able to produce typical syphilitic lesions in the testicles of a rabbit by inoculating with material removed from the brains of paretics during life. His method of procedure was as follows: 6 typical cases of general paralysis were chosen, and after painting the site with iodin and anesthetizing with ethyl chloride, a trephine hole was made over the frontal convolution at a point about one- half to one inch from the midline and well forward of the course of the middle meningeal artery. A small cylinder of brain substance and fluid from the ventricle were removed by means of a long, thin trocar needle and syringe and placed in a sterile Petri dish to which had been added a small amount of salt solution. In the material 1 .Jour. Am. Med. Assn., 1914, Ixiii, p. 142. 2 Ibid., 1913, Ixi, p. 1504. ' Dermat. Ztschr., 1906, xiii, p. 561. ^ Jour. Am. Med. Assn., 1913, Ix, p. 108. 6 Jour. Exper. Med., 1913. xvii, p. 232. « Jour. Am. Med. Assn., 1911, ixi, p. 85. ' Ibid., p. 120. 8 Jour. Exper. Med., 1916, xxiii, p. 199. MICROBIOLOGY 37 from 5 of the 6 cases treponemata were demonstrable by dark-field illumination, in that of one of the cases being extremely numerous. The material was then injected into the testicles of a large rabbit. In two weeks small hard nodules could be felt in both organs, while in four weeks large numbers of actively motile organisms were demonstrated in the aspirated fluid from the nodules. At the time of writing the strain had been cultivated and carried through four rabbits, seemingly increasing in virulence. Nichols^ has shown that the strain of pallida isolated by him and Hough from the spinal fluid showed marked peculiarities ; that the organisms were of thick form, resembling the thick form described by Noguchi; that they produced hard, well-demarcated lesions with necrotic centres ; that there was a characteristic location of the lesions; that the incubation period was short; and that a tendency to generalize, with lesions of the skin and eye following local inoculation of the testicle and scrotum, was noted. The same morphological characteristics are described by Wile in his original communication concerning the strain isolated by him from paretics. In a later paper,^ however, he states that such characteristics are not observed in cultures. From, these findings and from certain clinical data, Nichols suggests as did Noguchi, that there may be strains of Treponema pallidum which have certain definite predilections for certain tissues. In this connection it may be noted that Richard Carmicheal (1779- 1849), at a very early date, was of the opinion that not only did one virus of syphilis exist, but that there were a great number, varying according to the lesions the}' produced. Agglutination. — Ivolmer^ states that agglutination of Treponema pallidum does not occur with normal human or rabbit blood in dilution as low as 1 to 20, nor with the blood of individuals in the active stages of syphilis. However, agglutinins for Treponema pallidum are rapidly produced in young rabbits upon injection with living organisms. Zinnser and Hopkins* have shown that normal rabbit and human sera possess slight agglutinating properties for cultural pallida, that the sera of certain syphilitic individuals possess these properties and that rabbits injected with cultures of the organisms possess them in a marked degree. These authors state that no quantitative difference of diagnostic value between the sera of normal individuals and those of syphilitics has been demonstrated. In a subsequent paper, Zinnser, Hopkins and McBurney,^ point out that while antibodies may be produced in rabbits by injecting 1 Jour. Exper. Med., 1914, xix. p. 362. 2 Wile: Jour. Am. Med. Assn., 1916, Ixvi, p. 646. 3 Jour. Exper. Med., 1913, xviii, p. 109. ^ Ibid., 1915, xxi, p. 576. « jbid., 1916, xxxiii, p. 341. 38 ETIOLOGY with cultural organisms, which agglutinate these organisms, that they possess practially no agglutinating properties for virulent treponemata obtained directly from lesions. Cultivation. — Following the discovery of the Treponema pallidum the natural sequence was its attempted cultivation. Numerous investigators worked toward this end, but it was not until 1909 that Schereschewsky^ was able to show multiplication of the organism in gelatinized horse serum by planting deeply in this medium pieces of tissue from human syphilitic lesions. At this time he was not able to obtain pure cultures, but subsequently reported the successful accomplishment of this feat by planting anaseptically excised sj^phil- itic papule.^ Following Schreschewsky's technic, Muhlen'' and later Hoffmann^ suc- ceeded in obtaining cultures of treponemata which they were able to purify by the use of Muhlen's horse-serum agar. While it is probable that the above-men- tioned workers succeeded in cultivating the Treponema pallidum, their technic lacked re- finement and their cultures were not patho- genic. However, the researches of Noguchi^ culminated in 1912 in success, and we are now able to cultivate the Treponema pallidum direct from the lesion in the human syphilitic, to transmit the disease to the lower animals by inoculation with the cultures, and to recover the organism in pure culture from the lesions produced. Thus the requirements of Koch's law have been fulfilled and one battle in the long war against syphilis has been won. Two conditions for the direct cultivation of the treponemata are pointed out by Noguchi to be of the utmost importance: (1) absolute anaerobiosis, and (2), the prop- erty of the organism of migrating. The medium used in a solid one, consisting of two parts of a slightly alkaline 2 per cent, agar and one part of ascitic fluid. Large test-tubes are used (2 by 20 cm.), 15 c.c. of the medium are placed in each tube, and. in the bottom of the tube is placed a small piece of sterile rabbit kidney or testicle. Each organ will furnish enough tissue for about one dozen tubes. The object of the tissue 1 Deutsch. med. Wchnschr., 1909, xxxv, p. 835. 2 Schereschewsky: Ibid., 1915. xxxix, p. 1420. ^ Ibid., 1909, xxxv, p. 1261. ^ Ztschr., Hyg. v. Infectionskrankh., 1911, Ixviii, p. 27. 6 Jour. Exper. Med., 1912, xvi, p. 90. Fig. 1. — Pure culture of Treponema pallida. Noguchi's method. MICROBIOLOGY 39 is to remove slight traces of oxygen, and probably, also, to furnish a special kind of nutriment. In preparing the medium the tissue is first placed in the bottom of the tube and the melted agar at 45° to 50° C. and the ascitic fluid are added in the proper proportions. When the medium has solidified, a layer of sterile paraffin oil is added to prevent evaporation. The tubes should be incubated for several days to determine their sterility. The inoculation is made by snipping off suitable pieces of chancre, condyloma, or papule after first cleansing with sterile salt solution. The pieces are immediately placed in sterile salt solution to which has been added 1 per cent, sodium citrate. The pieces are cut into very small fragments. One piece is emulsified in a mortar and examined with the dark-field illuminator for the presence of the treponemata. If the organisms are shown to be present in sufficient numbers, a small piece is placed in a tube of the medium by forcing it to the bottom of the tube with a small glass rod. A few drops of the emulsified tissue are also "planted" deeply in the medium by means of a capillary pipette. It is desirable to inoculate several tubes. They are now incubated at a constant temperature of 37° C. for two or three weeks. On account of the contamination of the tissue with bacteria there is usually a dense growth along the stab canal. The rest of the medium takes on a milky appearance, due to the growth of the treponemata and bacteria. If a capillary pipette is introduced into the medium and some of the contents withdrawn, if there has been growth of the organisms they may be detected with the dark- field illuminator. Owing to the presence of putrefactive bacteria there is a foul odor to the tubes, and purification is accomplished by transplanting with the capillary pipette some of the growth to fresh media. After a sufficiently long incubation (two or three weeks) there will be a hazy appearance radiating from the stab canal toward the sides of the tube. A second transfer is made, and after a sufficient growth is observed the tube is marked about the middle with a diamond pencil or file and a red-hot pointed glass rod applied to the cut. When the tube cracks, the upper part being removed, the surface of the agar thus exposed is sterilized with alcohol. The agar is now broken transversely, leaving a clear surface on which the growth of treponemata is readily seen. The growth is taken up with a capillary pipette without touching the stab canal for dark-field examination and reinoculation. It is sometimes neces- sary to make several transplants before a pure culture is obtained. An easier and more simple method of obtaining a pure culture of Treponema pallidum was first described by Noguchi.^ It consists of inoculating a rabbit intratesticularly, and after a well-marked 1 Jour. Exper. Med., 1911, xiv, p. 99. 40 ETIOLOGY syphilitic nodule has developed to excise the testicle. After dark- field examination of the nodule has determined the presence of a large number of organisms it is planted in the ascitic fluid agar as described above for the direct cultivation. The advantage of this method is that the testicular lesion in the rabbit is much freer of contaminating organisms than are the lesions in the human subject. Zinsser, Hopkins, and Gilbert^ have reported the successful cultivation of Treponema pallidum on various media without the addition of fresh tissue. Thus they were able to obtain excellent growth in slightly acid broth and sheep serum with autoclaved tissue (kidney, liver, brain, lung, heart), and good growth with simple meat juice, autoclaved., without the removal of the clots. They also obtained growth of the pallida in ascitic fluid agar in symbiosis with various bacteria, the best with streptococcus. They, further, have been able to secure more luxuriant growths that have been produced heretofore. The standards laid down by Noguchi^ for the identification of the Treponema pallidum in pure culture are: (1) correct mor- phology; (2) necessity of the presence of fresh sterile tissue in culture medium; (3) strict anaerobiosis; (4) rather faint hazy growth in solid or fluid mediums without any noticeable change in the proteid constituents; (5) non-production of any oft'ensive odor in culture; (6) capability of inciting an allergic reaction on the skin of certain cases of syphilis and parasyphilis (so-called luetin reaction); (7) specific complement-fixation with the antipallida immune serum or certain serums from human cases of syphilis, provided that the antigen is suspended in saline solution and not prepared by alcoholic extraction; and (8) pathogenicity. The pathogenicity may be gradually attenuated in course of cultivation, but the other seven conditions should be constantly fulfilled. MODES OF TRANSMISSION. Now that the Treponema pallidum has been proved beyond the shadow of a doubt to be the infective agent in syphilis, the modes of transmission of the disease are better understood. It is at the present time almost universally accepted that in order that the treponema may gain access to the body, there must be a solution of the continuity of the epithelium. There are three methods by which syphilis may be contracted, viz., by direct contact, by intermediate contact and congenitally. Direct Contact. — By far the greatest number of cases of syphilis are acquired by direct contact, and of these the vast majority 1 Jour. Exper. Med., 1915, xxi, p. 213. 2 Jour. Am. Med. Assn., 1912, lix, p. 1236. MODES OF TRANSMISSION 41 are by direct contact during the sexual act. This is probably partly accounted for by the fact that the skin and mucous membrane of the parts involved are very delicate, and that slight abrasions are liable to occur. Other locations than the genitalia, such as the lips, tongue, tonsils, anus, etc., are occasionally the seat of syphilitic infection through unnatural sexual practices. Besides the acquiring of syphilis through sexual acts it not infrequently is disseminated through kissing. Not only is this true of the kissing of the roue, but often the disease is spread in ordinary family life, and even to young children in this manner. Shamberg^ reports a most distressing epidemic of 8 cases of syphilis transmitted through kissing. The infections occurred at a party where juvenile kissing games were indulged in, and were disseminated by a young man with a chancre of the lip. Seven young women and a second young man developed labial chancres. The latter probably was infected by organisms from the lips of one of the young women, as he did not come in contact with the original offender. Sucking is the source of a certain number of infections, although this was the case more when the professional breast drawer plied his trade. The practice of sucking the penis to stop the flow of blood following ritual circumcision has been known to spread syphilitic infection. Manual and corporeal contact come in for their share in the spreading of the Treponema pallidum. The practice of amorously dallying with the genital organs has resulted in inoculations, and a case of chancre of the great toe due to contact with the female genitalia is recorded. Many physicians have become infected with syphilis during examinations and operations on syphilitics, and even at necropsies. The author has seen a number of such cases. That syphilis may be acquired by corporeal contact, as during sleep or by carrying syphilitics, is beyond doubt. No case of laboratory infection through handling cultures of Treponema pallidum has been recorded, but such an occurrence is well within the range of possibility. Intermediate Contact. — By intermediate contact is meant the interposition of some object between the recipient of the infection and the source of the same. These objects are numberless, and to make even an approximate list would be impossible. Probably the most important of these is the common face towel, as Zinnser and Hopkins^ have shown the organism of syphilis may live for at least eleven and one-half hours under conditions that simulate those found on the towel. Drinking cups and glasses, even the sacred com- 1 Jour. Am. Med. Assn., 1911, Ivii, p. 783. 2 Ibid., 1914, Ixii, p. 1802. 42 ETIOLOGY munion cup, have been the means of spreading syphilitic infection. However, according to the above-mentioned authors, the treponema does not hve longer than one hour on glass. The seats of public toilets have been charged with frequently conveying syphilitic infection, but probably are not of as much importance in this respect as they once were considered. Any other object which may come in contact with lesions of a syphilitic and with the abraded epithelial surface of a non-syphilitic may convey the infection. One of the most extraordinary cases of infection by intermediate contact recently was called to the attention of the author. A man in passing along the street was accidentally struck on the nose by a whip lash in the hands of a teamster, and a §mall abrasion created which healed in a very few days. Some time later a chancre developed at the site of the injury, and upon investigation it was learned that the teamster was suffering from syphilitic lesions of the mouth and was in the habit of moistening the cracker of his whip with saliva. SECONDARY ETIOLOGICAL FACTORS. While, as has been shown, the Treponema pallidum is the infecting agent in syphilis there are certain secondary etiological factors which must be considered. Idiosyncrasy.— Immunity. — That some individuals are less suscep- tible than others to infectious diseases in general, and to syphilis in particular, is undoubted. That this is not due to the presence of specific antibodies on the one hand, but to the lack of resistance, inherited, or due to debilitating conditions, or perhaps to both, on the other, has been proved. It is a well-known fact that several men may have relations with a luetic woman and perhaps only one contract the disease. Of course, if we accept the theory that there must be a break in the continuity of the integument for infection this observation may be accounted for. Such a condition as absolute immunity probably does not exist in regard to any infectious disease. That is, if a sufficiently large number of the infective organisms are inoculated into the individual he will contract the disease, no matter what his resistive powers may be. Until recently it was thought that one attack of syphilis protected the person from a second attack, although a few cases of second attacks had been observed. But since the more modern methods of diagnosis and treatment have been evolved second attacks have been more frequent, and even third attacks have been reported. Colles' Law.- — Colles' law, named after Abraham Colles (1773- 1843), the celebrated Irish surgeon, who established it in 1837, stated that the mother of a syphilitic child could not become SECONDARY ETIOLOGICAL FACTORS 43 infected with the disease, that is, that she was immune. This later was described as being due to antibodies reaching her from the child through the placenta. This law has been disproved (1) by showing paternal congenital syphilis is impossible, and (2) that the mother already has syphilis. Profeta's law held that a healthy child could not become infected by a syphilitic mother, in other words, it was immune, and that the immunity was acquired from the mother through the placental circulation. This law, too, has been disproved. It is now recognized that no immunity to syphilis exists; that so long as Treponema pallida remain in the body no superinfection can occur, but that as soon as the organisms have all been destroyed the body is open to reinfection. Age. — No period of life is proof against the ravages of this most ubiquitous of diseases. Old age may contract it in the tottering years of its decline; youth, proud in its strength, may fall a victim, while the babe yet unborn may become infected. Of course, it is in the years following puberty and before "the grinders have ceased because they are few," that syphilis is most likely to be contracted. Wolbarst^ reports a chancre of the lower abdominal wall in a boy, aged two years, while syphilis insontium is far from unknown in the very old. Syphilis contracted during sexual intercourse has been observed at the extremes of life. Wolbarst^ saw a genital chancre in a boy, aged five years, while the author saw a similar lesion in a negro boy, aged six years, who said he had had intercourse with his sister. At the other extreme the author saw a chancre of the penis of a white man, aged sixty-six years. That young children sometimes are exposed to syphilitic infection of the genitals is due to the superstition still prevalent among certain classes that intercourse with a virgin will cure venereal disease. Syphilis in the very young or in the very old is usually more severe than others, although it may run a mild course at any age. Sex. — That syphilis should be more common in men than m women is almost self-evident. The social law which throws a cloak about the chastity of women in the home and permits with little or nothing more than a shrug the "sowing of wild oats" by men is in itself enough to cause the number of syphilitic men to exceed the number of women contracting the disease. Then, too, the fact that women remain more in the home keep them safer from extragenital infection from drinking cups, public toilets, etc. However, Hubert^ found of 8652 patients at the first medical clinic of Munich on whom Wassermann tests were performed that 1 Transactions of the Fifteenth International Congress on Hygiene and Demog- raphy, held at Washington, D. C, September 23-28, 1912. 2 Ibid. 'Miinch. med. Wchnschr., 1915, Ixii, p. 1314. 44 ETIOLOGY 759, or 8.8 per cent., were positive. Of the 8652 patients, 4739 were men and 3903 were women. Of the men 405, or 8.5 per cent., were found to be syphilitic, while of the women 354, or 9 per cent., were found infected. It has been stated that syphilis in women is more severe than in men, but Keyes^ has pointed out that this is not the case, except that there may be more profound toxemia in women. It is, however, a matter of common observance that the late nervous manifestations of syphilis, tabes, and paresis are of com- paratively rare occurrance in women. Montgomery^ has offered the following as a possible explanation of this: 1. The thyroid is more active in females than in males, as shown by the frequency of its enlargement in females, and by the much greater number of cases of Basedow's disease in females than in males. 2. A principal constituent of thyroid secretion is iodothyrin. 3. All the iodin compounds exert a marked influence on syphilis. 4. The influence of iodothyrin, although small, would be exerted continuously and for a long time, and it must be remembered that some of the greatest phenomena in nature are produced by small causes acting through a long time. 5. The course of syphilis, and especially of neural syphilis, is very different in men and in women, and this difference may be due to the greater activity of the thyroid in women, especially so modify- ing the virus that it does not affect the nervous system. Race. — It has long been considered that race has an important bearing on syphilis, that certain peoples show more resistance to the disease than others, and that in certain races the manifestations are more severe. That syphilis is more frequent among the American negroes than among whites has been shown statistically by numbers of writers. In 2200 cases of skin disease among negroes,^ Fox found 596 cases of syphilis, while in an equal number of whites there were but 279 syphilitics. Vedder^ has shown that among the colored enlisted men of the army 36 per cent, were probably syphilitic, while among the white enlisted men only 16.08 per cent, were infected. The author is of the opinion that this state of affairs is not due to a greater susceptibility on the part of the negro but to his almost absolute lack of morality and cleanliness. In regard to a greater virulence of the disease in certain races the 1 Syphilis, New York and London, 1908, p. 45. 2 Med. Rec, 1915, Ixxxviii, p. 820. ' Jour. Cutan. Dis., 1911, xxvi, p. 67. < The Prevalence of Syphilis in the Army, Bulletin No. 8, War Department, Office of the Surgeon General, Washington, 1915. SECONDARY ETIOLOGICAL FACTORS 45 author can find no convincing evidence. It has been stated that in the negro syphiHs is less severe than in the white. The author in dealing with quite a large number of negro syphilitics in the South has formed the opinion that this is ndt the case, that the disease shows about equal severity in the two races, except that the negro seems to be less prone to develop syphilis of the nervous system. It is true, however, that certain cutaneous manifestations are more often found in the negro; for example, the annular papular syphilo- derm is quite frequent in this race and is very rare in the white. Climate. — Climate appears to have very little influence on the course of syphilis. It has been claimed that in the extremely hot and extremely cold countries syphilis is more malignant than in the temperate regions. It is possible that the cutaneous lesions are more pronounced in hot countries. It would appear, however, that the main factor to be considered is whether or not the victim of syphilis has become acclimated to the region in which he is residing at the time he is suffering with the disease. In other words, in a native of a torrid or frigid zone contracting syphilis soon after his arrival in a temperate region the disease would possibly run a more severe course than it would had he contracted the disease and remained in his native land. Occupation. — That the occupation of an individual may be the means of him contracting syphilis is probably not taken into account by many in choosing a vocation. The importance of occupation in contracting genital syphilis or syphilis through the sexual act enters into the lives of but very few. Prostitutes and certain low individuals who give themselves up to unnatural sexual acts (if such may be said to have an occupation) are more liable to syphilitic infection than those who live moral lives. However, syphilis insonitinn perhaps not infrequently is con- tracted by intermediate contact by glass-blowers, musicians (by two men playing on the same wind instrument), laundresses (by handling soiled clothing), and by many others. Civil State. — It is quite evident that in men the unmarried are more exposed to syphilitic infection than the married, and that in women the reverse is true, since a large percentage of women con- tracting syphilis do so from their husbands. Of course, there are many exceptions to this rule, and we find syphilis in a large number of unmarried prostitutes and in married men of vicious habits, while the civil state would seem to have no bearing on extragenital infection. Divorcees of both sexes are perhaps more frequently infected with syphilis than individuals of other civil states. Social Condition. — Civilization. — Syphilis is no respecter of persons. It attacks the king in his castle and the beggar at his gate. How- ever, those low in the social scale are more prone to indulge in 46 ETIOLOGY sexual excesses, owing to the conditions of housing, etc., than those of high degree, and, further, they do not as often employ prophy- lactic measures, so contract syphilis more frequently. Among most savage people promiscuous sexual intercourse is the rule, therefore it is natural to expect that the infection of one individual with syphilis would mean the rapid spread of the disease. This is indeed the case, and we find many instances of almost entire tribes becoming luetic in an incredibly short time. CHAPTER IV. PATHOLOGY. In brief the pathology of syphilis may be said to consist of the reaction of the tissues to the invading treponemata, and the general picture is the same no matter what portion of the body is affected. There is proliferation of the fixed connective-tissue elements, infiltration of round and plasma cells and the formation of more or less circumscribed granulomata with or without giant cells. No organ or tissue is exempt from invasion, although as pointed out in the chapter on Etiology there seems to be some evidence to substantiate the theory that different strains of treponemata exist with greater affinity for certain tissues than for others. The isolating of similar short, thick organisms by both Nichols and Wile from cases of syphilitic involvement of the nervous'^system, and the well-established clinical fact that individuals who have but slight skin manifestations frequently later develop syphilis of the nervous system, certainly are suggestive. The bloodvessels play a most important part in the pathology of syphilis and are found almost from the first to be the seat of endarteritis and inflammatory infiltration. For reasons stated in the chapter on Clinical History it seems best to discard the stages of Ricord and to classify the various manifestations of syphilis upon anatomical and clinical grounds. Therefore in discussing the pathology of syphilis the various lesions will be described from an anatomical standpoint, although for convenience they will be discussed in the sequence in which they usually appear. Visceral pathology and the pathology of the osseous, muscular and nervous systems will be discussed in Part II. CHANCRE. The gross appearance of the chancre, which usually is the first manifestation of acquired syphilis and which is in reality a clinical symptom, varies greatly in size, shape and location and will be described fully in the chapter on Clinical History. Histopathology. — The epidermis is nearly always the first tissue to be affected by the invading organisms. Here they lodge in the 48 PATHOLOGY interephithelial lymph spaces. Soon they proceed to the peri- vascular lymph spaces and bloodvessels of the corium where they multiply rapidly. Regardless of the large number of treponemata usually present the tissues are little damaged. Only an occasional cell is destroyed and absorbed. There is very early the formation of new capillaries and a marked infiltration of lymphocytes and plasma cells and a slight infiltration of endothelial leukocytes. This infiltration affects mainly the periphery of the chancre and the walls of the bloodvessels. Polymorphonuclear leukocytes may be present in considerable numbers, or they may be entirely absent. Eosinophiles are occasionally seen. The outline of the process is sharply defined in the beginning but later becomes more diffuse. The newly formed capillaries as well as the old ones suffer from swelling and proliferation of the endothelium which narrows and sometimes occludes the lumen. Giant cells, which are rather common in some other syphilitic lesions, are rare in chancres. The induration is mainly due to a regenerative proliferation of fibroblasts, rather than to infiltration of leukocytes. The epidermis becomes either atrophied or hyper- trophied, or erosion or ulceration may take place. Lymphatic Glands. — The enlargement of the lymphatic glands adjacent to the chancre is the earliest symptom, showing that the infecting organisms have left the portal of entry. At this time the glands usually show nothing microscopically but hyperplasia of the lymphocytes with many treponemata. Later in the course of the disease there usually is an enlargement of certain groups of glands marked by more or less infiltration of small round cells in the follicles and lymph sinuses, with usually an increase in the connective tissue in the capsule and trabeculse. The reticular tissue may be thickened and infiltration of the walls of the bloodvessels is usually observed. Treponemata may also be demonstrated. The lymphatic glands may rarely be the seat of the so-called gummatous formation which is very different Jrom the above- described adenitis. There is a marked circumscribed infiltration of plasma cells and lymphocytes with thickening of the walls of the bloodvessels while in the larger gummata the central portion becomes caseous and necrotic. Amyloid degeneration of the lymphatic glands also may occur. Cutaneous Lesions. — It is not strange that lesions which exhibit so many and diverse forms as the cutaneous manifestations of syphilis should present difficulties of description and classification. While the all-important point for consideration of a pathological cutaneous condition is, whether or not it is syphilis, it is most desir- able for purposes of description to classify the lesion. The term SYPHILODERMATA 49 syphilide has most frequently been employed to designate the cutaneous manifestations of this disease, but it would seem that upon etymological grounds the term syphiloderm is more correct. Scarcely any two authors agree upon a method of classification of the syphilodermata. Torella, in 1498, described moist and dry syphilis with three forms each, and since his time the nomenclature of these lesions has been the subject of a vast amount of discussion. Practically all modern syphilographers describe the syphilo- dermata occurring in the various classical forms of skin eruption, macules, papules, vesicles, pustules, tubercles, etc., while each one divides the forms into sub-classes according to his own observation. The following classification, while perhaps open to some objec- tions, seems to the author to include all the known varieties of the skin manifestations of syphilis. SYPHILODERMATA. I. Macular. (a) Roseolar (6) Annular. • (c) Pigmentary. II. Papular. (a) Miliary (b) Lenticular or flat. III. Vesicular (rare). IV. Bullous (rare). V. Pustular. (a) Acuminate (large and small). (6) Flat (large and small). VI. Nodular or Tubercular. VII. Gummatous. While the above classification covers the general characteristics of syphilodermata, it is not unusual to find two or more varieties in the same individual. Thus a maculopapular syphiloderm or a papulopustular syphiloderm frequently is observed. The gross appearances of the cutaneous lesions of syphilis which, as will be seen, are many and varied and which occur at varying periods following infection are important symptoms of the disease and will be discussed in the chapter on Clinical History. Histopathology. — ^The histopathological picture presented by the syphilodermata, while showing many interesting features, is not nearly as striking as the gross manifestations. It may be said of these lesions that they truly represent the reaction of the tissue to the invasion of the treponemata and show various combinations of exudation and repair. 4 50 PATHOLOGY Macular Syphiloderm. — This type of lesion microscopically shows a mild reaction. The epidermis is either unchanged or flattened out, showing obliteration of the natural ridges. The papillary layer of the corium is the seat of the most marked change. Here the bloodvessels are found more or less dilated, filled with blood and surrounded by a moderate infiltration of lymphocytes and plasma cells. The endothelium of the vessels presents a swollen condition and in the adventitia of the larger ones are seen round and spindle cells. Sometimes the process extends a little more deeply and cellular infiltration is seen around the glandular elements. The treponemata are found both in the blood and the dilated vessels and distributed among the surrounding cells. In the pigmentary macular syphiloderm there is also an infiltra- tion into the adventitia of the bloodvessels, most of which, according to Maieff^ become obliterated. As a result the red blood corpuscles lose their pigment which infiltrates the adventitia of the vessels, the connective-tissue cells and is found even in the lymphatics. Later the pigmentation is absorbed, leaving the skin a whitish color. Papular Syphiloderm, — The miliaiy papular syphiloderm usually is associated with a hair follicle. Histologically the epidermis is seen to be more or less edematous and thinned, while there is noted an infiltration of lymphocytes with an occasional plasma cell and fibroblast around the hair papilla and around and below the follicle. The hair sac is dilated and ruptured by the pressure of the cell infiltration. The bloodvessels of the papilla are seen to be dilated, and are surrounded, as well as filled, with cells. At the periphery of the process some of the vessels are filled with blood, others are obliterated by thrombosis and appear like giant cells. Fordyce- . states that the giant cells which are very constant in the papular syphilodermata are probably vascular in origin rather than due to the fusion of plasma cells. The sebaceous and sweat glands usually are involved, while the latter are frequently the seat of fatty degeneration and are surrounded by lymphocytes and plasma cells. The erectores pilorum are also usually infiltrated with cells. Treponemata are found about the basal cells of the hair follicle, also in the spaces between the prickle cells of the rete. In the lenticular papular syphiloderm the histological picture is quite similar to that found in the miliary papular lesion except that it is more marked. The epidermis shows parakeratosis, edema and acanthosis, while there usually is an infiltration of polymorphonuclear leukocytes. While in the early stages of development there is some infiltration of lymphocytes, the papule is mainly due to epithelial hyperplasia, 1 Corap. rend, du cong. internat. de Derm, et de Syphil., Paris, 1890, p. 667. 2 Recent Studies of Syphilis, St. Louis, 1911, p. 49. SYPHILODERMATA 51 Later the infiltration is marked in the rete, in all layers of the corium and to some extent in the subcutaneous tissues. In some places the cell infiltration is dense and in others disseminated but is most marked about the bloodvessels, both of the deep and super- ficial plexuses. Most of the vessels show thickened walls with diminution of the caliber, and more are obliterated. Giant cells are found, but not as frequently as in the miliary papular syphilo- derm. The sweat glands usually are surrounded by cell infiltration as well as showing proliferation of the lining cells. In the annular papular syphilodermata the histological picture varies with the lesion from which it develops. According to Hazen\ if the lesion develops from the follicular syphiloderm, the histology is in no way different from the parent lesion. If it develops from the lenticular papular lesion, the infiltration around the bloodvessels is not so marked, as seen in the ordinary papules. However, the cells are chiefly plasma cells, especially in the older parts. In the circular rim both the corium and the rete are markedly thickened and the intrapapillary processes are elongated and marked decrease in the pigment of the basal layer is noted. The bloodvessels and lymphatics of the corium and papillse are found dilated and marked infiltration, especially in the papillae of lymphoid and fixed tissue cells, with a few polymorphonuclear leukocytes and plasma cells, is observed. The rete, especially the basal layer, is infiltrated with the above-mentioned cells. In the central portion of the lesion there is considerable absence of pigment and some plasma-cell infiltration about the bloodvessels. According to Dennie,^ the treponemata are found in the annular papular syphilodermata only among the leukocytes which fill the spaces between the prickle cells. When marked desquamation of the epidermis takes place in the lenticular papular syphiloderm the lesion is termed squamous papular syphiloderm. Microscopically the corium is seen thick- ened and exfoliating, while the rete is thickened and proliferating. In the moist papular lesion the picture is very similar to that observed in the ordinary papular lesion, except that the process may extend deeper. The rete is usually more thickened and more or less hypertrophy and elongation of the papillse are seen. The histopathology of the vegetating syphiloderm has been described by Dennie^ as follows: When divided the lesion is seen to consist of two parts, an upper, dense, finely striated portion, about 4 mm. thick, and a lower, narrowed core. Microscopically, the former shows many slender epithelial fingers, connected above by thin bridges and below penetrating the corium. The fingers 1 Jour. Cut. Dis., 1913, xxxi, p. 148. 2 Ibid., 1915, xxxiii, p. 509. . ^ ibij. 52 PATHOLOGY consist of marked hyperplasia of epithelial cells, principally prickle cells. The spaces between the prickle cells in some areas are widened and filled with leukocytes. The cells of the neighboring germinal layer are pushed apart and communicate with the underlying tissue, thus giving a direct path up to the prickle cells. In certain areas round spaces are observed filled with leukocytes. The papillae of the corium which dovetail with the epithelial projections are divided histologically into two parts. The first, consisting of the upper two-thirds, is characterized by numerous parallel capillaries mostly filled with red blood cells but occasionally one filled with leukocytes. The infiltration here is mainly lymphocytes and plasma cells, except in the top of the papillae where some leukocytes are noted. Many lymph spaces are seen which are differentiated from the bloodvessels by the thinner walls and absence of erythrocytes. A rather frail connective tissue is seen between the vessels. In the lower part of the papillae is seen a dense infiltration of plasma cells. Below this area the capillaries are seen to be increased but the larger vessels are not, while the walls do not show much change, although they present a collar of small lymphocytes. The coil glands show a slight periglandular lymphatic infiltration. The treponemata are not found in the dense infiltration nor in any place in the corium except in the tips of the intrapapillary masses. Here they are very numerous and many are observed half in the intrapapillary mass and half between the epithelial cells. The organisms are more numerous higher up in the spaces and with the leukocytes they form a network around the epithelial cells and hundreds are seen in one field. Between the prickle cells they are not very numerous but occur in colonies near the papillary cones. They are found only occasionally in other epithelial areas. Dennie states that the treponemata probably gain access from the top of the papillary cones through the interrupted basal layer of the priclde cells, and multiply there. Leukocytes apparently do not exhibit their growth, although the lymphocytes and plasma cells do, as the organisms are not found where marked infiltration of these cells exists.. This location of the treponemata probably accounts for the marked infectivity of this type of lesion as the organisms can by their motility migrate to the outside through the intracellular spaces. Vesicular Syphiloderm. — Dennie^ has described the histo- pathology of this lesion, stating that it is built about a hair follicle, and consists of a triangular mass of densely infiltrated lymphocytes and plasma cells, the apex beginning at the hair shaft, slightly below its origin from the skin, and its base below the fat glands. 1 Jour. Cut. Dis., 1915, xxxiii, p. 509. SYPHILODERMATA 53 The corium is seen to be pushed out in all directions, leaving the lesion sharply defined. In the infiltrated area are found numerous spaces, probably lymphatics but practically no bloodvessels. Connective-tissue fibers, probably of recent origin, are seen near the hair shaft. The cells of the basal area of the hair follicle show a narrow "halo" due to edema surrounding it. The bloodvessels beyond this and outside the area of infiltration show peri- and end- arteritis with a "collar" of small lymphocytes. Giant cells are not found and the epidermis shows little change. Treponemata could not be demonstrated by Levaditi's method. Bullous Syphiloderm. — As far as the author is aware no adequate description of the histopathology of this lesion in the acquired form of syphilis has been made, but as it differs grossly in no respect from the same lesion in the congenital form, its microscopic picture undoubtedly is the same. A description of the histopathology of this lesion as observed in congenital syphilis will be found in the portion of the book dealing with that subject. Pustular Syphiloderm. — The microscopic picture of this lesion varies with the extent of the process and is essentially the same as a papular syphiloderm to which is added the change due to pyogenic organisms. The pustular syphiloderm may or may not be connected with a hair follicle. It is, however, well defined, is sometimes limited to the corium and sometimes invades the connective tissue. The condition does not vary materially from other non-syphilitic pus- tular lesions such as variola. The pus cells are found between the strata of the epidermis, the rete or the corium forming the base, or sometimes the suppuration extends through the latter. In the rupial syphiloderm a marked parakeratosis with infil- tration of leukocytes of the entire corium is observed. The crust is formed of aggregations of cells, coagulated serum, and detritis. Nodular Syphiloderm. — ^The histopathology of this type of syphilitic lesion diifers but little, except in degree, from that of the papular syphiloderm. With the low powers of the microscope alternate light and dark areas are seen involving the entire cutis from the epidermis to the connective tissue. The high powers reveal the fact that the dark areas are composed of cellular infiltra- tion, while the light areas are made up of bloodvessels. The latter are increased in number and many of them obliterated, their former site being shown by solid cords and giant cells. The nodular syphiloderm does not develop as rapidly as the papular lesion, it persists longer, and is followed by atrophic and necrotic changes which go on to ulceration. Gummatous Syphiloderm. — This variety of the syphilodermata presents extensive vascular change and diffuse infiltration. The walls of the bloodvessels are thickened by an endarteritis, while 54 PATHOLOGY the caliber is reduced or obliterated. The infiltration consists of lymphocytes, plasma cells, and hyperplastic fibroblasts. Areas of caseation occasionally are observed, which contain poorly staining nuclei, fatty droplets, pigmentary granules, disintegrated elastic fibers and colloidal granulations. Giant cells rarely are observed in this type of lesion. MUCOUS MEMBRANES. The mucous membranes of the various openings of the body, mouth, nostrils, vagina and anus, are affected with syphilitic manifestations very similar to those occurring on the skin, although not all varieties are observed on the mucous membranes. These lesions differ from the syphilodermata only as the physical and anatomical conditions differ. Such lesions are usually termed syphilides of the mucous mem- brane or mucous syyliiUdes, but as the term syphilide is used by many writers to designate the skin manifestations of syphilis, as well as those of the mucous membranes, it seems most desirable to have a name which applies alone to the lesions of the latter. The term syyhilomycoderm {sypkilis, syphilis; mycoderm, mucous mem- brane, fjivKTis, mucous; bkpjxa, skin) is therefore proposed. As with the syphilodermata, so with the lesions of the mucous membranes, scarcely any two syphilographers agree concerning their classification. The following seems to the author to cover the principal varieties of these lesions: I. Macular. (a) Erythematous. (6) Erosive. II. Papular. (a) Erosive. (6) Ulcerative. (c) Vegetative. {d) Squamous. (e) Leukoplakia. III. Gummatous. The gross appearance of the lesions of the mucous membranes as well as the gross appearance of the syphilodermata constitute important symptoms of the disease and therefore will also be described in the chapter on Clinical History. The histopathological picture observed in these lesions presents little that is different from that seen in the homologous syphilo- dermata. There is found the same general reaction of the tissues to the invading organism, infiltration of cellular elements, swelling of the endothelium of the bloodvessels, proliferation of the fixed cells and more or less thickening and destruction of the epithelial cells. CHAPTER V. CLINICAL HISTORY. Syphilis is a chronic disease caused by a specific microorganism, the Treponema palhdum, which in the acquired form begins with a local lesion, later becomes systemic, and spreads through the lymphatics and blood to the various tissues and organs of the body. In the congenital form and in certain cases of experimental and accidental syphilis the local lesion is not manifest. Throughout the entire course of the disease syphilis tends to cellular proliferation and the formation of new connective tissue and at certain times to development of fibrous and caseous tumors. Jonathan Hutchinson^ has remarked that syphilis has long been said to constitute in itself an epitome of pathology and adds, "there is scarcely a malady which has received a name which may not be simulated by it, and still fewer which it may not modify." Ricord's Stages. — As pointed out in Chapter I, Ricord divided syphilis into three stages: primary, secondary, and tertiary, to which Fournier later added a fourth or quartenary stage. The primary stage, according to the great syphilologist, includes the development of the chancre and the adjacent adenopathy. During the secondary period the infection becomes systemic and the various superficial lesions of the skin and mucous membranes are manifest. During this stage also occur orchitis, alopecia, and iritis. The tertiary stage is marked by the involvement of the inner structures of the body such as the bones, joints, and viscera. The quartenary stage of Fournier consists of the so-called parasyphilitic diseases, paresis and tabes, which we now know to be true syphilis of the brain and spinal cord. Ricord's Classification Inadequate. — While the division of syphilis into stages by Ricord was a long step in advance, and has been followed by most «syphilographers up to the present time, it cannot today be considered scientific. Even at so early a date as 1843 Cazenave^ objected to Ricord's classification, stating that any lesions of syphilis may occur at any time no matter how near or how far it is removed from the first infection. Hyde^ also objected to 1 Power and Murphy: System of Syphilis, London, 1908, Introduction, p. xvii. 2 Quoted by Baumler: Encyclopedia of the Practice of Medicine, New York, 1875, iii, p. 27. 2 Morrow: A System of Geni to-urinary Diseases, Syphilology and Dermatology, New York, 1898, ii, p. 22. 56 CLINICAL HISTORY Ricord's classification, stating that it had served its day. He proceeded to point out that there is no sharp boundary line between the various manifestations of syphilis, that from the instant of infection to the terminal phenomena there is a gradual advance of the disease. These statements in the light of modern knowledge of the Treponema pallidum are seen to be most true. On purely anatomical grounds it is readily seen that we must discard the stages of Ricord. The non-gummatous orchitis has been classified by some as secondary and by others as tertiary. So why attempt to give it a chronological classification? Let it be termed a syphilitic orchitis or diffuse syphilitic inflammation of the testicle, and state that it may occur at any period subsequent to the systemic involvement. Another reason for abandoning Ricord's classification is that in hereditary syphilis and in syphilis of rabbits produced by intracardial inoculation as well as in such cases as reported by Fordyce^ in which in one instance infection accidentally occurred by a hypodermic needle which had been used for collecting blood for the Wassermann reaction and in another case by blood transfusion, no so-called primary stage exists. It would therefore seem that the only scientific classification of the phenomena of syphilis is one based upon anatomic and symptomatic grounds. Development and Course. ^ — It is an almost universally accepted belief today that there must be a solution of the continuity of the epithelium for the Treponema pallidum to gain entrance to the body. And after this direful germ has once penetrated the epithelial barrier, no matter in what location, there is a period during which it gives no outward evidence of its presence, and its host goes his way, blissfully ignorant of what is to follow. This time, known as the incubation period, varies from ten days to three months, although the average duration is from three to four weeks. Bronson^ states that Diday once saw a case with an incubation period of but twenty-four hours, and that LeFort mentions three cases with this period not exceeding seventy-two hours. In the light of modern knowledge of the infecting organism these reports of such extremely short incubation periods must be taken with great reserve. There are a number of causes operating which undoubtedly determine the length of the incubation period. The most important of these would seem to be : the number of organisms inoculated, the condition of the point of inoculation as to vascularity, etc., the nature and amount of the abrasion, the natural resistance of the individual and the virulence of the organisms. This virulence 1 Am. Jour. Med. Sc, 1915, cxlix, p. 781. 2 Morrow: A System of Genito-urinary Diseases, Syphilology and Dermatology, New York, 1898, ii, p. 73. DEVELOPMENT AND COURSE 57 would seem to depend upon the condition of the lesion from which the organisms are derived, that is, the age of the lesion, whether or not it has been treated, etc., and when inoculation takes place through intermediate contact upon the nature and condition of the object which carries the organisms and the length of time which elapses between the contact with the infected and the non-infected individual. During this varying incubation period the treponemata have been multiplying and in all probability spreading by way of the I>TQph channels and bloodvessels, although all evidence of the abrasion in the epithelium may have disappeared. However, at the end of this time the chancre appears at the sight of the inoculation. This lesion, which usually begins with a papule, takes many forms, which will be described later, lasts for a varying period and gives no evidence of the severity of the condition which is to follow. There is scarcely any pain connected with it, no apparent systemic involvement, very little discomfort, and the patient usually leads his accustomed life. There is soon, however, evidence that the treponemata have left the portal of entry and have invaded the lymphatic system. The adjacent glands become enlarged and hard, although usually not painful and they rarely suppurate. Following the appearance of this adenopathy there is another period of apparent quiescence, known as the second incubation period, which averages in length from six to seven weeks, although it may be shorter or be prolonged. In patients who are suf- fering from other diseases, or who are debilitated from excesses, the period is usually shortened, while specific treatment will tend to make it longer. It has been stated that this so-called second incubation period is usually shorter following extragenital than genital chancres but this contention lacks confirmation. However, during this time the germs have been multiplying and spreading through the lymph and blood, and presently all doubt of the nature of the disease is vanished by the appearance of the cutaneous manifestations. Although the vast majority of chancres, which receive no specific treatment, are followed by syphilodermata, this is not true in all cases, and in the days when physicians relied for a diagnosis solely upon the development of the so-called secondaries many errors were made. These syphilodermata, while usually easily recognized, may simulate almost any form of dermatological lesion. The lining membranes of the mouth and throat now usually develop lesions of varying appearance, while accompanying these conditions may be fever, headache, and other symptoms of more or less severity. From now on the disease is most protean. The acute symptoms 58 CLINICAL HISTORY may disappear either with or without treatment and the causative organisms apparently He dormant for years only to break out in unexpected places. As stated above, there is no tissue or organ of the body which is immune to their attack. The heart and blood- vessels very often are involved, even early in the course of the disease, and various symptoms arise which may or may not be recognized as syphilitic. Nephritis due to the treponemata is a frequent symptom, especially during the acute outbreak. Many cases of syphihs of the lungs have undoubtedly been diagnosed tuberculosis, while the liver is not infrequently involved, jaundice, acites and other symptoms resulting. The bones and joints are often the seat of the infection which is manifested by pain, tenderness, swelling and other symptoms. The most important portion of the body to be invaded by the organisms of syphilis, however, is the nervous system. Any or all portions of the nervous system may be attacked, the meninges, the brain, the spinal cord or the nerves, and in recent years it has been shown that such invasion may occur even as early as the time of the chancre. Although involvement of the bones, viscera, nervous system, etc., may take place early and probably usually does, symptoms refer- able to such involvement as a rule are among the late manifestations of the disease. Thus the brain substance may be attacked, six, eight, ten or more years after the chancre, paresis result and the chapter close with death. CHANCRE. Development. — The term chancre is a French word derived from the Latin cancer. This lesion, which in the acquired form of syphilis is the first manifestation of the disease, usually begins as a small reddish spot at the site of inoculation and soon develops into a papule. It may or may not at this time convey to the palpating fingers a sense of resistance. The surface may be moist with a light, sticky, clear, sanious, fluid or it may be perfectly dry. The attention of the individual may first have been called to it by itching, or it may have been observed by him as what is vulgarly known as a "hair cut." The lesion is generally nearly circular in outline and of a dark red color, which later changes to gray. It varies greatly in size, sometimes being so small as to pass unnoticed, and again it may be 4 or 5 cm. or over in diameter. While this lesion of syphilis is usually single, it may be multiple. It would seem that the number usually depends upon the number of abrasions which exist at the time of inoculation, but multiple chancres may occur by auto-inoculation. CHANCRE 59 In a few days a hard mass or induration develops in the vast majority of cases at the base of the chancre. This varies greatly in size and shape. It may be so slight as to be undetected except by the most skilful palpation, or it may be hard and nodular, being readily recognized on sight. At times it is thin and lamellar, resembling a piece of parchment or it may be of annular shape, forming a ring around the sore. The induration is not inflammation, as it takes place without the cardinal symptoms of that pathological process. It varies greatly with the location of the chancre. If the latter is in a spot where the tissues are firm and resistant, it is much more difficult of detection. Generally speaking, when the chancre is located on mucous membrane the induration may be felt more easily than when the skin is the seat of the infection. The induration usually lasts after the sore is healed. The sore itself generally heals even without treatment and leaves little or no trace of its existence. This is probably due to a local acquired immunity which causes the Treponema pallidum to die out in the sore. However, a pigmented spot may persist for some time and occasionally there may be a white spot left, due to loss of tissue, which may last for years. Location. — Genital. — The most frequent location of the chancre in men is the balano-preputial fold. This is undoubtedly due to the fact that in this location slight abrasions most frequently occur. The location, which next to the above, is most often affected is the lining mucous membrane of the prejmce. A chancre of this location often cannot be observed, owing to the presence of a phimosis, which may or may not be due to the lesion itself. In such a case circumcision should be performed to permit of an accurate diagnosis. The preputial orifice is next most frequently attacked- by the syphilitic organism, while the order of frequency of other genital chancres in the male is as follows: frenum, skin of penis, glans penis, urinary meatus, scrotum, prescrotal angle, and urethra. When the preputial orifice is the seat of the infection, the sore gives to the prepuce the appearance of having been split. At first the splits look like mere scratches which later become indurated and the prepuce thickened. A chancre of the skin of the penis begins as a small abrasion which gradually spreads until it may attain a diameter of 2 or 3 cm. The edges are hard and the induration is thin, parchment-like and quite easily detected by palpation. When the surface of the glans penis is the seat of a chancre it begins as a flat erythematous spot, which in a short time becomes depressed in the centre with hard, indurated edges. Either one or both lips of the urinary meatus may be inoculated with the Treponema pallidum and a chancre result. However, that both are aft'ected is the rule. Induration is invariably present, 60 CLINICAL HLSTORY though slight. A scanty, viscid, discharge is found which generally glues the lips together. There is usually some impediment to the flow of urine, which, however, disappears when the lesion heals. Chancre of the scrotum usually begins with a small, circular, reddish spot which gradually spreads in size. There is soon des- quamation of the superficial epithelium and small cracks occur which coalesce, forming a circular ulcer. This ulcer is usually not deep but has considerable induration. Chancres of the prescrotal angle are similar. Ricord^ taught that the urethra frequently lodged the syphilitic chancre and that it was due to this fact that many cases of syphilis remained unrecognized until further symptoms of the disease appeared. The majority of urethral chancres are just within the meatus or in the fossa navicularis, but may be so far from the opening that they cannot be seen except by the aid of the endo- scope. Genital chancres in the female are found most frequently on the labia majora and vary according to their location, whether on the internal or external aspect, or on the free margin. In these locations the chancre quite frequently is accompanied by an edema of the part. This is due to a superficial lymphangitis and may result in hyperplasia. If both labia are affected, it is usually due to a double infection and not to spreading from one labium to the other. According to Fournier, other genital chancres in the female occur in the order of their frequency on the labia minora, fourchette, cervix, region of clitoris, vestibule of the vagina, meatus urinarius, upper commissure of the vulva and vagina. Chancre of the cervix is perhaps relatively frequent, but is quite often unrecognized. That a chancre in this location is more common than chancre of some other regions is doubtless due to the frequency of abrasions of the mucous membrane of the cervix, and obviously it may easily be overlooked, owing to the anatomical construction of the parts. It is typical of chancre of the cervix that the edges are thick and sloping. It is usually round and smooth, with a glistening, dry floor, and bleeds easily when touched. A striking characteristic of chancre of the cervix is the rapidity of its healing which may occur before any other manifestations of syphilis appear. That vaginal chancres are extremely rare is not to be wondered at, owing (1) to the comparative toughness of the mucous membrane of this region, which makes abrasions infrequent, and (2) to the normal secretions which bathe the vagina and probably act as a treponemacide. 1 Letters on Syphilis, American edition, Philadelphia, 1857, p. 101. CHANCRE 61 Perigenital. — To this class of syphilitic chancres belong those of the anus and rectum, the groin, the upper and inner aspect of the thigh, and symphysis pubis. Chancres of the anus and rectum may occur, and usually do, in men as the result of sodomy. In women intercourse per rectum may be the cause, or a chancre of the anus may follow the flowing of vaginal secretions and semen, carrying the Treponema pallidum over the part. Chancres of these locations may result from inter- mediate contact with infected enema syringes, specula, etc. A chancre situated at the margin of the anus appears as a thickened, ulcerated fissure. It is of a rose-red tint and shows but slight induration. When located within the rectum a chancre shows a deep eroding or ulcerating surface which is more or less smooth. Induration, if present, is difficult of detection. Fig. 2. — Chancre of the nose. Venereal chancres of the groin and upper and inner aspect of the thigh in women may occur from an attempt at coitus or in both men and women from unnatural practices. Such chancres start as small papules which gradually increase in size to three or more centimeters in diameter. They are usually flat and dry, although they may be eroded and moist. Induration may be present, though difficult of detection. Extragenital. — There is scarcely any portion of the body which may not be the seat of syphilitic chancre. However, the most common locations of extragenital chancres in the order of their frequency are, the lips, tonsils, tongue, breasts, eyelids, and fingers. Such locations as the nose and great toe, as cited in Chapter III, are merely medical curiosities, but show that a suspicious-looking sore 62 CLINICAL HISTORY of any part of the body should be made the object of most careful examinations. ^1 % ^^^^^^^^^^^^^^^^Hm^^i ^'" ^^^IK ■i Fig. 3. — Chancre of the Hp. A labial chancre generally appears as a fissure or cleft but may appear as a papule. There is usually considerable induration and there may be ulceration. It may be so small as to pass unnoticed, or thought of as a crack due to cold, or it may be so large as to disfigure the face. Fig. 4. — Chancre of the Hp. While chancre of the tonsil is of comparatively frequent occurrence, its importance lies more in the great danger of it being incorrectly diagnosed. In this region the lesion partakes of the usual induration CHANCRE 63 of other chancres. It is usually unilateral but may be bilateral. The surface is generally eroded and may ulcerate. A grayish Fig. 5. — Chancre of the tongue. Fig. 6. — Chancre of the eyeUd. 64 CLINICAL HISTORY membrane may be present, which has often caused the diagnosis of diphtheria to be made. Certain cases may become phagedenic or gangrenous, when there may be considerable loss of tissue. More or less pain and difficulty in swallowing are experienced. A lingual chancre is ordinarily seen as an oval, flat surface or as a nodule with thickened edges and marked induration. It is usually eroded, and if on the tip, presents the appearance of the tongue having been cut off. Chancre of the breast may be situated on the nipple, on the areola, or on the breast itself and presents no peculiarities not found in chancres of other localities, except perhaps a greater tendency to multiplicity. Chancre of the breast has been observed in men. When the chancre develops on the eyelid there is usually more or less deformity, depending upon the extent of the lesion. Either one or both lids may be affected, the chancre starting on the skin Fig. 7. — Chancre of the finger. or palpebral conjunctiva, and rarely spreading to the ocular con- junctiva. In the beginning the chancre usually appears as a papule which soon ulcerates and becomes indurated to a marked degree. Chancre of the finger presents a class of syphilitic lesion, which, although probably m.ore frequent in physicians than any other class of individuals, very often remains undiagnosed until other manifestations of the disease occur. The usual location of chancre of the finger is on the site of a hang-nail, but it may be at any place where the treponema may gain entrance through a scratch or other abrasion. The most striking feature of digital chancre is the absence of demonstrable induration. This is probably due to the density of the tissues. However, there usually is swelling of the entire finger. Quite frequently the chancre may surround the nail in a horseshoe shape, destroying the nail and leaving considerable malformation of the finger-tip.*^ CHANCRE 65 Varieties. ^ — It will be seen from the above that the syphilitic chancre does not exist as a typical pathological lesion, that it may assume many shapes and forms. There are, however, a number of fairly constant varieties which, to a large extent, depend upon their location. The first is the indurated papule. This lesion begins as a slight, dark red elevation which may attain the size of 2 cm. or more in diameter. It is dry and hard and the surface is not broken through- out the entire course of the lesion. The eroded chancre is probably the most frequent form of this sore. It has the appearance of a rounded or oval spot with a smooth, raw surface. The edges are not elevated above the surrounding tissue, and while the centre is usually concave, it may be convex or dome-shaped. Such a chancre may be as small as a split pea or as large as a five-cent piece in diameter. Quite frequently a chancre assumes the form of an ulcerating sore which may involve only the superficial layers or may burrow deep into the tissues. Such a lesion has been termed a Hunterian chancre. Induration is usually quite marked in the beginning but may be covered with a grayish false membrane, and a slight, thin, sanious exudate is present. Occasionally in the beginning a chancre has the appearance of the mark left after the application of a stick of silver nitrate. This type of lesion has been called the silvery spot. It gradually assumes a dark yellow color and considerable induration exists. A recurring or relapsing chancre (chancre redux) is a lesion, probably a gumma, which has all the appearance of an original chancre and which develops on or near the site of a previous chancre. It may occur at any time, from a few weeks to ten or twelve years or longer after the healing of the first sore. The surface usually remains intact but it may become eroded. Complications of Chancres. — A chancre may be modified in appear- ance and course by inflammation, complication with chancroid or by phagedena. Inflammation of the chancre may be due to the application of caustics or to the presence of pyogenic organisms. In either case the appearance of the lesion will be modified greatly. The sore and adjacent tissues become red and swollen, while pain, which is rare in uncomplicated chancre, may be most intense. The complication of a chancre with chancroid, which is known as a mixed sore, is not infrequent. The double infection may occur at the same time from the same source or the chancre may be subsequently inoculated with the bacillus of Ducrey, the causative agent of chancroid. In the former case the typical chancroidal ulcer, which develops first, owing to the shorter incubation period, 5 66 CLINICAL HISTORY is gradually surrounded with the induration of the syphilitic lesion. While if the chancre is later infected with the chancroid bacillus, the induration is destroyed by ulceration. The most serious complication of chancre is phagedena, which, fortunately, is rather rare. This condition may develop in a chancre at the very beginning or it may not appear until quite late. It is probably caused by a mixed infection of pyogenic bacteria, although any lowering of the vitality, such as that resulting from drunkenness, diabetes, nephritis, etc., may predispose the individual to it. The ulcerative process usually spreads on all sides and deep into the tissues, although it may progress in only one direction (serpiginous ulceration). The sore is irregular with markedly congested and Fig. 8. — Phagedena. edematous edges. It bleeds easily and may even erode through a vessel of some size, causing considerable hemorrhage. There may be sloughing and loss of tissue. LYMPHATIC GLANDS. As stated above, the enlargement of the lymphatic glands adjacent to the chancre is an almost universal occurrence. Ricord said, " Pas de chancre infectant sans huhon." While the lymphatic glands nearest the initial lesion are the ones usually affected, this is not necessarily the case, as the glands involved are those which receive the afferent vessels which originate at the site of the chancre. The LYMPHATIC GLANDS 67 following table shows the glands which, as a rule, are enlarged with chancres of various localities: Site of Chancre. Glands Involved. Genitals, buttocks, aiw»s, thigh, leg, foot. Inguinal. Tongue. Submaxillary or submental. Lip. Submaxillary. Chin. Submental. Tonsil. Deep cervical. Finger, hand, forearm. ' Epitrochlear and axillary. Arm, breast. Axillary. No glandular enlargement which is palpable is produced by chancre of the cervix, but without doubt the internal iliac glands are enlarged with chancre of this location. The lymphatic enlargement usually is observed early in the course of the disease, during the first week following the appearance of the chancre, as a rule, but may be seen as late as the second week. While sometimes only one gland may be felt, it is usual for several to be involved. They appear as hard, round, freely movable nodules, which are sharply defined. They may pass unnoticed by the patient, as there rarely is any pain. When the chancre develops on those locations draining into the inguinal glands the so-called syphilitic bubo is formed. The enlarge- ment may be unilateral but usually is observed in both groins. Although the superficial inguinal glands are generally the only ones which can be felt, it has been determined in persons suffering with genital chancres, who have met violent deaths, that other glands also are involved. This undoubtedly is the case in chancres of other localities as well. As a rule no suppuration occurs, but in "mixed sores" and in ulcerating chancres this condition may be found. Aside from the lymphatic enlargement just described, and obviously depending upon the chancre of the region drained by the afferent vessels of the glands involved, the Treponema pallidupa seems to have a predilection for lymphatic tissue. Further, certain groups of glands for some inexplainable reason are more frequently attacked than others. This enlargement bears no relation to cuta- neous or other lesions, although it is seen more often during the first year of the disease than later. The most frequently affected glands are those of the neck, especially the posterior cervical, the occipital, and the epitrochlear. The axillary glands and the inguinal glands if not primarily involved, sometimes are enlarged independently of other lesions. This adenitis may appear before any cutaneous lesions are observed, is practically always noted with such lesions, and may persist for some time following the healing of the syphilodermata. The glands never suppurate except when complications exist and 68 CLINICAL HISTORY usually disappear with resolution. The size attained by the lym- phatic glands under these conditions varies from 1 or 2 mm. in diameter, and scarcely palpable, to 2 or 3 cm. and easily observed as distinct tumors. While usually only one gland is involved, two or even three may be enlarged and may be connected by an indurated cord. The lymph glands rarely may be the seat of gummatous formation. This condition usually occurs late in the course of the disease, but may be observed as early as the first year. Gummata of the lymphatic glands tend to soften and if superficial may form ulcers. Several gummatous glands may grow together by the development of connective tissue and form large masses. CUTANEOUS LESIONS. The syphilodermata, which are the most striking outward mani- festations of syphilis, as pointed out above, may assume almost any form and resemble any known skin disease. For example, the pigmentary syphiloderm m.ay resemble vitiligo, and the term vitiligoid syphiloderm or syphilitic leukoderma often is applied. Such terms not infrequently are misleading and should be dis- couraged. Macular Syphiloderm. — The most frequent form of the macular syphiloderm is the roseolar which is also the most common of all the skin manifestations of syphilis. This usually is observed six to seven weeks following the appearance of the chancre, although the time may be shorter or considerably longer. The roseolar syphiloderm in the majority of cases begins on the upper abdom.en, spreads to the thorax and later may involve nearly the entire surface of the body. The dorsal surfaces of the hands and feet usually escape. Occasionally the eruption begins on the face, being most prominent about the nose, mouth, chin and especi- ally the forehead. This syphiloderm consists of variously sized spots which usually are on a level with the surrounding skin but may be slightly elevated. The average size is about 1 cm. in diameter, although they may be considerably smaller and occasion- ally become much larger. The shape is round or oval with distinct or irregular outline. At first the color is a pale pink or a reddish violet which disappears on pressure, but later assumes a dark red, coppery tinge, often described as resembling the color of lean ham. The development of the roseolar eruption may be very sudden, sometimes being brought out by violent exertion or occasionally by a hot bath. Often the spots are faint in color and escape notice until the surface of the body is exposed, as for the purpose of physical CUTANEOUS LESIONS 69 examination. The number of the lesions varies from a few scattered spots to a profuse crowded condition, which occupies the greater portion of the skin, leaving a comparatively small area of normal skin between the macules. Rarely coalescence takes place. The eruption usually persists for several weeks and may disappear quickly or gradually. Ordinarily there is little or no desquamation, although with palmar lesions this is not infrequent. The annular macular syphiloderm is rare and generally is seen as a recurrence. While it usually appears within a few months following the chancre, it has been noted as late as four or five years after the initial lesion. It is, as the name implies, of ring-shaped Fig. 9. — Macular {roseolar) syphiloderm. outline and, as a rule, is limited in area and in the number of rings. A concentric arrangement of the rings is occasionally seen. This eruption is most frequently found on the neck, shoulders, and forearms. The pigmentary syphiloderm has been the subject of much dis- cussion and its existence as a distinct syphilitic eruption has been questioned. Fox^ states that it is neither pigmentary nor syphilitic, that the dark recticulum is secondary, and the whitish macules develop" first on the site of former syphilitic lesions. There seems 1 Jour. Cutan. Dis., 1913, xxxi, p. 224. 70 CLINICAL HISTORY Fig. 10. — Macular (roseolar) syphiloderm. Fig. 11. — Pigmentary (vitiligoid) syphiloderm. (Ormsby.) CUTANEOUS LESIONS 71 no doubt, however, that aside from the pigmentation of the skin following certain other syphilodermata there occasionally develops an original discoloration of the skin due to syphilis. According to Taylor^ three varieties of the pigmentary syphil- oderm are seen which are as follows: 1. Spots or patches of various sizes. 2. More or less diffuse pigmentation, sooner or later becoming the seat of leukodermic change in the shape of small retiform spots which gradually increase in size. 3. A so-called marmoraceous pigmentary syphiloderm formed by an abnormal distribution of the pigment of the skin, some places becoming whiter than normal by the lack or crowding out of pig- ment and others darker by the abnormal distribution of pigment. The first type consisting of spots or patches of rounder or oval form with sometimes irregular edges, varies in color from light to dark brown, the edges of the spots showing the darker color. The intervening skin is usually normal in color but appears whiter, owing to the pigmentation of the spots. The pigmentation may last for months, after which it may slowly fade and disappear. Some- times areas without pigmentation are left which are termed secondary or yseudoleukodervia by Taylor. However, as a rule, the skin returns to normal after the disappearance of the pigment. In the second form of pigmentary syphiloderm described by Taylor, the so-called lace or retiform variety, which is the most frequent, the sides or back of the neck either slowly or rapidly become discolored, sometimes extending to the shoulders or trunk. The color is described as that of cafe-au-lait or yellowish-brown. Gradually whitish spots develop in the pigmented area, beginning as minute specks and in a short time attaining considerable size and presenting round, oval, linear or irregular shape. The white spots may actually be lighter than the normal skin or they may only appear so by contrast with the pigmented areas. As the white spots increase in size the pigmented areas become smaller and may eventually consist of narrow bands which cause the lesions to have the appearance of lace, the white spots forming the interstices. The third form, termed marmoraceous on account of its supposed resemblance to som.e forms of marble, appears slowly, and, according to Taylor, only on the sides of the neck. It is the rarest variety of the pigmentary syphilodermata. Spots of the skin of varying size and shape become white, while the skin between the spots becomes brown. The margins are hazy and indefinite. There is no hyperpigmentation, the change in color seeming to be due to irregular distribution of the normal pigment. After a variable 1 The Pathology and Treatment of Venereal Diseases, Philadelphia, 1895, p. 638. 72 CLINICAL HISTORY period of time the lesions slowly disappear and the skin is left in a normal condition. The pigmentary syphilodermata occur at varying periods follow- ing the initial lesion, usually, however, from about the sixth month to the end of the first year. In one case seen by the author this manifestation was observed eight months following the chancre of the left labium majus. The pigmentary syphiloderm may be the Fig. 12. — Papular (lenticular) syphiloderm. (This eruption occurred fifteen years after the chancre.) only syphilitic lesion present or it may occur in connection with other syphilodermata. It is most frequently seen in females, males being rarely affected in this manner. The chief regions involved are the sides and back of the neck, rarely the face, trunk, arms and legs. Papular Syphiloderm. — This variety of syphilitic eruption may follow the macular syphiloderm, the latter merging into the papular variety gradually, so that the term maculopapular syphiloderm CUTANEOUS LESIONS 73 may be applied with perfect propriety. On the other hand, the papular syphiloderm may appear as the first rash of the disease. The time of the appearance of this syphilitic lesion is subject to great variations, it being observed sometimes as early as the second or third month or as late as several years following the initial lesion. One characteristic of the papular syphilodermata is their tendency to recurrence, and this phenomenon may be noted under one form or another for a number of years. The author has recently had under his care a caSe in which a lenticular papular eruption occurred fifteen years following the chancre (see Fig. 12). Fig. 13. — Papular (miliary) syphiloderm. While the miliary papular syphiloderm is of comparatively frequent occurrence, it is not noted as often as the lenticular form. The mihary eruption varies in size from a pin-head to that of a French pea, is usually associated with the hair follicles and is therefore sometimes termed follicular. This lesion consists of accuminate or rounded projections, solid and rough to the touch, which when large sometimes show a slight umbilication. Frequently early in the course of the development of the miliary papular syphiloderm there is a tendency shown by the larger lesions to form 74 CLINICAL HISTORY minute vesicles at the summit which last only a few days and upon drying show an epithelial scale. Occasionally also the summit is surrounded by a small pustule. The most frequent location of this syphiloderm is on the face, neck, shoulders, back, arms, and thighs. The separate lesions are often closely crowded and tend to form groups in circles or semicircles with 10 to 40 papules in a group, while the intervening skin is normal. This is especially true of the smaller form and in relapses or when the lesion appears late. It is frequently noted that the trunk is the seat of small papules, while at the same time larger papules are found on other portions of the bodv. ^B" . _ ■ ■■'■"fi* ') if^HHl^K^; ., Fig. 14. — Papular (le?iticular) syphiloderm. The color of the miliary papular syphiloderm is at first a bright red and later fading to a dark brownish or violaceous red. The course of this lesion tends to be chronic, lasting from a few weeks to several months and perhaps disappearing spontaneously, the color becoming duller and more somber. A bluish or brownish-red stain may persist for some time, but no scarring is noted except when the papule has contained a pustule. It is often noted that fresh papules develop scattered among the original lesions. The lenticular or flat papular syphiloderm is, next to the reseolar syphiloderm, the most frequently noted of the skin lesions of CUTANEOUS LESIONS 75 syphilis. The papules are round or oval, flattened, slightly convex, raised but little above the surrounding skin, have sharply defined borders and show some infiltration. They vary in size from that of a pea to a large bean or even larger. When very large this type of syphiloderm is sometimes termed nuvmiular, and is occasion- ally seen as large as a silver half-dollar or larger. The color is a dull brownish-red. The syphiloderm is distributed very extensively on the forehead, back of the neck, shoulders, scalp, arms and legs, especially the flexor aspect. The palms of the hands and soles of Fig. 15. — Papular (h'/UicuInr) syphiloderm. the feet are usually free from the eruption. These papules are usually not so abundant as the miliary type and are less frequently found with other varieties of syphilodermata, although sometimes a few macular and pustular lesions may be seen. The development of the lenticular papular syphiloderm is usuafly slow and often comes in successive "crops." As the papule develops the surface undergoes more or less change, the epidermis becoming red and shiny and later the centre desquamates, the papules gradu- ally becoming flatter and disappearing by resolution. There is usually some brownish or grayish pigmentation left which is very 76 CLINICAL HISTORY persistent. There is little tendency to grouping and ordinarily none to coalesce. A case which has recently come under the care of the author is a striking example of this type of eruption (see Fig. 16). It will be observed that almost the entire face is covered with a continuous dark red eruption, only a few spots of normal skin remaining, while small and large spots cover a large portion of the remaining cutaneous surface. Fig. 16. — Papular (nummular) syphiloderm. (Note that the face is almost com- pletely covered by the confluence of the eruptions.) In certain cases, especially in negroes, there is a tendency to ring formation, the eruption appearing as complete or partial circles, and is given the term annular or circinate syphiloderm. This condition is brought about, according to Hazen,^ in a number of different ways and may develop from the miliary lesions as well 1 Jour. Cutan. Dis., 1913, xxxi, p. 148. CUTANEOUS LESIONS 77 as from the lenticular. As it probably always develops from one or the other of the papular syphilodermata it should not be con- sidered as a distinct variety. The papules may be grouped in a circle, the central ones rapidly disappearing and the peripheral ones coalescing more or less and forming the circular lesions. Or the annular lesions may develop from a single papule which first Fig. 17. — Papular (annular) syphiloderm. spreads, after which the border becomes slightly raised and absorp- tion takes place either in the centre or more frequently just within the outer rim. Or finally a number of papules may form a ring without any lesions in the centre. Single miliary lesions rarely develop into the annular syphiloderm; the same is true of the smaller lenticular lesions but the larger ones 78 CLINICAL HISTORY quite frequently do so. The size of the annular lesion is usually about 1 or 2 cm. in diameter, although it may be considerably larger. Several may coalesce, forming fantastic patterns, and not infre- quently two or more may be concentric. The number varies from one to a hundred or more. The most frequent location of this syphiloderm is on the face but may be seen on the neck, body or limbs. It may be the only type of lesion present or may be accom- panied by others. The lenticular papular syphiloderm quite frequently shows a tendency to marked desquamation instead of the slight scaling usually noted, which has led to the term pajnilosquamous syphilo- FiG. 18. — Papular (annular) syphiloderm {concentric). derm. On account of the resemblance of this condition to psoriasis it has erroneously been designated syi^hilitic psoriasis. The papules at first usually become slightly less elevfited and an accumulation of epidermic scales takes place. This scaling may be very slight and the scales thin and wrinkled, or it may be very marked, the scales being dry, of a dirty grayish or brownish color, thick and usually friable. Occasionally they are hard and horny and adherent. When removed the papule is seen beneath, flat and of a dark red color. Pruritis is rare and never marked except in the negro. The papules which appear late in the disease or as recurrences are more likely to exhibit this tendency of desquamation. Also those of certain localities as on the face, along the eyebrows and chin. CUTANEOUS LESIONS 79 and on the palms and soles show a special predisposition to this condition. While the palms of the hands and the soles of the feet may be the seat of most of the syphilodermata, when they are attacked by the papulosquamous form the terms palmar and plantar syphiloderm are applied. Although these lesions are papular in character, they present certain peculiarities which account for the special terms. These peculiarities are due to the thickness of the epidermis of these regions and the firm adherence of the dermis to the underlying fascia. The papules are flat with scarcely any elevation above the surrounding surface, although there is distinct infiltration. At first they appear more as macules than as papules, are of a dull red or yellowish-red color and vary in size from that of a pea to the Fig. 19. — Papular {squamous) syphiloderm (palmar). diameter of a silver ten-cent piece. Later the epidermis becomes partially separated, the color being a dirty gray, while beneath, the underlying lesion retains the usual red color. The papules 'usually first develop in the centre of the palms or soles and may extend by creeping, with an elevated border, to the fingers and toes or even to the dorsal surfaces. There is also a tendency to coalesce, the whole surface of the palm or sole being covered by the lesion. Sometimes the natural folds or furrows of the skin of these regions become the seat of deep cracks or fissures which may become exceedingly painful and refractory. While this type of eruption is more frequently observed on the palms of the hands, it is sometimes seen on the soles of the feet as well and occasionally on the latter alone. Rarely only one hand 80 CLINICAL HISTORY . or one foot is attacked. This type of lesion appearing late in the course of the disease is often most resistant to treatment, and even when observed early with other syphilodermata, it is usually less am.enable to therapy than the concomitant lesions. When a lenticular papule, instead of desquamating, presents a more or less moist appearance, the term moist papular syphiloderm is applied. This type of lesion is usually met with early in the disease and may be observed with other types or alone. However, if not treated, it may persist almost indefinitely and has been Fig. 20. — Papular {squamous) syphiloderm (plantar). observed as a recurrence as late as twenty to thirty years following the chancre. The moist papule usually begins as a flattened ele- vation, circular, and varying in diameter from 2 or 3 mm. to 1 cm. The reason that certain papules develop into the moist type is to be found largely in the location. The thinness of the skin, the apposition of contiguous surfaces, the warmth and the moisture from perspiration all act as contributing factors. The most frequent location of the moist papule is about the anus and genitalia, especi- ally in women. Not infrequently in the latter this eruption may be CUTANEOUS LESIONS 81 the only skin lesion developing throughout the entire course of the disease. The corner of the mouth, the nasolabial fold, the axillae, the skin beneath the breasts, the interdigital spaces and the skin around the umbilicus may be the seat of this lesion. Fig. 21. — Papular (vegetating) syphiloderm. Fig. 22. — Vegetating condylomata of the vulva and anus. (Ormsby.) As stated, the moist papule begins as a flattened, elevated lesion which, instead of desquamating, becomes soft and the surface 6 82 CLINICAL HISTORY presents a grayish or brownish-gray, easily detached, mucoid pellicle, composed of macerated epidermis. Sometimes large, flat patches are formed by the coalescence of two or more lesions. Not infrequently these papules may become ulcerated. The moist papular syphiloderm instead of becoming flat occasionally hyper- trophies and becomes warty or papillomatous. Several lesions coalesce and a large cauliflower mass, surrounding the anus, or, in the female, the vulva, may develop, and is often termed vegetating syphiloderm or condyloma. These lesions may occur in other localities, as for example, the nose. (Fig. 21.) It is accompanied by more or less mucoid secretion and unless strict cleanliness is observed a most foul odor develops. Fig. 23.— Lenticular {moist) papular syphiloderm. (Condylomata.) These lesions are usually very amenable to treatment, but occasionally they break down spontaneously by a process of ulcera- tion. This latter process, however, does not, as a rule, involve the skin upon which the lesions are located, so there is little or no loss of tissue when cicatrization takes place. Vesicular Syphiloderm. — Fox^ flatly denies the existence of a cutaneous lesion in syphilis worthy of the name vesicular. Morrow^ states that vesicles are sometimes formed on erythematopapular lesions due to the intensity of the inflammatory process, but con- siders them as an accidental or accessory phenomenon and of 1 Jour. Cut. Dis., 1913, xxxi, p. 224. 2 A System of Genito-urinary Diseases, Syphilology and Dermatology, New York, 1898, ii, p. 146. CUTANEOUS LESIONS 83 limited duration. He therefore does not think that this type of lesion should be elevated to the dignity of a separate class. On the other hand, Duhring^ states that while the majority of so-called syphilitic vesicles may more properly be viewed as early pustules, occasionally lesions are observed that present throughout their course characters which entitle them to be termed vesicular. This author states that Bassereau and also Hardy have described these lesions at length and that they are of various size, from pin- head to split-pea, more or less acuminated, disseminated or grouped, flat or semiglobular with or without umbilication. They always occur within the first year, usually within the first six months and are generally associated with other lesions. Dennie^ describes the lesions of one case observed by him as being 1 to 4 mm. in diameter, sparsely scattered over the back and flanks, elevated considerably above the smrounding cutaneous surface and appearing t^ranslucent and tense with fluid as if quite deeply situated. In quite an extensive observation of syphilitics in Hot Springs the author has not seen the vesicular syphiloderm and on question- ing a number of physicians who have practised here, some of them as long as thirty years, he has been unable to learn pf a single" case in which the diagnosis was undoubted. Bullous Syjghiloderm.— This variety of syphilitic lesion is also very rare in the acquired form of the disease and its existence is denied by some authorities. Fox^ states that it is never seen when the patient is not suffering from iodism, and Morrow^ says that it cannot be considered as a distinct type, as the lesions which begin as bullse rapidly undergo a purulent transformation. This probably is usually the case but undoubtedly sometimes bullous lesions develop which do not become pustular. They are, as a rule, developed late in the course of the disease and generally in individuals of markedly lowered vitality. They are discrete, disseminated, round or oval blebs, pea- to walnut-sized and sur- rounded by a dark red areola. They either ruptm'e or collapse without rupturing and dry to brownish or greenish crusts. Beneath the crusts are erosions or ulcers which upon healing leave pigmented cicatrices. - This type of lesion is usually rather amenable to treatment. Pustular Syphiloderm. — This variety of syphilitic lesion may develop from a previous macular or papular eruption or it may appear as the first skin manifestation of the disease. It is rare to see all of the lesions in any one case of the pustular variety, papules 1 Diseases of the Skin, Philadelphia, 1882, p. 519. 2 Jour. Cut. Dis., 1915, xxxiii, p. 509. * Loc. cit. * Loc cit. 84 ■ CLINICAL HISTORY also being observed in greater or less profusion. This syphiloderm is most frequently seen in individuals of lowered vitality whose general health is not good. It is, however, undoubtedly caused, not by the Treponema pallidum alone, but secondary pyogenic organisms are responsible to a large extent for its development. While it usually appears within the first six or eight months following the chancre, it may be seen, especially as a recurrence, much later in the course of the disease. This variety of syphiloderm is a much less frequently observed lesion than either the macular or papular varieties. The acuminate pustular syphiloderm occurs, as the name implies, as pointed or rounded pustules. The size varies from that of a pin-head (small) to the size of a pea (large). The small-sized Fig. 24. — Biillous syphiloderm showing bullae and crusts. eruptions are often referred to as miliary and the large-sized as acneiform or varioliform. The small size are always, and the large size, sometimes, connected with the hair follicles. When the lesions begin as papules there is usually a pinkish-red to dark red base which may continue as such or be transformed into a part of the pustule. Even the small-sized pustules sometimes show a slight depression of the summit, while this umbilication is more frequently observed in the larger lesions. Both sizes are usually quite abundant and may be distributed over almost the entire cutaneous surface. There is, however, a tendency to form groups, especially when appearing as recurrences when, as a rule, also the eruption is more scanty. The development of the acuminate pustular syphiloderm is sometimes rapid, but CUTANEOUS LESIONS 85 usually is more or less gradual, lasting several weeks, showing little disposition to spontaneous cure. The pustules dry to crusts which fall off and leave a fringe-like exfoliation of epidermis around the base which has been termed the "collaret." In the larger lesions a superficially eroded base is found beneath the crusts when first formed. The small lesions may heal with no trace left behind but a slight pigmentation or they may leave small pits, while the larger lesions occasionally leave atrophic thinning with slight scarring. The large and small, flat pustular syphilodermata resemble each other in many respects but in certain other respects they are so markedly different that it is thought best to describe them under separate headings. Fig. 25. — Papulopustular syphiloderm. The small, fiat, imstular syphilodern, often called impetigoform, is a rounded or oblong, flattened, pustular eruption, varying in size from 2 or 3 mm. to 1 cm. in diameter. It is usually superficially located but rarely is deep. It is found particularly on the hairy parts, the scalp, the pubes, in men on the chin, but is also seen in other localities, as the forehead, nasolabial fold, and rarely on the abdomen or back. The lesion is usually observed as a discrete eruption but irregular grouping sometimes is seen, while in certain localities, especially the scalp, coalescence is not uncommon. The development of the 86 CLINICAL HISTORY small, flat pustular syphiloderm is usually somewhat rapid and soon dries into a thick, dirty yellow or brownish crust which may or may not be adherent. Beneath the crust, which sometimes does not completely cover the base, is seen a slight ulcerated area, which upon healing, leaves little scarring, but a pigmented spot may persist for considerable time. As a rule this type of lesion is readily amenable to treatment, although if very extensive and the ulceration deep may be difficult to cure. Fig. 26. — Pustular (acuminate) syphiloderm. The large, fiat pustular syphiloderm is observed as a superficial or as a deep lesion, the latter being seen later in the disease and is rarer. The superficial lesion does not differ materially from the small, flat pustular syphiloderm except in size and in the usual CUTANEOUS LESIONS 87 location which is on the lower extremities, neck, inguinal and gluteal regions and rarely on the trunk. These pustules dry to yellowish brown or brownish crusts, are more or less adherent, and when removed leave an ulcerated base with an infiltrated, dark red border. A crust may reform several times before the process of healing is complete. Occasionally the crusts form so rapidly that the term inistulocrustaceous syphiloderm is applied. Fig. 27. — Pustular {fiat) syphiloderm. The deep-seated, flat, pustular syphiloderm is usually a late manifestation of the disease, but has been noted during the early course in severe or so-called malignant syphilis. In this type of lesion the crust is thicker and of a darker color, even a brownish- black, with sometimes a greenish tinge. Upon removal of the 88 CLINICAL HISTORY crust a punched-out ulcerative area is revealed, which is grayish, dark brown or bright red in color and secretes a purulent bloody fluid which in a short time forms another crust. Or the crust formation may go on without removal of the superficial crust and several layers be formed, one beneath the other, until a laminated shell-like lesion, which is termed nqna, is observed. Sometimes the crust is slightly smaller than the underlying ulcer and has the appearance of having been "cut to fit." Fig. 28. — Pustular crustaceous syphiloderm. The most frequent location of this type of lesion is on the face, arms, back, and shoulders. It may be rather abundant but rarely is profuse. Sometimes two or more lesions may coalesce, forming large crustacous areas. The healing process is usually slow. The floor of the ulcer clears up and is filled with healthy granulations; however, the crust may persist until complete healing has taken CUTANEOUS LESIONS 89 place. A red, depressed scar is left which is surrounded by a coppery areola and persists for a long time. It may later fade to a dead white color. It has been observed that extensive pustular syphilodermata frequently follow severe chancres. Fig. 29. — Pustular syphiloderm (rupia). Fig. 30. — Nodular (serpiginous) syphiloderm. Nodular Syphiloderm. — ^This type of syphilitic lesion is, as a rule, a comparatively late manifestation of the disease, but it may develop within the first year when it usually is associated with the papular 90 CLINICAL HISTORY syphiloderm or the lesion may partake more of a papular nature and the condition is spoken of as [japulonodular. The true nodular or tMhercular syphiloderm consists of a firm, circum.scribed, more or less elevated lesion, which may involve the whole thickness of the skin. It is of a reddish-brown or copper color and varies in size from a pea to a good-sized hazel nut. The surface is sometimes smooth and glistening or it may be covered by a thin scale of exfoliating epitheliLim. This type of syphiloderm may develop on any portion of the body, but it is most frequently seen on the head Fig. 31. — Extensive nodular (sorpiginous) syphiloderm. and face, also on the back of the neck and shoulders, the extensor surfaces of the joints and the buttocks. It may be generalized or it may occur singly or in groups. The coalescence of several nodules may form a circinate or serpiginous lesion which terms have been applied. The development and retrogression of the nodular syphiloderm is usually chronic and as new lesions appear the duration of the condition may be months or even years. The termination is either by absorption, exfoliation, pustulation or ulceration. When absorption takes place a brownish pigmentation is left. When CUTANEOUS LESIONS 91 exfoliation is excessive the terms tuherculosquamous is applied, and if a pustule is developed in the lesion, as rarely occurs, it is called tuber culopustular. However, ulceration is the usual termina- tion of the nodular syphiloderm. The lesion becomes soft in the centre, breaks down and an open ulcer results. This may be superficial or deep and crusting usually occurs. The ulcer has a punched-out appearance with sharp-cut edges and is either round or crescentic in shape. The condition may be progressive, either by Nodular syphiloderm (confluent). the extension of a single ulcer, or by the confluence of two or more, and wide areas may be affected. Upon healing there is a more or less irregular reddish cicatrix, which eventually assumes a shining white color and is depressed according to the depth of the lesion. This type of lesion is, as a ride, quite amenable to treatment. Gummatous Syphiloderm. — ^This variety of syphilitic lesion is usually the latest of the skin manifestations of the disease to develop. As a rule it does not occur before the third or fourth 92 CLINICAL HISTORY year following the initial lesion but may be as late as the twentieth, thirtieth or even fortieth year (Morrow). On the other hand, gummata of the skin have been noted within a few months following the chancre. The essential difference between the gummatous and the nodular syphilodermata is that the former is subdermal in origin while the later is intradermal. A gummatous syphiloderm first appears as a Fig. 33. — Nodular syphiloderm (squamous). small nodule beneath the skin, gradually increasing in size, stretch- ing the skin and changing its color to a dull red. The growth may be slow or rapid until the size of a walnut or larger is attained. While at first hard and firm, it usually soon becomes necrotic and soft, owing to the paucity of bloodvessels, the centre breaks down and a deep, punched-out ulcer is formed. It may, however, rarely resolve without ulceration. If, as often occurs, instead of developing as a circumscribed tumor the gumma becomes diffuse, a consider- CUTANEOUS LESIONS 93 ./sr'.« k^l ^^tta^Mh... ^H ^^^^^^^^•* ^^^^H^HRHpiP ^^j^H ^1 Hfetti ^^H Fig. 34. — Nodular syphiloderm (ulcerating). Fig. 35. — Gummatous syphiloderm. 94 CLINICAL HISTORY able area may be affected from the beginning. The skin over the lesion is at first pinkish but later becomes a dull red. Ulceration usually takes place in several places and soon the entire area may be converted into an ulcerating lesion. The edges of the ulcer are usually straight and sharp-cut, but may be slightly sloping. Fig. 36. — Gummatous syphiloderm {ulcerating). While no part of the cutaneous surface of the body is immune to syphilitic gummata the lower extremities are most frequently attacked. Sometimes gummatous syphilodermata upon ulceration penetrate the underlying structures and great destruction of tissue follows. Fig. 37. — Gummatou? syphiloderm (ulcerating). On the other hand, the lesion may be comparatively superficial, be small, slow of development, with little or no tendency to ulceration. Such lesions not infrequently appear on the penis and have undoubt- edly been mistaken for chancres. (The so-called chancre redux.) SYPHILIS OF THE APPENDAGES OF THE SKIN 95 This type of lesion shows Uttle or no tendency to spontaneous healing but upon treatment usually improvement is prompt. There is left a dark red scar of more or less depth, depending upon the depth of the ulceration, which eventually becomes white in the centre but permanently pigmented at the periphery. SYPHILIS OF THE APPENDAGES OF THE SKIN. Hair. — Alopecia. — The loss of hair due to syphilis is a well-known symptom of the disease. It occurs most frequently during the jBrst year following infection, generally soon after the first cutaneous manifestation. It may, however, be seen much later; in fact may follow any of the syphilodermata which have attacked the portion of the body covered by hair. The alopecia following the syphilodermata is due to interference with the nutrition of the hair, and its extent depends upon the extent of the lesion. On the other hand, alopecia may occur independently of the syphilodermata and varies from the falling of a few hairs of the head to complete alopecia of the entire body. These extreme cases are exceedingly rare, the process visually being limited to the scalp. Preceding the falling of the hairs they usually lose their normal lustre and become stiff, dry, and wiry. This latter condition may not occur and the alopecia is the only symptom observed. The hair may come out in patches or there may be a general thinning. The loss of the hair of the eyebrows is occasionally noted, especially in women. CorniP states that the loss of the hair of the eyebrows in spots is an almost pathognomonic sign of syphilis. Alopecia of the genitals, axillae and beard also occur but comparatively rarely. The loss of hair due to the presence of the syphilodermata is usually permanent, while that occurring independently of the skin manifestations is generally' temporary, the hair growing back upon the institution of proper treatment. The pathogenesis of the latter type of alopecia is not definitely settled. Dennie^ is of the opinion that it is not directly due to the activity of the treponemata but to the pressure of the infiltrating substances. As stated above, complete syphilitic alopecia is unusual. It is not mentioned by most text-books or is dismissed with the statement tha't it is a rare condition. Abraham and Davis^ state that "more cases than one" of complete syphilitic alopecia have come under their notice. Chambers presented a case before the Toronto Clinical Society, 1 Syphilis, American edition, Philadelphia, 1882, p. 185. 2 Jour. Cut. Dis., 1915, xxxiii, p. 509. 3 Power and Murphy: System of Syphilis, London, 1910, v, p. 100, 96 CLINICAL HISTORY November 14, 1900.^ His patient was a female, aged twenty years, in whom the hair began to fall at five, and again at twelve. At the age of eighteen she was treated for interstitial keratitis. At the time of presentation there were but two hairs on the body, these being located on the anterior portion of the scalp. The author reported the following case in 1916:^ J. F., male, aged twenty-three years; Jew; printer. Admitted to the Leo N. Levy Memorial Hospital, October 2, 1914. Family History. — Mother died after parturition. Father, brothers and sisters, negative. No history of baldness in family. Fig. 38. -Alopecia (early form). (Note line where head has been shaved to stimu- late growth of hair.) Past History. — Negative. Present Hlness. — Chancre, May, 1912. The hair of the eyebrows began to fall out two weeks after the appearance of the chancre, the right side being first affected. Following this the hair of other regions began to fall out, and in two months the body was entirely denuded. Three weeks following the appearance of the chancre the mouth was sore, and a rash appeared on the abdomen, back and left fore- arm. At this time the Wassermann reaction was strongly positive. One week later he received an intravenous injection of salvarsan (dosage not known) and two more doses at weekly intervals. Following the second dose he had fever for four days. 1 Jour. Am. Med. Assn., 1901, xxxvi, p. 57. 2 Thompson: Ibid., 1916, Ixvi, p. 1303. SYPHILIS OF THE APPENDAGES OF THE SKIN 97 The patient came to Hot Springs, in September, 1913, at which time he complained of headache, which was worse at night. He then received injections of mercury on alternate days for two weeks (dosage and salt not known) and 4 ounces of mercurial ointment by inunctions. Potassium iodide was administered by mouth up to 150 grains per day for two weeks. From that time until admission to the hospital no treatment was administered. At the time of admission the patient complained of insomnia and nervousness. Examination. — The most striking feature of this case is the absolutely complete alopecia, there not being a single hair on the entire body. «i Vf : ;■'■■:. P ^Hk flSP ^bH ymmamm Vf w WM ^^^m' umw W :' jp wHMSKHpP 1 "■1 Fig. 39. — Alopecia (complete). No skin lesions are present and no scars. The epitrochlear glands on both sides are palpable. The inguinal glands are slightly enlarged while the cervical glands are not palpable. The left tonsil is greatly hypertrophied with a denuded area covering one-fourth of the surface. The right tonsil is only slightly hypertrophied. The pharynx is normal. The superficial veins of both legs show slight varicosity, while there is a varicocele of the left side. 7 98 CLINICAL HISTORY Pulse is 60; systolic blood-pressure, 130. Neurological examination, negative. Urine, normal. Wassermann, negative. Lumbar puncture, refused. Treatment. — The patient was placed on daily inunctions of 4 grams of mercury with potassium iodide by mouth up to 30 grains t. i.d. He remained in the hospital until November 30, and as no improvement was observed was discharged. This patient left Hot Springs early in 1915 and returned in January, 1916, during which time he received no treatment. He still showed a condition of complete alopecia. Nails. — The affections of the nails in syphilis occur with com- parative infrequency, those of the fingers being affected more often than those of the toes. Such affections usually occur during the first two years of the disease, but may be observed much later. Onychia. — ^This condition is observed in four different varieties: Onychia sicca, or dry onychia, consists of a thinning and loss of lustre of the nail. It becomes ragged, brittle and easily broken. The free edge is thickened and of a dull yellow color. The surface is rough and presents fissures and depressions. One or several nails may be affected. Hypertrophic onychia is rare, and is marked by thickening of the nail. Usually more than one nail is affected. Partial detachment occurs gradually, the process beginning at the distal end of the nail and more or less of the nail is detached and elevated. The separated portion assumes a dirty yellowish- white tint, with a white line marking the extent of the detachment. Complete detachment is merely a continuation of the process de- scribed above until the entire nail becomes loosened and drops off, leaving the nail bed bare. The latter soon becomes covered with fairly thick epidermis. Only one nail may be affected or several may be involved at one time or in succession. The nail is usually replaced by a new one if antisyphilitic treatment is instituted. A fifth variety of luetic onychia has been described by Taylor/ which appears to be a local necrosis. Two to ten opaque whitish spots the size of a pin-head are observed. These are formed by depres- sions of the surface of the nail, and soon reach the matrix, leaving minute sharply cut holes. Sometimes the depressions do not completely perforate the nail and the surface appears, as Taylor expresses it, like the surface of a thimble. Paronychia. — This syphilitic process may begin in the skin around the nail and extend to the matrix or it may spread from the 1 The Pathology and Treatment of Venereal Diseases, Philadelphia, 1895, p. 661. SYPHILIS OF THE APPENDAGES OF THE SKIN 99 nail. This condition is observed both on the toes and on the fingers, and may be confined to one nail, or, as is usually the case, several may be affected at once or successively. The course is generally very chronic. Fig. 40. — Onychia and parony According to Taylor,^ three varieties of paronychia are observed: Indolent or non-ulcerative paronychia may attack the entire attached margin of the nail, the lunula, or only one of the lateral margins. A dull red papular rim about 2 mm. broad is seen around jg^ S mim*-^ ^^% ^, Fig. 41. — Onychia and paronychia. the border of the nail. The condition may be acute or chronic. In the chronic form the nail itself may become involved. Ulcerative paronychia may begin as a papule or pustule at the nail margin or as a small ulcer at the lunula. The process gradually 1 The Pathology and Treatment of Venereal Diseases, Philadelphia, 1895, p. 662. 100 CLINICAL HISTORY extends and may undermine the entire nail, the latter falling off. If the condition is not too severe, a new nail will develop. Diffuse paronychia begins as a hyperemia and reddened condition of the distal ends of the digit. Later the red fades to a coppery hue and the part becomes swollen and club-shaped. The nail becomes affected, being swollen, uneven and of a black and green color. While the process usually is not severe enough to cause the loss of the nail, this does sometimes occur. If the matrix is not destroyed, a new nail will develop. MUCOUS MEMBRANES. The syphilomycodermata are among the most important symptoms of syphilis and a thorough understanding of them is most desirable. Macular Syphilomycoderm. — ^The erythematous macular syphilo- mycoderm occurs early in the course of the disease, usually with the first cutaneous lesions, although it may be the first manifestation of syphilis following the chancre, ana often passes unnoticed by the patient. This lesion is most frequently located upon the fauces, the Schneiderian membrane and genital organs. The tongue, inner surfaces of the cheeks and larynx also sometimes are affected while it sometimes occurs in the vagina and on the cervix. The erythema may occur in spots or patches of varying size and shape similar to the roseolar macular syphiloderm, or, as is usually the case, it is diffuse, presenting a hyperemia of dark red color with sharply defined outline. It may be dry or it may be covered by a moist secretion. Usually there is no swelling but when the Schneiderian membrane, tonsils, and vulva are affected there may be considerable enlargement. This lesion may disappear very suddenly but recur- rences are often observed. Usually, however, after a short time the affected area assumes a milky hue and the superficial layers become detached, forming erosions. The erosive macular syphilomycoderm is found most frequently in the mouth, on the lips, tonsils, tongue and cheeks, on the vulva and on the glans and prepuce. It is also noted in the larynx and on the Schneiderian membrane. There are usually multiple lesions, consisting of small rounded or oval spots of a reddish color, denuded of the superficial layers and secreting a thin fluid in which are found many treponemata. This type of lesion is very amenable to treat- ment, disappearing rapidly under the influence of specifics. It is also rather prone to recur. Papular Syphilomycoderm. — ^This variety of syphilitic lesion corresponds quite closely in many respects to its homologue of the skin. MUCOUS MEMBRANES 101 The erosive form of the papular syphilomycoderm is usually an early manifestation, appearing during the first year of the disease, but may be observed later. It is found most frequently in the* mouth, on the external genital organs of the female and around the anus. The Schneiderian membrane and the larynx are also some- times affected, while this lesion has been described as occurring in the vagina and on the cervix uteri. It is the most common of all the syphilomycodermata and is the one most frequently designated mucous patch. It usually begins as a round red spot on the mucous membrane. It may be single but more frequently is multiple. It is slightly elevated above the surrounding membrane, the surface is denuded of epithelium, as in the erosive macular lesion, and is covered by a moist secretion containing many treponemata. This lesion varies in size from a millimeter to 1 or 2 cm. in diameter and several papules may become confluent. At first reddish in color it may deepen almost to a purple, or it may become lighter in shade, even assuming a grayish or whitish color. Not infrequently the centre of the lesion may be of a light color while the periphery remains a dark red. The shape depends somewhat on the location but generally is circular or nearly so. The ulcerative papular lesion of the mucous membrane usually follows the last-described lesion and generally is produced by such untoward circumstances as uncleanliness, the use of tobacco, the irritation of a decayed or jagged tooth, etc. It is essentially a papule with an ulcerating surface. The ulceration may be super- ficial or deep, the former being little more than an erosion. The deep ulcer presents a raised, sharply cut edge with an indurated dark red or yellow base. Occasionally the lesion is covered by an exudation which resembles the false membrane of diphtheria, therefore the term diphtheroid is sometimes used. Sometimes, especially upon the tongue and lips, deep ulcerating cracks or fissures may develop. When upon the lips considerable deformity may result, due to the formation of crusts by the secretions and hemorrhage from the lesion. Upon the tongue the fissures may be parallel to the long axis of the organ or star-shaped. Permanent " scars may be left upon healing. Multiple lesions are usually present and they vary greatly in size and shape. The vegetative or hypertrophic papular syphilomycoderm is less frequently observed than the ulcerative types. It is, however, a later stage of the erosive papular lesion and is practically only found where cleanliness is not practised. The most frequent location in which this condition is observed is around the anus and vulva, less frequently it is found in the mouth, especially on the under surface of the tongue, and occasionally in the larynx. It is also sometimes 102 CLINICAL HISTORY observed on the cervix uteri. It appears as a roughened, warty mass and when situated about the anus or vulva usually involves the surrounding skin as well as the mucous membrane. It varies in size from two or three millimeters to several centimeters and may be elevated as much as one centimeter or more above the surrounding surface. When occurring on the under surface of the tongue the vegetating syphilomycoderm rarely is elevated more than 1 or 2 mm., and instead of the usual reddish color of this lesion in other localities a dull gray or whitish color is observed. The surface of this lesion may be dry or ulcerative. If the latter condition is present, there is usually a more or less profuse secretion which contains many treponemata and may have an extremely foul odor. The squamous papular syphilomycoderm is a comparatively rare condition, and consists of a papular lesion on the mucous membrane, which, instead of becoming eroded or ulcerated, is dry, smooth and shiny, while desquamation of the superficial layers of the epithelium usually occurs. It is generally found during the first two years of the disease but may appear much later and is most frequently noted in the mouth. Leukoplakia is a condition of the mucous membrane which consists of a grayish or whitish discoloration and more or less thickening and has been described as appearing as if the part had been touched with silver nitrate. While leukoplakia is more frequently seen in the mouth, it is found on most of the other mucous surfaces, especi- ally on the vulva and penis. One striking feature of this condition is the frequency with which it is followed by epitheliomata. Leukoplakia has been described as the homologue of the palmar and plantar syphilodermata. When the condition is very severe this description is very apt. Erosion and ulceration of the patches of leukoplakia is a not infrequent occurrence and fissures may develop with or without the last-mentioned condition. Gummatous Syphilomycodermata. — The mucous membranes are very prone to be attacked by gummatous formation and as with the gummata of the skin usually occur late in the course of the disease, but may develop early. Gummatous syphilomycodermata are found on all of the mucous surfaces and present more or less varying pictures, depending upon their location. Gummata of the mucous membranes of the mouth may occur upon the tongue, lips, cheeks, tonsils or palate. They vary in size from 1 mm. to 1 or 2 cm. in diameter and may be single or multiple, circumscribed or con- fluent. When situated on the tongue this type of lesion is usually found on the dorsum near the tip or edges. Multiple lesions are generally observed. The mucous membrane is at first of natural color but soon becomes redder and smoother, and usually in a few GENERAL SYMPTOMS 103 weeks the lesions soften and ulceration takes place. On the palate the gumma is comparatively frequent and when present projects as a flattened tumor above the surface. Gummata of the lips and mucous membrane of the cheeks are exceedingly rare. Gummata of the larynx is not infrequently observed but are usually seen after ulceration takes place. Ulcerating gummata are not rare on the Schneiderian membrane. Gummata of the mucous membranes of the female genital organs are noted rather rarely, and more often seen on the vulva than in the vagina in which latter location they are exceedingly rare. While generally multiple and of small size they may be single and rather large. Ulceration usually is delayed but when started develops with great rapidity. Gummatous lesions of the mucous membrane of the penis are seen not infrequently, and are most often observed from the fourth to the tenth or fourteenth year. This type of lesion is the so-called chancre-red'ux, and the most common location is at the balano- preputial fold or at the urinary meatus. Ulceration, either super- ficial or deep, may occur. Gummata of these regions are important, especially on account of the differential diagnosis from chancre. GENERAL SYMPTOMS. Malaise. — Soon after the appearance of the chancre, but before any evidence of further invasion of the body has occurred, there may be a general malaise. The patient feels weak and tires easily. The expression of the face is sad and there is a tired, dejected look from the eyes. This condition may also be observed at nearly any period during the subsequent course of the disease. Anorexia. — The appetite of the syphilitic is usually more or less impaired, especially during the so-called second incubation period and during the active manifestations of the disease. However, during the second incubation period bulimia may exist and may be very suggestive. Temperature. — During the course of the chancre there is usually no deviation of the temperature from normal. In the phagedenic type of chancre, however, there may be a rise of temperature. The early adenitis also is rarely accompanied by fever but in mixed infections when suppuration takes place a rise of temperature may be observed. The so-called syphilitic fever occurs, as a rule, late in the second incubation period and also as an accompaniment of the cutaneous lesions. It is not at all constant but is usually found in weak and undernourished individuals and more frequently in women than in men. Two types of fever are observed: the continous and the remittent. The temperature occurring before the 104 CLINICAL HISTORY cutaneous manifestations is usually continuous, rarely going above 38.5° C. (101° ¥-.). In rare cases the temperature may rise to 39.5° C, or even 40.5° C. (103° F. to 105° F.) during the second incubation period and then fall to 39° C, (102° F.), upon the appear- ance of the syphilodermata, to remain at that period for some time. The remittent fever of syphilis, as a rule, occurs late in the course of the disease but may be observed early. It is usually quotidian in type, generally beginning in the late evening with chilly sensa- tions, although distinct rigors seldom if ever occur. These are followed by an elevation of temperature to 39° C. to 40.5° C. (102° F. to 105° F.). Marked perspiration following the rise in temperature is rare but a slight amount may be noted. Pulse. — ^The pulse rate in syphilis usually is increased in pro- portion to the temperature, although in some instances this is not the case, and with a high temperature the pulse rate may be increased only moderately. Respiration. — ^The respiratory rhythm also, as a rule, is increased in proportion to the temperature. Polydipsia. — Polydipsia is quite frequently noted during syphilitic fever, especially if the temperature is high. Blood-pressure. — ^The blood-pressure in syphilis varies according to the portions of the body involved. For example, the blood- vessels are very prone to be the seat of pathological change which will raise the intravascular pressure. Syphilitic nephritis may also be the cause of an increase in the blood-pressure. On the other hand, the myocarditis so frequently found in syphilis will lower the pressure. However, it may be said that, as a rule, the the blood-pressure of syphilitics is lower than normal. Blood. — It cannot be said that the blood in syphilis ever presents a picture that is pathognomonic. However, there are certain changes which are fairly constant at times during the course of the disease. The most constant of these is an anemia which may occur at nearly any time, but is more frequently observed during the active eruption. This anemia is secondary in type, the hemoglobin being reduced more markedly than the number of the erythrocytes. It is rarely very severe, the hemoglobin seldom dropping below 60 to 70 per cent., and the number of erythrocytes very infrequently falling below 3,500,000 to 4,000,000. Andrews^ quotes the case of Miiller in which the erythrocytes were reduced to 720,000 and the hemoglobin to 18 per cent., giving a high color index. Poikilocytes, normoblasts and megaloblasts were present, thus with the high color index producing a picture of pernicious anemia. It would seem that this condition must have 1 Power and Murphy: System of Syphilis, London, 1908. i, p. 123. GENERAL SYMPTOMS 105 been due to other causes than syphilis and possibly it was a true pernicious anemia in a syphilitic. Leukocytes.— The most complete study of the white blood cells in syphilis which has been made in recent years was that of Hazen^ published in 1913. In 125 cases of syphilis with 175 differential counts this author reached the following conclusions: 1. In normal persons the average total count is about 7500, the neutrophile count 55 per cent., and the lymphocyte count 33 per cent. 2. In the untreated secondary cases there is a slight leukocytosis, an occasional case showing as many as 20,000 white blood cells. The eosinophil es is higher at this time than in control cases or in cases of late lues. Treatment causes a slight drop in the total count, with a slight actual and marked relative increase in the lymphocytes. 3. Under treatment a secondary case may show a lymphocytosis as high as 65 per cent., a condition that may persist for many months or that may tend to approach normal in from three to five months, even though treatment is continued. 4. Cases of tertiary syphilis very rarely show an increase in leukocytes. The differential count in untreated cases is usually not far from normal. Myelocytes are very rarely found, even with moderate anemia. Treatment usually, but not invariably, causes a rise in both the relative and absolute number of lymphocytes, 5. The cases with a large papular eruption, all in this series occurring in negroes, show a higher percentage of lymphocytes than do the other types of secondary eruption. The average is 42 per cent. 6. In cases of secondary syphilis negroes show a higher lympho- cytosis (35 per cent.) than do whites (26 per cent.) . In the late cases there is not so marked a difference. 7. Males show a slightly greater increase in the total count than do females; females show a higher lymphocyte count than do males. 8. Age makes very little difference in the count. The very young tend to have a high neutrophile and a relatively low lymphocyte count. 9. Marked glandular enlargement does not mean a high lympho- cytosis, in fact there seems to be very little relationship between glandular involvement and the number of small mononuclears in the circulating blood. 10. All cases of secondary syphilis that did badly under treatment showed before treatment was begun a high neutrophile and a 1 Jour. Cut. Dis., 1913, xxxi, p. 618. 106 CLINICAL HISTORY low lymphocyte count; all cases that showed a low neutrophile and high lymphocyte count did well. 11. Cases of late hereditary syphilis do not necessarily show a high lymphocyte count. 12. Eosinophil ia in case of a skin eruption speaks against syphilis. Finally, it must be remembered that evidence of involvement of the viscera, and the osseous, muscular, and nervous systems may or may not be present with outward manifestations of the disease. These conditions will be discussed in Part II. CHAPTER VL CLINICAL DIAGNOSIS. The importance of the diagnosis of syphilis is hardly to be over- estimated. Not only must the presence of syphilis be recognized that its course may be checked and the individual restored to normal for his own sake as well as for the protection of others, but it is also of the utmost importance that the absence of syphilis be determined that the individual may not be stamped with the stigma of a disease which might be fraught with dire consequences. Three classes of patients present themselves for diagnosis: (1) those with symptoms or lesions which they themselves consider syphilitic, (2) those with symptoms or lesions of which they them- selves are doubtful, and (3) those with absolutely no thought of syphilis in their minds. The latter class is probably the most important and in the vast majority of cases they are the ones which most try the acumen of the physician. The first and one of the most important features of the diagnosis is the history, not only the history of the present illness, but the family and past history of the individual. It is a fact, however, that quite a large percentage of syphilitics will not tell the truth, or at least the whole truth, concerning their past, therefore too much reliance is not to be be placed upon a negative history. The next step in the diagnosis is physical examination. Not only should the lesions or symptoms which have brought the patient to the physician be considered but the entire body should be examined, including a thorough neurological examination and the use of such instruments as the sphigmomanometer, the stethoscope, and the opthalmoscope. The use of the .T-rays may be desirable in certain cases, and these will be suggested by the history or physical examination. The laboratory procedures will also be determined by the history and physical examination and should always include a urinalysis and a Wassermann test upon the blood. The latter should be per- formed in some cases, perhaps not so much for the diagnostic value as for a guide to treatment. The author is of the opinion that all cases of proven syphilis, especially those with abnormal neurological findings, should have a spinal puncture performed to determine whether or not the central 108 CLINICAL DIAGNOSIS nervous system has been invaded, so that if it has, specific treatment may be directed toward it. Finally, the diagnosis may have to rest upon therapeutic grounds. That is, if all other means fail, the improvement of certain symptoms and lesions upon the adminis- tration of specific remedies will be very strong presumptive evidence that the symptoms and lesions are due to syphilis. CHANCRE. The diagnosis of chancre of all the manisfestations of syphilis is perhaps of the most importance. This is true, because in the vast majority of cases if diagnosed while the chancre is the only lesion present, the successful outcome of the treatment may be assured. Genital Chancre. — The presumptive diagnosis of genital chancre can probably be made in the majority of cases by the history, if this can be obtained, by the general appearance and by the indura- tion, but the author is of the opinion that a definite diagnosis of syphilitic chancre without further clinical evidence is seldom, if ever, justifiable without the finding of the Treponema pallidum or a positive Wassermann test. The most important condition to be differentiated from chancre is chancroid. The following table shows the main points of differentiation: Chancre. Chanceoid. 1. Incubation three to four weeks, 1. Short. Usually under five days, rarely under ten days. 2. Papule, erosion or ulcer with slop- 2. Pustule or ulcer with sharply cut ing edges. 3. Usually single. 3. Usually multiple. 4. Scanty serosanguineous discharge. 4. Abundant purulent discharge. 5. Indurated base. 5. Soft or inflammatory base. 6. Treponema pallidum. 6. Bacillus of Ducrey. 7. Wassermann positive or negative. 7. Always negative. It must be remembered that chancre and chancroid are very frequently associated in the so-called mixed sore which will render the diagnosis less certain owing to the greater difficulty of demon- strating the organisms of syphilis. It is the custom of the author with all cases diagnosed chancroid by the finding of the bacillus of Ducrey and the failure to find the Treponema pallidum to make Wassermann tests quite frequently, at least every two or three days, for several weeks, until all danger of a concomitant syphilitic infec- tion is past. . Chancre must be differentiated from simple erosion, and can usually be done by the absence of induration and adenitis in the latter condition as well as by the failure to find treponemata. CHANCRE 109 Herpes may sometimes be mistaken for chancre, but in the majority of cases the multiphcity of the lesions, or if single they are made up of numerous small intersecting segments of circles, the presence of burning and itching, the usual absence of induration and adenitis, and the absence of treponemata, will serve to diagnose the condition. Occasionally the ulcerated or papular lesion of scabies may be mistaken for chancre. As with herpes, there is usually little or no induration and adenitis and of course the organism of syphilis is never found. Gummata sometimes very closely resemble chancre and consti- tute, at least in most instances, the so-called chancre redux. They are to be differentiated from true chancre by the history, that is with gummata, a history of sjqDhilis, and with chancre a history of exposure, and by the typical adenitis seen with chancre and almost always absent with gumma. Treponemata may be found in both conditions, although more abundantly in the chancre. The Wasser- mann test may be positive or negative in either, while the luetin test is more frequently positive with gummata. Chancre of the urethra may simulate gonorrhea but shows less discharge, the nature of which is serosanguineous rather than puru- lent, as with gonorrhea. The chancre can usually be palpated or observed by the endoscope and treponemata demonstrated in the discharge. Chancre of the cervix may be mistaken for epithelioma. In the latter condition cachexia is usually marked, even early, hemorrhage is frequent, pain is present, also the discharge is more copious and very offensive. Treponemata cannot be found in epithelioma, while the typical histological picture of the latter may be demon- strated by making a section of the lesion. Chancre of the rectum may resemble simple fissure, but is less painful and is associated with an adenitis of the inguinal region, which is not observed with simple fissure, while treponemata may be demonstrated. Extragenital chancres usually present more difficulty of diagnosis than genital chancres. This is due, partially at least, to their com- parative rarity and to the fact that often neither the patient nor the physician is suspicious of s}T)hilis. Labial chancre is not infrequently mistaken for epithelioma. The latter, however, occurs, as a rule, later in life than chancres, presents an irregular vegetating surface with thickened edges, bleeds easily, is followed by adenitis much later, and, finally, con- tains no treponemata, but does present on section the tj^jical histological picture of malignant growth. Chancre of the tonsil may present considerable difficulty in diag- 110 CLINICAL DIAGNOSIS nosis. It is to be differentiated from cancer, abscess, simple angina, diphtheria, Vincent's angina, and gummata. Cancer usually appears later in life than does chancre, bleeds easily, there is more cachexia, the adjacent glands enlarge later, and the histological picture of cancer is found on section. Abscess of the tonsil is usually of more sudden onset, the pain is more severe, swallowing and even motions of the head and neck are more difficult, while chills and fever with headache, backache, and general malise are more frequent and severe. Simple angina is to be differentiated from chancre of the tonsil by the ease with which it usually improves under treatment and from the fact that simple angina is generally bilateral, while chancre is most often found on but one tonsil. Diphtheria and Vincent's angina should always be diagnosed by the finding of the causative organisms. Gumma of the tonsil may resemble chancre, but may be distin- guished from the latter by the absence of glandular enlargement. Lingual chancre may simulate epithelioma and the differential diagnosis is the same as labial chancre. Simple or dental ulcer may be mistaken for chancre of the tongue, but the presence of a broken tooth and the absence of glandular enlargements are usually sufficient to establish the diagnosis. Chancre of the tongue sometimes resembles a tubercular ulcer; however, tubercular lesions are usually multiple, while chancre is generally single, induration is present in chancre and is not in tuber- cular ulcer unless it has been cauterized, and with tubercular ulcer other tubercular lesions are usually seen. Finally, in tubercular ulcer the tubercle bacillus can usually be demonstrated, either by microscopic examination or by inoculation of a guinea-pig. It must be remembered in examining the secretion of all oral chancres for the Treponema pallidum that the Treponema micro- dentium very closely resembles the organism of syphilis and must be differentiated from it. (See page 125.) Chancre of the breast may be confounded with fissure of the breast, carcinoma, or gumma. Fissure of the breast is more painful than chancre, bleeds more easily, is less indurated, and is not associated with glandular enlargement. Carcinoma of the breast presents practically the same points of differential diagnosis as carcinoma of the lip and tongue. Gumma of the breast is not associated with glandular enlarge- ment. Treponemata should be found in all untreated chancres of the breast, and very sparingly if at all in gummata. Chancre of the eyelid should present little or no difficulty of recog- nition, though it may be mistaken for a tubercular lesion or a LYMPHATIC GLANDS 111 carcinoma. The differential diagnosis is the same as that described under Lingual Chancre. Digital chancre more frequently remains undiagnosed until other manifestations of syphilis appear than chancre of any other locality. This is probably due to the fact that induration can rarely be demonstrated in chancre of the finger, and that it is very frequently complicated by suppuration. The latter condition renders the diagnosis most difficult owing to the uncertainty of demonstrating the treponema. In some cases the diagnosis may have to be deferred until the Wassermann becomes positive. LYMPHATIC GLANDS. The diagnosis of the adenitis occurring soon after the chancre and in the glands adjacent to this lesion will largely depend upon the diagnosis of the chancre. However, the nature of this adenitis may assist in the diagnosis of the latter. In chancre more than one gland is usually enlarged, they are hard, firm, and painless, and present a marked contrast to the single large soft, boggy, and painful gland of chancroid. With chancre, also, bilateral enlargement is the rule, while with chancroid the enlargement is usually on one side only. Treponemata may also be found. The later enlargement of the lymph glands, especially the epi- trochlears, occipital and posterior cervical, are of more or less diag- nostic importance. Friedlander^ has shown that unilateral enlarge- ment of the epitrochlears is found in 86 per cent, of syphilitics, while such enlargement is present in only 42.5 per cent, of non- sj^hilitics; the occipitals show 82 per cent, unilateral enlargement in syphilitics and 52 per cent, in non-syphilitics ; and the posterior cervicals 84 per cent, in syphilitics and 60 per cent, in non-syphilitics. Bilateral enlargement is more striking, the epitrochlears being enlarged in 77 per cent, of syphilitics and in only 27.5 per cent, of non-syphilitics. The occipital glands also show enlargement in 77 per cent, of syphilitics and in 45 per cent, of non-syphilitics, while the posterior cervicals show 80 per cent, bilateral enlarge- ment in syphilitics and 47 per cent, in non-syphilitics. It is therefore seen that bilateral enlargement, especially of the epitrochlears, is to be looked upon with marked suspicion. The enlarged epitrochlears lie in the groove above the epicondylar ridge of the humerus, behind the inner margin of the biceps and usually about one inch above the condyle, although they may be considerably higher. The elbow should be flexed for palpation, the most important condition from which syphilitic lymph glands 1 Jour. Cut. Dis., 1912, xxx, p. 14. 112 CLINICAL DIAGNOSIS are to be distinguished in tubercular enlargements. This may usually be accomplished by the history, by the finding of other clinical evidence of one or the other of the two diseases, and by the tuberculin and Wassermann tests: CUTANEOUS LESIONS. The skin lesions of syphilis may simulate almost any form of cutaneous disease. There are, however, in the majority of cases certain distinguishing features which enable the clinician to make a correct diagnosis. The chief of these characteristics of the syphilo- dermata are the following: 1. Their dark red, ham, or coppery color. 2. Their usual freedom from pain or pruritus. 3. Their usual development with little or no fever. 4. Their comparatively slow development. 5. Their tendency to polymorphism. 6. Their frequent location on flexor surfaces. 7. Their usual firm consistency. 8. Their tendency to circular arrangement. 9. The frequent development of papules. 10. The usual circular formation and small size of the lesions developing early in the course of the disease. 11. The usual white color and non-adherence of the scales. 12. The greenish or black color,, the irregularity, thickness and adherence of the crusts. 13. The tendency of the ulcers to kidney or horseshoe shape. Nevertheless even with these characteristics in mind in some cases the diagnosis on clinical evidence alone cannot be made and recourse to laboratory procedures or even therapeutic tests must be had. The roseolar macular syphiloderm usually presents little or no difficulty in diagnosis. The chancre is generally still present when this type of lesion is seen and other evidences of syphilis, such as sore throat, lesions of the mouth, falling of the hair, adenitis, etc., are nearly always to be found. The principal conditions from which this sjT^hiloderm must be differentiated are rubeola, rubella, tinea versi- color, and the rashes sometimes following the use of such drugs as belladonna, cubebs, copaiba, opium, sulphonal, etc. Measles is to be differentiated by the catarrhal symptoms and fever, the eruption, which is generally crescentic and blotchy in character, and begins, as a rule, on the face and neck. It must be remembered, however, that in syphilis the fever may at times be high. In German measles the eruption shows no tendency to pigmenta- tion, is of short duration, and is accompanied by slight catarrhal symptoms. CUTANEOUS LESIONS 113 Tinea versicolor can usually be diagnosed by the peculiar distri- bution and the finding of the Microsporon furfur. Of the drug rashes that following the ingestion of copaiba is prob- ably of the most importance, owing to the frequency of the adminis- tration of this drug in gonorrhea. The drug rashes are, as a rule, of a much more vivid "red or scarlet color than the roseolar syphiloderm, are of short duration and almost always accompanied by more or less pruritus. The annular macular syphiloderm, which is a rare condition, should be diagnosed by the history, the character of the eruption, and some- times the presence of concomitant lesions of syphilis. The pigmentary syphiloderm in the superpigmentation stage, according to Taylor,^ is to be differentiated from chloasma, and this may usually be accomplished by the history. Later when the white spots are present vitiligo may be simulated. The location, usually on the sides of the neck, of the syphiloderm and the absence of a distinct brown, narrow margin which is characteristic of vitiligo should serve as distinguishing features. Tinea versicolor may be differentiated by the location, which is rare on the sides of the neck alone, the darker color, the slightly elevated, scaly lesions, the itching and the finding of the causative organism. The diagnosis of the miliary papular syphiloderm is usually quite easily made by the history (perhaps the presence of the chancre) by the color, distribution, and grouping of the eruption and by other evidences of syphilis. Scabies may be mistaken for this lesion, but should not be so on account of the itching of scabies, the excoria- tions caused by scratching, and the finding of the ascarus scabiei. Keratosis pilaris may simulate the miliary papular syphiloderm but may be differentiated by the fact that it is most marked on the thighs, often limited to these regions, is acccompanied by pruritus, and shows no tendency to group formations. The extreme pruritus of lichen planus, its usual limitation to the legs and forearms, its slow progression and its tendency to conflu- ence should serve to distinguish it from the miliary papular lesion of syphilis. The early lesions of psoriasis may appear like this syphiloderm, but are not follicular, are more pronounced on the extensor surfaces of the arms and legs, do not form groups, and are always scaly and never pustular. Papular eczema should be differentiated by the pruritus, the ten- dency to confluence, the bright red color, the usual limited distribu- tion and the frequent vesicular formation. 1 The Pathology and Treatment of Venereal Diseases, Philadelphia, 1895, p. 641. 114 CLINICAL DIAGNOSIS Pityriasis rubra -pilaris is sometimes diagnosed as syphilis, but this error should not be made when the tendency of the lesions of this disease to confluence, scaliness, and lack of pustulation is considered. The miliary papular syphiloderm may simulate acne, especially when it occurs on the forehead, the so-called corona veneris. The dark color and flat surface of the syphilitic lesion should distinguish it from the conical acne pimple. Lichen scrojulosus, while a very rare disease, may mimic the miliary papular syphiloderm very strikingly. The lesions are, however, of a lighter color, are usually limited to the trunk, are very chronic, and occur almost exclusively in childhood and nearly always other evidence of scrofulous diathesis may be found. The lenticulor or flat pajmlar syphiloderm, as it most frequently appears, should be easy of diagnosis. The color, the distribution, the symmetrical development, and the usual absence of subjective symptoms are characteristic, while other manifestations of syphilis, such as adenitis, syphilomycodermata and alopecia are usually present. Some of the rarer varieties of this lesion, however, may present more difficulty. Thus, the annular or circinate syphiloderm may be mistaken for erythema multiforme, which, however, is of more sudden onset, does not show the whitish appearance of the syphilitic lesion, is most frequently found on the hands and forearms, and is accompanied by more or less pruritus. This lesion may also be mistaken for psoriasis, but the scaling in the latter disease is more severe, it is seldom seen on the face and never when not found elsewhere, while slight bleeding occurs upon the removal of a scale, which does not occur in syphilis. Tinea circinata should present no difficulty of differentiation, as it is of slower development than the annular syphiloderm, the edge is less indurated and more inflammatory, while the causative organ- ism can usually be demonstrated. The papulosquamous syphiloderm, owing to its marked resemblance to psoriasis, is not infrequently mistaken for that disease and is sometimes erroniously designated syphilitic psoriasis. The following table shows the main differential points : Papulosquamous Syphiloderm. Psoriasis. 1. Location, may be on face, on flexor 1. Rarely on face or palms and soles, surfaces, perhaps on palms and soles. More on extensor surfaces. 2. Scaliness slight or moderately 2. Scaliness very marked, marked. 3. Dull ham or coppery color. 3. Bright or dark inflammatory red color. 4. Scales dirty gray or brownish gray. 4. Scales shining, white and lustrous. 5. Pruritus slight or absent, except 5. Pruritus rather frequent, in negro. 6. History of chancre and concomi- 6. Not present, tant symptoms of syphilis. CUTANEOUS LESIONS 115 When the papulosquamous syphiloderm is found on the palms and soles the terms palmar and plantar syphiloderm are applied. When the lesion is limited to the palms it frequently presents considerable difficulty of diagnosis. It may somewhat resemble psoriasis, but this disease rarely or never is confined to these regions. Squamous eczema should be differentiated by the greater inflam- matory condition Math more or less heat and itching, the more fre- quent location on the fingers or finger ends, the presence or history of discharge or moisture and the absence of a tendency to annular formation. The greatest difficulty may be encountered in distin- guishing the palmar syphiloderm from dermatitis seborrhoica, which however, is rare in this region. Further, the latter disease shows less tendency to form serpiginous or annular lesions and does not show the usual infiltration of the syphiloderm. The moist papidar syphiloderm, the lenticular papular lesion which instead of desquamating, presents a more or less moist appearance, is usually easy of diagnosis. The history, the location on areas which are kept moist with perspiration, and the usual accompani- ment of other syphilitic manifestations, in the majority of cases will enable the clinician to reach a correct diagnosis. Veruca acuminata sometimes quite closely resembles this lesion, but the syphiloderm usually is as broad at its base as at its summit, while the acuminate lesion is pedunculated. This pedunculated condition may be destroyed by pressure and in the absence of his- tory and other manifestations of syphilis the diagnosis must rest on laboratory procedures. The vesicular syphiloderm undoubtedly is of rare occurrence, however its rarity should make its diagnosis more important. The appearance of small acuminated, translucent, tense, vesicles on the back or flanks should be looked upon with suspicion. The history of chancre, the presence of other syphilitic manifestations or positive laboratory evidence should make the diagnosis certain. The diagnosis of the bullous syphiloderm, which is also a most rare lesion in acquired s^'philis, will rest upon practically the same points as the vesicular lesion. The pustular syphilodermata usually present such characteristic appearances that an error in diagnosis should not be made. The acuminate type of this lesion, however, often quite markedly mimics acne or variola. In acne there is never any fever, it is usually seen about the age of puberty and is confined to certain regions. It has an inflamed, non-indurated base and the suppuration extends deeper than in the syphilitic lesion. Furthermore, this type of syphiloderm usually is accompanied by other manifestations of syphilis. The resemblance of the acuminate pustular syphiloderm to variola 116 CLINICAL DIAGNOSIS is sometimes so striking as to deceive even the most skilled. Not only in the occasional development of the lesions through papules, vesicles, and pustules, but in the occasional presence of high fever and more or less umbilication is the similarity seen. In the majority of cases of syphilis, however, the chancre or other luetic manifesta- tions are present and the development is slower. The distribution of the syphilitic lesion is, as a rule, general, while the lesions of smallpox are usually more marked on the face, backs of the hands and on the wrists. The lesion of syphilis ordinarily has a firm papular base, while the variola lesion is all pustule. Further, aside from the fever, other systemic symptoms of syphilis are slight, while in smallpox they may be severe. The small flat, pustular syphiloderm must be differentiated from pustular eczema, especially when the lesions are on the scalp or beard and from impetigo. The syphilitic lesion differs from the eczematous lesion in the underlying ulceration, which is not seen in eczema, and in the absence of pruritus with which eczema is usually associated. Impetigo, as a rule, occurs on the face and hands, runs a mild, short course, is not accompanied by ulceration, and is more super- ficial than the syphiloderm. The only condition that may be mistaken for the large flat, pus- tular syphiloderm is ecthyma. The syphilitic lesions are generally more numerous and are accompanied by ulceration, while the lesions of ecthyma are more painful, are not surrounded by the coppery red border, and show less tendency to crust formation. The rupial syphiloderm is so characteristic that its diagnosis should present no difficulty.- It is also sometimes necessary to differentiate the pustular syph- ilodermata from the eruption caused by the administration of iodin. As a rule this can be accomplished without much difficulty by the quicker onset of the iodin eruption, the brighter red color and the softer base. The withdrawal of the iodin will in the vast majority of cases clear up the diagnosis, as an iodin eruption gen- erally disappears when the administration of the drug is stopped. The diagnosis of the nodular syphiloderm is sometimes attended with considerable difficulty. If, however, the history, the color, the tendency to form serpiginous or circinate lesions, the usual ulceration and the pigmentation are considered, errors should be rare. The nodular syphiloderm may be mistaken for epithelioma, but this condition usually presents a single lesion, occurs, as a rule, later in life than syphilitic lesions, has an infiltrated, everted border, is slower of progress and is accompanied by glandular enlargements and more or less cachexia. A section of the growth, however, will at once settle the diagnosis. CUTANEOUS LESIONS 117 Acne rosacea may resemble this syphiloderm, but in the former disease the nodules are uneven, usually vividly red, and situated on a reddened, hypertrophied skin. There is no tendency to form serpiginous or circinate lesions, no ulceration occurs and dilated capillaries are generally present. Leprosy has not infrequently been mistaken for the tubercular syphiloderm and vice versa. In leprosy there is usually a history of attacks of fever, while the lesions are generally softer, larger, and are found most frequently on the face, ears, back of the hands and forearms, and areas of anesthesia among or around the lesions are noted. The syphilitic lesions are, as a rule, accompanied by a history of chancre or other syphilitic manifestations. The gummatous syphiloderm may present some difficulty of diag- nosis, especially in the early stages of its development, at which time it may be mistaken for tumors of various kinds, such as fibroid, lipoma and sarcoma. Later, when softening takes place, a resem- blance to abscess, or suppurating gland may be seen. In the ulcerat- ing stage the gummatous syphiloderm must be differentiated from chancre, chancroid, epithelioma, lupus and varicose ulcer. The history in cases of gummatous syphiloderm may be of no value, as quite frequently this lesion develops many years after infection and the original disease is forgotten. Fibroid is usually more or less pedunculated and the skin over it is normal in color, while gummata are sessile and are covered by a dull reddish skin. Lipoma is more flattened, less globular, of softer consistency and is less compressible than gumma. Sarcomata are, as a rule, more generally distributed than gummata and have a predilection for the trunk. The skin over sarcomata is bluish or purplish in color while the skin over gummata is of a dull red. With any of the above tumor formations, however, it may be necessary to resort to section of the growth and microscopic examination. A softening gumma may be mistaken for an abscess or suppurat- ing gland, as such symptoms as redness, tenderness and swelling with even fluctuation may be present. There is, however, scarcely ever any fever with gumma, or at most a degree or so, and the leukocytes are, as a rule, normal in number while in abscess and suppurating glands fever and leukocytosis are usually present. Further, an incised gum.ma will exude only a small amount of seropurulent fluid, while the fluctuation will persist. The differential diagnosis of gumma and chancre has been given above. (See page 109.) Chancroid is to be distinguished from ulcer- ating gumma by the history, the abundant purulent discharge, the adenitis and the finding of the bacillus of Ducrey. 118 CLINICAL DIAGNOSIS Epithelioma may present some difficulty of differentiation, but if the characteristics of epithehoma as mentioned under the diag- nosis of the nodular syphiloderm be remembered, an error should not be made. Lupus, while resembling the ulcerating gummatous syphiloderm, presents a thin, irregular, detached, undermined and non-infiltrated border, an irregular base, which may not be depressed, and is surrounded by a rose-red or bluish areola. Not infrequently errors in the differential diagnosis of the ulcerat- ing gummatous syphiloderm and varicose ulcers are made. The following table gives the main characteristics of each, which will be seen are quite different: Gummatous Ulcer. 1. Usually on upper part of leg, may be lower (see Fig. 37). 2. Often multiple. 3. Circular or polycyclic in outline. 4. Edges sharply cut, deep, some- times undermined. 5. Base graduating or sloughing. 6. Slight areola, perhaps scars of other ulcers on surrounding skin. 7. Other evidences of syphilis, as scars in other locations. 8. Varicose veins usually not present. 9. Wassermann and luetin tests may be positive. (See Chapter VII.) Varicose Ulcer. 1. Usually on lower part of leg. 2. Usually single. 3. Irregular in outline. 4. Edges, rounded, never undermined. 5. Ease red, or gray, sometimes diphtheroid. 6. Surrounding skin pigmented, thick- ened and often eczematous. 7. None. 8. Varicose veins always present. 9. Wassermann and luetin tests never positive. Finally, in making a diagnosis of the skin manifestations of syphilis, it must be remembered that nearly any of the skin diseases which simulate the syphilodermata may occur with the latter or in indi- viduals suffering with syphilis but without syphilitic skin lesions. In such cases the diagnosis may be extremely difficult. If, however, the history or the laboratory procedures pointed to syphilis, specific therapy would be justified, and the healing of the lesions would be very strong presumptive evidence of their syphilitic nature. SYPHILIS OF THE APPENDAGES OF THE SKIN. Hair. — As a rule the diagnosis of syphilitic alopecia is attended with no great difficulty, owing to the usual presence of other mani- festations of syphilis. In certain cases, however, as in the author's case of complete alopecia (see Fig. 39), the absence of hair may be the only symptom present. In this case there was a definite history of chancre, followed by a cutaneous eruption, which disappeared under treatment, the hair beginning to fall within two weeks after the appearance of the chancre. SYPHILIS OF THE APPENDAGES OF THE SKIN 119 Syphilitic alopecia must be differentiated from senile alopecia, alopecia areata and premature alopecia. The diagnosis of the alopecia due to the presence on the hairy regions of the various syphilodermata, will depend upon the diagnosis of those lesions, which has been discussed above. Senile alopecia differs from that due to syphilis in the date of its appearance, by its location and by its permanent character. The falling of the hair in senile alopecia begins in the region of the temples and on the posterior part of vertex and from these locations spreads backward and forward Syphilitic alopecia, on the other hand, consists of patches of baldness scattered over the scalp. Alopecia areata is distinguished from syphilitic alopecia in that the spots are rounded, are absolutely denuded of hair, and the skin is glossy, white and atrophic, while in alopecia of syphilitic origin the spots are irregular in shape, are not, as a rule, completely denuded of hair and the skin is normal. In premature alopecia the loss of hair corresponds in location to that observed in senile alopecia, is gradual and permanent, so little or no difficulty should be encountered in differentiating it from syphilitic alopecia. Nails. — Onychia and 'paronychia due to syphilis present in the majority of cases little or no difficulty of diagnosis. They are usually accompanied by other syphilitic lesions or the history of such lesions may be obtained. Certain cases of eczema and psoriasis may present lesions resem- bling syphilitic onychia, and if the history does not clear the diag- nosis it may be necessary to resort to laboratory procedures. Paronychia may be mistaken for chancre of the finger, but in chancre there will be found enlarged epitrochlear and axillary glands. Mucous Membranes. — The diagnosis of the syphilomycodermata when the history is negative and other lesions of syphilis are absent may become most difficult and recourse to laboratory procedures must be had. The erythematous macular lesion of the mucous membrane of the mouth and throat usually occurs very early in the course of the disease, and when it is the only lesion present and no history of chancre is given ma,y readily be mistaken for a simple catarrhal angina, and diagnosis without the aid of the laboratory be impossible. The erosive macular syphilomycoderm may be mistaken for simple erosion of the mucous membrane, and the diagnosis of this lesion as well as the foregoing in the absence of history of chancre or other syphilitic lesions may have to rest on laboratory procedures. Treponema pallida are usuall}^ abundant but must be differen- tiated from the Treponema microdentium. 120 CLINICAL DIAGNOSIS The erosive papular syphilomycoderm must be differentiated from simple erosions and when occurring in the mouth from "aphthous sores," from herpes of the mouth and from mercurial ulceration. " Aphthous sores" are usually more acute and more sensitive than the syphilitic lesions and are, as a rule, associated with attacks of indigestion. In herpes of the mouth the individual lesions are, usually, smaller than syphilitic lesions and more frequently occur in groups. The differentiation of mercurial ulcers from the ulcerative papular syphilomycoderm may be most difficult. However, the mercurial lesion rarely is found on the tongue or fauces which are frequent sites of the syphilitic lesion. The mercurial ulcer is found very often on the cheeks or gum behind the last molar tooth and on the gum around the upper or lower central incisors. These lesions are also more sensitive than the syphilitic lesions, and are usually accompanied by other signs of salivation. Of course the finding of the Treponema pallidum will differen- tiate the syphilomycoderm from all similar lesions, but if the patient has been under mercurial treatment the organisms in all probability will not be found. In such a case it will be necessary to discontinue the mercury, when if the condition be due to the drug, the lesions will promptly heal and if they are syphilitic, they will not improve. The ulcerating papular syphilomycoderm is, as a rule, a further development of the erosive lesion and the diagnosis will depend upon the same factors. Sometimes an exudation is seen on this type of lesion which markedly resembles the false membrane of diphtheria. The differential diagnosis will depend upon the more frequent and higher fever in diphtheria and the finding of the causative organism of diphtheria or syphilis. The vegetating or hypertrophic lesion of the mucous membrane presents the same diagnostic features as its homologue of the skin. Leukoplakia is such a characteristic lesion that it could scarcely be mistaken for any other condition. Psoriasis of the mucous mem- branes might possibly be confused with leukoplakia, but the history, the presence of other syphilitic manifestations and positive labora- tory evidence would clear up the diagnosis. The gummatous syphilomycoderm may present similar difficulties of diagnosis as its homologue of the skin. Thus in its early stage gumma of the mucous membrane may be mistaken for lipoma, fibroid, or sarcoma, while the ulcerating gumma of the mucous membrane must be differentiated from chancre, chancroid and epithelioma. There are, however, no essential features of the diag- nosis of these conditions which differ from similar conditions found on the skin. GENERAL SYMPTOMS 121 GENERAL SYMPTOMS. There is nothing in the general symptoms of syphihs which may be regarded as at all pathognomonic. The malaise and anorexia common early in the course of syphilis are, as a rule, accompanied by external manifestations of the disease, such as chancre and lesions of the skin and mucous membranes. If these are not present and laboratory evidence is negative, a diagnosis may be impossible. Syphilitic fever, also, in the majority of cases is accompanied by external manifestations of the disease. If these are not present, it may rarely be necessary to differentiate syphilis from malaria. This, as a rule, can be done by microscopic examination of the blood for plasmodise and by the Wassermann " test, which will almost invariably be positive in syphilis of severe enough type to cause fever simulating malaria. It must be remembered, however, that the Wassermann test may be positive in malaria in the absence of syphilis and it may be necessary to resort to therapeutic tests. The other general symptoms of syphilis, the blood picture, the pulse, the respiration, the polydipsia and the blood-pressure present little or nothing of diagnostic value. (See page 104 et seq.) CHAPTER VII. LABORATORY DIAGNOSIS. DEMONSTRATION OF TREPONEMA PALLIDUM. Since the epoch-making work of Schaudinn the diagnosis of syphilis has been very materially aided by the demonstration of the Treponema pallidum. While, as has been pointed out, this minute organism has be,en found in every class of syphilitic lesion and in all organs and tissues of the body, it is in the chancre that it is most searched for, for diagnostic purposes. This is because at this time other manifestations usually are absent and no one could make a positive diagnosis of syphilis without the finding of the infecting organism. It is of the utmost importance to make a search for the treponema in all suspicious-looking sores, because, if found, and it should be in a very large percentage of uncompli- cated chancres, treatment may be instituted at once and a cure accomplished in a comparatively short period. In the later manifestations of syphilis other means of diagnosis are much more frequently resorted to, and, usually, with more satisfactory results. However, occasionally it is desirable to look for Treponema pallidum in papules (this was the lesion in which they were first found), in condylomata, in enlarged glands, and even in the blood. The most frequently used methods for the demonstration of the organism of Schaudinn are dark-field illumination, staining of smears, the so-called India-ink method, and staining sections of tissue. Inoculation experiments which have been described in Chapter III are too uncertain and consume too much time to be of much value in diagnosis. Collection of Material. — When material is to be collected from a chancre for examination by the first three methods mentioned, no caustic or antiseptic should be used for at least twenty-four hours. As the chancre is usually situated on a very sensitive portion of the body, it should be handled with as much gentleness as possible to avoid unnecessary pain. It should first be cleansed thoroughly with soap and water, rinsed and dried. This procedure will free the area of the majority of Spirocheta refringens and to a certain extent of other contaminating organisms. It may now be possible to squeeze a drop of clear serum from the lesion, especially if it be DEMONSTRATION OF TREPONEMA PALLIDUM 123 ulcerated. If no serum exudes, it will be necessary to puncture the sore, which should be done at the edge. As more treponemata usually lie deeply embedded in the lesion than superficially it is desirake to remove the outer layers of epithelium or to pierce beneath them. The edge of the sore may be punctured by a Hage- dorn needle, a scapel, or it may be scraped with a small curette or similar instrument. Sometimes it is sufficient to rub the lesion with a piece of gauze. When the area is now squeezed a few drops of blood will usually exude which should be removed with a piece of gauze or absorbent cotton. Pressure should be continued until a drop of clear or faintly pink serum is obtained. This may be taken up with a platinum loop, a capillary pipette, or directly on a slide or cover-glass by touching it to the lesion. Stitt^ has recommended the introduction of a capillary pipette beneath the epidermis and aspirating a drop of fluid from the deeper layers of the chancre. Similar methods of procedure are employed in collecting material for examination from papules, condylomata, and mucous patches. In obtaining material from an enlarged gland the area over the gland should first be sterilized with alcohol or tincture of iodin. A small hypodermic needle on an all-glass syringe is now plunged into the gland. If the gland moves with the needle, it is proof that the needle is within the gland. The latter is held steady with the fingers of one hand while the point of the needle is moved about within its substance, after which as much as possible of the gland juice is aspirated, and, after removal of the needle, forced out into a watch-glass or other suitable receptacle. When it is desirable to examine the blood for the organism of syphilis, 1 or 2 c.c. should be withdrawn by venipuncture and diluted with ten times its volume of a 0.1 per cent, solution of acetic acid, centrifugalized thoroughly, and smears made of the sediment. It should seem hardly necessary to sound a note of warning against infection during these procedures, yet the author has seen one case of chancre of the finger probably due to carelessness in collecting syphilitic material for examination. Dark-field Illumination. — This method of procedure is without question by far the most satisfactory for demonstrating Treponema pallidum, as the organisms may in this way be seen alive and in the actively motile state. The apparatus for dark-field illumination consists of (a) a special condenser which replaces the ordinary substage condenser of any good microscope, (6) a rubber funnel stop which is screwed into the oil-immersion objective just beneath the lens, (c) a powerful 1 U. S. Nav. Med. Bull., 1914, viii, p. 242. 124 LABORATORY DIAGNOSIS light, such as a small arc lamp, with a biconvex lens, (d) slides of a suitable thickness, generally about 1 mm., and (e) especially thin cover-glasses (not more than 0.17 mm.). The condenser is so constructed that the central rays of light from the mirror of the microscope are blocked out by means of an opaque stop, while the peripheral rays are reflected from the paraboloidal sides of the condenser and strike solid objects in the specimen at a very oblique angle. After leaving the top of the condenser the rays pass unre- fracted to a sharp focus, which should be on the upper surface of the slide. In order to bring this about there must be a drop of cedar oil, or distilled water, placed upon the upper surface of the condenser to keep the rays from refracting, and further, the slide must be of suitable thickness for the condenser employed. At least it must be no thicker, or the rays will come to a focus between the surfaces of the slide. After coming to a focus on the upper surface of the slide, the rays of light which meet no obstruction pass on to the cover-glass, and if a dry objective is being employed they now are reflected from the upper surface and are lost. With an oil-immersion objec- tive, which has been stopped down with the rubber funnel so that the numerical aperture is less than 1, the rays pass on but are not taken up by the objective. The result, as can readily be seen, will be darkness which makes the dark field. The rays of light which meet with some obstruction. on the upper surface of the slide, such as bacteria, blood cells or treponemata are reflected upward into the objective and are seen as bright objects on a dark background. Technic. — After replacing the ordinary substage condenser of the microscope with the dark-field condenser the lamp is placed some 30 to 50 cms. distant, and so adjusted that the beam of light is thrown forward and completely fills the plain mirror. With a low- power objective the upper surface of the condenser is viewed, and by means of the centring screws the small circle engraved on its upper surface is brought into the centre of the field. A drop of cedar oil, or better, distilled water, is now placed on the upper surface of the condenser and the latter is lowered a few millimeters. The slide, which should be perfectly clean, is now prepared by placing on it a drop of the serum which has been collected, as de- scribed above, and carefully lowering a cover-glass over it, avoiding the forming of air bubbles. Should the drop of serum be too small to fill the space between the slide and the cover-glass, or if it con- tains too much blood, a drop of salt solution should be added. Occasionally there is so much blood that even by adding the salt solution so many corpuscles remain in the field that the dark- ground effect is largely destroyed. The author has overcome this difficulty by adding, instead of the salt solution, a drop of 0.1 per DEMONSTRATION OF TREPONEMA PALLIDUM 125 cent, acetic acid, which lakes the red corpuscles, but at the same .time destroys the motility of the treponemata. The film between the slide and cover-glass should be as thin as possible and should be ringed with vaselin. After preparing the slide it is placed on the stage of the micro- scope and the condenser racked up into position. Great care should be exercised in raising the condenser that no air bubbles are formed in the oil or water which is interposed between the condenser and the slide. For if such" a bubble be present, no matter how small, the rays of light meeting it are reflected upward and pass through the specimen almost vertically and illuminate the whole field, destroying the dark-ground eft'ect. If the light has been properly adjusted and no bubbles are present, either in the specimen or in the film between the slide and condenser, a light area should be seen in the centre of the cover-glass. If it is not present, it may readily be produced by manipulating the mirror. The specimen is now viewed with the low-power objective and a bright spot will be seen in the centre of the field when it is in focus. By manipulations of the condenser up and down the bright spot is reduced to the smallest size possible. The high-power objectives may now be used. For diagnostic purposes the high-power dry objectives are more satisfactory, while for studying minute details of the treponemata oil-immersion objectives, stopped down as described above, should be employed. The Treponema pallida appear as bright, shining, motile spirals on a dark background. Their extreme delicacy, characteristic motility,^ and the regularity and depth of the spirals, serve to differentiate them from other organisms except Treponema pertenue, Treponema microdentium, and Treponema mucosum. It is not necessary to give much consideration to the first of these organisms, owing to the limited area in which yaws is found. The two other organisms, Treponema microdentium and Treponema mucosum, which, while resembling the Treponema pallidum, are shorter and thinner and are found only in the mouth. It may, however, be necessary to resort to staining absolutely to differentiate them, the pallidum staining with much more difficulty. All other organisms which occur in chancres and con- dylomata, such as Spirocheta balantidium, Spirocheta phagedenis, Spirocheta refringens, and Spirocheta gracilis, may be distinguished from Treponema pallidum by their motility and morphology. ' It is well, however, for the beginner to have the distinguishing features of the various organisms pointed out to him by an experi- enced worker, or, at least, to study carefully the treponemata 1 See Chapter III, p. 34. 126 LABORATORY DIAGNOSIS from a syphilitic papule, where they occur free from other organisms, or in a preparation from a pure culture. India-ink Method. — By this method, originally described by Burri^ for demonstration of bacteria, a similar effect to that of the dark-field illuminator is produced. It depends upon the fact that when India ink is mixed with the material in which are found the treponemata, bacteria, etc., these are not penetrated, and, there- fore, appear white upon a black background when a thin film is made of the mixture. A drop of the material is collected as described above, placed on one end of a slide, a drop of the ink added (Gunther-Wagner Chin Chin) and with the end of another slide a film is made in a similar manner to preparing a blood film. The film is allowed to dry and is examined with an oil-immersion lens. Walters^ has pointed out that many makes of India ink contain organisms which appear like the treponemata when the ink alone is smeared on the slide. To obviate this he advises the use of a solid dry stick of India ink rubbed up in a small mortar with a few drops of sterile distilled water. The author has found this very satisfactory. Another method of obtaining perfectly clear ink is to centrifugalize it thoroughly before use. The main objection to the India-ink method is that the trepone- mata loose their most distinguishing characteris-tic, namely, their motility. However, the fact remains that after preparing a specimen in this manner the Treponema pallida maintain their spiral contour while certain other similar organisms loose their formation to a more or less extent. Collargol. — This silver compound has been used as a substitute for India ink, but in the author's experience possesses no advantage over the latter. Staining of Smears. — The number of methods described for staining the parasite of syphilis is legion, but of some half-dozen tried by the author Giemsa's method is unquestionably the best. The formula for preparing Giemsa's stain is as follows : Azure II eosin 3 grams Azure II 8 " Glycerin (Merk, c. p.) 250 " Methyl alcohol (Kahlbaum) . 250 " This stain may be purchased prepared ready for use from any dealer in bacteriological supplies. For use the stock stain is freshly diluted in the proportion of one drop of stain to one cubic centimeter 1 Centralbl. f. BacterioL, 1908, 2 Abth., xx, p. 95. 2 Jour. Am. Med. Assn., 1914, Ixiii, p. 1666. DEMONSTRATION OF TREPONEMA PALLIDUM 127 of water, and to this is added one drop of potassium carbonate (1 to 1000) to each cubic centimeter. Great care is needed in preparing the film for staining. The slide or cover-glass should be perfectly clean and free from grease. Further, the film should be spread as thinly as possible, and this may be accomplished satisfactorily in a manner similar to pre- paring a blood film. If the film is too thick, the organisms will not take the stain well, and also, a deposit of the stain is likely to occur which will interfere greatly with finding the parasites. After drying in the air the films are fixed in absolute alcohol for fifteen to twenty minutes, and stained with the diluted stain for forty-five minutes to one hour. They are then washed with distilled water, blotted with filter paper, and if on cover-glasses mounted in Canada balsam. By this method the Treponema pallidum usually appears as thin, rose-colored spirals, while the Spirocheta refringens and other similar organisms are colored violet. This, however, cannot be used as an absolutely distinguishing feature, as it is by no means constant. Goldhorn's Stain. — This stain has the advantage of being much more rapid than Giemsa's, but, owing to the difficulty in manu- facturing it, variations occur which make it less reliable. The method of preparation is as follows: Dissolve 1 gram of lithium carbonate in 200 c.c. of distilled water. Add 2 grams of methylene blue, heat carefully, filter, and divide into two parts. Add 5 per cent, acetic acid to one part until it is acid to litmus and then mix with the other part. After this add a weak solution of erosin until a pale blue color is obtained. Let stand for twenty-four hours and then filter oft' the precipitate which forms, and dry without heat. Dissolve 1 gram of powder in 100 c.c. of absolute methyl alcohol. Smears are fixed in methyl alcohol fifteen minutes and the stain applied five to ten minutes. The specific organisms appear a violet color. Jenner's Stain. — While most of the Romanowsky stains will demonstrate the Treponema pallidum fairly well, Jenner's modi- fication is one of the best for this purpose. The staining fluid is prepared by dissolving 5 grams of the powdered stain, which is an eosinate of methylene blue, in 100 c.c. of absolute methyl alcohol. Smears are first fixed one minute in methyl alcohol and stained five to ten minutes. They should be kept covered air-tight and free from water. Staining Sections of Tissue. — While the organism of syphilis may be demonstrated quite readily in sections of luetic tissue, this method is not of much diagnostic importance, owing to the time consumed in preparing the sections. It has, however, added much 128 LABORATORY DIAGNOSIS to our knowledge concerning the location of the Treponema pallidum in various syphilitic lesions, and very materially strengthened its position as the causative agent. At first the greatest difficulty was encountered in staining the treponemata in sections. Bertarelli and Volpino^ applied Van Ermenghem's method of staining cilia to cut sections with fairly good results. However, by this method it is very difficult to keep a precipitate of metallic silver from being deposited upon the specimen. A great advance was made by Levaditi,^ who adapted Ramon-y- Cajal's method of staining nerve fibrils. By this method the tissues are stained en bloc instead of in sections. The original method of Levaditi consists of impregnating the tissues with silver nitrate and subsequently reducing the silver with pyrogallic acid. Later, in conjunction with Manouelian, Levaditi^ changed the proceeding somewhat, and, while it is slightly more complicated, better results are obtained, especially with tissue removed from the living body. The details of the technic are as follows: 1. Fix small pieces of tissue (1 to 2 mm. in thickness) in 10 per cent, formalin (4 per cent, formaldehyde) twenty-four hours. 2. Dehydrate in 96 per cent, alcohol twelve to twenty-four hours. 3. Wash in distilled water until tissue sinks to the bottom of the containing vessel. 4. Place in a tightly stoppered bottle in a 1 per cent, solution of silver nitrate in distilled water, to which has been added just before use 10 per cent, of pyridin. A considerable quantity of this solution should be used and the tissue allowed to remain in it at room temperature two or three hours, and then at a temperature of 50° C. four to six hours. The permiability of the tissue will determine the length of time for it to remain in this solution. 5. Wash rapidly in a 10 per cent, solution of pyridin. 6. Place for reduction in a 4 per cent, solution of pyrogallic acid, to which is added just before use 10 per cent, of pure acetone and 15 per cent, of the total volume of pyridin. Reduction will be completed in two or three hours. 7. Dehydrate in graded alcohols as follows: 30 per cent., 50 per cent., 70 per cent., 85 per cent,, 95 per cent., and absolute, allowing tissue to remain two or three hours in each. 8. Clear in xylol until tissue sinks. 9. Immerse in melted paraffin at 52° C. (melting-point 50° C.) three changes, one-half hour each. 1 Rivista d'Igiene, 1905; Centralbl. f. Bacteriol., 1906, xli, p. 74. 2 Compt. rend. Soc. de biol., 1905, lix, p. 326. 3 Ibid., 1906, p. 134. DEMONSTRATION OF TREPONEMA PALLIDUM 129 10. Block in paraffin and cool rapidly by immersion in cold water. 11. Section (sections should not be thinner than 5 microns). 12. Attach sections to slide with Mayer's glycerin-albumin mixture. (Equal parts of egg-white and glycerin, well beaten and filtered through paper, plus a small amount of phenol as a pre- servative.) 13. Heat over flame just sufficiently to melt paraffin. 14. While still warm place in xylol a few seconds. 15. Mount in balsam. The treponemata are stained an intense black with the silver nitrate and stand out most distinctly from the surrounding tissues. Some authorities advocate counter-staining the sections with various agents to bring out more distinctly the cellular structure of the tissues. The author has not found this necessary, as the relation of the treponemata to the tissues is sufficiently evident without this precedure. Paretic Brain Tissue. — Many investigators attempted to demon- strate the Treponema pallidum in the brains of paretics without success until Noguchi and Moore^ accomplished this feat. In their original article these authors fail to describe- their technic, stating that a modified Levaditi method was employed. However, in a later communication by Noguchi,^ the technic is described as follows : Specimens 5 to 7 mm. in thickness are cut from the gyri frontali, gyri recti, or any other region, and hardened in 10 per cent, formalin. Noguchi states that specimens which have remained in formalin at least one year give best results, owing to the fact that the formalin interferes with the staining of the neuroglia fibrils and accelerates the staining of the treponemata. From the formalin the specimens are removed to a mixture containing 10 per cent, formalin, 10 per cent, pyridin, 25 per cent, acetone, 25 per cent, alcohol, and 30 per cent, aqua destillata, in which they are permitted to remain for five days at room temperature. Following this they are thoroughly washed in distilled water for twenty -four hours. Next they are transferred to 96 per cent, alcohol for three days and again washed in distilled water for twenty-four hours. The specimens are now treated as follows, using a dark bottle as a container: 1. Bath in 15 per cent, silver nitrate solution for three days at 37° C. (or five days at room temperature), 2. Reduce in 4 per cent, pyrogallic acid solution with the addition of 5 per cent, formalin for twenty-four hours at room temperature. 3. Wash thoroughly in distilled water. 1 Jour. Exper. Med., 1913, xvii, p. 232. 2 Jour. Cutan. Dis., 1913, xxxi, p. 543. 130 LABORATORY DIAGNOSIS 4. Transfer to 80 per cent, alcohol for twenty-four hours. 5. Transfer to 95 per cent, alcohol for three days. 6. Absolute alcohol for two days. 7. Xylol, xylol-paraffin, paraffin. Sections should be cut 3 to 5 microns in thickness. Noguchi advises the impregnation of other treponemata con- taining tissue at the same time as control. If the staining is successful, the various tissues will vary in color from a pale yellow to a yellowish brown, while the specific organisms are a distinct black. COMPLEMENT-FIXATION TESTS. Principles. — The principle of complement-fixation was discovered by Bordet and Gengou^ in 1901, but it was not until 1906 that Wassermann, Neisser, and Bruck^ utilized this phenomenon for the diagnosis of syphilis. Since that time this method, almost uni- versally known as the Wassermann reaction, has been studied and modified by many investigators and hps developed into one of the most valuable clinical laboratory tests of all time. When the animal body is subjected to an infecting agent, substances, known as antibodies, which combat the infecting agent and which are present normally to a varying extent, are formed within the organism. Antibodies are also formed when the animal body is injected with various foreign proteins, either organized, as living or dead bacteria, or unorganized, as egg albumen. The substances injected are known as antigen and the antibodies pro- duced are of various kinds and are known as agglutinins, pre- ciintins, lysins, etc. It is with the latter antibodies that we have to deal in the complement -fixation tests. It has long been known that the blood of an animal of one species cannot be transfused into an animal of another s'pecies without danger of fatal results. The reason for this was shown to be that the blood of the first animal contained certain substances which destroys the red blood corpuscles of the second animal. These substances, or antibodies, which belong to the class of lysins and are therefore known as hemolysins, are normally ptesent in nearly all blood, or rather in the serum of nearly all blood. It was discovered by Bordet and Gengou^ that if the corpuscles of an animal of one species be injected into an animal of another species, in doses small enough not to injure the animal injected, the serum of the latter animal develops to a remarkable extent the 1 Ann. de I'Inst. Pasteur, 1901, xv, p. 289. 2 Deut. med. Wchnschr., 1906, xxxii, p. 745. 3 Ann. de I'Inst. Pasteur, 1901, xv, p. 289. COMPLEMENT-FIXATION TESTS 131 property of destroying or hemolyzing the corpuscles of an animal of the first species. That is, while the serum of the guinea-pig normally possesses comparatively little hemolyzing power for the erythrocytes of the rabbit, if a guinea-pig be injected intraperito- neally with a few small doses of rabbit erythrocytes his serum soon acquires the ability to hemolyze quickly and completely rabbit corpuscles, that is, hemolysins are developed. It was further found that this property of hemolysis was soon lost by the serum on standing, or could quickly be removed by heat, and that it was restored by the addition of fresh normal serum. The phenomenon of hemolysis therefore depends upon two sub- stances, one resisting heat or thermostabile, and present to a slight extent in nearly all normal sera, but capable of being greatly increased by the injection of specific erythrocytes, the other easily destroyed by heat, or ihermolabile and present in all normal sera, although to a variable extent, and incapable of being increased by injection. These two substances have received various names, but the ones by which they are most frequently known are those given them by Ehrlich, viz., amboceptor^ for the theromostabile substance, and complement- for the thermolabile substance. Neither amboceptor nor complement acting alone can produce hemolysis, nor can the antibody or amboceptor produced by infec- tion, either accidental or experimental, produce lysis of the infecting organism without complement, which, as stated, is present in all normal sera. The mechanism of the phenomenon of lysis is believed to be that of a simple chemical action, the amboceptor acting as a connecting link between the cells or antigen (bacteria or erythro- cytes) and the complement. The action of the amboceptor is specific, that is, it will unite with only one kind of cell, while comple- ment is thought to act with any amboceptor to produce lysis (Bordet). When these three factors (antigen, amboceptor, and complement) are brought together in the proper proportions the complement is bound or fixed tightly to the amboceptor and none is left free in the serum. This is the phenomenon of complement- fixation. When working with the various organized antigens, such as bacteria and erythrocytes, it is easy enough to demonstrate the combination of the amboceptor and complement with the antigen, that is, the fixation of the complement. For example, a suspension of red corpuscles in normal salt solution presents an orange-red, opaque appearance, while after specific amboceptor and comple- ment have been added, and hemolysis has taken place, the color is 1 Called substance sensibilisatrice by Bordet and fixateur by Metchnikoff. 2 Called alexin by Bordet and cytase by Metchnikoff. 132 LABORATORY DIAGNOSIS seen to have changed to a cherry red and the solution is perfectly clear. But if the antigen be unorganized, such as an extract of bacteria, the demonstration of the fixation of complement becomes more difficult. The difficulty is overcome, however, by adding to the solution of antigen, amboceptor, and complement, which has stood for a period sufficiently long to allow the fixation of the complement to take place, some red blood cells and their specific amboceptor. If the complement has been bound, no hemolysis will take place, as it is impossible without complement. But, if, on the other hand, the complement has not been bound, hemolysis will occur. It will readily be seen that the presence of specific amboceptor or antibodies in the sera of human beings may be demonstrated by this method. In other words, that various diseases may be diagnosed by complement-fixation. Indeed, soon after the discovery of the phenomenon by Bordet and Gengou several investigators made use of this method for the diagnosis of typhoid fever, tuberculosis, meningitis, etc. The antigen employed by Wassermann and Bruck^ was an extract of cultures of the bacteria in sterile distilled water. Wassermann was apparently early struck with the thought of diagnosing syphilis by complement-fixation, but was confronted with the difficulty of being unable at that time to cultivate the infecting organism, the Treponema pallidum. He, however, soon conceived the idea of utilizing the liver of a fetus, dead of congenital syphilis, which is particularly rich in treponemata, for the prepara- tion of his antigen. Only fourteen days after the publication of their technic by Wassermann, Neisser and Bruck, Detre,^ working independently, published a method differing only in minor details in which he used chiefly an extract of condylomata as antigen. Before long the whole medical world was interested in the "Wassermann reaction," and many investigators attempted to improve and simplify it. In the original technic Wassermann, Neisser and Bruck used a watery extract of syphilitic fetal liver as antigen. This was found by most investigators to be very unstable, although Citron^ thinks this due to carelessness in handling. However, as congenital syphilitic livers are comparatively difficult to procure, it was soon evident that in order to make the test practical some other method of preparing antigen must be found. Michaelis^ preserved the liver of a syphilitic fetus in the frozen 1 Med. Klinik, 1905, i, p. 1409. 2 Wien. klin. Wchnschr., 1906, xix, p. 619. 3 Immunity, Philadelphia, 1912, p. 162. ^Berl. klin. Wchnschr., 1907, xliv, p. 1103. COMPLEMENT-FIXATION TESTS 133 state, while Marie and Levaditi/ after pulverizing it, dried it in vacuo to preserve it. The first real step in advance, however, was made when it was discovered that alcoholic extracts of syphilitic liver were capable of acting as antigen. ^ It was not long, also, before a number of investigators found that the alcoholic extracts of normal organs of man and animals possessed considerable antigenic value.^ It was therefore proved that the complement-fixation test for syphilis was not altogether, at least, a true antigen-antibody reaction. Many other methods of preparing antigens have been devised and the more important ones will be dealt with later. In the original technic Wassermann, Neisser and Bruck heated the patient's serum which was to be examined to destroy the native complement. This process, known as inactivation, is followed by most serologists today. Normal guinea-pig serum was used as complement while the sheep-rabbit hemolytic system was employed to demonstrate the fixation of complement. That is, sheep's corpuscles and, as ambo- ceptor the serum of a rabbit injected with sheep's corpuscles, were used. While, as stated above, most serologists use inactivated patient's serum in the complement-fixation test for syphilis, some have employed a non-inactivated serum. Thus Noguchi^ uses non- inactivated serum but in such small quantities (0.02 c.c), that the native complement may be ignored. He also used guinea- pig serum for complement but the human-rabbit hemolytic system instead of the sheep system. Bauer^ also proposed the use of a non-inactivated serum, but utilized the normal anti-sheep amboceptor in the serum being tested, instead of adding sheep-rabbit amboceptor. He, of course, used sheep's corpuscles. Hecht® went still further and relied upon the native complement of the patient's serum as well as the natural anti-sheep amboceptor. Other investigators used other hemolytic systems. Thus, Detre^ used the horse-rabbit hemolytic system, Boas^ used the goat-rabbit system, Browning^ the ox-rabbit system, and Jobling^" the hen-rabbit system. 1 Ann. de I'lnst. Pasteur, 1907, xxi, p. 138. 2 Plaut: The Wassermann Sero Diagnosis of Syphilis in its Application to Psy- chiatry, New York, 1911, p. 11. 3 Ibid. * Serum Diagnosis of Syphilis, second edition, Philadelphia and London, 1911, p. 59. ' Cited by Noguchi, ibid., p. 39. 6 Wien. klin. Wchnschr., 1909, xxii, p. 265. ' Ibid., 1906, xix, p. 619. 8 Cited by Noguchi, Serum Diagnosis of Syphilis, second edition, Philadelphia and London, 1911, p. 41. 9 Ibid. 1° Personal communication. 134 LABORATORY DIAGNOSIS Technic. — Preparation of Reagents. Patient's Serum. — ^The patient's serum may be obtained in a variety of ways. Noguchi^ collects the blood in a Wright's capsule after puncturing with a Hagedorn needle the ventral side of the last joint of the middle finger. The blood is allowed to clot at room temperature and the serum drawn off with a capillary pipette. This method will suffice when Noguchi's technic for the performance of the test is to be employed, where only small quantities of serum are needed, but is not to be recommended when larger amounts of serum are desired. Some workers prick the finger or lobe of the ear and "milk" the blood into a sterile test-tube. To the author's mind this is a most barbarous method and has nothing to commend it. Probably the most frequently used method of collecting blood, and also one of the most satisfactory, especially for amateurs, is by puncture of one of the veins of the elbow with a hypodermic needle attached to an all-glass syringe of sufficient capacity. A 20- to 25-gauge needle may be used with success, while a 5 c.c. Luer syringe is very satisfactory. The pain is slight and a sufficient quantity of blood may be collected in a minimal period of time. A rubber tourniquet is placed around the arm just above the elbow, the patient requested to close and open the fist two or three times, when, in thin individuals, the veins usually will stand out prominently. If they are not prominent, a little snapping with the finger will sometimes render them so. In fleshy individuals the veins are sometimes so obscure that they cannot be seen but may be palpated, and occasionally, in extremely fleshy persons, even palpation does not reveal their presence. Sometimes, if it is impos- sible to demonstrate a vein at the elbow, one on the back of the hand or at the ankle may be utilized. The site of the puncture should be sterilized by rubbing it with a little alcohol or painting it with iodin and the needle inserted in the direction of the blood stream. Successful venepuncture can only be accomplished by having a sharp needle and by keeping the vein steady. In fleshy individuals the latter is accomplished by the perivascular tissues, but in thin persons the vein must be steadied by the operator. The author has found that this can best be accomplished by encircling the arm of the patient with the thumb and middle finger of the left hand and drawing the skin taut over the vein. If the plunger of the syringe does not fit too snugly when the vein is punctured, the blood will flow into the syringe. Care must be exercised not to pierce the posterior wall of the vein. Traction may then be exerted on the plunger until a sufficient quantity of blood is collected. The tourniquet is loosened, 1 Serum Diagnosis of Syphilis, second edition, Philadelphia, 1911, p. 54. COMPLEMENT-FIXATION TESTS 135 the needle removed and a piece of sterile cotton or gauze pressed tighth' over tlie puncture wound and held by an assistant or by the patient himself. If the patient is told to elevate the arm over the head, there usually will be no ecchymosis, which may occur if this is not done. The blood is placed in a sterile test-tube and allowed to clot at room temperature. In about fifteen minutes clotting will have occurred and the separation of the serum progressed to a sufficient degree that centrifugalization will cause the clot to be forced to the bottom of the tube and the serum may be poured or pipetted off. The author sterilizes small test-tubes (15 mm. X 10 cm.) for this purpose by boiling them for fifteen minutes in normal salt solution. After this sterilization the blood rarely becomes contaminated and much more serum can be collected than by using test-tubes sterilized by dry heat. If it is desirable to use the blood imme- diately after collection, it may be placed in a centrifuge tube and centrifugalized at a very high speed for several minutes when the clear plasma may be pipetted off. Some authors^ advocate collecting blood by puncturing a vein with a needle and allowing the blood to run through a rubber tube into a test-tube without the use of a syringe. This is very satis- factory, except that a larger needle must be used and more skill is required, and, further, if many specimens are collected the cleaning and sterilizing of the needles entail considerable labor. A very convenient method of collecting blood by venepuncture is by the use of a Keidel tube. This apparatus consists of a sealed vacuum ampule, over the small end of which is slipped a short piece of rubber tubing attached to a needle. When the needle is inserted into a vein and the neck of the ampule within the rubber tubing broken, the vacumn creates suction and draws the blood into the ampule. The main objection to these tubes are their expense, and also, that if the needle is not within the vein when the neck of the ampule is broken the vacuum will be destroyed without collecting any blood and another tube must be used. A method of collecting blood has been devised by the author, which, to his mind, overcomes all objections. The apparatus is shown in Figs. 42 and 43. A special platinum needle is employed which has a square " collar" firmly attached to it, as shown in the illustration. A platinum needle is used because it may be quickly and absolutely sterilized by placing in a Bunsen flame for a few seconds. Further, the blood will not clot as rapidly in such a needle as in a steel needle. The 1 Kaplan: Serology of Nervous and Mental Diseases, Philadelphia, 1914, p. 52. 136 LABORATORY DIAGNOSIS reason for this is probably, as Kolmer^ suggests, that the bore of the platinum needle is smoother, and perhaps also that there is some direct biological influence exerted upon the process of coagu- lation. The needle is caught at the collar with a pair of artery forceps which have had their tips bent at a right angle, the collar protecting the needle from being dented. A sterile test-tube of convenient size is placed in the right angle of the forceps so that the proximal end of the needle projects into its mouth, and is held against the forceps either by a rubber band or by the right hand of the operator. A tournequet is placed around the arm of the patient in the usual way, and after sterilizing the area the needle is thrust Fig. 42 Fig. 43 Figs. 42 and 43. — Author's apparatus for collecting blood. into one of the veins of the elbow, the forceps holding it steady and furnishing a convenient handle. The blood usually will flow in a stream and 5 or 6 c.c. may be collected in a very few seconds. By holding the needle under running water the blood will be washed out and it may be resterilized . A 19-gauge needle is best for ordinary purposes, but different sizes may be used as occasion demands. In very young children it sometimes is desirable to puncture the external jugular vein or one of the veins of the scalp, although a very satisfactory method of collecting blood from such patients is ^ Personal communication. COMPLEMENT-FIXATION TESTS 137 by cupping. An area of the back is cleansed by rubbing with alcohol, after which a few superficial linear incisions are made. A sterile cup is applied and a sufficient quantity of blood usually flows into the cup, from which it may be emptied into a sterile test- tube. This method may be applied to exceedingly fleshy individuals when it is impossible to demonstrate a vein. The blood of the patient should not be collected during the process of active digestion, as, if collected at that time, the serum will sometimes be quite "milky" in appearance. This milkiness does not interfere with the reaction except, perhaps, to obscure slightly the end-results. Collecting blood with author's apparatus. If kept perfectly sterile, syphilitic sera will retain their comple- ment-fixation properties for several months, except that they may develop so-called anticomplementary bodies, which usually may be removed by heating to 55° C. for thirty minutes. Normal sera also develop anticomplementary bodies on standing, but from these sera also they usually may be removed by the process of inactivation. Antigens. — Wassermann's Original. — The liver of a congenitally syphilitic fetus is weighed and cut into small pieces. To this is added four times its weight of 0.5 per cent, phenol solution in normal saline. The mixture is placed in a brown bottle and shaken with a shaking apparatus for twenty-four hours. Following this it is centrifugalized until the larger pieces of liver settle to the bottom of the tubes, leaving the supernatant fluid slightly turbid. The latter is poured off into a brown bottle and placed in the ice-box, 138 LABORATORY DIAGNOSIS where, after a few days of sedimentation, it assumes a yellowish- brown color and is ready for use. It should be kept in the ice-box, and when it is to be used only a sufficient quantity is carefully poured off without disturbing the sediment. Aqueous extracts are used but little today and are to be considered more of historical interest than of practical value. Alcoholic Extract of Syphilitic Liver. — This antigen, which is one of the most extensively used, is prepared by mincing finely a syphilitic fetal liver, then adding to it absolute ethyl alcohol in the proportion of 10 c.c. of alcohol to each gram of tissue. The mixture may be shaken in a shaking apparatus for twenty-four hours and then placed in an incubator at 37° C. and allowed to remain for ten days. Or, if a shaking machine is not available, it may be placed in the incubator at once, in which case it should be allowed to remain a few days longer. The containing vessel should be tightly stoppered to prevent evaporation. After having remained in the incubator a sufficient length of time it is filtered through a fat-free filter paper, or one washed with ether and alcohol, which removes any hemolytic substances which may be present. The filtrate, which is the antigen, is collected and stored in a tightly stoppered bottle in the ice-box. The sediment which forms after the antigen has stood for a few days should not be removed or disturbed. The alcoholic extract of luetic fetal liver has been the standard antigen with the majority of workers for years and is to be recommended highly. Alcoholic Extracts of Normal Organs. — ^Human, guinea-pig, and beef heart or liver may be employed, and the process of preparing the antigen is the same as that described for the alcoholic extracts of syphilitic liver. Care should be exercised not to include any fat in the mixture. Of the alcoholic extracts of normal organs that of guinea-pig heart seems to give the best results. Cholesterinized Antigens. — These antigens are prepared by adding 0.4 per cent, of pure cholesterin to alcoholic extract of normal human, beef or guinea-pig heart. The cholesterin is not readily soluble in the alcohol, so it should be permitted to stand for about one week, when it may again be filtered and stored in tightly stop- pered bottles. After a time a slight sediment usually forms which should not be disturbed. Sachs^ was the first to use cholesterin reinforced heart extracts as antigen. Mcintosh and Fildes^ next employed this antigen and reported very favorably upon its use. 1 Berl. klin. Wchnschr., 1911, xlviii, p. 2066. 2 Ztschr. f. Chemotherapie, 1912, 1, p. 79. COMPLEMENT-FIXATION TESTS 139 The work of Walker and Swift/ which was very comprehensive, showed conclusively the value of the cholesterinized antigens, especially the reinforced human heart extracts, and soon a number of investigators'^ reported series of cases in which it had been used with great satisfaction. It was found to be more sensitive than any antigen yet produced, giving more positive results in known specific cases, and by most investigators found not to give positive results in known negative cases. Thomas and Ivy,^ however, decried the use of cholesterinized antigens, claiming that many positive results were obtained by them in non-syphilitic cases. Their observations have not been con- firmed, except that perhaps an occasional slightly positive reaction may be obtained, upon which with any antigen (except Treponema pallidum extracts), and in the absence of clinical symptoms, no one would make a positive diagnosis of syphilis. Acetone-insohihh Lipoids. — Noguchi* devised this method of preparing antigen, which is as follows : The heart, liver or kidney of a man, beef, guinea-pig, rabbit or dog is finely minced and mixed with 10 parts of absolute alcohoP and extracted for several days at 37° C. After filtration through paper the filtrate is evaporated to dryness by the use of an electric fan. The residue is taken up with a sufficient quantity of ether and placed in a tightly stoppered receptacle and kept overnight in a cool place. The turbidity will now be seen to have cleared up by the settling of the insoluble particles to the bottom. The clear supernatant fluid is carefully decanted off, and placed in a clean beaker. The author has found it most convenient to place the etherial solution in a separatory funnel, as, after the insoluble particles have settled to the bottom, they may be drawn oft' by opening the stop-cock, leaving the clear solution. The latter is now condensed to a small quantity by evaporating off the ether, after which the concentrated solution is mixed with 10 volumes of pure acetone. A light brownish precipitate is formed, which soon settles to the bottom of the vessel. After decantation of the supernatant fluid the precipitate becomes a sticky mass, which may be stored in this form, or it may be dissolved in ether in the proportion of 0.3 gram to 1 c.c. and mixed with 9 volumes of pure methyl alcohol. This is the antigen and should be stored in tightly stoppered bottles in a cool place. Noguchi claims for this antigen that it is more 1 Jour. Exper. Med., 1913, xviii, p. 75. 2 Jour. Am. Med. Assn., 1914. Ixii, p. 1458; Jour. Michigan Med. Soc, 1914, viii, p. 421; Arch. Int. Med., 1914. xiv, p. 563. 3 Jour. Am. Med. Assn., 1914. Ixii, p. 363. ^ Serum Diagnosis of Syphilis, second edition, Philadelphia and London, 1911, p. 79. ^ The author has used 95 per cent, alcohol with excellent results. 140 LABORATORY DIAGNOSIS sensitive than any other, owing to the fact that by its use non- inactivated sera may be employed. Trepo7iema Pallidum Antigens. — Aqueous or alcohoHc extracts of pure cultures of Treponema pallidum may be employed as antigen. Noguchi^ prepared an aqueous extract as follows : Several strains of treponemata should be used and tubes containing good growths, cultivated after the method described by Noguchi, are selected. The oil is poured off, the tube filed and broken just above the tissue, and the agar column removed. The upper or uninfected portion is cut off and discarded and the remainder is ground by shaking with marbles and a sufficient quantity of normal saH solution in a seal- able porcelain jar in a shaking apparatus until the treponemata are disintegrated. The emulsion is transferred to a sterile bottle, heated to 60° C. for thirty minutes and 0.4 per cent, phenol added. Alcoholic extracts were prepared by Craig and Nichols''^ by mix- ing the treponemata containing agar with ten times its weight of absolute alcohol and extracting for ten days with frequent shaking. Following the extraction the mixture is filtered and the filtrate evaporated to one-third its volume. Noguchi found that the aqueous extracts gave a positive reaction in certain cases of treated syphilis or in those in which the infection has existed for a long time without symptoms when the lipoidal antigen was negative or faintly positive. He thinks that the value of the pallidum extracts is as a "gauge for the defensive activity of the infected host." Craig and Nichols, using their alcoholic extracts of Treponema pallidum, found 17 sera gave the same results as the alcoholic extracts of syphilitic liver, 4 gave weaker reactions, 6 stronger, and 4 gave positive reactions where the liver antigen gave negative reactions. But of 20 sera which gave positive reactions with the liver antigen 7 gave negative reactions with the pallidum antigen. These investigators also showed that positive reactions could be obtained in syphilitics with antigens prepared by cultures of Spirocheta pertenuis and Spirocheta microdentia, although usually weaker than those obtained with the Treponema pallidum antigen. The Author's Antigen. — ^A normal human heart is removed at autopsy with aseptic precautions as soon after death as possible. The muscular portion, avoiding all fat and connective tissue, is ground in a sterile meat grinder and mixed with absolute alcohol in the proportion of 10 grams to 100 c.c. The mixture is placed in a sterile tightly stoppered jar and extracted at 37° C. for two weeks. The jar should be shaken thoroughly several times daily. 1 Jour. Am. Med. Assn., 1912, Iviii, p. 1163. 2 Jour. Exper. Med., 1912, xvi, p. 336. COMPLEMENT-FIXATION TESTS 141 Following the extraction, to the filtrate is added 0.4 per cent, of pure cholesterin. After standing about one week it is again filtered. Several strains of Treponema pallidum are grown in large quan- tities and sedimented after the method of Zinnser, Hopkins and Gilbert/ and extracted and filtered in a manner similar to that described for the extraction of the sterile human heart. The two extracts are mixed in equal proportions and stored in tightly stop- pered bottles in a cool place. The reason for preparing the antigen with aseptic precautions is to avoid including extracts of contami- nating microorganisms which might lead to false binding of com- plement. This undoubtedly has sometimes been the case with extracts of old syphilitic fetal liver. Complement. — While, as stated above, all normal sera contain complement in variable amounts, it has been found that the serum of the guinea-pig is best suited for the piu-pose of supplying com- plement for the Wassermann reaction. Large, healthy animals should be selected and should not be used during the process of active digestion, as the serum of blood collected at this time may be quite "milky" in appearance. While this does not interfere with the complemental properties of the serum, it does somewhat obscure the reaction. The blood may be collected by severing the carotid arteries with a quick slash of a sharp knife and allowing it to flow into a large Petri dish or other receptacle in w^hich it is allowed to clot and the serum collected. This is an unnecessary sacrifice of pigs, as from 5 to 10 c.c. of blood may be withdrawn with a hypodermic needle and syringe from the heart of a good-sized animal without killing him, and in two weeks he may be bled again. The author has removed blood in this manner eight to ten times at intervals of two or three weeks from large, healthy animals. The pig should be etherized, the hair of the precordia clipped, and the site wiped with a little alcohol or touched with iodin. A 19-gauge, 1-inch needle is most satisfactory, and a 10 c.c. Luer syringe may be used. The pulsations of the heart can usually be seen and can always be felt. The thorax of the pig should be steadied with the left hand and the needle thrust through the chest wall and into the pulsating heart, care being exercised not to pierce the rear wall. When the point of the needle is well within the chamber (ventricle) of the heart the blood will usually be seen to rise and fall in the syringe with the pulsations. Slight traction should now be exerted on the plunger and from 5 to 10 c.c. of blood slowly withdrawn. This should be placed in test-tubes which have been prepared by boiling in normal salt solution, as described for 1 Jour. Exper. Med., 1915, xxi, p. 213. 142 LABORATORY DIAGNOSIS the preparation of tubes for patient's serum. After about one hour the clot will have formed and partial separation of the serum occurred, when the tubes may be centrifugalized and the serum poured or pipetted off into a sterile tube and placed in the ice-box. The tubes containing the blood should also be placed in the ice-box, as more serum will separate off on standing. While absolute asepsis in collecting guinea-pig serum for complement is not impera- tive, the author considers it well to use reasonable aseptic precautions. Aher emptying the syringe of blood it should be filled with warm sterile normal salt solution and injected intra- peritoneally into the pig. The author has found that by following this procedure a considerably greater number of pigs survive than by not following it. Fig. 45. — Method of bleecliug guinea-pig for complement. In small serological laboratories the problem of securing guinea- pig serum for complement is one of more or less seriousness, and where only a few tests are made at a time, a considerable quantity of complement may be lost owing to its rapid deterioration. Com- plement may be frozen and preserved at a low temperature ( — 15° C.) for several months, but most small laboratories are not equipped for such procedures. Austin^ advocated making a 40 per cent, dilution of the guinea-pig serum with 25 per cent, sodium chloride solution. Then, in his tests he used 0.6 per cent, salt solution instead of the usual 0.9 per cent, and states that by so doing he gets approximately 0.9 per cent, in his tubes. 1 Jour. Am. Med. Assn., 1914, Ixii, p. 868. COMPLEMENT-FIXATION TESTS 143 In order to secure accuracy of diJution as well as to seciu-e a suit- able dilution for titration the following technic has been devised by the author and is now used in his laboratory: An 8.1 per cent, sodium chloride solution is prepared and auto- claved. Fresh guinea-pig seriun is diluted with this solution 1 to 1, and sealed in small tubes, 2 c.c. to the tube. It will be seen that each tube contains 1 c.c. of pm-e guinea-pig serum containing (supposedly) 0.9 per cent, of sodium chloride or 0.009 gram, and 1 c.c. of an S.l per cent, sodimn chloride or 0.081 gram. The entire sodimn chloride content of each tube is 0.09 gram, corresponding to the quantity each 10 c.c. of normal salt solution should contain. There- fore, in order to make a solution containing 0.9 per cent, sodimn chloride it is only necessary to add 8 c.c. of distilled water to the contents of each tube, and 1 to 10 dilution of guinea-pig serum is produced. It is the custom in the author's laboratory to bleed from the heart three to five good-sized guinea-pigs at one time, secm-ing from 20 to 50 c.c. of blood, which lasts from ten days to two weeks, depending upon the nmnber of tests being made. \Miile the complement usually is not kept longer than two weeks, some six weeks old has been used and was apparently as active as ever. Amboceptor. — The amboceptor of the hemolytic system used for the complement-fixation test for syphilis must, of coiu-se, correspond to the erythrocytes employed. That is, if sheep's corpuscles are used, the amboceptor must be anti-sheep immmie sermn prepared by injecting an animal of some other species with sheep cells. While the rabbit is usually employed for this pmpose the author has been able to produce a very good anti-hiunan amboceptor by administering intravenously large doses (as much as 30 c.c.) of human erythrocytes to a goat. The blood for administration should be collected aseptically. If the sheep is used the wool should be clipped from the side of the neck, a toiu-nequet placed around it as low down as possible, when the external jugular vein will stand out prominently. Usually not more than 20 or 30 c.c. of blood are desired, and thisamoimt is best collected in a large sterile Luer s\Tinge, or a trocar may be introduced and the blood allowed to run into the collecting vessel. In either case the blood should be placed in a sterile tiask con- taining a fevv' glass beads, in which it should be shaken for several minutes to "whip" out the fibrin and prevent clotting. After this it should be poured into sterile centrifuge tubes and centrifugalized at a high rate of speed until the corpuscles have settled to the bottom of the tubes and the clear serum remains on top. This should be carefully pipetted oft' without distiu-bing the corpuscles and the 144 LABORATORY DIAGNOSIS tubes filled with sterile normal salt solution (0.85 per cent.). This should be mixed with the corpuscles with a sterile glass rod or by drawing the mixture up into a sterile pipette and forcing it out several times. ^ The tubes should again be centrifugalized until the corpuscles are forced to the bottom and the fluid above is perfectly clear, when it should be removed and replaced with more salt solution. This process, known as "washing the corpuscles," is for the purpose of removing all traces of serum and should be repeated four or five times. The reason for removing the serum is that if it is left other antibodies, than hemolysins, such as precipitins, will be formed in the body of the injected animal and interfere with the reaction. After thorough washing of the corpuscles they are made up with normal salt solution to the volume which existed before pipetting off the serum. Either intraperitoneal or intravenous irjections may be made, although anaphylaxis often results from the latter method. How- ever, ether administered to an animal suffering from anaphylactic shock will usually overcome the symptoms, saving the animal. Intraperitoneal Injections. — If the intraperitoneal method is chosen the hair should be clipped and shaved from the belly of a large, preferably male, rabbit. The animal is held by an assistant in a vertical position with the head down and the hind legs up. This causes the intestines to gravitate toward the diaphragm, making their puncture by the needle less likely. The site of injec- tion should be painted with iodin and the cells slowly injected by means of a syringe and needle. A good amboceptor is not always produced, and the amount of corpuscles injected and the number and frequency of the injections do not seem to bear a constant relation to the quality of the amboceptor. The author has usuaUy been able to produce a satisfactory amboceptor by injecting 4, 8, 12, 16, and 20 c.c. of blood with four- or five-day intervals and bleeding the rabbit on the ninth or tenth day after the last injection. Simon^ recommends the injection of the washed corpuscles of 30 c.c. of blood on two occasions seven days apart, and bleeding the rabbit from nine to eleven days after the latter injection. This method has not proved satisfactory in the hands of the author. Intravenous Injections.— The marginal vein of the ear of the rabbit is chosen as the best one for injection. A considerable area over the vein should be shaved and wiped with alcohol. An assistant holds the animal, blindfolding the eyes with one hand and compress- 1 The author has found that when the corpuscles are to be injected immediately, and they should be, they may be mixed with the salt solution by placing the thumb over the mouth of the tube and inverting several times. 2 Manual of Clinical Diagnosis, Philadelphia and New York, 1911, p. 143. COMPLEMENT-FIXATION TESTS 145 ing the vein near the root of the ear with the thumb and forefinger of the other hand. The reason for bHndfolding the eyes is that when this is done the rabbit generally offers no resistance. The com- pression of the vein will usually cause it to become distended sufficiently to allow the introduction of a small needle. A 22- or 23-gauge needle should be used with a 5 c.c. liUer syringe, and the corpuscles should be drawn up into the syringe through the needle, not poured into it, to avoid particles of fibrin getting into the mixture and clogging the needle. The injections should be made slowly. A very satisfactory amboceptor usually may be produced by injecting 2, 3, 3, 4, and 4 c.c. of corpuscles four or five days apart and bleeding on the ninth or tenth day following the last injection. The author prefers the intravenous method, as less blood is required, although it is slightly more dangerous to the rabbit. Fig. 46. — Intravenous injection of rabbit for amboceptor. On the ninth day following the last injection of corpuscles, whether the intraperitoneal or intravenous route has been employed, a small quantity of blood should be drawn from the rabbit, allowed to clot, and the serum tested for its hemolytic properties. Blood for this purpose is best removed from one of the marginal ear veins in a manner similar to the injection of the corpuscles, except that a smaller needle should be used (25- or 26-gauge), and the needle directed against the blood stream; 1 or 2 c.c. may be removed in this manner. If the serum shows a sufficiently strong hemolytic activity, the rabbit may either be bled from the heart in a manner similar to that described for the bleeding of guinea-pigs for com- plement, or after etherizing the carotid artery may be dissected 10 146 LABORATORY DIAGNOSIS out, a cannula inserted, and the blood collected in sterile containers, allowing the animal to bleed to death. In either case the blood should be placed in tubes sterilized by boiling in normal salt solution. These are allowed to stand for two or three hours at room temperature and then placed in the ice-box overnight. The next morning the serum may be poured or pipetted off, that which is perfectly clear being placed in a test- tube and that containing blood in a centrifuge-tube and centri- fugalized until clear. The serum may be preserved by adding 10 per cent, of a 5 per cent, phenol solution, or 50 per cent, of pure glycerin, after inacti- vation at 55° C. for thirty minutes. Corpuscle Suspension. — The corpuscle suspension for the hemo- lytic system may be prepared by collecting the blood in a sterile flask and shaking with glass beads, as described under the Prepara- tion of Amboceptor, and the proper dilution made. Or a small quantity of blood may be collected in a tube of sodium citrate solution (20 per cent, in normal saline), which prevents clotting and centrifugalized at once, the corpuccles washed as in the other method, and the proper dilution made. Technic of Performing the Test. — ^Wassermann's Method. — Before the actual performing of the test the amboceptor must be titrated to determine its strength. Aseptic technic is enjoined. A series of test-tubes is prepared by placing in each 1 c.c. of a 1 : 10 dilution of fresh guinea-pig serum (0.1 c.c. pure serum), 1 c.c. of a 5 per cent, solution of washed sheep's cells, increasing amounts of anti- sheep serum, and making the whole amount up to 5 c.c. with normal salt solution. The tubes are incubated at 37° C. for two hours, when the tube containing the smallest amount of amboceptor which showed complete hemolysis is determined and this amount of ambo- ceptor considered as one V7iit. The aqueous extract of syphilitic fetal liver, or antigen, must also first be titrated to determine the smallest amount which of itself will inhibit hemolysis, that is, its anticomplementary dose. This is determined by adding to a series of test-tubes increasing amounts of the extract, 1 c.c. of complement, 2 units of ambocep- tor, and 1 c.c. of corpuscle suspension, and the whole made up to 5 c.c. The tubes are incubated for two hours at 37° C. and only such extracts are used which in a dose of 0.4 c.c. do not interfere with hemolysis. It must also be determined that in considerably larger doses (0.8 c.c.) the extract of itself will not hemolyze the dose of corpuscles. Three tubes are used for each serum tested, three each for the positive and negative control sera, and three tubes for control of the hemolytic system. COMPLEMENT-FIXATION TESTS 147 Into the first tube of each serum, including the positive and negative sera, is placed 1 c.c. of a 1 to 5 dilution of antigen and into the second 0.5 c.c; the third tube receives no antigen. The first and third tubes receive 0.2 c.c. of inactivated serum and the second 0.1 c.c. Each tube, including the first two of the hemolytic system control tubes, receives 1 c.c. of the diluted guinea-pig serum, and the total amount made up to 3 c.c. The tubes are now incubated for one hour at 37° C, after which 2 units of amboceptor, diluted so that each cubic centimeter contains two units, and 1 c.c. of the corpuscle suspension are, added to each tube, except the last two tubes of the hemolytic system control, to each of which are added 1 c.c. of salt solution and 1 c.c. of curpuscle suspension. The incubation is now continued for two hours, when the tubes are placed in the ice-box overnight. The following morning the results are read as follows: If tubes 1 and 2 of a serum show complete inhibition of hemolysis the corpuscles have settled to the bottom, and the fluid above being perfectly clear and free of color, the reaction is strongly positive and designated, + + + + • If tube 1 shows complete inhibition and tube 2 faint hemolysis, the reaction is designated + + + • If tube 1 shows complete inhibition of hemolysis and tube 2 complete hemolysis, ++ is recorded, while if tube 1 shows partial hemolysis and tube 2 shows complete hemolysis, the reaction is faintly positive and marked +• If tube 1 shows doubtful binding of complement and tube 2 shows com- plete hemolysis, the reaction is doubtful and designated ± . Com- plete hemolysis in both tube 1 and tube 2 constitutes a negative reaction and is recorded — . Both tubes 1 and 2 of the negative control should show complete hemolysis, and 1 and 2 of the positive control complete inhibition of hemolysis. Tube 3 of all sera should show complete hemolysis as no antigen is placed in these tubes. Tube 1 of the hemolytic system control tubes should show complete hemolysis and tube 2 and tube 3 complete inhibition. Noguchi's Method. — Aseptic technic is not necessary, although thorough chemical cleanliness is prescribed. Noguchi's conception was to so modify the Wassermann reaction as to place it within the hands of the practising physician. He therefore prescribed the preservation of antigen, amboceptor, and complement by drying on filter paper. This, however, except for amboceptor, was soon found to be unsatisfactory and was abandoned. As stated above, this investigator uses the anti-human hemolytic amboceptor, the acetone insoluble lipoids as antigen, and the patient's sermn in non-inactivated state. For complement he uses 40 per cent, solution of fresh guinea-pig serum in normal saline, 148 LABORATORY DIAGNOSIS and his corpuscle suspension consists of a 1 per cent, solution of washed human corpuscles in normal saline. The antigen and amboceptor (either a liquid or dried on filter paper) should be titrated before use. The alcohol stock solution of antigen is made into an emulsion by diluting 1 to 10 with normal salt solution. According to Noguchi^ an antigen is suitable for use if 0.4 c.c. of this emulsion will not produce hemolysis when added to the dose of corpuscle suspension or interfere with hemolysis when added to the complete hemolytic system, and will bind complement with a known luetic serum in a dose of 0.2 c.c. The method of titrating amboceptor is similar to that described under the Wassermann Technic, except that the amboceptor is dried on filter paper and increasing numbers of small regular squares of this are added to the tubes. A test-tube rack having two parallel rows of holes is secured. Two tubes, one in the front row and one in the rear row of holes, are used for each serum to be tested and two each for positive and negative controls. Tubes 10 mm. X 10 cm. are recommended. One drop from a capillary pipette of non-inactivated serum is placed in each of the two tubes of the test. (Four drops of inacti- vated serum should be used.) The positive and negative sera are used in like amounts or the negative control tubes need contain no serum. To each tube is added 0.1 c.c. of complement (40 per cent, guinea-pig serum), and to the front tubes 0.1 c.c. of the antigen emulsion. (If the antigen is up to Noguchi's standard, it will be seen that at least 5 antigenic units are used.) Finally, to each tube is added 1 c.c. of the corpuscle suspension. Incubation is carried out for one hour at 37° C., or for thirty minutes in a water-bath at a like temperature. Following this a slip of amboceptor paper containing 2 units is added to each tube and incubation continued for two hours, or one hour if the water-bath is used. The tubes are now removed and kept for two hours at room temperature, when the results are recorded. All of the tubes in the rear row should show complete hemolysis as well as the front tube of the negative control. The front tube of the positive control should show complete inhibition of hemolysis and the front tubes of the sera being tested will indicate positive or negative, depending upon whether there is hemolysis or inhibition. Should any of the rear tubes show partial or complete inhibition of hemolysis it is an indication that anticomplementary substances are present in the serum. These substances usually are thermo- labile and may be destroyed by inactivation at 37° C. for thirty 1 Serum Diagnosis of Syphilis, second edition, Philadelphia and London, 1911, p. 83. COMPLEMENT-FIXATION TESTS 149 minutes when the serum may again be tested or a fresh specimen secured. The Author's Method. — The anti-human hemolytic system is employed. This system is used, in the first place, because of the ease of securing human blood, and in the second place because of the fact that all human sera contain to a variable extent normal hemolysins for most foreign corpuscles. Of course, these hemo- lysins may be removed by adding corpuscles to the serum and centrifugalizing. This is a laborious process and there is absolutely no advantage to be gained in using any other than the human hemolytic system, therefore the author does not recommend it. As complement, either fresh undiluted guinea-pig serum or "salted" serum diluted with distilled water is used. The patients' sera are used in 0.1 c.c. doses and should be fresh, at least they must be sterile. Craig^ has shown that the contami- nation of normal sera by certain bacteria may cause the develop- ment of thermostabile anticomplementary substances which with antigen cause inhibition of hemolysis. It has also been shown that these substances may in rare instances develop in sterile normal sera, but that in this case they also inhibit hemolysis without antigen. The corpuscle suspension is a 2 per cent, dilution of human cor- puscles in normal saline. This is best prepared, as practised in the author's laboratory, by withdrawing 5 or 6 c.c. of blood by venepuncture from a patient whose serum is to be tested, adding exactly 2 c.c. of it to a centrifuge-tube of sodium citrate solution and placing the remainder in a test-tube to clot for the test. After washing the corpuscles three or four times they are made up to 50 c.c. with normal salt solution, which makes approximately a 2 per cent, dilution, as the corpuscles constitute about one-half of the whole blood. An absolutely accurate dilution is not essential, as the same suspension is employed for the test as for titration; 0.5 c.c. of the suspension is used in each tube and the total volume made up to 2.5 c.c. Since, as Noguchi^ has shown, the relation of amboceptor and complement may be greatly varied within certain limits, it makes no difference whether complement or amboceptor is titrated before each test as long as the approximate titer of the other one is known. It is, of course, necessary to titrate each new amboceptor serum and as it has been found that the pooled sera of two or three guinea- pigs varies but little in complementary value, the author has chosen 0.1 c.c. of guinea-pig serum as the unit of complement when titrating amboceptor. 1 Jour. Exper. Med., 1911, xiii, p. 521. 2 Serum Diagnosis of Syphilis, second edition, Philadelphia and London, 1911, p. 12. 150 LABORATORY DIAGNOSIS It will be noted that the titration of amboceptor by the original Wassermann method as well as by the Noguchi method the unit of amboceptor is considered to be the smallest amount which will completely hemolyze the dose of corpuscles in the presence of 0.1 c.c. of guinea-pig serum. For the actual performance of the test 2 units are employed. The reason for employing 2 units is that all sera and all antigens possess more or less of anticomplementary substance, so the addition of the extra unit of amboceptor is deemed necessary to overcome these substances. To the author's mind this appears as an inaccurate procedure, in that the worker does not know that twice the amount of the amboceptor unit will just produce hemolysis in the presence of a negative serum and antigen. He also does not know but that when a small amount of complement is bound by a slightly positive serum enough complement may be left to produce complete hemo- lysis and a weakly positive test be changed to a negative. The Author's Method of Titrating Amboceptor} — In order to overcome these objections the author adopted the following method of titrating amboceptor. Actual test conditions are imposed throughout. Fifteen tubes are required for the actual titration and eight tubes for controls. These should be chemically clean, but not necessarily sterile. Into each of the fifteen tubes is placed 0.1 c.c. of known negative inactivated serum, or better still, a like amount of the pooled sera of several known non-luetic individuals, 0.1 c.c. of complement, 1 unit of previously titrated antigen (diluted so that 1 unit equals 0.1 c.c.) and the amount of normal salt solution required to bring the total volume up to 2.5 c.c. after the addition of the amboceptor and corpuscles. The tubes are now incubated for one-half hour in the water-bath at 37° C, after which the amboceptor and corpuscles are added. Tube 1 receives 0.5 c.c. of a 1 to 10,000 dilution of amboceptor serum in salt solution and the amount is increased in each tube until tube 15 contains 1 c.c. of a 1 to 1000 dilution or 0.01 c.c. of pure serum. The eight control tubes receive the various reagents as indicated in Table I, and if all reagents are working properly the results will be as indicated. Table I also indicates the results of the titration of a good ambo- ceptor. It will be seen that tubes 1 and 2 show no hemolysis, tubes 3, 4, 5, 6, and 7 show partial hemolysis, which varies from slight to almost complete, and that the remainder of the tubes of the titration test show complete hemolysis. Tube 8, containing 0.3 c.c. of a 1 to 1000 dilution, is the tube which contains the least 1 Thompson: Arch. Int. Med., 1914, xiii, p. 904. COMPLEMENT-FIXATION TESTS 151 amount of amboceptor which shows complete hemolysis, and there- fore 0.003 c.c. is the unit. TABLE I. — Titration op Amboceptor. Tube. Serum. Comp. Ant. NaCl. Amboceptor. Corp. Total. Results. 1 0.1 0.1 0.1 1.2 0.5 of 1 to 10,000 0.5 2.5 NH 2 0.1 0.1 0.1 1.1 0.6 of 1 to 10,000 0.5 2.5 NH 3 0.1 0.1 0.1 1.0 0.7 of 1 to 10.000 0.5 2.5 PH 4 0.1 0.1 0.1 0.9 0.8 of 1 to 10,000 0.5 2.5 PH 5 0.1 0.1 0.1 0.8 0.9 of 1 to 10,000 0.5 2.5 PH 6 0.1 0.1 0.1 1.6 0.1 of 1 to 1,000 0.5 2.5 PH 7 0.1 0.1 0.1 1.5 0.2 of 1 to 1,000 0.5 2.5 PH 8 0.1 0.1 0.1 1.4 0.3 of 1 to 1,000 0.5 2.5 H 9 0.1 0.1 0.1 1.3 0.4oflto 1,000 0.5 2.5 H 10 0.1 0.1 0.1 1.2 0.5oflto 1,000 0.5 2.5 H 11 0.1 0.1 0.1 1.1 0.6oflto 1,000 0.6 2.5 H 12 0.1 0.1 0.1 1.0 0.7 of 1 to 1,000 0.5 2.5 H 13 0.1 0.1 0.1 0.9 0.8 of 1 to 1.000 0.5 2.5 H 14 0.1 0.1 0.1 0.8 0.9 of 1 to 1,000 0.5 2.5 H 15 0.1 0.1 0.1 0.7 l.Ooflto 1,000 0.5 2.5 H 16 0.0 0.1 0.0 0.9 l.Ooflto 1,000 0.5 2.5 H 17 0.0 0.1 0.1 0.8 l.Ooflto 1,000 0.5 2.5 H 18 0.0 0.1 0.1 1.8 0.5 2.5 NH 19 0.0 0.1 0.0 1.9 0.5 2.5 NH 20 0.0 0.0 0.1 0.9 l.Ooflto 1,000 0.5 2.5 NH 21 0.0 0.0 0.1 1.9 0.5 2.5 NH 22 0.0 0.0 0.0 1.0 l.Ooflto 1,000 0.5 2.5 NH 23 0.0 0.0 0.0 2.0 0.5 2.5 NH In the actual 'performance of the test 1 unit and only 1 unit is employed. It has been objected that sera vary in their anticomplementary effect, and that a false positive may result from using an amount of amboceptor, which, while it will completely hemolyze the corpuscles when used with the titration serum, will not do so with all the nega- tive sera tested, owing to a greater amount of anticomplementary substances in the latter. That sera do vary in their anticomple- mentary effect is undoubtedly true, but it is hard to believe that any serum to be tested will contain more anticomplementary sub- stance than the pooled sera of several known non-luetic individuals. In fact, this has been found to be true in practice, especially when the pooled sera are obtained, as in the author's laboratory. Here the practice is to preserve all negative sera and just before titrating to pool a sufficient quantity of those sera remaining uncontaminated and inactive. This inactivation destroys to a large extent the anticomplementary substances. If there is any discrepancy between the anticomplementary substances contained in the titrating sera and the sera to be tested, there certainly would be more of such substances in the titrating sera, as the sera to be tested are usually fresh. Owing to the fact that a good amboceptor varies little if any in its titer over periods as long as several months, it has been found more 152 LABORATORY DIAGNOSIS convenient when "salted" complement is used to fix the amboceptor unit and titrate the complement before each series of tests. If, for example, the amboceptor unit with 0.1 c.c. of pure guinea-pig serum as complement has been found to be 0.3 c.c. of a 1 to 1000 dilution or 0.003 c.c, a slightly greater quantity, that is, 0.4 c.c. of a 1 to 1000 dilution, is used as the unit, and complement is added to each tube in increasing amounts, asjndicated in Table II. The control tubes and the results of an average titration also are indicated. TABLE II. — Titration of Complement. Tube. Serum. Comp. Ant. NaCl. Amboceptor. Corp. Total. Results. 1 0.1 0.5 0.1 0.8 0.4 of 1 to 1000 0.5 2.5 PH 2 0.1 0.6 0.1 0.9 0.4 of 1 to 1000 0.5 2.5 PH 3 0.1 0.7 0.1 0.7 0.4 0.5 2.5 PH 4 0.1 0.8 0.1 0.6 0.4 0.5 2.5 H 5 0.1 0.9 0.1 0.5 0.4 0.5 2.5 H 6 0.1 1.0 0.1 0.4 0.4 0.5 2.5 H 7 0.0 1.0 0.0 0.6 0.4 0.5 2.5 H 8 0.0 1.0 0.1 0.5 0.4 0.5 2.5 H 9 0.0 1.0 0.1 0.9 0.0 0.5 2.5 NH 10 0.0 1.0 0.0 1.0 0.0 0.5 2.5 NH 11 0.0 0.0 0.1 1.5 0.4 0.5 2.5 NH 12 0.0 0.0 0.1 1.9 0.0 0.5 2.5 NH 13 0.0 0.0 0.0 1.6 0.4 0.5 2.5 NH 14 0.0 0.0 0.0 2.0 0.0 0.5 2.5 NH. The Author's Method of Titrating Antigen. — The first and most important factor to be considered in the titration of antigen is its hemolytic effect, and no antigen should be used, which, of itself, in an amount considerably in excess of the antigenic unit, will cause hemolysis. This is determined by adding to the corpuscle suspension increasing amounts of antigen, as indicated in Table III, and the tubes incubated for one hour. TABLE III. — Titration of Antigen. (Hemolytic Effect.) Tube. Ant. Corp. NaCl. Total. Results. 1 0.5 of 1 to 100 0.5 1.5 2.5 NH 2 0.6 of 1 to 100 0.5 1.4 2.5 NH 3 0.7 of 1 to 100 0.5 1.3 2.5 NH 4 0.8 of 1 to 100 0.5 1.2 2.5 NH 5 . 9 of 1 to 100 0.5 1.1 2.5 NH 6 0.1 of 1 to 10 0.5 1.9 2.5 NH 7 0.2 of 1 to 10 0.5 1.8 2.5 NH 8 . 3 of 1 to 10 0.5 1.7 2.5 NH 9 0.4 of 1 to 10 0.5 1.6 2.5 NH 10 0.5 of 1 to 10 0.5 1.5 2.5 NH 11 . 6 of 1 to 10 0.5 1.4 2.5 NH 12 . 7 of 1 to 10 0.5 1.3 2.5 NH 13 . 8 of 1 to 10 0.5 1.3 2.5 NH 14 0.9 of 1 to 10 0.5 1.1 2.5 NH 15 1 . of 1 to 10 0.5 1.0 2.5 NH 16 1 . 5 of 1 to 10 0.5 0.5 2.5 PH 17 2.0 of 1 to 10 0.5 0.0 2.5 H COMPLEMENT-FIXATION TESTS 153 A good antigen will show no hemolysis in amounts up to 1 c.c. of a 1 to 10 dilution. The second point to be determined is the anticomplementary effect of the antigen. In a good antigen this effect must not be evident in an amount considerably greater than the antigenic unit. A series of eight tubes is arranged, as in Table IV; 0.1 c.c. of a known negative, inactivated serum is placed in each tube; 0.1 c.c. of complement, increasing amounts of antigen, and enough salt solu- tion to bring the total volume, when amboceptor and corpuscles are added, to 2.5 c.c. The tubes are now incubated thirty minutes in the water-bath at 37° C, after which 1 unit of previously titrated amboceptor and 0.5 c.c. of corpuscle suspension are added, and the incubation continued one hour. The tube which contains the largest amount of antigen in which hemolysis is complete is recorded. TABLE IV.- —Titration of Ant IGEN. ( Anticoii iplemeni tary Eff ect.) Tube. Serum. Comp. Ant. NaCl. Amb. Corp. Total. Results. 1 0.1 0.1 0.6 of 1 to 100 1.1 0.1 0.5 2.5 H 2 0.1 0.1 . 8 of 1 to 100 0.9 0.1 0.5 2.5 H 3 0.1 0.1 1.0 of 1 to 100 0.7 0.1 0.5 2.5 H 4 0.1 0.1 1.2 of 1 to 100 0.5 0.1 0.5 2.5 H 5 0.1 0.1 1.4 of 1 to 100 0.3 0.1 0.5 2.5 H 6 0.1 0.1 1 . 6 of 1 to 100 0.1 0.1 0.5 2.5 H 7 0.1 0.1 . 9 of 1 to 50 0.8 0.1 0.5 2.5 PH 8 0.1 0.1 . 2 of 1 to 10 1.5 0.1 0.5 2.5 PH The next and final point in the titration of antigen is the deter- mination of the antigenic unit. This titration is identical with the determination of the anticomplementary effect, except that instead of using a known negative serum, a known positive serum is employed. In fact, these two titrations may be, and usually are, carried out at one time. After the final incubation the tube is determined which contains the smallest amount of antigen in which inhibition of hemolysis is complete. TABLE v.— Titration of Antigen. (Antig< enic Unit.) Tube. Serum. Comp. Ant. NaCl. Amb. Corp. Total. Results. 1 0.1 0.1 0.6 of 1 to 100 1.1 0.1 0.5 2.5 PH 2 0.1 0.1 0.8 of 1 to 100 0.9 0.1 0.5 2.5 NH 3 0.1 0.1 1.0 of 1 to 100 0.7 0.1 0.5 2.5 NH 4 0.1 0.1 1 . 2 of 1 to 100 0.5 0.1 0.5 2.5 NH 5 0.1 0.1 1.4 of 1 to 100 0.3 0.1 0.5 2.5 NH 6 0.1 0.1 1.6 of 1 to 100 0.1 0.1 0.5 2.5 NH 7 0.1 0.1 0.9 of 1 to 50 0.8 0.1 0.5 2.5 NH 8 0.1 0.1 0.2 of 1 to 10 1.5 0.1 0.5 2.5 NH The antigenic unit is that amount of antigen which is the average of the smallest amount which will completely inhibit hemolysis with a known positive serum, and the largest amount w^hich will cause 154 LABORATORY DIAGNOSIS no inhibition with a known negative serum. For example, if it has been found that 0.8 c.c. of a 1 to 100 dilution completely inhibits hemolysis with a known positive serum, and 1.6 c.c. of a 1 to 100 dilution is the largest amount which does not inhibit hemolysis with a known negative serum, 1.2 c.c. of a 1 : 1000 dilution, or, for practical purposes, 0.1 c.e. of a 1 to 10 dilution is the antigenic unit. Performance of Test. — In the actual performance of the test a tube rack with two parallel rows of holes is used. Two tubes are required for each serum, as well as two tubes each for positive and negative control sera. Into the rear tube for each serum is placed 0.1 c.c. of the serum, 1 unit of complement, and a sufficient quantity of salt solution to bring the total volume in each tube up to 2.5 c.c. when amboceptor and corpuscles are added. Into the front tubes are placed like amounts of serum, complement and salt solution and 0.1 c.c. of antigen (so diluted that 0.1 c.c. equals 1 unit). The tubes are now incubated thirty minutes in the water- bath at 37° C, after which 0.4 c.c. of amboceptor, or 0.1 c.c. (so diluted that 0.1 c.c. equals 1 unit) and 0.5 c.c. of corpuscle suspension are added. Following this, incubation is continued one hour, after which the tubes are removed to a cool place and permitted to stand two or three hours, when the results are read. Complete hemolysis of the corpuscles in the front tube is negative and is recorded — . Complete inhibition of hemolysis in the front tube is strongly positive and is designated + + + + • Varying degrees of inhibition are indicated differently, such as 25 per cent. + , 50 per cent. ++, and 75 per cent. + + + . The estimating of inhibition must, in the nature of things, depend largely upon the personal factor, and different workers read the results differently. Theory of Complement-fixation in Syphilis. — As stated above, since the discovery that positive complement-fixation reactions may be obtained in syphilis with antigens prepared from extracts of normaf organs it has been known that this phenomenon is not wholly, at least, a true antigen-antibody reaction. However, since positive reactions are obtained with some syphi- litic sera and negative reactions with all non-syphilitic sera, when treponemata culture antigens are used, it is probable that true syphilitic antibodies are produced. Nevertheless, as pointed out above, other extracts are much more reliable and therefore the sera of syphilitics must contain some substance which resembles anti- bodies, and which in the presence of complement has a special affinity for lipoidal substances. The nature of this substance is still in doubt. It is surely developed in the body by the presence, and probably by the activity, of the Treponema pallidum, and it may be a true antibody acting in a deleterious manner on the invading organism. PLATE 11 ++++ +++ ++ End-results of Wassermann Reaction, showing Varying Reactions from + + + + to — . COMPLEMENT-FIXATION TESTS 155 The author's antigen is prepared from lipoidal extracts and Treponema pallidum extracts so that it will react with the lipoido- trophic or antibody-like substance present in luetic sera as well as with any true Treponema pallidum antibodies which may be present. Value of Complement-fixation Tests in Syphilis. — The Wasser- mann reaction and its modifications have developed into one of the most useful of laboratory tests, yet in the hands of the inex- perienced they may lead to most disastrous resuHs. Not only may a negative be recorded when it should have been positive and the patient go his way infecting others in the thought that he is free from taint, but a false positive may be registered for an uninfected one, and the stigma of thinking he has syphilis be carried through life. But in the hands of one skilled in serology and understanding the factors for error and the limitations of the test its value is inestimable. The author does not consider the complement-fixation test for syphilis as the suiimm honum in the diagnosis of this disease. It is but one sjinptom, but one link in the chain of evidence, and must be interpreted in the light of the history and clinical findings. A weakly positive Wassermann test in the absence of history or clinical evidence of syphilis should never be taken as final. And even a strongly positive test in such a case should be repeated and sent to another serologist for corroboration. One negative test should not be taken as disproving the presence of syphilis, especially in cases with suspicious history or clinical evidences of the disease, as it has been shown that the reaction may vary from day to day in untreated syphilitics.^ However, several negative tests, including the so-called provocative Wasser- mann, performed at considerable intervals, should be accepted as evidence of the absence of syphilis, save in the presence of unmis- takable clinical sjTuptoms. This latter condition is extremely rare, except during the early course of the disease when the lesions are limited to the chancre, at which time Craig^ has shown, as would be expected, the percentage of positives varies from 27.6 in the first week to 79.4 in the fifth week. In regard to the percentage of positive Wassermaim reactions obtained during the later course of the disease investigators differ. The consensus of opinion, however, seems to be that in untreated cases practically 100 per cent, of s\T)hilitics will give a positive Wassermann during the first year. Treatment during this period of the disease has a marked effect upon the Wassermann reaction, and if sufficiently intensive and carried out over a considerable length of time will usually cause a positive test to become negative. 1 Craig: Jour. Am. Med. Assn., 1914, Ixii, p. 1232. 2 Studies in Syphilis, War Department Bulletin No. 3, Washington, 1913, p. 37. 156 LABORATORY DIAGNOSIS There are some cases, however, which resist all treatment, the Wassermann always remaining positive. It is in the later course of syphilis, especially when lesions of the viscera develop, that the Wassermann reaction has its greatest value. In untreated cases of this nature the test is positive in about 95 per cent, of the cases. Treatment in these conditions also will markedly influence the reaction. In syphilis of the nervous system, especially in tabes and paresis, the Wassermann reaction of the blood is quite constantly positive. In paresis it varies from 90.9 per cent. (Kaplan^) to 100 per cent. (Nonne^). While in tabes the reaction is positive in about 70 per cent, of the cases. In syphilitic involvement of the central nervous system other than tabes and paresis the blood serum reacts positively in from 75 to 80 per cent, of the cases. In congenital syphilis, according to Holt, ^ practically 100 per cent, of cases show a positive Wassermann even if treated with mercury, unless the treatment has been most vigorous and protracted. "One other very important factor which influences the Wassermann reaction has been pointed out by Craig and Nichols.^ These investigators have shown that the ingestion of considerable quan- tities of alcohol by the patient within twenty-four hours of taking his blood, and in some cases as long as three days, may change a posi- tive into a negative reaction. This observation the writer has confirmed in a number of instances. That two or more serologists may differ materially, or even have contradictory findings, on the same sera has been shown by Wol- barst.^ In 85 cases specimens of blood collected in three test-tubes at the same time were sent to three different well-known serologists for examination. Of the 85 cases the serologists obtained the same results in 36 cases, slightly different results in 16 cases, and abso- lutely contradictory findings were reported in 33 cases. The obvious reason for these discrepancies is to be found in the differences in technic employed by the three serologists, and the obvious remedy is to standardize the complement-fixation test for syphilis, and to have the reagents prepared on a large scale in a central laboratory to he distributed to the various serologists. And, finally, it should be reiterated that this reaction should be interpreted only in the light of clinical evidence. Extensive as is the value of the complement-fixation test in the diagnosis of syphilis it is in the control of the treatment that its 1 Serology of Nervous and Mental Diseases, Philadelphia and London, 1914, p. 191. 2 Syphilis and the Nervous System, Philadelphia and London, 1913, p. 352. 3 Am. Jour. Dis. Child., 1913, vi, p. 166. ^ Jour. Am. Med. Assn., 1911, Ivii, p. 474. 6 Interstate Med. Jour., 1915, xxii, p. 109. COMPLEMENT-FIXATION TESTS 157 greatest value is observed. This phase of the test will be discussed fully in the chapter on Treatment. Provocative Wassermann Test. — It has been observed that in certain individuals who give a negative complement-fixation test for syphilis this negative may be converted into a positive by the injection of a dose of salvarsan, or by the administration of mercury, either internally or by inunction, for a period of ten days to two weeks. The explanation of this phenomenon is that by killing the treponemata present in the body and the consequent liberation of endotoxins, the substances concerned in the binding of complement with antigen are stimulated to greater production. Or it may be that the drug administered is insufficient to kill the organisms but stimulates them to greater activity. If we are to believe, as we have good grounds for doing, that a positive Wassermann denotes the presence of living treponemata, the latter explanation is the more plausible. The usual method of procedure is to administer 0.2-0.4 gram of salvarsan intravenously, taking the blood for examination at the same time, and to test it on several succeeding days. It has been found that it is most likely to become positive on the first or second day following, but it may remain negative for as long as two weeks, finally becoming positive. It is the custom of the author to collect the blood for examination twenty-four and forty-eight hours after administration of the salvarsan, and if negative, to test it again after one week and finally after two weeks. Wassermann Reaction in Diseases other than Syphilis. — Some diseases other than syphilis will occasionally give a positive Wassermann reaction. In framhesia (yaws) in which the infecting organism, the Treponema pertenue is similar to the Treponema pallidum, a positive Wassermann has been reported. Leprosy of the tuberous type also has been shown to give positive results,^ although in two cases of leprosy of this type recently seen by the author the Wassermann was negative. Malaria during the febrile stage when plasmodioB are present will often cause a positive reaction. The author has had occasion to observe several such cases. One in particular is striking. Upon performing the Wasser- mann with the blood of this patient a 4 plus reaction was observed. Subsequent to taking the blood for the Wassermann it was dis- covered that the patient had a temperature of 101° F., and a smear of the blood revealed many plasmodise of the estivo-autumnal type. He was thoroughly cinchonized, and one week later his blood was absolutely negative to both the complement-fixation test and to malaria] parasites. 1 Fox: Am. Jour. Med. Sc, 1910, cxxxix, p. 725. 158 LABORATORY DIAGNOSIS In pellagra, Bass^ and Fox^ each secured faintly positive Wasser- mann reactions at times. The author in 35 cases secured no positive findings. Richards^ and later Keyes^ pointed out that a condition of acidosis in a person free from syphilis will make his blood positive to the Wassermann reaction. This was strikingly illustrated in a case seen by the author. This patient, a Catholic priest, consulted a neurologist near Chicago for a chronic headache and a numbness of the extremities. A Wassermann test was performed which was positive, and anti- syphilitic treatment recommended. Soon after this the patient came to Hot Springs. At this time a neurological investigation revealed that the lower tendon reflexes were markedly diminished, the left knee-jerk being practically abolished. The left pupil was slightly larger than the right, although both reacted to light and accommodation. The Wassermann on the blood being found negative and the urine showing sugar, a lumbar puncture was suggested. This was consented to and the spinal fluid showed a negative Wassermann, no increase in globulin and only 7 lympho- cytes per cubic millimeter. Diabetic treatment caused the dis- appearance of the sugar from the urine and a marked improvement in the general condition. It will be seen from the above that all of the diseases other than syphilis, with the possible exception of yaws, which react positively to the Wassermann test can usually readily be excluded. It is possible, however, for a patient to be suffering with syphilis as well as one of the above-mentioned diseases. In regard to a positive Wassermann in cases of acidosis, Warthin and Wilson^ recently have shown that of six diabetics coming to autopsy all six showed unmistakable evidences of syphilis, Tre- ponema pallida being found in four of them. These authors state that ''it seems very probable, therefore, that latent syphilis is the chief factor in the production of the form of pancreatitis most frequently associated with diabetes." The Hecht-Weinberg Reaction.^ — ^This test, which depends upon complement-fixation, is used quite extensively by some serologists as a control of the Wassermann. The natural complement, present in all human sera, and the natural anti-sheep amboceptor present in nearly all human sera, are utilized, which, of course, makes it essential to employ only fresh sera. The technic followed by the author is the modification of Grad- 1 New York Med. Jour., 1909, xc, p. 1000. ^ ibid., p. 1206 3 Jour. Am. Med. Assn., 1913, Ix, p. 1139. " Ibid., 1915, Ixiv, p. 804. 5 Am. Jour. Med. Sc, 1916, clii, p. 157. 6 Hecht: Wien. klin. Wchnschr., 1909, xxii, p. 265. OTHER SEROLOGICAL TESTS 159 wohl/ and consists of first determining tlie so-called hemolytic index of each serum. This index is the amount of natural anti-sheep amboceptor present, and is determined by adding varying amounts of sheep's corpuscles to 0.1 c.c. of the serum and incubating-. The actual test is performed by combining the serum and antigen (the acetone, insoluble lipoids are best) in increasing quantities and incubating for one-half hour to fix complement. Following this the corpuscles are added in an amount depending upon the hemo- lytic index, and the incubation continued for one-half hour when the results are read; complete hemolysis denoting a negative and complete inhibition denoting a strong positive. While this reaction is quite sensitive and is comparatively simple, it should never be relied upon except when controlled by the Wassermann. To the author's mind even this combination is not to be preferred to the complement-fixation test as performed in his laboratory. OTHER SEROLOGICAL TESTS, A number of other serological tests for syphilis depending upon other principles than the phenomenon of complement-fixation have been devised. Cobra Venom Test of Weil.^ — This test depends upon the fact that the natural hemolyzing effect of cobra venom on human corpuscles is resisted to a marked degree by the corpuscles of a syphilitic. It is performed by adding varying dilutions of cobra venom to the carefully washed corpuscles of the patient and incubating. Its simplicity is practically the only feature which recommends this test, as it is not as sensitive as the Wassermann reaction, especially with the newer titration technic and antigens, and occasionally a positive is found in cancer. In the differentiation of tuberculosis and syphilis of the lungs this test may be of value, as in the former disease the red cells are hypersensitive to the cobra venom. Precipitin Tests. — A number of workers have attempted to diagnose syphilis by the use of precipitin tests, and while with some methods of technic a certain percentage of positive results may be obtained in syphilitic individuals, a large number of non-syphilitics will also be positive. Olitsky and Olmstead,' after citing the work of a large number of investigators in this field and giving the results of their own tests, reach the conclusion that the Wassermann reaction is by far more reliable. 1 Jour. Am. Med. Assn., 1914, Ixiii, p. 240. 2 Proc. Soc. Exper. Biol, and Med., 1909, vi, p. 49; ibid., 1909, vii, p. 2; Jour, [nfect. Dis., 1909, vi, p. 688. 3 Jour. Am. Med. Assn., 1914, Ixii, p. 293. 160 LABORATORY DIAGNOSIS Enzyme Test. — The principle of Abderhalden's dialyzing test has been applied to syphilis but as yet has not been demonstrated to be of practical value. The method of procedure usually employed is to add the serum of a patient and the tissue obtained from a human condyloma or syphilitic lesion of a rabbit testicle prepared after the method of Abderhalden, to a dialyzing thimble, place in a suitable capsule with distilled water, cover with toluol and incubate. After twelve to eighteen hours the dialysate is tested with ninhydrin for evidences of enzyme action. Landau's Color Test.^ — The reagent for this test as first reported consists of iodized petrolatum (0.025 c.c. iodin in 50 c.c. white petrolatum), but was later changed to a 1 per cent, solution of iodin in methanetetrachlorid. To 0.2 c.c. of the patient's serum in a small test-tube is added 0.01 c.c. of the iodin reagent. The solutions are well mixed and set aside for four hours at room temperature. A normal serum is said to assume a whitish-gray appearance and is opaque, while the serum of a syphilitic is a clear transparent yellow. This test has little to recommend it, as it has been shown to sometimes give positive results with non-luetic sera and negative results with luetic sera. LUETIN REACTION. From time to time since the discovery of tuberculin skin reactions investigators^ have attempted to apply the principle to the diagnosis of syphilis. However, to Noguchi,^ belongs the honor of having developed an allergic reaction which is a most valuable aid in the diagnosis of this disease. Preparation. — ^The material used, which Noguchi so aptly calls luetin, is prepared from pure cultures of Treponema pallidum grown after the method described by its originator. At first only two strains of the organisms were used, but later six strains were employed. Tubes of the treponemata are selected which have grown for six, twelve, twenty-four, and fifty days, and which show good growths of the organisms. The oil is poured off, the tube cut, the agar column removed, and the tissue cut off. The medium containing the cultures is carefully ground in a sterile mortar until a thick paste results. To this is added slowly a fluid culture of the organisms until a homogeneous liquid emulsion is secured. This is heated for one hour in the water-bath at 60° C, and 0.5 per cent. 1 Wien. klin. Wchnschr., 1913, xxvi, p. 1702. 2 Kolmer: Infection, Immunity and Specific Therapy, Philadelphia and London, 1915, p. 601. 3 Jour. Exper. Med., 1911, xiv, p. 557; Jour. Am. Med. Assn.. 1912, Iviii, p. 1163. LUETIN REACTION 161 tricresol or phenol added as a preservative. Its sterility is tested by planting on suitable culture media and inoculating rabbits intratesticularly. Experimentation. — At first the new preparation was tried only on rabbits. These animals were given repeated intravenous injections of pallidum antigen for a period of several months followed by a month's rest. After which the luetin was injected intradermally with the result that marked inflammation was produced, some even showing pustulation. Normal animals injected showed no reaction. While the experiments with the animals were still being carried on, at the suggestion of Professor Welch, Noguchi made the test on human beings. Later, luetin was distributed by its originator to a large number of physicians both in Europe and America, and before long it was placed upon the market by a number of manu- facturers of biological preparations. Mode of Application. — Luetin is injected intradermally by means of a very fine sterile needle and a small all-glass syringe graduated in one-hundredths of a cubic centimeter. Just before use the material, as prepared by Noguchi, is diluted one-half with sterile normal salt solution.^ The dose of the diluted luetin for adults is 0.07 c.c, while children are given 0.05 c.c. The site of injection is usually the upper arm, which is prepared by rubbing with alcohol. The skin is drawn taut by encircling the arm from the inner side with the thumb and middle finger of the left hand. The injection is made with the right hand, the bevel of the needle being directed outward. A slightly raised white papule is produced if the point of the needle is within the skin and disappears in about ten minutes. If the needle has pierced the skin, no papule results. At first Noguchi recommended a control injection of a fluid prepared in exactly the same manner as luetin from the sterile culture media. Reaction. — Negative. — Following the injection of luetin into the majority of normal individuals there may be seen after twenty-four hours a small erythematous area at and around the site of injection. This reaction, which is traumatic in nature, produces no pain or itching, and gradually disappears within twenty-four to forty- eight hours, leaving no induration. Occasionally the injection will cause the formation within twenty-four to forty-eight hours of a small papule which commences to subside within seventy-two hours. Following even this kind of negative reaction no induration is left. Positive. — Pcipular Form. — From twenty-four to forty-eight hours after the injection a red, indurated, raised papule of 5 to 10 mm. 1 Some of the commercial luetin is injected undiluted, 11 162 LABORATORY DIAGNOSIS in diameter makes its appearance. The lesion is sometimes sm*- rounded by an erythematous zone which may be slightly edematous. Unlike the negative papule, it gradually progresses for forty -eight to seventy-two hours, assuming a dark bluish-red color, and then slowly subsiding, entirely disappearing within a week or ten days. A slight induration may be left for a longer period. This type of reaction is most frequently observed during the first year of the disease in individuals who have had some mercurial treatment and who show no clinical evidences of syphilis. It is also frequently observed in hereditary lues, especially during the first year. Pustidar Form. — In the beginning this type of reaction assumes the papillary form, which lasts four or five days. The surface of the indurated papule then shows a number of small vesicles and the centre will be observed to have become slightly soft. After this the lesion becomes a definite pustule, at first filled with a slightly opaque serum, which later develops into true pus. At this stage there are more or less pain and itching. The pustule soon ruptures either spontaneously or by contact with the clothing, leaving an open sore surrounded by an indurated margin. Following the evacuation of the pus the cavity is covered by a thin scab, which falls off in the course of a few days, and the induration gradually disappears, leaving little or no scar. However, the skin remains pigmented and this pigmentation may persist for several months. Occasionally this form of lesion does not break down, the pus being gradually absorbed. The pustular type of reaction is seen most frequently in hereditary syphilis of long standing, and in the acquired form in the later years of the disease. Torpid Form. — This type of reaction appears to be negative at first and then after a period varying from one to five weeks it shows itself positive by assuming either the papular or pustular form and progressing in a manner as described for those lesions. The torpid or delayed form of reaction may occur at any time in the course of the disease and practically always when the patient is under treatment. Hemorrhagic Form. — A reaction consisting of a hemorrhagic exudate has been described as occasionally occurring. In this type the lesion usually breaks spontaneously and is of about the same severity and duration as the pustular form of reaction. Kilgore^ has reported a fifth type of reaction appearing in twenty- four to forty-eight hours, consisting of a small, slightly indurated reddened papule surrounded by a light purplish or violet areola of 35 to 40 mm. in diameter. The areola is seen to fade in the next 1 Jour. Am. Med. Assn., 1914, Ixii, p. 1236. PLATE III Positive Luetin Reaction. Pustular Type. LUETIN REACTION 163 three or four days and the papule to increase in size and in amount of induration, after which the reaction progresses in a manner similar to the ordinary papular form. Value of Luetin Reaction. — Since the discovery of the luetin test in 1911 it has been used very extensively by many different investi- gators and its value established beyond dispute. It has not in any sense usurped the place of the Wassermann reaction, but merely acts as a supplement to that most valuable test. While the Wasser- mann reaction is of most value in the early course of the disease, especially in untreated cases (except paresis) the luetin test is of prime value in the latter stages when clinical evidence is lacking. Sherrick^ recently has thrown some doubt on the specificity of the luetin reaction. This writer states that a positive luetin reaction can be obtained in 99 per cent, of all cases, irrespective of the pres- ence of syphilis, by the administration of potassium iodide or other iodin-containing drugs either simultaneously, or shortly before or after the injection of the luetin. He also points out that other substances, such as agar and starch, injected intradermally will produce reactions similar to the luetin if iodin is administered, but with these substances it must be administered within a shorter time of the injection than is the case with the luetin. The time of administration of the potassium iodide may vary greatly. In one case giving a negative luetin test the drug was administered in small doses two months later which was immediately followed by a positive nodular reaction. On discontinuing the iodide the reaction underwent complete involution, but returned again when the drug was resumed several weeks later. By studying the observations of about fifty investigators Noguchi^ has presented the following statistical estimation of the practical value of the luetin reaction in the various stages of syphilis according to the classification of Ricord: Primary Syphilis. — Positive in less than 30 per cent, of cases and. then reaction usually very mild. Secondary Syphilis. — Positive in 47 per cent, of 630 cases. Usually mild reactions. Tertiary Syphilis. — Positive in about 80 per cent, of cases. Very severe type of reaction, usually pustular. Congenital Syphilis. — Positive in about 70 per cent, of cases. One observer finding 93 per cent, of 75 cases positive. Syphilis of the Nervous System. — Rarely positive in acute syphilitic meningitis, but positive in about 60 per cent, of cases of paresis and tabes. Visceral Syphilis. — Positive in nearly 90 per cent, of such cases, especially marked in aortic insufficiency. 1 Jour. Am. Mtd. Assn., 1915, Ixv, p. 404. 2 Ng-^y York Med. Jour., 1914, c, p. 34. 164 LABORATORY DIAGNOSIS CEREBROSPINAL FLUID. Anatomy. — The cerebrospinal fluid is found in the subarachnoid spaces of the brain and spinal cord. These spaces are formed by the inner wall of the subarachnoid and the outer wall of the pia, and there is direct communication between the fluid of the brain and that of the spinal cord. The fluid in the ventricles probably also comes in contact with the fluid of the subarachnoid spaces. Physiology. — The cerebrospinal fluid was for a long time considered to be an ordinary tissue lymph bathing the nervous structures. It is now, however, almost universally regarded as mainly a true secre- tory substance, a product of the choroid plexus, and it has also been shown that the injection of extract of this plexus will cause an increase in the secretion of the spinal fluid. The normal quantity of fluid secreted is an unsettled question. It has been demonstrated, however, that following puncture of the subarachnoid space a con- tinuous flow of fluid at the rate of 100 c.c. per hour or more may be observed, and which may last for weeks. ^ The functions of the spinal fluid are: (1) it protects the delicate structures of the central nervous system from jar; (2) it takes up and neutralizes certain substances formed by the metabolic changes in the brain and from them forms inert organic compounds of a complex nature ; (3) according to Mott,^ by the presence of glucose in the spinal fluid it seems to supply the nervous system with energy; and (4) it aids in keeping up the physiological equilibrium of volume during dilatation and contraction of the bloodvessels and in certain pathological conditions such as the development of tumors. The absorption of the cerebrospinal fluid seems to be mainly, at least, through the venous channels, the lymphatics being a negli- gible factor. Physical and Chemical Properties. — The normal cerebrospinal fluid is a thin, clear, watery, fluid of a specific gravity of 1.003 to 1.008, and an alkaline reaction. It is odorless and tasteless. The chemical composition, according to Karpas,^ is as follows: Water, 98.74 per cent. Solids, 1.25 per cent. Albumin (in form of globulin and albumose), 0.03 to 0.6 per cent. Dextrose, 0.4 to 1 per cent. Potassium salts, phosphate and urea, 0.15 to 0.35 per cent. The number of cellular elements in normal cerebrospinal fluid 1 Kusonoki: Virchows Arch. f. path. Anat., 1914, ccxv, p. 184. 2 Cited by Kaplan: Serology of Nervous and Mental Diseases, Philadelphia and London, 1914, p. 19. 8 Jour. Am, Med. Assn., 1913, Ixi, p. 262. CEREBROSPINAL FLUID 165 is variously stated to be from none to 10 per c.mm. The author has never seen a normal individual with more than seven lympho- cytes per c.mm. in his spinal fluid, and regards five as the usual limit for normal cell counts. In fact, it is probable that strictly normal cerebrospinal fluids are entirely free from cellular elements and that their presence, even in numbers under 5 per c.mm., denotes some slight irritation, perhaps transitory in character. Under pathological conditions the composition of the cerebro- spinal fluid may vary greatly. This is especially true of the protein content which in certain conditions is markedly increased. The number of cells present also may be greatly raised. It has been shown that while the potassium content of the fluid may vary to a considerable extent no clinical significance can be attached to these variations.^ Rachicentesis. — Probably the first person to perform spinal punc- ture was Doctor J. Leonard Corning,^ who, in 1885, demonstrated the induction of analgesia by the injection of cocain into the sub- arachnoid space. It was not, however, until 1891 that rachicentesis was performed for the purpose of withdrawing spinal fluid, and in that year Quincke^ published his technic for this procedure. Indications. — The indications for spinal puncture are mainly for diagnosis, although therapeutically this procedure is of value for reducing intracranial pressure and for the intraspinal administra- tion of remedial agents. It is indicated in all suspected cases of meningitis, including syphilis, in suspected syphilitic involvement of the brain and cord, in poliomyelitis, and in tumors of the cord. Contraindications. — Spinal puncture is contraindicated in any markedly weakened physical condition, in brain tumors of the pos- terior fossa, except in the most urgent cases, when a very small quantity (not over 1 or 2 c.c.) may be withdrawn, and immediately replaced with sterile normal salt solution, in marked arteriosclerosis and in advanced cardiac affections. Technic. — The author has found the most convenient position in which to place the patient for lumbar puncture is sitting, although it can easily be performed with the patient in bed, in which case he should lie on his right side near the edge of the bed and be instructed to draw his knees well up over the abdomen. If the sitting posture is chosen, the patient is placed in a chair sidewise with his back toward the operator and his left side toward the back of the chair. He is instructed to thrust his folded hands 1 Rosenbloom and Andrews: Arch. Int. Med., 1914, xiv, p. 536. 2 Bush: A Reference Handbook of the Medical Sciences, New York, 1900, vii, p. 291. 3 Berl. klin. Wchnschr., 1891, No. 38, p. 929. 166 LABORATORY DIAGNOSIS between his knees and "bow" his back. The hand of the operator placed under the patient's abdomen will sometimes assist in securing the necessary curve to the spine. The operator now places the index finger of each hand on the pos- terosuperior spines of the ilii and with the thumb of the left hand searches for the soft spots between the third and fourth and the fourth and fifth lumbar vertebrae. Having by this preliminary examination determined the location of the soft spots, an area of five or six centimeters around them is painted with iodin. The ventral side of the thumb of the operator's left hand is also painted with iodin and the exact spot for the puncture is determined. The space between the third and fourth Fig. 47. — Method of performing spinal puncture. vertebrae is usually the one of choice, as it is naturally wider, but occasionally the operator finds the one between the fourth and fifth better adapted. This is purely a matter of training. As a rule no anesthetic is necessary, but in hysterical or nervous individuals the skin may be infiltrated with a 2 per cent, novocain solution or anesthetized with ethylchloride. The needle should be slightly flexible and provided with a stilet. The bore may vary from 14- to 20-guage. The author's needle is of 16-gauge and is provided with an outflow tube about 2 centimeters from the distal end, so that after the spinal canal is pierced and a tube held under this, while the stilet is partially withdrawn, the fluid will flow directly into the tube and none will be lost. CEREBROSPINAL FLUID 167 The needle is inserted with a steady thrust directly in the median line and straight in. At a variable distance from the surface the point of the needle will meet with the slight resistance of the mem- branes which, wheri overcome, will indicate that the subarachnoid space has been pierced. Fig. 48. — Author's spinal puncture needle. It is advisable to collect the spinal fluid in two or three tubes, as the first fluid which escapes, even with the most careful technic, may contain slight amounts of blood. Sometimes the entire amount of fluid withdrawn may contain blood to a greater or less extent, due to having severed a small vessel in making the puncture. It is needless to say that such fluid cannot be used for protein determina- tions or for estimating the cellular elements. Slight traces of blood, however, do not interfere with the Wassermann reaction; () or 8 c.c. are usually sufficient. Fig. 49 It occasionally occurs that upon withdrawing the stilet from the needle no fluid escapes. It may be that the needle is inserted too far and has entered the anterior wall of the subarachnoid space. If this is the case, a slight withdrawal of the needle will start the flow. Or it may be the needle is not inserted far enough, when upon farther insertion the fluid will escape. Finally, the bore of the needle may be occluded by a plug of fibrin which may be removed by replacing the stilet and again withdrawing it. That true "dry punctures" do occur was demonstrated by 168 LABORATORY DIAGNOSIS Leszynsky/ who, by inserting one needle between the third and fourth lumbar vertebrae and another between the fourth and fifth, injected sterile salt solution through the first needle and observed its escape through the second needle. Many workers estimate the pressure of the fluid by attaching a manometer to the needle, but this seems to the author a useless procedure, as the pressure may vary greatly in normal individuals and is not constant for any given pathological condition. After obtaining the fluid the stilet is replaced, the needle with- drawn and a drop of collodion or a strip of adhesive plaster applied. The patient is placed in bed and instructed to keep his head low, preferably without a pillow, for twenty-four to forty-eight hours. It is also desirable to place the patient in bed for twenty-four hours before the operation. Untoward Effects. — The most frequent untoward effect of spinal puncture is headache, although nausea and vomiting may occur. Sudden death may follow this procedure in cases of cerebral tumor. Paretics and tabetics rarely show any untoward symptoms. The headache is usually controlled by the administration of asperin or some other mild sedative or the application of an ice-bag. Bromides and potassium iodide have also been recommended. METHODS OF EXAMINATION. Estimation of Protein. — Nonne-A-pelt Test. — This test, devised by Nonne and Apelt,^ is performed as follows: 1 c.c. of saturated solution of ammonium sulphate in a test-tube is heated to boiling and then permitted to cool. To this is now added 1 c.c. of spinal fluid by overlaying with a pipette. If the globulin is increased a more or less distinct gray ring will occur at the point of contact. The tube is now shaken and if in three minutes there is a distinct cloudiness the reaction is positive. Noguchi Butyric Acid Test.^ — To 0.2 c.c. of spinal fluid in a test-tube is added 1 c.c. of a 10 per cent, solution of butyric acid (Merck) in normal salt solution. The mixture is boiled over a Bunsen flame for several minutes, after which 0.1 c.c. of normal sodium hydroxide solution is quickly added and the boiling continued for a few seconds. A granular or flocculent precipitate will indicate an excess of globulin. 1 Cited by Kaplan: Serology of Nervous and Mental Diseases, Philadelphia and London, 1913, p. 21. 2 Nonne: Syphilis and the Nervous System, Philadelphia and London, 1913, p. 341. * Noguchi: Serum Diagnosis of Syphilis, second edition, Philadelphia and London, 1911, p. 156. METHODS OF EXAMIXATIOX 169 The Author s Modification. — The author has modified the Xoguchi technic by adding the sah solution and but\Tic acid separately, as follows: To 0.2 c.c. of spinal fluid are added 0.9 c.c. of normal salt solution and 0.1 c.c. of pure but\Tic acid. The remainder of the procedure follows the Xoguchi technic. Kaplan's Methods — 0.5 c.c. of spinal fluid in a test-tube are heated until boiling occurs, removed from the flame and boiled again. Three drops of a 5 per cent, solution of butyric acid in normal saline are added, followed quickly by underlying 0.5 c.c. of super- saturated ammonium sulphate solution and the tube set aside for twenty minutes. An excess of globulin is shown as a "thick granular, pot-c-heese- like ring."' Normal fluid shows no ring. A rough quantitative estimation of positive fluids is made by using five tubes, placing in each, respectively, 0.1, 0.2, 0.3, 0.4 and 0.5 c.c. of fluid and bringing the total in each up to 0.5 c.c. with distilled water, then proceeding as above. If an excess of globulin is observed in the tube containing 0.1 c.c. of spinal fluid, the reaction is termed 0.1 excess, if the tube containing 0.2 c.c, 0.2 c.c. excess, and so on. Significance of Protein Increase. — An increase in the protein of the spinal fluid indicates an organic afi^ection of the central nervous system, and is observed in practicaUy all s\-philitic involvement of these organs. It will not, however, distinguish between s\-phihtc and non-s\'philitic diseases, nor will it differentiate the various s^'philitic processes. Lange Collodidal Gold Test.- — ^AVhile this test is dependent upon an iacrease in the protein content of the spinal fluid, it does not, however, depend upon the quantitative increase, as the strength of the reaction bears no constant relation to the amount of protein present. And further, it is impossible in our present state of knowl- edge to account for aU the factors concerned in the phenomena of the reaction. Colloidal gold was first prepared in 1857 by ^Michael Farada\'^ by reducing gold chloride with phosphorus. To the work of Zsigmody,^ however, we are indebted for the preparation of clear solutions or suspensions of coUoidal gold. This investigator also demonstrated that the red color of the solution changes to a blue with the precipitation of the gold as an extremely fine powder upon the addition of most electroh-tes. It was further discovered that solutions of protein in the presence of an electrohte inhibited the precipitate (Goldschutz), that the inhibitive points (Goldzahl) - Kaplan: Serologj- of Nervous and Mental Diseases, Philadelphia and London, 1914, p. 29. 2 Lange: Berl. klin. Wchnschr., 1912, xlix, p. S97. ' Proc. Roy. Soc, 18-57, viii, p. -356. 'Ann. d. Chem. (Liebig'sj, 1898, ecci, p. 30. 170 LABORATORY DIAGNOSIS for the various proteins could be determined, and that the Goldzahl is constant for each protein. Lange, with these facts at his command, was able to demonstrate that the excessive amounts of protein found in the spinal fluid under pathological conditions caused the precipitation of the gold solution, and that this precipitation occurred within definite dilution limits that were practically specific for the syphilitic conditions of the central nervous system, especially paresis and taboparesis. Technic. — The most important point in the technic is absolute chemical cleanliness. All glassware should be boiled in ivory soap- suds, thoroughly rinsed in hot running water, then with hydro- chloric acid and followed by plain distilled water and triple distilled water. Complete sterility of glassware is not necessary. The spinal fluid must be fresh when tested or else kept absolutely sterile. 'Preparation of Reagent. — The preparation of the reagent is the most difficult point of the technic and unless the instructions are followed absolutely to the letter failure may be expected. Solutions required: 1. Triply distilled water. This is prepared by redistilling freshly distilled water in an all-glass still without rubber connections. 2. Gold chloride solution. (Merck) (1 per cent, in triply dis- tilled water.) 3. Potassium carbonate solution. (Merck's Blue Label) (2 per cent, in triply distilled water.) 4. Formalin solution. (Merck's 40 per cent.) (1 per cent, in triply distilled water.) 5. Oxalic acid solution. (Merck's Blue Label) (1 per cent, in triply distilled water.) Li a Jena glass beaker are placed 500 c.c. of triply distilled water and slowly heated over a large Bunsen burner to 50° C, when the temperature is quickly raised to 60° C. To this are added 5 c.c. each of the gold chloride solution and the potassium carbonate solution, and the heating continued as rapidly as possible. At 80° C. five drops of the oxalic acid solution are slowly added and at 90° C. the flame is withdrawn and 5 c.c. of the formalin solution are added drop by drop while stirring. The change of color to a clear brilliant red with a slight bluish nuance usually is gradual. It may occur before all of the formaldehyde is added, in which case it should be stopped. A good reagent will remain unchanged for months if placed in a Jena flask and kept in the dark. Miller^ and his associates recently have pointed out that even beautifully clear solutions sometimes fail to respond to the action of paretic spinal fluids. These investigators state that there are 1 Johns Hopkins Hosp. Bull., 1915, xxvi, p. 391. METHODS OF EXAMINATION 171 two types of solutions, the ''protected" and the "non-protected." The former is one in which no agglutination takes place after the addition of any amount of any electrolyte, and the latter is one in which agglutination takes place in the presence of very small amounts of one electrolyte. It was then found that for practical purposes a non-protected solution was one that would be completely precipitated by 1.7 c.c. of a 1 per cent, sodium chloride solution in one hour's time. These writers further observed that the solutions varied considerably as to their acidity and alkalinity; that alkaline solutions were almost inert to a positive spinal fluid ; that a strongly acid solution gave very little if any reaction to a known positive spinal fluid and an atypical reaction to a normal fluid; that slightly acid solutions while giving a typical reaction with paretic fluids, gave a quite typical reaction in the so-called luetic zone with normal fluids, and only an intensification of the reaction with a fluid from a case of cerebrospinal syphilis; and finally that neutral solidions gave typical reactions with paretic fluids and never any reaction with normal fluids. It was then found that if non-protected solutions which were either acid or alkaline were neutralized they fulfilled all requirements. The following steps are taken in neutralizing such solutions: Alizarin-red (1 per cent, solution in 50 per cent, alcohol) is used as an indicator; with alkaline colloidal gold solutions this indicator produces a purplish-red color. Acid solutions give a lemon-yellow color, while neutral solutions are yellowish red. Two drops of the indicator are added to a test-tube containing about 5 c.c. of the gold solution and the reaction noted. If this is found to be neutral, the solution is, of course, satisfactory. If it is not neutral, the test-tubes are placed in a rack and to each is added 1 c.c. of freshly distilled water. Then if the gold solution was found acid, 1 c.c. of |^ NaOH is added to the first tube. If the solution was alkaline, 1 c.c. of ^ HCl is added. This is thoroughly mixed and 1 c.c. with- drawn and placed in the second tube and the process is repeated until the tenth tube is reached when 1 c.c. is discarded from it. It is seen that the first tube contains 0.5 c.c. of acid or alkali and that each successive tube contains just one-half the amount in the preceding tube. Two drops of the indicator and 5 c.c. of the gold solution are added to each tube. The tube which shows a neutral reaction shows the amount of acid or alkali necessary to neutralize 5 c.c. of the gold solution, and the amount necessary to neutralize the entire quantity can readily be calculated. This should be added gradually to avoid precipitation, and the solution should be at least forty-eight hours old before neutralization. Performance of Test. — Ten tubes (15 mm. x 15 cm.) which have been thoroughly cleansed by boiling in 10 per cent, potassium 172 LABORATORY DIAGNOSIS chromate solution, rinsed in distilled water, and drying in the hot- air sterilizer, are used for each fluid. Into the first of these tubes are placed 1.8 c.c. of a 0.4 per cent, sodium chloride solution prepared with triply distilled water from a stock solution (10 per cent. NaCl (Merck) in triply distilled water), and into each of the suc- ceeding tubes is placed 1 c.c. Into the first tube is placed 0.2 c.c. of the spinal fluid, and thoroughly mixed with the salt solution by drawing the contents into a pipette and expelling it two or three times. Then from the first tube 1 c.c. of the mixture is withdrawn, placed in the second tube and thoroughly mixed. This process is repeated with each succeeding tube, the 1 c.c. withdrawn from the tenth tube being discarded. Each tube now contains 1 c.c. and the dilutions of spinal fluid vary from 1 to 10, 1 to 20, 1 to 40, etc., up to 1 to 5120. To each tube are now added 5 c.c. of the reagent and thoroughly mixed. While the change of color in the tubes often occurs almost immediately it is best to let them stand for twelve to twenty-four hours before reading the final results. The usual method of indicating the color changes is as follows : Complete precipitation, fluid clear and colorless 5 Almost complete precipitation, fluid pale bluish gray . . ... 4 Moderate precipitation, fluid almost blue 3 Slight precipitation, fluid lilac or purple 2 Faint precipitation, fluid reddish blue 1 No precipitation, fluid red The method of recording the reaction employed in the author's laboratory is to plot a curve. The tubes are indicated by a vertical column of numbers and the type of color change by a horizontal column. A negative reaction in which all tubes show no color change would be recorded as follows: 1 2 3 4 7 8 9 As stated above, it is in paresis and taboparesis that the most typical colloidal gold reactions are found. Grulee and Moody^ go so far as to state that so constant and typical is the reaction for 1 Am. Jour. Dis. Child., 1915, ix, p. 19. > I— I w < o o METHODS OF EXAMINATION 173 paresis that a diagnosis may be ventured on that finding alone without other clinical or laboratory evidence. With this extreme view the author cannot agree, as he has seen a case of syphilitic meningitis giving a reaction typical for paresis. Kaplan^ reports a similar case and also one of multiple sclerosis with a typical paretic curve. It must be admitted, however, that there is a possibility of paresis developing in all cases of syphilis of the central nervous system, and the fact remains that the colloidal gold test is today our greatest aid in the diagnosis of general paralysis. A typical paretic curve which is self-explanatory would be recorded as follows: 1- 2 i 3 ^'\ 5 -^^ 8 ' " 9 nl 1 1 1 1 The following curve was recorded in taboparesis : ^\^ \ . 5 \i ; 2 ] While the curve of tabes is not at all typical or constant, it always is positive in untreated cases. The type of curve is what is known as the "luetic zone," and similar reactions are observed in so-called cerebrospinal syphilis. Such a curve as the following not infrequently is seen in tabes : 1 3 \ ^ 4 5 6 7 8 9 ft ^^ ^^^ ' Serology of Nervous and Mental Diseases, 1914, Philadelphia and London, p. 186. 174 LABORATORY DIAGNOSIS Cytology. — While several varieties of cellular elements are encountered in the spinal fluid in syphilitic involvement of the central nervous system, the majority are small, markedly basophilic, lymphocytes. Attempts have been made by different observers to attach diagnostic significance to the finding of different kinds of cells, but it would seem from our present state of knowledge, at least, that such an assumption is unwarranted. Origin of Cytological Elements. — Two theories have been advanced to account for the origin of the cellular elements in the cerebro- spinal fluid. The first is that they are blood cells which have trans- migrated to the spinal fluid, and the second is that they are of histological origin coming from the leptomeninges. In all prob- ability the true explanation of their origin is to be found in a combination of the two theories. Technic. — ^The most simple and satisfactory method of counting the cellular elements in the spinal fluid is, after thoroughly shaking the containing tube, to place a drop, undiluted, on a Fuchs-Rosen- thal counting chamber and with a low-power objective to count all of the cells present. Quite frequently it is impossible with a low-power objective to distinguish between lymphocytes and eryth- rocytes. Where there is doubt a high-power dry objective should be employed. Lymphocytes show upon focussing a distinct flatness and appear to be covered with small dots which are corrugations of the protoplasm. Erythrocytes, on the other hand, do not appear flat, gradually disappear upon focussing and even when old do not present the dotted appearance of the lymphocytes. The Fuchs-Rosenthal counting chamber measures 4 mm. square and 0.2 mm. deep. The contents therefore are 3.2 cubic millimeters, and to determine the number of cells per cubic millimeter the total number counted should be divided by 3.2. If a Fuchs-Rosenthal counting chamber is not available the ordinary Zappert or Turk blood-counting chamber may be used with quite accurate results. The margin of error with the original Thoma-Zeiss chamber is too great for it to be recommended for this purpose. Many workers advocate diluting the spinal fluid in a blood- counting pipette with a staining solution. This, to the author's mind, is an unnecessary procedure. It ma}^ however, be desirable, when the fluid contains a very few red blood cells, to dilute it with an equal volume of 0.5 per cent, acetic acid which lakes the erythro- cytes. If much blood is present, however, even this expedient will not answer, as the white cells of the blood cannot be distinguished from the cellular elements originally in the fluid. The spinal fluid should be examined when fresh, as standing may cause disintigration of the lymphocytes. METHODS OF EXAMINATION 175 Significance of Pleocytosis. — Any increase in the number of cellular elements in the cerebrospinal fluid denotes an inflammatory irritative condition of the leptomeninges, but is not necessarily syphilitic. The highest number of cells in syphilitic afi'ections of the central nervous system are found in syphilitic meningitis, when the count may run as high as 1680 (Kaplan). Gummata and syphilitic arteritis of the central nervous system, on the other hand, usually show low counts. In paretics the cell count generally runs from 15 to 75 per c.mm., although the number may drop markedly during the final decline, or following a series of convulsions. The spinal fluids of tabetics show the greatest variations, the cell counts in some cases being normal and in others running' up into the hundreds. Comparatively high counts are the rule. The operation of spinal puncture will produce a local inflammation of the leptomeninges that will i^e/)- se cause a pleocytosis, so should not be repeated under ten days. Reduction of Fehling's Solution. — All normal spinal fluid contains a substance which will reduce Fehling's solution, but in certain pathological conditions this substance is absent. It is usually absent in epidemic cerebrospinal meningitis and occasionally in syphilitic meningitis. Complement -fixation with Spinal Fluid. — The technic of performing the complement-fixation test with spinal fluid is the same as that employed with blood serum except that larger quantities are used and that it is never inactivated. It is the custom in the author's laboratory to employ five tubes for each fluid, using 0.2, 0.4, 0.6, 0.8 and 1 c.c, 1 c.c. is also used in the control tube without antigen. The author does not consider a slightly positive Wassermann reaction with 1 c.c. of spinal fluid absolutely indicative of syphilis, nor a negative reaction with 0.2 c.c. as excluding syphilis, but he does consider an absolutely negative test with 1 c.c. of fluid as essential to a cure. In diagnosis the same statements apply to the spinal fluid Wassermann as were made concerning the blood Wasser- mann, viz., that the reaction must be interpreted only in the light of clinical evidence, or at least, in the light of other laboratory findings. The Wassermann reaction on the spinal fluid has been found positive in nearly 100 per cent, of fully developed cases of paresis, even with small amounts (0.2 c.c), and, as a rule, the inhibition of hemolysis is complete. In the early and late stages of paresis it may be positive or negative. In the majority of cases of tabes dorsalis (about 80 per cent.) the spinal fluid reacts negatively to the Wassermann test with 0.2 176 LABORATORY DIAGNOSIS c.c, but when large quantities are employed (1 c.c.) it is positive in approximately 80 per cent, of cases. In the late stages it may be negative. In syphilitic involvement of the meninges and arteries of the central nervous system, the result of the spinal fluid Wassermann, as Head and Fearnsides^ have pointed, out will depend upon the location of the lesion. If the spinal cord, its membranes or nerve roots be aft'ected, the reaction is usually strongly positive; while if the process be confined to the intracranial contents, the reaction is negative or weakly positive. 1 Brain, 1914, xxxvii, p. 79. CHAPTER VIII. PROGNOSIS. Usually the first question asked by the syphilitic upon being informed of the nature of his disease is, "Can I be cured?" In the majority of cases this can be answered in the affirmative, although the answer should be qualified by certain provisos, the principal one of which is that treatment be followed energetically and consistently. The answer also must be qualified by the length of time the disease has existed, the amount and nature of the treatment already received and the portions of the body involved. Certain other factors which are almost obvious influence the prognosis to a greater or lesser extent. Such are the general physical condition of the patient, the presence or absence of intercurrent disease, the habits, the use or abuse of alcohol and tobacco, age, etc. Some of the older writers^ have asserted that spontaneous recoveries from s>T)hilis occasionally occur, but in the light of modern knowledge of the subject it would seem that such recoveries are impossible. It is true that all outward manifestations of syphilis may disappear and the individual seem in perfect health and die from some other cause, but nevertheless the treponemata are undoubtedly present within the body. The Wassermann Reaction and Prognosis. — ^Little prognostic value can be attached to a single Wassermann reaction. If, as is prob- ably the case, the Wassermann reaction depends upon the production of a certain type of antibodies, it is also probable that either these antibodies combat the treponemata or that other antibodies are produced at the same time which act in such a manner, and that a strongly positive Wassermann reaction, sometimes at least, may be considered as indicative of a more favorable outcome. Certainly it is true that not infrequently the cases showing the strongest four-plus Wassermann reaction are most amenable to treatment. On the other hand, cases showing the weakly positive reaction are sometimes very refractory. However, a strongly positive Wasser- mann reaction persisting over a considerable period of time in spite of energetic treatment must be looked upon with grave concern. Chancre. — ^It may safely be said that practically 100 per cent, of all chancres are cured, and even without treatment the vast majority disappear in from two or three weeks to a few months. 1 Lang in Steadman's Twentieth Century Practice of Medicine, New York, 1899, xviii, p. 283. 12 178 PROGNOSIS However, the cure of the chancre does not necessarily mean the cure of the syphihs. Yet with modern methods of treatment the prognosis of syphihs observed during the presence of the chancre is excellent, and the earlier the chancre is seen and treatment is instituted, the greater will be the prospect of cure. The mildness or severity of the syphilitic process in the chancre seems to bear but little relation to the subsequent course of the disease, although quite frequently a chancre with marked ulceration is followed by severe cutaneous manifestations. On the other hand, a chancre showing but little or no ulceration may be followed by an equally severe cutaneous outbreak. The location of the chancre also bears but little relation to the prognosis. It has been stated that the second incubation period is shorter and that the subsequent course of the disease is more severe following extragenital than genital chancres. These con- tentions, however, lack confirmation. It has been thought that the demonstration of the nature of the treponemata found in the chancre might be of prognostic value. That is, that certain strains of organisms have a predilection for certain tissues and the differentiation of these strains determine the likelihood of involvement of the tissues most vulnerable to the strain demonstrated in a certain chancre. However, in our present state of knowledge such a differentiation is impossible. Lymphatic Glands. — The prognosis of the glandular enlargement accompanying the chancre is excellent, as in the vast majority of cases this enlargement disappears promptly under specific treat- ment or even spontaneously. The later adenitis also disappears with or without treatment and no prognostic importance in regard to the syphilis can be attached to this condition. Skin Lesions. — The syphilodermata are the most striking mani- festations of the syphilitic process, and in a general way it may be said that the prognosis for the cure of these lesions is good. This is especially true of the macular and papular s;^^hilodermata, which, as a rule, are self-limited and disappear sooner or later even without treatment, while under specific therapy the healing of these lesions is sometimes truly marvelous in its rapidity. The palmar and plantar papulosquamous syphilodermata, especially when occurring late in the course of the disease should be excepted from this state- ment, as these lesions are very chronic in their tendency and even with the most vigorous treatment are often most refractory. The moist papular lesion also is very persistent if left untreated, but, as a rule, readily yields to proper medication. After healing of the macular and papular syphilodermata little or no trace of their presence is left, although in some instances a pigmentation is noted which gradually disappears. SYPHILIS OF THE APPENDAGES OF THE SKIN 179 The prognosis of the very. rare vesicular and bullous syphilo- dermata is good as they are very amenable to specifics. The pustular lesions are quite persistant, rarely healing spon- taneousl}^ although, as a rule, yielding quite easily to antisyphilitic treatment, yet if very extensive and with deep ulceration may present considerable difficulty of cure. The smaller acuminate pustular lesions may heal with no trace left behind but a slight pigmentation or small pits may remain, while the larger lesions are sometimes followed by atrophic thinning with slight scarring. The healing of the flat pustular syphilodermata W!M leave scarring and pigmentation, depending upon their extent and the depth of the ulceration. The nodular syphiloderm, except in rare instances, is quite amenable to treatment, but upon healing leaves more or less scarring and depression depending upon the depth of the lesion. Gummata of the skin are, \nth the exception of the palmar and plantar papulosquamous syphilodermata, the most difficult of the skin lesions of syphilis to cure. Even these are usually quite amen- able to treatment, sometimes healing without ulceration, even though they may have become quite soft. If specific medication is not instituted, gummata of the skin may penetrate the underlying structures and great destruction of tissue takes place. The healing of a superficial gumma leaves a dark red scar of more or less depth which gradually becomes white in the centre, although permanently pigmented at the periphery. The prognosis of syphilis when seen during the activity of the cutaneous manifestations will depend ■ upon the same conditions as stated above for the prognosis of sj^hilis in general, that is, the length of time which the disease has existed, the amount and nature of the treatment already received and with the syphilodermata the extent of the involvement of other portions of the body. Syphilis of the Appendages of the Skin. — Hair. — ^The prognosis of syphilitic alopecia will depend upon whether or not it is due to the presence upon the hairy parts of the sj'philodermata. If it is due to such lesions, the alopecia is, as a rule, permanent, while if occurring independently, the hair ^dll generally return when proper treatment is carried out. In the case of complete sj-philitic alopecia observed by the author, however, the most vigorous antisyphilitic therapy failed to stimulate the growth of hair. Nails. — The prognosis of syphilitic onychia and paronychia will depend upon the extent of the processes. As a rule, if the matrix of the nail has not been destroyed, it "uill return to normal, a new nail developing if the old one has been lost, upon the institution of proper therapy. Nothing of prognostic value as to the cure of syphilis can be deduced from syphilis of the appendages of the skin. 180 PROGNOSIS ) Mucous Membranes. — As with the syphilodermata, so with the syphilomycodermata, it may be said that the prognosis of their cure is good, and especially is this so with the macular and papular lesions. The papular lesions of the mouth, however, may be aggravated and rendered more refractory by the use of tobacco. Leukoplakia also may present great difficulty of cure. The gummatous syphilomycodermata, as a rule, readily yield to specific treatment, although if left untreated, may affect the deeper structures and cause great loss of tissue with marked deformity. General Symptoms. — Little or nothing of value from a prog- nostic standpoint can be learned from the general symptoms of syphilis. Marked fever, however, may be considered as indicative of a severe luetic infection, or a contamination with other organisms. Blood. — As with any anemic condition the lower the erythrocyte count and the percentage of hemoglobin, the graver will be the outlook. According to Hazen^ considerable of prognostic value may be learned from the leukocyte count in the so-called secondary stage of syphilis. Those cases of his series showing a high neutrophile count and a low lymphocyte count did not do well under treatment, while when the conditions were reversed and the neutrophiles were low and the lymphocytes high the case did well. The prognosis of visceral syphilis and syphilis of the osseous, muscular and nervous tissues as well as that of the organs of special sense will be discussed in Part II. SYPHILIS AND MARRIAGE. One of the most frequent questions asked by the syphilitic is, "Can I ever marry? And if so, when?" In the pre-Wassermann days a time limit was usually set after which it was considered safe for the syphilitic to marry. Thus, Fournier^ stated that a minimum period of three or four years following the chancre devoted to a most careful treatment should elapse before marriage should be permitted. Keyes^ answered the question by saying that a period of four years, during the last one of which no symptoms of syphilis have been observed and during at least the last six months no treatment has been taken. He, however, considered five years after the chancre to be the safer limit. Since the development of the Wassermann test most syphilog- raphers have considered that permission to marry should not be 1 Jour. Cut. Dis., 1913, xxxi, p. 618. 2 Syphilis and Marriage, New York, 1882, p. 92. 3 Genito-urinary Diseases with Syphilis, New York, 1894, p. 538. SYPHILIS AND MARRIAGE 181 given to a syphilitic while the Wassermann is still positive, even in spite of the absence of other symptoms or lesions of the disease. Keyes, Jr./ states that this is no more warrantable now than when we did not have the Wassermann reaction and insists that the syphilitic may safely be told to marry after five years of his disease, during the first three of which he has taken treatment and during the last two from which he has taken no treatment and shown no symptoms. This in spite of a positive Wassermann. With this view the author cannot agree. If we believe that a positive Wassermann is an indication of the presence of living treponemata in the body, and we have every reason to so believe, there certainly is danger that these organisms will get into the blood stream and become the source of infection. Most writers on the subject of syphilis and marriage refer only to the disease in men. This is undoubtedly due to the fact that syphilis is so much more common in marriageable men than in marriageable women. Nevertheless syphilis is of sufiicient fre- quency in the latter to warrant a consideration of the subject. Keyes^ stated that in the female five years is little enough time and that more would be better. In this connection the observation of Graefenberg,^ who found living treponemata in the secretion from the cervix of four syphilitic women, should be mentioned. Two of these were pregnant and all four had condylomata of the vulva, but with no lesions of the cervix. In five other women who had had treatment no organisms could be found. Chase* quotes Mueiler as having found treponemata in the leucorrheal and menstrual discharges in a prostitute who had been suspected of infecting men but who presented no symptoms or lesions of the disease but a positive Wassermann. Gellhorn and Ehrenfest^ found living treponemata in the normal cervical secretion in two cases. In the first case an ulcer of the fourchette was present while the vagina and cervix were normal. In the second case the organisms were found two months following the healing of lesions of the cervix under energetic treatment. To the author it seems that permission to marry should not be given, either to men or women, until a complete cure of the disease has resulted. The standard for cure will be discussed in the chapter on Treatment. It is admitted that in some instances, perhaps in many, infection will not follow the marriage of syphilitics with 1 Jour. Am. Med. Assn., 1915, Ixiv, p. 804. 2 Genito-urinary Diseases with Syphilis, New York, 1894, p. 538. 3 Arch. f. Gynak., 1909, Ixxxvii, p. 190. * Texas State Jour. Med., 1913, ix, p. 95. 6 Am. Jour. Obst., 1916, Ixxiii, p. 864. 182 . PROGNOSIS positive Wassermann reactions, but certainly it is safer to wait for a complete serological as well as clinical cure> Possibly there are individuals who are so anxious to marry that they are willing to assume the risk of infection. Such individuals should be examined very carefully at frequent intervals for evidences of syphilis. MORTALITY. As pointed out in Chapter II, the old adage that "syphilis never kills" is false. However, it is most difficult to determine the true case mortality of this disease. This is mainly due to the fact that in the majority of instances deaths only of such cases as exhibit outward manifestations of syphilis are reported as such, and the true state of affairs can be learned only when syphilis is ruled out absolutely as the cause of deaths in all cases, both by laboratory and clinical evidence antimortem, and by careful autopsy findings. Syphilis is essentially a chronic disease, and undoubtedly many cases which have been discharged from hospital or private practice as cured, or have passed from observation without being discharged are not cured, and perhaps years later develop visceral syphilis and die from its effects without a correct diagnosis being made. Ravogli^ states that of 7824 cases of syphilis in the Cincinnati City Hospital during the nineteen years between 1888 and 1906 there were but 168 deaths. This gives a case mortality of 2.14 per cent. The following table shows the number of cases of syphilis, the deaths and the case mortality of this disease in the Canal Zone during the seven years from 1907 to 1913.^ Case mortality. Year. No. cases. No. deaths. per cent. U907 245 2 0.8 1908 143 0.0 1909 168 0.0 1910 221 1 0.45 1911 340 1 0.29 1912 544 1 0.18 1913 570 3 0.52 These figures show little concerning the true case mortality of syphilis. The figures from the Bellevue Hospital, New York,^ probably come nearer revealing the true state of affairs. During 1911 in this institution there were 555 cases of syphilis and 44 deaths, giving a case mortality of 8 per cent, 1 Syphilis, New York, 1907, p. 147. 2 Annual Reports, Department of Sanitation Isthmian Canal, Comm., 1907-13. 3 Annual Report, Bellevue Hospital, New York, 1911. MORTALITY ' 183 It goes almost without saying that death due directly to chancre, the syphilodermata or the syphilomycodermata does not occur, although it is conceivable that death due to a superimposed bacterial infection acquired through these lesions might take place. In syphilis of some of the viscera and of the central nervous system it is different and deaths due directly to these conditions are more or less frequent. This will be fully discussed in Part II under the proper headings. CHAPTER IX. PROPHYLAXIS. The prophylaxis of syphilis presents one of the gravest problems before the medical profession today. And yet it is not altogether a medical problem; it involves the whole fabric of society, and its solution must rest upon sanitarians, sociologists, educators, and statesmen, as well as upon physicians. The prevention of syphilis is naturally divided into personal measures and public measures. PERSONAL MEASURES. As the majority of cases of syphilis are contracted through sexual intercourse, the first and most effective method of personal prophylaxis is the avoidance of sexual intercourse with anyone not absolutely above suspicion, in other woids, the avoidance of sexual intercourse out of the marriage bed. In our present state of social development this is of course an ideal which cannot be attained. So if men will indulge in ilicit intercourse, some method of prevent- ing the spread of venereal disease, and especially syphilis, must be adopted. It has been said that one who indulges his sexual passions illicitly deserves the penalty of venereal disease. This might be all well enough if the offender were the only one to suffer, but every syphilitic becomes at least a potential source of danger to many others. It is therefore the duty of physicians to prescribe prophylactic measures for patients who desire them. Probably the best and safest method of preventing the spread of syphilis through sexual intercourse is the use of the so-called "condom." This will prevent the spread of the disease from either party affected. Ablutions with antiseptic liquids such as weak solutions of potassium permanganate by both parties both before and after intercourse is also quite efficacious. One of the most widely practised prophylactic measures is the use of calomel ointment (calomel 20, lanolin 40) as advocated by Metchnikoff and Roux and proved by animal and human experi- mentation an absolute preventative of syphilis if used within one hour after inoculation and almost always a sure preventative if used within six hours after exposure. PUBLIC MEASURES 185 The thorough application of Neisser's paste to the parts within a few hours after intercourse is probably better. This paste has the following composition: Hydrarg. chlor. corrosivi 0.3 Sodii chloridi 1.0 Tragacanth 2.0 Amylum ■ 4.0 Gelatini 7.0 Alcoholis 25.0 Glycerini 17.0 Aquae q. s. ad 100.0 Circumcision has been advocated as a prophylactic measure for syphilis, but to the author's mind this seems a rather useless pro- cedure, as he has seen many chancres in the circumcised as well as in the uncircumcised. Purely as a measure of cleanliness and as a prophylaxis of masturbation in the young circumcision is highly to be recommended. The prophylaxis of genital and perigenital chancres not acquired through sexual acts rests upon care in using public toilets. Chancres of the lips, tongue, tonsil, etc., are to be prevented by avoiding promiscuous kissing, the use of eating utensils, drinking cups, pipes, etc., after others. Physicians could remove absolutely the danger of chancre of the fingers by the use of rubber gloves in all procedures in which there is any possibility of infection. And in fact if personal pro- phylaxis could be systematically employed, syphilis could be stamped out in a comparatively short time. It has been hoped that a vaccine or a serum might be found which would immunize the individual against syphilis. But up to the present time no such prophylactic has been produced, although it is well within the range of possibility. In fact Zinnser, Hopkins and McBurney^ have shown that the sera of rabbits and sheep immunized with cultures of Treponema pallidum acquire tre- ponemacidal properties for the cultivated organisms, although the normal sera of these animals possesses such properties but to a lesser degree. In a subsequent paper,^ however, it has been shown that immune sera exert practically no action upon virulent organ- isms obtained directly from lesions. Nevertheless these authors do not feel discouraged and state that the work is being continued. PUBLIC MEASURES. Regulation of Prostitution. — Prostitution is as old as civilization, and volumes have been written upon its social, its moral, and its medical aspects. It is not within the scope of this work to deal with prostitution in all its phases, nor to discuss the various methods 1 Jour. Exper. Med., 1916, xxiii, p. 323. 2 Ibid., p. 341. 186 PROPHYLAXIS of regulation which have been tried. But the author does wish to state that in his opinion some regulation of prostitution with regular medical inspection of prostitutes will greatly reduce the prevalence of syphilis. Americans are prone to turn their backs on the prob- lems of prostitution, to ignore its existence, and to consider its recognition by law as an admission on the part of the State that it cannot be eradicated. Therefore in most American cities prosti- tution is regulated by a system of fines and bribes, or "hush money" paid to the police for their protection, and no medical inspection is made. A number of cities have closed all houses of prostitution. This has undoubtedly but served to increase the amount of clandestine prostitution, and it is a well-known fact that syphilis is more pre- valent among this class of prostitutes than among the inmates of regular houses. If, however, the houses are in reality kept closed, this measure certainly diminishes the total amount of prostitution. Its effect upon youths is especially good, as not infrequently such are lead into beginning the practice of illicit intercourse by being taken to houses of prostitution by older men, and if there are no such houses, they cannot be taken to them. It is also a well-known fact that prostitution and the use of alcohol are closely interwoven, so to a considerable extent the problem of prostitution becomes the problem of prohibition. Education. — Education is a great factor in the prophylaxis of syphilis. Most youths when they begin a life of licentiousness do not realize the danger to which they are exposed. They have been told that a "dose of clap is no worse than a bad cold," and perhaps know nothing of syphilis. Further, they have been led to believe that sexual intercourse is a necessity to their health. If all the young men of the land could be taught that continence is entirely compatible with health, and that in indulging themselves they are being exposed to diseases which not only may cause them great suffering but may remain with them throughout life, and may lead them to an early death, a great advance in the prophylaxis of syphilis would have been made. This brings up the question of the best means of bringing about such education. Should young men be taught sex hygiene in the home, in the school, by the church, or by the family physician? It seems to be the consensus of opinion of the majority of workers along this line that the home is the proper place for such knowledge to be taught. However, with the vast majority of parents, even if they do recognize the need, this is no easy matter, and they must be taught the impor- tance to the child of such instruction and how best to impart it. This could readily be accomplished by public lectures or visits to the home by district nurses. There are also many pamphlets and books dealing with these problems which could be circulated. PUBLIC MEASURES 187 Education alone will not solve the problem of the prophylaxis of syphilis, at least there are other means at hand which can be employed which would stamp out the disease long before all the young men of the land could be taught the folly of illicit intercourse and be persuaded to refrain from indulging in it. Legislation. — The segregation of all syphilitics during the infective stage would, of course, stamp out the disease, but in our present state of social development this is impossible. Syphilis, however, should be made a reportable disease, and a severe penalty should be imposed upon physicians for not reporting cases. Wassermann surveys of the inmates of all prisons, eleemosynary institutions, etc., should be made. All immigrants should be care- ully examined for evidence of syphilis, including a Wassermann test, and if found luetic, should be denied entrance to the country. All applicants for civil service positions should be compelled to have Wassermann tests, and if found positive should not be given employment. From this it would not be a far cry to persuading employers in all lines to compel their employees to present a clean bill of health in regard to syphilis. A marriage license should not be granted to anyone without a thorough physical examination and a negative Wassermann reac- tion showing the probable absence of syphilis. These examinations should be made by the city or county physicians, and for a nominal charge. When prostitution is permitted at all it should be under strict surveillance and regular medical inspection, including a Wassermann reaction of all prostitutes, should be made. By these procedures, especially making syphilis a reportable disease, it would not be long before the health authorities would have a fairly complete knowledge of the prevalence of syphilis in a given community. With this accomplished all syphilitics should be forced to take treatment, from private physicians if they prefer or from the city or county physicians, until they are cured. The standard of cure should be fixed by law arid all patients compelled to conform to it. A severe penalty should be imposed on those failing to report for treatriaent. During the time when infection through intermediate contact is most likely to occur, all patients whose employment makes them especially dangerous to others should be compelled to stop work. This in the majority of cases would not be for long. The author is aware that such drastic procedures as have been outlined would be extremely costly, but the benefit to be derived could not be estimated in dollars and cents. Undoubtedly if such methods were employed, in a few years syphilis would be as rare as smallpox, and eventually be wiped off the face of the earth. CHAPTER X. TREATMENT. With a disease so protean in its manifestations as syphilis it may well be said that each case is more or less of a law unto itself. Therefore, as no two cases are exactly alike the treatment must be made to conform to each individual case. There are, however, certain general factors which enter into the management of all cases. The treatment of syphilis may be divided into general, specific, and symptomatic. GENERAL TREATMENT. Hygienic. — The importance of the hygienic treatment of syphilis is hardly to be overestimated. Too many physicians are prone to rely solely upon the specifics and totally disregard hygienic measures. The author does not wish to minimize the importance of the syphilitic specifics, for without them syphilis could not be cured; but he does wish to emphasize the importance of proper hygiene in the control of this disease. It goes almost without say- ing that sanitary surroundings are most desirable for all syphilitics, and the author is of the opinion that hospitalization is to be recom- mended when possible. Not only should the surroundings of the syphilitic be sanitary, but they should be pleasant and congenial. The life of the syphilitic should be very regular; regular sleep, regular meals, a certain amount of regular exercise, depending upon the individual, should be insisted upon. He should not overwork, and above all he should not worry. He should have plenty of diversion, with outdoor exercise, such as golf, when not contra- indicated. The use of alcohol in any form should be totally interdicted, and the patient should be warned that even small amounts are detri- mental In fact, it is probably better for the syphilitic to get com- pletely intoxicated once or twice a year and totally abstain in the meantime than to drink even very moderately all the time. The use of tobacco is to be curtailed as much as possible, especially should this be done in cases with lesions of the mouth and throat. The syphilitic should be warned against sexual excesses, and of course during the infective stages should not be permitted to indulge his sexual appetite under any circumstances. GENERAL TREATMENT 189 Dietetic, — Little can be said concerning the dietetic treatment of syphilis, as no special diet is required except in gastric and intestinal syphilis, and perhaps in syphilitic nephritis. Certain general rules, however, should be followed. Overeating certainly should not be indulged in, and the quality of the food should be good. Hydrotherapeutic; — ^Almost from time immemorial, baths, espe- cially baths in water from natural hot springs, have had a great reputation in the treatment of syphilis, and many syphilitics have journeyed each year to the great watering places of the world, especially Aix-la-Chappelle in Europe and the hot springs of Arkansas in this country. The latter have probably held the fore- most place both in the minds of the laity and medical profession as a mecca for syphilitics in America. The hot springs of this resort are located upon the United States Government Reservation, and the use of the water from them is controlled by the Department of the Interior. The water from the springs varies in temperature from 35.2° C. (95.4° F.) to 63.9° C. (147° F.), and according to the analyses made by Haywood^ the chemical composition of the water from the various springs is practically the same. The following are the figures for the so-called Big Iron Spring, the largest of the group, which has a flow of 201,600 gallons per day. Parts per Million. Si02 45.59 SO4 . 7.84 HCO3 168.10 NO3 0.44 NO2 0.0016 PO4 0.05 As04 None BO2 1.29 CI 2.53 Br ' trace I w trace Fe Al / 0-1^ Mn . . . • 0.34 Ca 46.93 Mg 5.10 K 1.60 Na 4.76 Li trace NH4 .' . . . 0.04 Boltwood^ found that the waters from the hot springs as well as those from one of the cold springs of the vicinity possess con- siderable radio-activity, the highest amount found being 265 Mache 1 Analyses of the Waters of the Hot Springs of Arkansas, Washington, 1912, p. 34. 2 Am. Jour. Med. Sc, 1905, xx, p. 128. 190 TREATMENT units. This amount, according to Hammeter and Zueblin/ is higher than that recorded for any other spring in this country. The benefits to the syphiHtic derived from a sojourn and a course of treatment at Hot Springs have variously been ascribed to a specific action of the waters, both as baths and taken internally, to the greater elimination produced, to stimulation, to the routine life, and to the effects of the salubrious climate. The alleged specific effect of the waters has been said to be due to some peculiar chemical combination of the solids in solution, to electricity pro- duced by chemical decomposition, to a peculiar heat with which they are imbued, and latterly to the radio-activity which they have been shown to possess. Keyes^ says of the Arkansas hot springs: "The hot springs of Arkansas require a word of serious comment here. That they have a positive value, I am sure. I visited the springs a few years ago and remained there long enough to see their workings. I have sent many patients there, have deterred many others from going, and seen patients in all stages of syphilis who had been to the springs before their first visit to me. From such premises I think I may reach conclusions which shall be reasonably just. The physicians who practise at the springs are not in accord as to the special property of the waters which gives them their value. Some think that the water is like any other hot water, and that patients do well at the springs simply because they come there determined to take care of themselves and to make the treatment of their malady their first object. True it is that the waters are almost void of any mineral ingredient. The waters of the so-called Old Iron Spring (I think it is called so because the house erected over it is made of corrugated iron and not because of the iron in its water) deposit a tuft which clings in masses to the hill out of which the spring flows, but I am informed that the actual mineral contents of the water is only about eight grains to the gallon, which is practically nothing. Lime seems to be the main ingredient. The water of this spring is used at the main hotel of the place for drinking water, and it is as pure, bright, sparkling, and tasteless as any water I have ever seen. Taken cold, it certainly has no obvious effect; taken hot, it is diuretic and diaphoretic more positively than ordinary hot water. It does not nauseate. "Others of the local physicians impute the effect of the waters to something sui generis in the quality of the heat they contain; others to electricity, in which also the water is said to abound. My own investigations showed me that a foot-bath at 110° F. was 1 Arch. Int. Med., 1915, xv, p. 188. 2 The Surgical Diseases of the Genito-urinary Organs, Including Syphilis, New York, 1894. p. 553. GENERAL TREATMENT 191 impossible. The feet could not possibly be retained in water of that temperature, a thing perfectly possible (but not pleasant) at home in croton water. A thermometer held in the mouth while making the attempt to take this foot-bath was raised to 103° F. An ordinary bath at 98° F. was unpleasantly hot and caused the perspiration to trickle from the face in streams. The immediate after-effect of the bath (unlike that of an ordinary hot bath) is one of exhilaration, followed in a couple of hours by reaction and a desire to sleep. The immediate effect of the water I found to be stimulating, not soothing. An inflamed joint soaked in this water is harmed by it and the pain intensified, contrary to what is expe- rienced with ordinary hot water; acute eruptions are said to be aggravated by the water. This I did not personally have an oppor- tunity of testing except in a case of generalized eczema, which certainly was aggravated at the hot springs, and began to get well at the (cold) sulphur potash spring a few miles away. Old chronic ulcers, whether scrofulous, syphilitic, or accidental, are stimulated promptly into granulation by the local effect of these waters. The appetite improves under their use and the ordinary functions seem to be performed better than when they are not used by the visitors to the place. The uterine function seems to be stimulated by the baths, and stories of a return of menstruation after the change of life, of impregnation after long sterility, and the like, are told by the natives. Paralytics, and people recovering from apoplexy, seem to thrive at the springs. "But all this is not the cure of syphilis, and my observation showed me plainly that the physicians who did well at the springs used most unsparingly mercury by inunction and iodide of potas- sium internally in enormous doses. And this is exactly wherein the value of the springs seems to lie. Patients broken down, cach- ectic, with faulty stomachs, who have syphilitic lesions which fail to yield at home because they cannot tolerate a sufficiently high degree of medication, these are the patients to send to the hot springs. There, under the assistance of the hot water internally and the baths, they can take a mercurial friction day after day, without salivation, which would overwhelm them at home, and their doses of iodide of potassium can be quadrupled without upsetting the stomach. I have verified this over and over again. This is the only class of patients I ever send to the springs — those requir- ing stiff medication for serious lesions who cannot at home be made to tolerate a sufficiently high dose to pull them through. "I could multiply illustrative cases of this order almost indef- initely. One patient, several years ago, I sent to the springs under escort of a nurse and a relative. He had been going persistently out of his mind while under my treatment and that of several other physi- 192 TREATMENT cians. He had had several hemiplegic attacks, serious ocular troubles, aphasia, double vision, and mental derangement. His mind was useless for all purposes and he was obliged to give up busi- ness entirely. No efforts of mine or others could by any of the adju- vants, belladonna, arsenic, milk, carbonated water, alkaline water, get the daily dose of this patient above 300 grains of the iodide of potassium — and his symptoms were gradually gaining upon him until his case seemed hopeless. Then he went with difficulty to the springs, and there, with no aid beyond the use of the waters, his daily dose of the iodides was run up to 800 grains, and under this he recovered, and by after-treatment at home became able again to resume his business. I have had a number of cases of this sort, and, particularly when the brain and cord are seriously involved, I advocate the hot springs at any price in money, time, or comfort. It is certainly worth while. But for ordinary syphilis I do not consider the springs of any value. They do not shorten the duration of the disease, prevent relapse, or cure it in any sense. The lesions of early syphilis disappear rapidly under the heavy medication administered at the springs, but I do not think there is any special value in this, because it makes the patient less willing to take prolonged continuous treatment, in which alone, in my opinion, lies his best hope." White^ has this to say concerning the class of patients who should be sent to the hot springs: "1. The patients whose mode of life is objectionable and who cannot be controlled while under home or other customary influ- ences. This includes not only the large class of hard drinkers, who are apt also to use tobacco too freely and to indulge in various other excesses, but also the much smaller class whose excessive devotion to work or business interferes with their general health and lessens their strength and vitality. "2. Patients whose symptoms resist full doses of the specific drugs and who are unable to take larger doses without a break- down of the digestive apparatus, or the production of mercurial or iodic intoxication. Those especially should be sent who have involvement of the viscera and still more particularly if the brain or spinal cord is affected. "3. Patients who with syphilis have intense syphilophobia and require the mental impression, and in addition the tonic influence of change of scene and climate. "4. Patients with defective elimination or with marked idio- syncrasy as regards either mercury or the iodides." 1 Morrow: System of Geni to-urinary Diseases, Syphilology, and Dermatology, New York, 1898, ii, p. 786. GENERAL TREATMENT 193 Fordyce, who resided in Hot Springs for three years, says in part as quoted by White :^ " It would be quite rational to suppose that the increased tissue change which hot baths are known to produce could be utilized to advantage in combating a new growth of such unstable character as the neoplasms of syphilis; and, in fact, the last stages of the disease seem to be especially benefited by the use of the baths in connection with specific remedies. How much of the cure depends upon the increased power of digestion and assimilation caused by the change of air, scene, and diet, and how much on the baths, is difficult to say. I have seen, however, patients in a profound state of cachexia from old syphilis improve rapidly at the springs, patients who had been in charge of competent physicians at home, and who had taken mercury and iodide of potassium to the limit of tolerance." From the above it would seem that there is no doubt of the benefit to the syphilitic derived from a sojourn and course of treatment at Hot Springs. That the waters of the hot springs possess any specific action on the Treponema pallidum the author does not believe. It is a fact, however, that patients bathing in these waters are able to take much more mercury without any untoward effects than others. It is furthermore highly probable that some of the benefits derived are due to increased elimination of the products of catabolism. To these benefits derived from the increased ability to take mercury and the increased elimination must be added the benefits derived from the regular life the patient usually leads, the outdoor exercise, the freedom from business cares and worries, and finally, the fact that the average patient who comes to this or any other resort follows the physician's directions more implicitly than when at home; in short, makes a business of getting well. While each case of syphilis is a law unto itself in regard to bathing as well as in other features, the following may be said to be fairly representative of the usual method of administering the baths to syphilitics in this resort: The patient is placed in a tub of the hot water at a temperature of 35.5° C. to 38° C. (96° F. to 100° F.) where he remains from eight to fifteen minutes. When free diaphoresis is desired he is placed in a hot wet pack and covered with blankets for fifteen to thirty minutes, and when more profuse sweating is wanted the vapor cabinet is used for three to five minutes Usually in the tub and in the pack the hot water is taken to drink to assist in promoting diaphoresis. Generally following the pack a shower and needle 1 Morrow: System of Genito-urinary Diseases, Syphilology, and Dermatology, New York, 1898, ii, p. 788. 13 194 TREATMENT is given for two or three minutes beginning at a temperature of 38° C. (100° F.) and being reduced to 32° C. or 27° C. (90° F. or 80° F.) . Following this the patient sits or lies in the cooling room until cool and the skin is dry. Ordinarily the patient spends from one and a half to two and a half hours at the bath house. Tonic. — A great many syphilitics are more or less cachectic and anemic, and quite frequently need tonic treatment. It is also true that following a severe course of treatment, patients are some- times found to have lost weight and are greatly benefited by tonics. The author has been in the habit of prescribing in such cases a tonic similar to the following: I^ — Tinct. nucis vom 45 . Tinct. cardamom, comp., Glycerini aa 90.0 Aquae q. s. ad 240.0 M. et Sig. — From one to two teaspoonfuls in water before each meal. SPECIFIC TREATMENT. There are two known specifics for syphilis, mercury and arsenic, and according to some a third, iodin. Mercury. — According to Buret^ the Chinese as far back as 2637 B.C. prescribed mercurial frictions in the treatment of syphilis. Whether or not this is true, it is a fact that Fracastor^ wrote in 1530 concerning the use of mercury in syphilis as follows: ''As a fact, the action of mercury on the scourge is marvelous, either because its natural affinity for heat and cold renders it proper to absorb the devouring fire of the disease; or, because its surpris- ing density permits it to divide and to dissolve the humors for a reason that is analogous to that which gives to incandescent iron a caustic action more marked than that of a light flame; or that its mobile and penetrating molecules, apt to infiltrate themselves in the warp of tissues, have the power of pursuing and consuming even to the bottom of organs the impure yeasts of the disease; or finally that its magic virtues are derived from some occult force whose mystery escapes us." From the day of Fracastor to now mercury in some form or other has been used in the treatment of syphilis, and in spite of the newer arsenic preparations has held its own with the vast majority of physicians as a specific. Methods of Administration. — Mouth. — Probably the most fre- quently used method of administering mercury is by mouth, and it is also the easiest and most convenient method. Numerous 1 Syphilis in Ancient and Prehistoric Times, American edition, Philadelphia, 1891, p. 61. 2 Syphilis, St. Louis, 1911, p. 35. SPECIFIC TREATMENT 195 preparations of mercury have been used in this manner, the principal ones of which are the gray powder, the protiodide, the bichloride, blue pill, and calomel. Gray Powder (hydrargyrum cum creta) is employed most exten- sively in England and is usually prescribed in the form of a pill of 0.065 gram (1 grain). Numerous schedules for its administration have been used, but the one adopted by the Royal Army Medical Corps^ seems to be the most popular. This plan of treatment covers a course of nearly two years, and is as follows: First course: Months. Pills. One month, taking six pills a day 1 180 Interval of three days without taking pill. One month, taking four pills a day ...... 1 120 Interval of seven days. One month, taking three pUls a day ' 1 90 Interval of one month 1 Second Course: Three months, taking three pills a day 3 270 Interval of one month 1 Third Course: Three months, taking two pills a day 3 180 Interval of one month 1 Fourth Course: Three months, taking one pill daily ...... 3 . 90 Interval 6f three months 3 Fifth Course: Three months, taking one pill daily 3 90 21 1020 Protiodide {hydrargyrum iodidum viride or hydrargyrum iodium fiavum). — This is the form of mercury most frequently employed in France as well as in this country for internal administration. It also, as a rule, is given in pill form and in doses of 0.008 to 0.05 gram (| to f grain) after each meal. In the rare cases in which the author prescribes mercury by mouth the usual dose is 0.016 gram (| grain). In weak, debilitated individuals and in women this may be too large a dose, while men of robust constitution may be able to stand as much as 0.05 gram (f grain). However, it is always well to start with the smaller doses. If after a few days no evident improvement has taken place and no untoward effects are noted the dosage may gradually be increased every two or three days by 0.004 to 0.008 gram (xg- to | grain) until the maximum dose of 0.05 gram (| grain) is reached, or until improvement is seen when the dose may remain stationary until toxic effects are noted. Bichloride {hydrargyrum chloridum corrosimim) is seldom used alone, owing to its toxic effect and irritative action on the mucous 1 Power and Murphy: System of Syphilis, London, 1909, ii, p. 190. 196 TREATMENT membranes of the mouth and throat. It is very frequently pre- scribed with small doses of opium and usually forms the mercurial portion of the so-called mixed treatment to be described later. The continued use of opium with mercury is never to be recom- mended, as there is too much danger of the opium habit being formed. Ravogli^ recommends very highly the so-called Liquor of Van Swieten which has the following formula: I^ — Hydrarg. bichlorid. corros 0.90 Alcohol 96.00 Aq. destillat 928.00 This he prescribes in tablespoonful doses, well diluted in water after breakfast, and after the evening meal, thus giving the patient 0.025 gram (| grain) of the bichloride per day. Ravogli claims never to have seen any untoward effects of this medication. Blue pill {inassa hydrargyri) has had considerable vogue in the treatment of syphilis. It usually is prescribed in 0.065 gram (1 grain) doses, but owing to its great tendency to produce ptyalism has little to recommend it. Calomel (hydrargyrum chloridum mite) while formerly extensively employed in the treatment of syphilis is today rarely if ever administered by mouth as a specific in this disease. Other forms of mercury which are sometimes administered by mouth as mentioned by Lambkin^ are the tannate, the corbolate, the peptonate, the salicylate, the acetate, the sozoiodolate, and mercuric cholate. Inunctions. — The use of mercury by inunction is probably the oldest method of administering this drug in the treatment of syphilis. As pointed out above, Buret^ states this procedure was employed by the Chinese as far back as 2637 B.C. Be that as it may, there is no doubt but that it was employed in Europe at an early date, as the writings of the physicians of the sixteenth century abound in references to the use of mercurial ointments, and although this method of treating syphilis fell somewhat into disrepute, it was revived from time to time and today constitutes one of the most frequently used methods of administering mercury. The preparation most generally employed is the official blue ointment (unguentum hydrargyrum), although various substitutes have been used, such as unguentum cinereum, vasogen mercurial ointment, etc. The average amount used for one treatment is 4 grams (1 dram) 1 Syphilis, New York, 1907, p. 188. 2 Power and Murphy: System of Syphilis, London, 1909, ii, p. 193. ' Syphilis in Ancient and Prehistoric Times, American edition, Philadelphia, 1891, p. 61. SPECIFIC TREATMENT " 197 and the rubbing can be done either by the patient himself or by another. As usually prescribed the patient is instructed to take a hot bath before retiring, or if this is impossible the portion of the body which is to be rubbed is washed with soap and water and carefully dried. The ointment is then smeared on and thoroughly rubbed into the skin with the hands, using a circular movement for twenty to twenty-five minutes. When the rubbing is complete most of the ointment should have disappeared. Following the inunction the patient puts on a shirt or pair of drawers, depending upon the part rubbed, which he uses continuously for a week, and over this his regular sleeping garments. Each physician usually has his own schedule for the part selected for the rubbings, although the order is immaterial. The following schedule is very satisfactory: First night. Inner surfaces of right thigh. Second night. Inner surface of left thigh. Third night. Inner surface of right arm. Fourth night. Inner surface of left arm. Fifth night. Abdomen. Sixth night. Right side of thorax. Seventh night. Left side of thorax. This schedule is then repeated as frequently as necessary. As employed in Hot Springs inunctions are, as a rule, given by a professional "mercury rubber," who uses a rubber mit or a mechanical apparatus, and the back is always the seat of the application. (See Fig. 72.) The blue ointment is prescribed in what are locally known as "fours," "sixes," "eights," etc., and signifies that one ounce of the ointment is divided into four, six, or eight equal parts, one part being used for each inunction. The patient usually takes his bath some time after breakfast then repairs to the "rubbing parlor," where the inunction is given. The patient sits astride a chair facing the back, folds his arms on it and places his chin on his arms, the rubbing continuing for twenty to twenty-five minutes. He then puts on a thin undershirt, which is used as a "mercury shirt" for one week without change, the inunction usually being given daily. The treatment, as a rule, is continued until signs of ptyalism are noted. Plasters. — ^IVIercurial plasters of various kinds have been employed, probably the most famous being the emplastrum de Vigo invented by John of Vigo. This was a complicated mixture containing as well as the mercury such ingredients of witchcraft as fat of the viper, frogs, and worms^ to which latter were principally ascribed the beneficial results. 198 TREATMENT Quinquad/ in 1890, proposed a plaster with the following formula: Emplast. diachyli. 3000 parts Hydrarg. chloridi mite 1000 " 01. ricini 300 " For its general effect this was applied on linen, usually over the spleen and locally to various lesions. Fumigation. — The treatment of syphilis by mercury vapor for- merly was employed quite extensively, but is little used today, except in the local treatment of some of the syphilodermata. The method consists of covering the body, with the exception of the head, with a specially devised cabinet or tent or with blankets, the patient sitting on a cane-bottom chair. The mercury, usually calomel, is then burned by placing it over an alcohol lamp. The heat from the lamp soon excites perspiration and the vapor of the calomel clings to the body. The treatment is usually continued twenty minutes, with the lamp burning and ten minutes allowed for cooling after the lamp is extinguished. Hypodermic. — Hebra,^ in 1861, probably was the first to employ hypodermic injections of mercury in the treatment of syphilis. This investigator used injections of the bichloride and treated two patients. In 1864 Scarenzio^ reported the use of calomel in this manner, while Berkley Hill,* in 1863, reported the injection of eleven cases with bichloride. It was not, however, until after the appearance of Lewin's^ work, in 1869, that the hypodermic treatment of syphilis became at all popular. Since that time this method of medication has been used most extensively, and many different preparations of mercury have been employed. It will be impos- sible even to mention all of the preparations of mercury which have been recommended for hypodermic use in the treatment of syphilis, but the most important ones will be described. At first the injections were all given subcutaneously and some- times frightful abscesses followed, but according to Lambkin,^ Balzer, in 1888, pointed out the advantages of deep intramuscular injections, and since that time this method has grown in favor until today it is practised almost to the exclusion of the subcutaneous route. The preparations of mercury used for the hypodermic treatment of syphilis may be divided into the soluble preparations and the insoluble preparations. 1 Bull. Soc. franc, de dermat. et de syph., 1890, p. 63. 2 Allgemeine wiener med. Zeitung, 1861, No. 30. 3 Annali di Medicina, August and September, 1864. 4 Lancet, 1866, i, p. 498. 5 Behandlung der Syphilis mit subcutanen Sublimat-injectionen, Berlin, 1869. 8 Power and Murphy: System of Syphilis, London, 1909, ii, p. 281. SPECIFIC TREATMENT 199 Insoluble Preparations. — Metallic mercury was first used by Furbringer/ in 1879, who used a mixture of metallic mercury, 2 parts; mucilage of acacia with glycerin, 10 parts. While this method was given a trial by some other investigators, by most of them it received but scant approval. Gray oil {oleum cinereum), which is in reality a preparation of metallic mercury, was introduced into the therapy of syphilis in 1884 by Lang.^ According to this author the preparation of gray oil is as follows: A certain amount of lanolin is dissolved in a large quantity of chloroform and while still in the fluid state double the quantity of metallic mercury is added and thoroughly triturated. During the latter process the chloroform evaporates, leaving the so-called unguentum cinereum lanulatum forte, which as will be seen, is an ointment consisting of two parts of mercury and one part of lanolin. By adding 1 part of olive oil or liquid paraffin to 3 parts of this basic ointment the 50 per cent, oleum cinereum is prepared. This contains 0.81 gram per cubic centimeter and is given in doses of 0.05 c.c. or 0.04 gram of metallic mercury. The "course" as recommended by Lang consists of eight to twelve doses given at first every second or third day but later, as improvement is noted, every five or eight days. The oleum cinereum should be kept in a wide-mouthed, glass- stoppered bottle and in a cool place, and when used is warmed and thoroughly shaken. Lambkin's Mercurial Cream. — This preparation of metallic mer- cury proposed by Lambkin^ has the following formula : Hydrargyrum pur 10 grams "Creo-camph." equal parts Solute creosote and camphoric acid 20 c.c. Palmitin basis to 100 c.c. Each cubic centimeter of this preparation contains 0.1 gram of metallic mercury or 10 minims contain 1 grain. According to Lambkin, injections are to be made on an average of once a week in doses of 10 minims. Calomel. — This salt of mercury was, as stated above, one of the first to be used hypodermically in the treatment of syphilis. Scarenzio employed it suspended in glycerin or mucilage of acacia and injected 0.4 gram (6 grains) in two doses, eight, ten, fourteen, or twenty-one days apart, and considered this amount sufiicient 1 Deutsch. Arch. f. kHn. med., 1879, xxiv, p. 129. 2 Stedman: Twentieth Century Practice of Medicine, New York, 1899, xviii, p. 312. ^ Power and Murphy: System of Syphilis, London, 1909, ii, p. 292. 200 TREATMENT for a cure. The injections were almost invariably followed by abscesses, but apparently were not considered serious. Lambkin^ has proposed a preparation containing calomel similar to his mercurial cream, which has the following formula: Calomel 5 grams "Creo-camph." 20 c.c. Palmitin basis to 100 c.c. It will be seen that each cubic centimeter of this preparation contains 0.05 gram of calomel while 10 mininis contain ^ grain. The dose recommended is 10 to 15 minims once a week for not more than four wrecks in succession. The salicylate has been employed quite extensively both by mouth and by hypodermic injection. When administered hypo- dermically it is usually suspended in some oily liquid. Candler^ proposed the following formula, which has given excel- lent results in the hands of the author: 10 per cent, mercury salicy- late in albolene oil, plus 1 grain of novocain to the ounce. The dose is 1 c.c. which contains 0.1 gram (1| grains) of the mercury and 0.002 gram (^ grain) of the novocain. The author 'RTites the following prescription for this preparation: I^ — Hydrarg. salicylat 3.0 Albolin (sterUized) ■" 30.0 Novocaiu 0.065 Other Tnsoluhle Preparations. — Numerous other insoluble prepa- rations of mercury have been recommended from time to time for the treatment of syphilis, and usually have been heralded by their exploiters as superior to all others. The most important of these are the yellow oxide, the black oxide, the yrotoiodide, the thymolace- tate, the tannate, the sulphate, the yelloio sulphate, and the red sulphate Soluble Preparations. — The bichloride, as stated above, was probably the first preparation of mercury to be administered hypodermically, and is also the most extensively used of the soluble salts in the treatment of syphilis. It is usually given in doses of 0.005 gram (yj grain) to 0.048 gram (f grain) daily or every other day. The following prescription, each cubic centimeter of which contains 0.02 gram (y% grain), may be used: IJ — Hydrarg. chlorid. corrosiv. 2.0 Sodii chlorid 1.0 Aquae destillat 100.0 1 Power and Murphy: System of Syphilis, London, 1909, ii, p. 294. - Jour. Michigan Med. See, 1915, xiv, p. 225. SPECIFIC TREATMENT 201 The henzoate is only slightly soluble in water, but upon the addition of sodium chloride readily dissolves. This preparation was first used by Stukobenkoff/ and has been employed quite exten- sively since. The author uses the following formula, which has proved very satisfactory: I^ — Hydrarg. benzoat 2.0 Sodii chloric! 2.-5 Aqu£e sterilat 100.0 The initial dose is 0.5 c.c, which contains 0.01 gram (^ grain) of the mercury. The succinimide is one of the most popular of the soluble salts of mercury for the hypodermic injection in syphilis. It is readily soluble in water and is procurable in convenient tablet form from the various pharmaceutical houses. The usual dose is 0.013 gram (i grain), is given daily, and may be increased as high as 0.05 gram (4 grain) . To overcome the pain which sometimes is observed following the injection of the succinimide the author has been in the habit of using a solution of this salt to which has been added 0.5 per cent, of beta-eucaine as follows: I^ — Hydrarg. succinimid 2.6 Beta-eucaine 0..5 Aquse 100.0 It will be seen that each \ c.c. contains 0.013 gram (4 grain) of the salt, which is the usual dose, but which may be increased to 2 c.c The hiniodide {hydrargyrum iodidum riihrum). — According to Power- this preparation of mercury was first used by Panas in the proportion of 4 cgms. of the salt to 10 c.c. of sterilized oil. It is also prepared under various proprietary names and has given verv' good satisfaction in the hands of the author. The cyanide, which has been employed quite extensively, was introduced as a hypodermic injection for sj'philis by Cullingworth.^ It is usually prescribed with some form of analgesic, such as' cocain, acoin, beta-eucaine, etc. The technic of administration is the same whether the soluble or insoluble preparations are used. An all-glass syringe is much to be preferred, and either a gold or a platinum-iridium needle is desirable, as steel needles are amalgamated by the mercury. The needle should be sharp, as there is much less pain when a sharp 1 Vrac, 1884, iv, p. 9.3. 2 System of Syphilis, London, 1909, ii, p. 2-3.5. 3 Lancet, 1874, i, p. 653. 202 TREATMENT needle is used than accompanies the use of a dull one. The size of the needle should not exceed 20-gauge and for the soluble mercury salts in watery solution a much smaller needle may be used. The length should be about. 5 cms. (2 inches), and longer for very fleshy individuals. If the syringe is used for nothing but the hypodermic injections in the treatment of syphilis and the same mercurial preparation is employed, it is not necessary to sterilize it between injections if it is kept where it will be free from dust. The needle, however, should be sterilized before and after each injection. The site of injection is usually the buttock, although the pectoral, the deltoid, or the muscles of the interscapular region may be employed. The injections are to be given on alternate sides of the body, and about' 2 cm. should separate the injections on the same side. It is imperative to avoid piercing important structures, so the actual site of injection should be chosen with care. Galliot's rule is the simplest guide for injections in the buttock. A line is drawn vertically at the junction of the inner and middle thirds of the buttock, while another line is drawn horizontally two finger- breadths above the top of the great trochanter. The intersection of the two lines and points above and to the outer side of it may be used with impunity. The injections may be made with the patient standing or lying. The site of injection should be painted with iodin and the needle plunged directly into the muscle with a swift stroke. When the needle is in position the plunger of the syringe is withdrawn slightly to ascertain if a vein has been pierced. If such is the case, blood will appear in the syringe and the needle should be withdrawn and a new site selected. If no blood is seen, the dose is slowly injected and the needle withdrawn with a swift jerk, to avoid leaving any of the mercurial preparation, which may have remained in the needle, in the subcutaneous tissues. The author massages the spot gently for two or three minutes, which assists in the absorption of the mercury (if a soluble salt) and renders the pain less severe. Usually no dressing is necessary, although a drop of collodion may be applied. Comparative Value of Various Preparations. — The insoluble prepa- rations of mercury are to be desired in certain cases, owing to the infrequency with which it is necessary to administer them, thus making the visits to the physician less frequent. Of the insoluble preparations, calomel is the most efficient, but causes more pain than the gray oil. Lambkin's preparation of calomel, however, may be injected with comparative freedom from pain. The injec- tion of the salicylate prepared after Candler's formula also usually is practically painless. SPECIFIC TREATMENT 203 The disadvantages of the insoluble preparations of mercury lie in the danger of them causing embolism and mercurial poisoning from accumulation and that their action is slower than that of the sol uble preparations. The former should not occur if the precautions outHned above in the technic of injection are observed. The pre- vention of mercurial poisoning by the injection of the insoluble preparations of mercury is sometimes impossible, as the drug is so slowly absorbed that a large quantity may be left at the site of injection after the beginning of symptoms and can be removed only by excision. This is a difficult and serious procedure, and is to be recommended only in case of the most urgent nature. Recent experiments^ seem to show that the salicylate, at least, has little or no effect on the Wassermann reaction even when given over a considerable period of time, and to the point of tolerence, although active manifestations of syphilis may disappear under its use. The advantages of the soluble preparations of mercury are that they are usually less painful than the insoluble, that their action is quicker, owing to the fact that they are more readily absorbed, thus reducing the danger of mercury poisoning to a minimum; and when the latter does occur it can be stopped much more readily than when the insoluble preparations are used. The disadvantage of the soluble preparations is that they must be given more frequently. In the author's practice, which consists almost entirely of visitors to Hot Springs who come here with the sole object in view of getting well, the soluble preparations are invariably used, for it has been found that the majority of patients much prefer to visit the physician daily for their injections. They also want as quick results as possible, and as the soluble preparations act more quickly than the insoluble ones, the former are employed exclusively. The choice of the various soluble preparations is largely a matter of personal preference, although undoubtedly some of the salts are more toxic than others, depending upon the actual mercury content. It sometimes happens that with one salt the patient complains of more pain than with another, so it may be advisable to change if much pain is complained of. The salt most frequently employed by the author is the benzoate in the formula given above. This preparation rarely causes pain, produces quick results, and is only slightly toxic. The succinimide and the cyanide formerly were used by the author quite extensively, but he found a considerable number of his patients developed a slight nephritis after only a small quantity had been administered. 1 See page 243. 204 TREATMENT This untoward effect has been observed with benzoate in but one case, and this only after 0.4 gram (6 grains) had been given. Intravenous. — This method of administering mercury in syphihs was first practised by Bacelli^ in 1893, and has been used by many other investigators. In this country, Bernart,^ Crume,^ Lydston,^ Kingsbury and Bechet,^ Stukes,^ and others have practised this method with more or less success. However, it never has come into general use, owing probably to the comparative difficulty of the technic. The bichloride is the most frequently used salt, and is given in doses varying from 0.005 gram (yV grain) to 0.045 gram {-j-o grain). The cyanide, the biniodide, the benzoate, and sublamine have also been used. The usual method of procedure is to dissolve the salt in 5 to 12 c.c. of freshly distilled water, or in a like amount of normal salt solution, and inject directly into one of the veins of the elbow by means of a hypodermic syringe and needle. Most of the investigators using this method have reported more or less phlebitis and periphlebitis, even to the extent of obliteration of the vein. The author has overcome this to a certain extent by using two 20 c.c. syringes and the specially constructed three- way cock devised for the administration of neosalvarsan in con- centrated solution^ (see Fig. 54), and following the injection of the mercury with 10 to 15 c.c. of normal salt solution. Even with this precaution these unpleasant results sometimes follow. However, the author has been able completely to eliminate phlebitis by inject- ing mercurialized serum. This was suggested by Byrne's^ article on the intradural administration of mercurial serum in the treatment of cerebrospinal syphilis. The method of procedure is as follows:^ From 40 to 50 c.c. of blood are collected by venipuncture and placed in a large test- tube which has been autoclaved. After separation the serum is poured off and thoroughly centrifugalized. A watery solution of mercuric chloride is prepared so that each cubic centimeter con- tains 22 mgs. (§ grain) of the salt. The serum is now measured and divided into two parts, one-third of the amount placed in one tube and the remainder in another. The mercury solution is added to the first part in the proportion of 1 c.c. to each 2 c.c. of serum. A heavy precipitate of albuminate of mercury appears which is completely dissolved on the addition of the remainder of the serum. 1 Gaz. Med. Roma. 1893, xix, p. 241. 2 New York Med. Jour., 1909, xc, p. 693. 3 Jour. Am. Med. Assn., 1909, li, p. 2155. 4 Ibid., 1907, xlix, p. 1662. ^ Ibid., 1914, Ixiii, p. 563. s .Jour. Med. Assn., Georgia, 1915. ^ Thompson: Jour. Cut. Dis., 1915, xxxLii, p. 631. 8 Jour. Am. Med. Assn., 1914, Ixiii, p. 2182. 9 Thompson: Ibid., 1915, Ixiv, p. 1471. SPECIFIC TREATMENT 205 It will be seen that the mixtiy-e contains 22 mgs. (| grain) of mercuric chloride in each 7 c.c. At first there was great difficulty found in keeping the albumiriate of mercury in solution for any length of time, and it was necessary to prepare the solution fresh before each injection; but later it was discovered that if the mix- ture is heated in the water-bath for one-half hour at 55° C. (131° F.) it will remain in solution indefinitely. It is not necessary to use autogenous serum. Blood may be collected from any individual and the mercurialized serum prepared and kept in sealed ampules. The injections are made into one of the veins at the elbow with an all-glass syringe and a 20-gauge needle. It is imperative that the needle be sharp. A tourniquet is applied above the elbow until the veins stand out prominently. The field is sterilized with alco- hol and the needle inserted in the direction of the blood stream, into the most prominent vein. A slight flow of blood into the syringe will indicate that the needle is within the lumen of the vein. The tourniquent is removed and the serum slowly injected. A drop of collodion is placed on the wound. The initial dose is 1.75 c.c. or 5 mgs. (yV grain) of mercury, and is increased to 7. c.c. or 22 mgs. (^ grain). Nixon^ has proposed a method for intravenous injection of mercury which is highly satisfactory, and owing to its simplicity has recently been employed by the author more frequently than the injection of mercurialized serum. However, instead of injecting the mercury simply dissolved in water, as Nixon advises, the following method is employed : A 2 per cent, solution of bichloride or benzoate of mercury is prepared. When an injection is to be made a 20 c.c. Luer syringe is filled to the 10 c.c. mark with sterile normal salt solution and the plunger removed. The dose of mercury is then measured with a graduated pipette and dropped into the barrel of the syringe. The plunger is replaced, the solution thoroughly mixed, and the air expelled. The needle (No. 19-gauge is most satisfactory) is then inserted into a prominent vein at the elbow, traction made on the plunger until 10 c.c. of blood have been with- drawn and mixed with the mercury solution, when the entire quantity of blood and mercury is reinjected. By withdrawing the blood into the syringe it mixes with the mercury and forms an albuminate which is non-corrosive and does not cause phlebitis. The use of salt solution instead of water obviates the danger of hemolysis. Suppositories. — This method of administrating mercury was advocated by Audry,' who employed suppositories containing 1 Jour. Am. Med. Assn., 1916, Ixvi, p. 1622. 2 Ann. de dermat. et de syph., 1905, vi, p. 793. 206 TREATMENT gray oil and cocoa butter. These he used with varying amounts of gray oil so that they would contain from 0.02 to 0.04 gram of mercury. A suppository is inserted into the rectum nightly for a month, when treatment is discontinued for four or five days, after which it is again resumed. Precautions in Administering Mercury. — Owing to the marked tendency of mercury to produce stomatitis, the greatest care should be exercised in the hygiene of the mouth. Before beginning the administration of this drug the patient should be sent to a com- petent dentist and have his teeth treated, including the filling of cavities, the removing of old stumps, and a thorough cleansing. If pyorrhea exists, it should be determined by microscopic exam- ination if the Endameba buccalis is present, and if so some emetine should be administered. During mercurial treatment all particles of food should be removed from between the teeth with dental floss and they should be brushed carefully after each meal with some good dentifrice. A mouth wash should also be used frequently during the day. This may consist simply of 4 per cent, solution of potassium chlorate. A little peppermint-water may be added to this or the following prescription may be used: I^ — Potass, chloratis 10.0 Tinct. myrrhse 15.0 Aquae camphorse q. s. ad 250.0 The urine should be examined at frequent intervals for evidence of nephritis. Contraindications. — That the use of mercury in syphilis is ever absolutely contraindicated is doubtful. There are, however, cer- tain conditions in which its use should be attended with the greatest care and perhaps entirely withheld temporarily. In acute infectious fevers complicating syphilis mercury should be used only sparingly if at all during the febrile stage. In tuberculosis associated with syphilis mercury should be given in minute doses and its action carefully watched, as any untoward symptoms developing from its use would have an unfavorable effect on the course of the tuberculosis. However, if by admin- istering mercury the syphilis can be overcome, the tuberculosis should be favorably influenced. Nephritis is probably the most frequently mentioned contra- indication to the administration of mercury, and certainly when the nephritis is not directly due to syphilis mercury should be given with the greatest care and its action on the kidneys most carefully watched. SPECIFIC TREATMENT 207 If, on the other hand, the nephritis is due directly to the syphiUs, mercury will have a beneficial effect upon the kidney condition. (See page 293.) Malaria. — According to Lambkin,^ syphilitics who are suffering from malaria stand mercury badly and become salivated easily. This, to the author's mind, applies only to malarial cachexia, and while mercury should probably be withheld from syphilitics during the febrile stage of acute malaria, there is no reason for so doing as soon as the paroxysms are controlled by quinine. Physiological Actions. — There is no doubt but that mercury in small doses acts as a tonic, increasing the number of red cells and the percentage of hemoglobin. But in large doses mercury becomes a poison and may cause many untoward symptoms. Long before the discovery of the Treponema pallidum it was thought that the good effects of mercury on syphilis were due to its parasiticidal effects upon the hypothetical causative organism. This has now been abundantly conJfirmed both by clinical observa- tion on the effects of mercury on the treponemata in syphilitic lesions in human beings and by its effects on the treponemata in experimental syphilis in rabbits.^ It has also been thought by some that the beneficial effects of mercury are due not to the actual destruction of the infecting organ- ism by the mercury itself, but to the stimulation of the formation of antibodies. This latter contention probably is not correct and the action of the mercury is direct on the treponemata. The fate of the mercury in the body is of a great deal of interest. It has been shown that no matter by what method mercury is administered some of it remains in the body tissues for a consider- able length of time. This is especially true of its administration by inunction and intramuscular injections. According to Lang,^ mercury was demonstrated to be in the system in two of his cases three years and in another ten years after the last course of inunction. It has also been shown that the greater part of the mercury administered is eliminated from the body by the secretions and excretions. Thus, according to Lang,^ it has been found in the saliva, the sweat, the bile, the milk, the urine, and the feces, but most in the urine and feces. It is sometimes found in the urine within a few hours after administration and is eliminated chiefly by the tubules. That the mercury reaches all the tissues of the body has been demonstrated by numerous investigators. Lang states that the 1 Power and Murphy: System of Syphilis, London, 1909, ii, p. 302. 2 Nichols: Jour. Exper. Med., 1911, xiv, p. 196. 3 Stedman: Twentieth Century Practice of Medicine, New York, 1899, xviii, p. 326. * Ibid., p. 325. 208 TREATMENT greatest amount can be found in the kidney, next in the liver; the intestine and spleen contain large quantities, the thymus not so much, while in the bones, muscles, brain, and lungs are found but small amounts. Untoward Effects. — Scarcely any two individuals react alike to the effects of mercury, so it is most essential with the use of this drug to be on the lookout for untoward effects. The chief of these are salivation, nephritis, gastro-intestinal disturbances, cutaneous eruptions, and malnutrition and is eliminated chiefly in the tubules. Salivation, once the bugbear of the use of mercury, is rarely seen nowadays in the severe types formerly encountered. At one time it was not rare to see marked inflammation of the mucous membrane of the mouth with ulcerations, bone necrosis of the jaw and loss of teeth, while a copious flow of ropy saliva continuously drooled from between the swollen lips. A mild type of salivation not infrequently is seen and this to the author's mind is a condition not to be deplored. The first symptom of salivation is usually a metallic or coppery taste in the mouth, although the actual increase in the flow of saliva may be noted first. There is a disagreeable odor to the breath, while the gums are found to be congested and bleed easily. Upon "clicking" the teeth together they are found to be sore, and the tongue is swollen and edematous, showing the marks of the teeth upon its surface. Ulceration, especially behind the lower incisors, and back of the third lower molars also sometimes is seen. Between this mild type of salivation and the severe type described above are found all degrees of severity. The treatment of mild salivation consists of withdrawing the mercury, touching any ulcerations with an antiseptic solution, such as a solution of equal parts of tincture of myrrh and tincture of iodin, and washing the mouth several times daily with a potassium chlorate solution. If in spite of all precautions severe stomatitis should occur, the patient should be placed in bed on a milk diet and saline laxatives and diuretics given. Diaphoresis should be stimulated by wrap- ping the patient in blankets and surrounding him with hot-water bottles. Or, if possible, hot-air baths should be administered. Potassium chlorate internally has been recommended very highly, but its value probably has been overestimated. However, it cer- tainly does no harm and may be administered in 0.3 gram (5 grain) doses in solution every two or three hours. The mouth and gums should be swabbed frequently with hydrogen peroxide or some astringent. Nephritis. — It has long been recognized that nephritis occasionally is seen during or following the administration of mercury, so it is SPECIFIC TREATMENT 209 of the utmost importance that the urine be examined frequently for evidence of renal irritation. Should mercurial nephritis occur the mercury should be withdrawn and the patient purged and sweated freely. After the urine has returned to normal the mercury may be resumed in carefully guarded doses. G astro-intestinal Disturbances. — Indigestion, loss of appetite, more or less severe pains in the abdomen, and diarrhea not infre- quently accompany the ingestion of mercury. The administration of mercury by mouth as well as by other methods is rarely accompanied by more severe symptoms of enter- itis; severe griping pains, bloody, mucoid stools, tenesmus, etc., while even death has been observed. As a rule these symptoms are observed with severe salivation, but may occur alone and with no warning. Mild gastro-intestinal symptoms generally will abate upon the withdrawal of the mercury. If the drug is being admin- istered by mouth, it usually can be resiuned by some other method with impunity. In the severe types of enteritis caused by mercury it is needless to say the drug should be discontinued at once. Castor oil should be administered and morphin hypodermically to control the pain. The castor oil should be followed by bismuth and perhaps Dover's powders. The diet should be liquid but without milk. Cutaneous Eruptions. — The administration of mercury by inunc- tion is not infrequently accompanied by more or less severe der- matitis, due to the irritating action of the mercurial ointment. These irritative conditions are found most frequently in individuals with sensitive skins or when the inunctions are applied in hairy regions. Aside from these conditions directly due to the local action of the mercury, certain other cutaneous eruptions rarely are noticed. These latter are due to the systemic effect of the mercury and occur as oval erythematous patches, sometimes elevated and resembling urticaria. Minute purpuric spots are seen between the erythema- tous patches, especially on the legs. Sometimes the eruption is of a marked red color. There is always burning and pruritus, and usually more or less fever and anorexia with general depression. As a rule the eruption subsides promptly with desquamation upon the withdrawel of the mercury. Soothing lotions should be applied and cathartics administered. Mercury should be resmned with great care and in small doses. Malnutrition. — During a vigorous course of mercurial treatment, occasionally it is found that the patient is losing weight and beconiing anemic. This, however, as a rule, occurs only after a considerable quantity of mercury has been administered, and is usually indicative of an approaching stomatitis. That death rarely follows the use of mercury in the treatment of 14 210 TREATMENT syphilis is well known. Wolffenstein,i \^ 1913^ found records in the literature since 1883 of 108 fatalities. Only 1 death resulted from the internal administration of mercury. In this case the patient died following the ingestion of five pills of 0.06 gram each. One death followed the inhalation of mercury fumes by Walander's method. Nine fatalities followed the use of mercurial oil {Merkur- iolol) and 10 the use of mercuric salicylate. One of the latter cases undoubtedly exhibited an absolute idiosyncrasy, as a single injec- tion of 0.05 gram proved fatal. Seven deaths followed the injection of the soluble preparations, 78 the insoluble, 31 of the latter occurred following the use of gray oil, while 19 fatalities resulted from the use of inunctions. Comparative Value of Methods of Administering Mercury. — Mouth. — The advantages of the administration of mercury by mouth are that it is the easiest method, both for the physician and the patient, and that this method can be carried out at a distance from the physician with only occasional visits to the latter. It, however, has the following decided disadvantages: it is the least efficient of the ordinary methods of administering mercury; it is more liable to cause gastro-intestinal disturbances than other methods; and finally, even the most intelligent patients and those with the best intentions not infrequently fail to follow instructions to the letter, and more or less often neglect to take their medicine. Inunctions. — The only advantages of the inunction method of administering mercury are that it usually is efficient in its action and that the mercury can be administered by the patient himself. However, the disadvantages are so many that, except in rare instances the author does not employ this method. The inunction method is inexact, as it is never possible to deter- mine the amount of mercury which is being absorbed; in fact, it has been demonstrated that it may not be absorbed at all. Power^ states that a patient was exhibited by Ehrmann at the Dermatolog- ical Congress at Vienna in 1901 in whose urine mercury could not be demonstrated in spite of the fact that he had received twenty inunctions of mercurial ointment. At the same meeting another patient was shown by Mracek with an extensive maculopapular syphiloderm who had received 400 inunctions while mercury was absent from the urine and the eruption had actually increased during the treatment. Further disadvantages of the inunction method are that it is dirty and disgusting to many patients, its administration usually cannot be kept secret, it requires considerable time, and it may cause dermatitis. 1 Berl. klin. Wchnschr., 1913, 1, p. 1925. 2 System of Syphilis, London, 1909, ii, p. 214. SPECIFIC TREATMENT 211 Fumigation. — The administration of mercury by fumigation is little used, owing to the trouble it incurs, although it is fairly efficacious (fully as much so as the inunction method), is less dirty than inunctions and less painful than injections. Intramuscular. — -The ease of the intramuscular injections of mer- cury, the exactness of the dose, and the great efficiency of the drug administered in this manner makes it the method of choice in nearly all cases of syphilis. It has the further advantage of requiring more or less frequent visits of the patient to the physician. The only disadvantage is the pain which occurs in some individuals in spite of all precautions. But, as a rule, the pain is so slight that it is willingly borne by the vast majority of patients. In such patients who cannot, or will not, stand the pain it is, of course, necessary to resort to other methods of administration. In such instances the author usually employs the intravenous method or rarely the inunction method. The relative merits of the various soluble and insoluble prepara- tions of mercury used intramuscularly have been discussed above. Intravenous. — The only advantages of the intravenous adminis- tration of mercury are its direct introduction into the blood stream, thus giving it a more rapid action and the comparative freedom from pain. The disadvantages are the difficulty of technic and the phlebitis and periphlebitis which sometimes follow, except when mercurialized serum or the method of Nixon is employed. However, it is to be recommended highly in severe cases where quick results are wanted and in patients who complain of much pain on intramuscular injections. Suiypositories. — This method of administering mercury has received but slight notice in this country, although Audry considers it as efficient as the ingestion method and open to no objections. Arsenic. — Herzfeld^ states that according to Harles the use of arsenic in the treatment of syphilis dates as far back as the time of Fallopius and Libavius, and that in the middle of the eighteenth century Hoffmann employed the "fiores auri pigmenti diaphoretici" in the treatment of " lues venerea inveterata" in cases which resisted mercurial treatment and also in cases in which ptyalism and mer- curial poisoning developed. Herzfeld further quotes Ziegenbuehler as having used arsenic internally successfully for the treatment of syphilitic arthritis in 1809, while Horn and Renner are said to have employed white arsenic with success in old inveterate syphilitic lesions. After the introduction of the hypodermic needle this method was employed for the administration of arsenic. The most fre- 1 Jour. Am. Med. Assn., 1911, Ivi, p. 588. 212 TREATMENT quently used preparations were the liquor potassii arsenitis (Fowler's solution) and the liquor sodii arsenitis Pearson (Pearson's solu- tion). On account of the irritating action of these solutions which sometimes caused them to produce abscesses, or even gangrene, Ziemssen^ was led to employ a 1 per cent, solution of sodium arsenite. This solution also, according to Herzfeld,^ proved irri- tating and painful. The latter author therefore prepared an arsenical solution for hypodermic injection as follows: One gram of arsenous acid and 2.25 c.c. of normal soda solution are added to 100 c.c. of distilled water and boiled until the solution is clear. It is then filtered and made up to 100 grams with distilled water. The initial dose recommended is 0.25 c.c. which is to be increased gradually to 1 c.c. or even 2 c.c. No untoward results except a slight burning were observed. In 1911 Herzfeld^ reported the cure of two cases of syphilis, both of which had resisted active treatment with mercury, one for six months and the other for five years, by fourteen and twenty-four injections, respectively, of his solution. About this time numerous investigators reported on the use of the organic compounds of arsenic in the treatment of syphilis. Atoxyl or Sainine. — Atoxyl or samine, as it is sometimes called, was one of the first of these compounds to be employed. Chemically this drug is para-amidopheyiyl-sodiitm arsenate, and has the follow- ing structural formula: 0-H / As— O \ 0-Na / C / \ H-C C-H H-C C-H \ / C H- N -H It is a white crystalline powder and has been used both internally and hypodermically. Metchnikoff found that atoxyl was quite valuable both in treatment and as a prophylactic measure in experi- mental syphilis. It was therefore tried in human syphilis by Lambkin, Uhlenhuth and Manteufel and others in doses of 0.2 to 1 Deutsch. Arch. f. klin. med., 1889, Ivi, p. 124. 2 .Jour. Am. Med. Assn., 1909, lii, p. 557. 3 Ibid., 1911, hd, p. 588. SPECIFIC TREATMENT 213 0.6 gram (3 to 10 grains) . It was soon found, however, that while atoxyl was very effective in the treatment of certain cases of syphilis, especially those that were resistant to mercury, its toxic qualities occasionally were so great that its use was attended with consider- able danger. Even in minute doses sometimes it was found to cause nephritis, gastro-intestinal disturbance, and even blindness. A bright rose-colored rash also not infrequently is observed following the use of this drug. Soamin. — Soamin is the trade name for a similar preparation which is said by its manufacturers to be much less toxic than atoxyl. This drug has had considerable vogue both in England and America as a specific for syphilis, but upon the introduction of salvarsan largely fell into disuse. Sodium Cacodylate. — Sodium cacodylate, which has been known for many years, probably has been used in this country more than any of the other compounds of arsenic in the treatment of syphilis, with the exception of the Ehrlich preparations. Chemically sodium cacodylate is dimethyl-sodium-ar senate, and has the following for- mula: (CH3)2 AsO.ONa + 3H2O. It is a white amorphous powder, soluble in water and usually is used in doses of from 0.03 to 0.3 gram (| to 5 grains) by mouth, intramuscularly or intravenously. One of the earliest and most enthusiastic advocates of sodium cacodylate in the treatment of syphilis was Murphy^ and even in spite of the wide-spread use of salvarsan as late as October, 1914, had the following to say concerning the use of the former drug:^ "We have two very interesting cases that came into the office yesterday. The first is that of an engineer who contracted a chancre of the tongue at its middle from smoking a pipe that had been used by his syphilitic fireman. At the time of his first visit eight days previously we immediately scraped his tongue, excised a piece, and stained for spirochetes, the detection of which confirmed the diagnosis. Then we instituted what we believe to be the best method of treating early syphilis, namely, daily hypodermic injec- tions of sodium cacodylate. I recently recommended salvarsan, but I have returned to sodium cacodylate, which I originally suggested and used before we had "606." Upon his return yesterday the chancre was shrunken to one-sixth its original size. I know that it will be healed when he returns for the next visit, six days hence, allowing just two weeks from the time of the original sodium caco- dylate injection to that of complete healing. Usually chancres heal within from six to seven days and much faster with sodium cacodylate than with salvarsan. As to the permanency of the cure we are not so certain, but we do know that " 606" has been a failure, 1 Jour. Am. Med. Assn., 1910, Iv, p. 1113. 2 Clinics of John B. Murphy, M.D., 1915, iv, p. 574. 214 TREATMENT as regards permanency of cure, and a great disappointment. I give the sodium cacodylate immediately after the appearance of the initial lesion, and keep it up until the external manifestations have entirely disappeared — two weeks, three weeks, four weeks. First we commence with 2 grains once a week, always starting with the smaller doses. Why? Because some patients have an idiosyn- crasy to arsenic. This has been known as long as arsenic has been known. If the idiosyncrasy is marked, it gives the patient the garlic breath. If there is no idiosyncrasy, the sodium cacodylate is pushed up to 5 grains." Other investigators, however, have not been so enthusiastic over the use of sodium cacodylate. Long^ reported the injection of this drug in 4 cases, 3 of "secondary", and 1 of "tertiary" syphilis in which it was useless, in fact harmful, as all of the patients suffered relapses under its use. The injection of sodium cacodylate intravenously has been prac- tised by several workers, the average dose being 0.32 gram (5 grains) , although as much as 1 gram (15 grains) has been injected at one dose without any untoward effects.^ , The author recently has used this method in several cases with apparently favorable results. It has, however, been employed with mercury, so definite conclusions cannot be drawn. The drug as placed upon the market in sterilized ampules is used, is diluted to 10 to 20 c.c. with normal salt solution, and injected in a similar manner to neosalvarsan. (See page 229.) A solution of sodium cacodylate has been placed upon the market in this country under the trade name of " Venarsen," and has been advertised most extensively. This compound, according to the label appearing on the wrapper, is a "comparatively non-toxic organic arsenic compound, 0.7 gm., representing 288 mgs. (4.37 grains) of metallic arsenic and 0.78 mg. {-jf-Q grain) metallic mercury in chemical combination." The report of the Council on Pharmacy and Chemistry of the American Medical Association^ states that Venarsen is a simple solution containing approximately 9 grains of sodium cacodylate, 4^ grain of mercury biniodide, and f grain of sodium iodide to each full dose It was rejected by the Council on the grounds of unwarranted therapeutic claims, poisonous ingredients not stated on the label (this objection has now been removed) , the name does not express the chemical composition, and unscientific combination. There is no doubt that the intravenous injection of sodium cacodylate and 1 Jour. Am. Med. Assn., 1911, Ivii p. 23. ^ Stukes: Jour. Med. Assn. Georgia, 1914. 3 Jour. Am. Med. Assn., 1915, Ixv, p. 1780. SPECIFIC TREATMENT 215 mercury in syphilis is of benefit, but if the physician wants to use these drugs in this manner it would be far better to prepare them himself after the methods described above, as by so doing he can gauge accurately the dose of each and know the purity of his prepa- rations. Further, the cost of Venarsen as marketed is very much greater than the cost of the drugs if prepared by the physician. Salvarsan. — History. — Probably no other therapeutic agent in all the history of medicine created the furor that did the introduction of this arsenical compound, and probably no other drug has been so widely praised or so widely condemned. Salvarsan was not the result of an accident. It was the outcome of many painstaking experiments, and was built up step by step with the ultimate goal in view of finding the ideal remedy for syphilis. Its production and its underlying principle place the name of Ehrlich by the side of those of John Hunter and Lord Lister as among the greatest medical men of all time. Ehrlich approached the problem from an entirely new stand-point. From the very beginning of his experimental work this great scientist was imbued with the idea that a specific chemical affinity exists between specific living cells and specific chemicals. This idea is seen in his work with the leukocytes, and in his vital staining experiments. From this basic idea it was an easy step to the theory that for each parasite a specific curative drug could be found, and Ehrlich's aim was to produce a drug which would completely destroy all of the specific parasites in a given body with one injection. The term "tropism" was used to designate the relations of the chemical compounds to the organs of the host as well as to the parasites, and the complete destruction of the parasites with one injection was termed "therapia magna sterilisma." His first work along this line was with the trypanosome of sleep- ing sickness in mice, and in a short time a new dye, trypan-red, was produced which completely sterilized the body of the mouse with one injection. Atoxyl was next employed and from this by changing the amido group a very large number of preparations were produced and tested. The object was to find the compound which would produce a maximum parasiticidal effect (maximum parasitotropism) , with a minimum toxic eft'ect on the organism (minivium organotropism) . It was soon demonstrated that arsenic in its trivalent state was much more effective on trypanosomes than in its pentavalent state, and of hundreds of compounds produced and experimented with only a few were found to be at all suitable. The principal ones of these are arsacetin, arsenophenylglycin, arsanilate of mercury, and finally dioxydiamidoarsenobenzol or salvarsan. This now famous remedy was the six hundred and sixth compound tried, and has 216 TREATMENT therefore popularly been known as "606." Wechselmann^ quotes Hata, who conducted the animal experiments for Ehrlich, concerning the action of the above-mentioned compounds on chicken spiril- losis, as follows: liESTTLTS OF TREATMENT FOR ChICKEN SpIRILLOSIS. Infection intramuscular. Treatment two days after infection; also intramuscular. Remedy. Dosis tolerata per kilo. Dosis curativa per kilo. C T Atoxyl Arsacetin Arsenophenylglycin .... Arsanilate of mercury Salvarsan 0.06 gm. 0.1 gm. 0.4 gm. 0.1 gm. 0.2 gm. 0.03 gm. 0.03 gm. 0.12 gm. 0.04 gm. 0.0035 gm. 1.0 i.o tV.o "This comparison clearly shows that the results with the first four remedies are far less satisfactory than that with the salvarsan, in which the ratio ^ is actually ideal." Later the new remedy was tried on experimental syphilis in rab- bits, and it was found that one intravenous injection of salvarsan in doses of 0.015 to 0.04 gram would cause the disappearance of the treponemata from chancres of the scrotum within twenty-four hours and a complete cure resulted in from two to three weeks. Smaller doses 0.0075 to 0.005 gram caused the treponemata to vanish in from two to three days, while complete cure followed in from two to four weeks. Smaller doses failed to cause the disap- pearance of the organisms. The first use of salvarsan in human beings was the injection of two physicians who volunteered for the experiment, and no untoward effects were noted except pain and swelling at the site of innoculation. It was then employed in twenty-three cases, mostly paretics, in Alt's^ clinic. The dose used was 0.3 gram. Alt then requested Schreiber, of the Altstaditische Krankenhaus in Magdelburg, to try the new drug in recent cases of syphilis. This was done with twenty-seven patients suffering from various syphilitic manifestations, with some most startling results. On February 18, 1910, Ehrlich turned over a quantity of salvarsan to Wechselmann^ for further and more extensive experiments. It was to be used in doses of at least 0.3 gram, and only in syphili- tics otherwise healthy but who had not been treated with mercury. 1 The Treatment of Syphilis by Salvarsan, New York and London, 1911, p. 12. 2 Miinchen. med. Wchnschr., 1910, Ivii, p. 561. 3 The Treatment of Syphilis with Salvarsan, New York and London, 1911, p. 19. SPECIFIC TREATMENT 217 The first results of his work were reported by Wechselmann^ before the Berlin Medical Society June 22, 1910. Other investigators, including Neisser,^ Schreiber and Hoppe,'^ Fischer and Hoppe,* Loeb,'^ and Treupel,*' were entrusted with salvarsan and reported upon its use. The new preparation was received in America early in May, 1910, and soon several reports concerning its use appeared. Among the first American physicians to use salvarsan may be mentioned Nichols and Fordyce,^ Eisner,^ Engmann, Mook and Marchildon,^ and Fox.^" Early in 1911 the drug was placed upon the market in this coun- try, and soon an enormous literature sprang up concerning it. Salvarsan is a patented preparation, and for a long time was manufactured exclusively by Farbwerke vorm. Meister Lucius and Bruning, Hoechst O.M., but since the beginning of the great European war has been prepared in England under the name of Kharsivan, in France under the name of Arsenohensol- Billon, and in Canada under the name of diarsenol. It has also been pre- pared in this country by Schamberg and his associates,^^ and is termed arsenohenzol. The author has used over 200 doses of this latter preparation and finds it apparently identical with the German product, except, perhaps, slightly less soluble. The therapeutic effects are equally as good. Physical and Chemical Properties. — Salvarsan is a yellowish, crystalline, hydroscopic powder, containing, according to its manu- facturers, about 34 per cent, of arsenic. The chemical name is dioxydiamidoarsenobenzol dihydrochloride, and the structural formula is as follows: As ==As C . C / \ / \ H— C C— H H— C C— H CIHNH2— C C— H H— C C— NH2CIH \ / \ / c c OH OH It is very unstable in air and therefore is sealed in vacuum tubes. Upon the addition of water a sticky, gelatin-like mass is formed 1 B'erl. klin. Wchnschr., 1910, xlvii, p. 1261. 2 Deutsch. med. Wchnschr., 1910, xxxvi, p. 1212. 3 Miinchen. med. Wchnschr., 1910, Ivii, p. 1430. ^ Ibid., p. 1531. 6 Ibid., p. 1580. ^ Deutsch. med. Wchnschr., 1910, xxxvi, p. 1393. 7 Jour. Am. Med. Assn., 1910, Iv, p. 1171. 8 Ibid., p. 2052. s Ibid., 1911, Ivi, p. 87. i» Ibid., p. 650. 11 Ibid., 1915, Ixv, p. 1387. 218 TREATMENT which readily dissolves in an excess of water, especially if hot. The solution formed is a clear yellow color of a depth depending upon the amount of water and of a distinct acid reaction. The addition of sodium hydroxide causes a precipitate to be formed which redis- solves upon the further addition of the alkali. According to Puckner and Hilpert^ the reaction which takes place apparently consists in the liberation of the water insoluble free base: thus, HCl.NHa.OH.CeHg.As: As.CeHg.OH.NHa.HCl + 2NaOH— > NHa.OH.CeHg.As: As.C6H3.OH.NH2 + 2NaCl + 2H2O, the phenolic hydroxyl of which then reacts with the alkali to form the water soluble sodium salt (the phenolate of the base) ; thus, NH2OH.C6H3.As: As.C6H3.0H.NH2 + 2NaOH.— >NH20Na. C6H3.AS: As.C6H3.ONa.NH2 + 2H2O The addition of a solution of sodium carbonate to an aqueous solution of salvarsan also causes a precipitate which, however, does not dissolve upon the addition of a further quantity of the alkali carbonate. The aqueous solution of salvarsan is not affected by the addition of weak nitric, hydrochloric, or sulphuric acids. Strong nitric acid, however, causes a yellowish-white precipitate which redissolves upon the addition of more acid, leaving a dark red solution. A yellowish-white precipitate also is formed upon the addition of strong sulphuric acid. This is redissolved when more acid is added and an almost colorless solution remains which becomes brown and finally black, apparently through carbonization. Ferric chloride added to an aqueous solution of salvarsan produces a violet coloration, similar to many other phenols, which, upon stand- ing, becomes dark red and finally turbid. A solution of salvarsan treated with diluted nitric acid and then silver nitrate develops a yellow precipitate which rapidly darkens and soon becomes black. An alkaline solution of potassium permanganate added to the salvarsan solution and warmed is reduced and an odor of ammonia observed. The addition of y^ iodin solution to a solution of sal- varsan causes the gradual disappearance of the iodin color as well as the yellow color of the salvarsan until a colorless liquid is obtained. This appears to be a perfectly definite reaction, 0.0651 gram of the salvarsan requiring 10.5 c.c. y^ iodin solution, regard- less of the dilution. Methods of Administration. — Salvarsan has been injected into the body, subcutaneously, intramuscularly, and intravenously, although the latter method has superseded the two other methods almost altogether with the majority of workers. Salvarsan has 1 Jour. Am. Med. Assn., 1910, Iv, p. 2134, SPECIFIC TREATMENT 219 also been administered by mouth and by enteroclysis. It goes without saying that all apparatus used in the preparation and injection of salvarsan, whether the subcutaneous, the intramus- cular, or the intravenous method is employed, should be sterilized thoroughly, preferably by autoclave, and all manipulations should be carried out with scrupulous aseptic technic. Subcutaneous and Intramuscular Injection. — Salvarsan may be administered by subcutaneous or intramuscular injection either in simple acid solution, in alkaline solution, in neutral suspension, or in oily or paraffin suspension. Acid Solution. — Salvarsan is prepared for injection in acid solu- tion by simply dissolving in a sufficient quantity of hot sterile distilled water to make a 10 per cent, solution. The local reaction following either the subcutaneous or intramuscular injection of salvarsan prepared by this method usually is so great that it is rarely used nowadays. Alkaline Solution (Alt). — Ten c.c. of sterile distilled water are placed in a beaker or mortar of about 50 c.c. capacity, the salvarsan added and triturated with a glass rod or pestle until completely dissolved. Normal (4 per cent.) sodium hydroxide solution is now added in the proportion of 0.5 c.c. to each 0.1 gram of the drug. The stirring is continued until a precipitate is formed and is par- tially redissolved. The alkali solution is now added drop by drop until the opacity nearly clears. It is not desirable to permit the solution to become completely clear, as such a solution is more irritating to the tissues than the slightly turbid solution. The total volume is now made up to 20 c.c. Alkaline Solution. — The following method for preparing sal- varsan for intramuscular injection in alkaline solution is described in the wrapper of each ampule of the drug put out by the manu- facturers : The drug, for example 0.5 gram, is triturated in a sterile mortar with 0.95 c.c. (19 drops) ^ of 15 per cent, sodium hydroxide solution and diluted to the desired volume, usually 5 c.c, with sterile distilled water. Neutral Suspensicm (Wechselmann) . — At first Wechselmann^ dis- solved the salvarsan in a small amount of methyl alcohol or glycol, added about 10 c.c. of distilled water, and then 1 to 2 c.c. of -j-q sodium hydroxide. To this he then added distilled water up to 25 c.c. and injected the solution intragluteally. However, this investigator later adopted the following technic: The salvarsan is placed in a mortar and dissolved in 1 or 2 c.c. of 15 per cent, sodium hydroxide solution. To this glacial acetic 1 See table under Preparation for Intravenous Injection. 2 The Treatment of Syphilis with Salvarsan, New York and London, 1911, p. 73. 220 TREATMENT acid is added, drop by drop, until " a fine yellow, shiny sediment is precipitated," when 1 or 2 c.c. of sterile distilled water are added. The reaction is determined by the use of litmus paper and 15 per cent, sodium hydroxide or glacial acetic acid added, drop by drop, until a neutral reaction is secured. A platinum loop is used to transfer a drop of the mixture to the litmus paper. The emulsion is now centrifugalized, the supernatent fluid pipetted off and dis- carded, the emulsion taken up in 4 to 6 c.c. of sterile distilled water or salt solution and injected either subcutaneously or intra- muscularly. Neutral Suspension (Michaelis). — The salvarsan is dissolved in a solution prepared by adding 0.3 to 0.6 gram of sodimn hydrochlo- rate to 16 c.c. of very hot sterile distilled water in a wide graduated cylinder. A glass rod may be used as an aid in dissolving the sal- varsan. When this is accomplished, from 3 to 5 c.c. of normal sodium hydroxide solution are added and the mixture thoroughly stirred. Three drops of a 0.5 per cent, solution of phenolphthalein in 70 per cent, alcohol are added as an indicator, which causes a red color to develop. Then 1 per cent, acetic acid solution is added, drop by drop, until the red color disappears. The salvarsan is precipitated as fine yellow floculi and finally a few drops of the nor- mal sodium hydroxide solution are added to recolor slightly the the phenolphthalein. The solution is then ready for injection either subcutaneously or intramuscularly. Oily and Paraffine Emulsions. — Salvarsan may be prepared for subcutaneous and intramuscular injection by rubbing it up with sterile olive oil, oil of sesame, oil of bitter almond, liquid vaselin or liquid paraffin, usually in the proportion of 0.1 gram to 1 c.c. Intravenous Injection. — Numerous methods have been described for preparing salvarsan for intravenous injection. The one most frequently employed, perhaps, is that described in the wrapper of the salvarsan ampule, and is as follows: " Into a, narrow-necked graduated glass-stoppered sterile cylinder measure of 300 c.c. capacity, containing about 50 sterile glass beads, 30 to 40 c.c. sterile distilled water is measured. Then the salvarsan, e. g., 0.5 gram, is added. With vigorous shaking the substance goes into solution. To this solution, but only after it has become absolutely clear and no undissolved particles can be seen, 19 drops of a 15 per cent, caustic soda solution in accordance with the fore- going table are added. This causes a precipitate to form, which again dissolves on shaking. The clear yellow solution is now filled up to 250 c.c. with sterile 0.5 per cent, saline solution, which is prepared from chemically pure sodium chloride and sterile freshly distilled water. Should the solution not be quite clear or become slightly turbid after a few minutes a few more drops of caustic soda SPECIFIC TREATMENT 221 solution should be added, a drop at a time, and waiting two or three minutes after each drop to see if this quantity sufRces to clear the solution. Each 50 c.c. of this solution contains: 0.1 gram (1^ grains) salvarsan; consequently in 100 c.c. 0.2 gram (3 grains), in 150 c.c. 0.3 gram (4^ grains), in 200 c.c. 0.4 gram (6 grains), salvarsan." The following table is given as a guide to the amount of sodium hydroxide to use. for the various doses of the drug : Solution of Sodium Hydroxide. (Rp. Purified Sodium Hydroxide 1.5 gram.) Salvarsan. Distilled water. 8.5 c.c. 0.6 gram 1 .308 gram = circa 1 . 14 c.c. = circa 23-24 drops 0.5 " 1.090 " = " 0.95 c.c. = " 19-20 " 0.4 " 0.872 " = " 0.76 c.c. = " 15-16 " 0.3 " 0.654 " = " 0.57c.c.= " 12 0.2 " 0.436 " = " 0.38 c.c. = " 8 The manufacturers insist that the . salvarsan be dissolved in distilled water, not in salt solution, that the sodium hydroxide be added all at once, not gradually, that chemically pure sodium chlo- ride be used in preparing the saline solution, and finally that the water be freshly distilled. Carter^ advocates the intravenous injection of salvarsan in con- centrated solution and prepares it as follows: The salvarsan is dissolved in from 5 to 10 c.c. of sterile distilled water, 15 per cent, sodium hydroxide solution is added as outlined above and the total volume made up 15 c.c. with sterile distilled water. The author for some time has employed a method which is a compromise between the use of the usual highly diluted solution and the concentrated method. The salvarsan is placed in a sterile glass graduate of 100 c.c. capacity and 5 to 10 c.c. of hot sterile distilled water added. It is then stirred with a sterile glass rod until the salvarsan is completely dissolved. Fifteen per cent, sodium hydroxide solution is added according to the above table and the stirring continued until the solution is perfectly clear. If necessary a few drops of normal sodium hydroxide are added, the mixture being stirred after the addition of each drop. Normal sodium hydroxide is used here instead of the 15 per cent, solution to obviate the danger of making the solution too alkaline. The solution is now filtered through a filter paper sterilized in the hot- air sterilizer and made up to such a quantity with 0.5 per cent, sodium chloride solution that each 10 c.c. contains 0.1 gram of sal- varsan. If several patients are to be treated in succession three or four doses may be prepared at one time. Freshly distilled water, 1 South. Med. Jour., 1915, viii, p. 882. 222 TREATMENT not over six hours old, is used in the preparation of the salt solution. This is distilled each morning into flasks which have been sterilized in the hot-air sterilizer, chemically pure sodium chloride added, and the solution autoclaved for fifteen minutes at 15 pounds pressure. A flask of the freshly distilled water for making the original solu- tion of the salvarsan is also autoclaved. Neosalvarsan. — The great difficulty encountered by many workers in preparing salvarsan for injection lead Ehrlich to seek a substance of equal potency but requiring a less complicated technic in preparation. On his 914th experiment this was found, was desig- nated ''914," and owing to its resemblance to the original prepara- tion the new one was termed neosalvarsan. Physical and Chemical Properties. — Neosalvarsan is an orange- yellow powder of peculiar odor. It resembles salvarsan in that it is very unstable in the air. It is much more soluble in water than the older preparation, its aqueous solution being of a yellow color of a depth depending upon its concentration, and of neutral reac- tion. Upon standing the aqueous solution turns a dark brown color and forms a brown precipitate. According to the label which accompanies each ampule of neosalvarsan the chemical compo-. sition is dioxydiamido-arsenobenzene-monomethane-sulphinate of sodium (Ci2Hii02As2N2CH20.SONa), together within organic salts. The structural formula may be represented as follows: ^g :: As H— C C— H H— C C— H H— C C— NH2 H— C C— NH(CH20)0SNa \ / \ / c c I I OH OH According to the report of the Council on Pharmacy and Chem- istry of the American Medical Association,^ neosalvarsan has the following chemical properties : A precipitate is formed upon the addition of mineral acids to an aqueous solution (1 to 100). Upon the addition of a silver nitrate test solution to an aqueous solution of neosalvarsan (1 in 100) a brownish color should be pro- duced, quickly followed by the formation of a black precipitate. Ferric chloride test solution yields a violet color which soon turns to a dark red. The addition of 5 c.c. of diluted hydrochloric acid to 10 c.c. of 1 New and Non-official Remedies: Jour. Am. Med. Assn., 1912, lix, p. 879. SPECIFIC TREATMENT 223 an aqueous solution of neosalvarsan (1 in 100) and the application of heat produce the irritating odor of sulphur dioxide. If 5 c.c. of diluted hydrochloric acid be added to 19 c.c. of the aqueous solution of neosalvarsan (1 in 100), the precipitate collected on a filter and treated with zinc dust and warm diluted hydro- chloric acid in a test-tube, and if paper moistened with a 5 per cent, sodium chloride solution be held in the mouth of the tube, the paper should be stained yellow in a few minutes (distinction from salvarsan) . If to 10 c.c. of the aqueous solution of neosalvarsan (1 in 100) 5 c.c. of diluted hydrochloric acid be added, the precipitate removed by filtration, 2 c.c. of barium chloride test solution added to the filtrate, the mixture boiled and evaporated to dryness, the residue should not be completely soluble in 50 c.c. of hot water slightly acidified with hydrochloric acid. According to the manufacturers, the arsenic content of neosal- varsan is less than that of salvarsan, 0.9 gram, the maximum dose of the newer preparation, corresponding to 0.6 gram of the older preparation. Neosalvarsan may be administered subcutaneously, intramus- cularly or intravenously, the latter method being the most frequently employed. Wechselmann^ is probably the most ardent advocate of the sub- cutaneous method and prepares the drug for injection by dissolving it in 1 c.c. of 0.9 per cent, salt solution made from freshly distilled water. According to the manufacturers, neosalvarsan should be used for intramuscular injection in approximately 5 per tent, dilution as 1 gram of the drug dissolved in 22 c.c. of water gives an isotonic solution. Therefore for each 0.15 gram 3 c.c. of freshly distilled water should be used. Neosalvarsan may be injected intravenously in comparatively high dilution or in concentrated solution, the latter method, how- ever, being the easier, fully as free from untoward effects and reduces to a minimum the danger of "water faults." The drug should be dissolved in freshly distilled water either in the propor- tion of 0.15 gram to 25 c.c. or 0.15 to 2 c.c. The water must not be hot (not over 20° to 22° C. (68° to 71.6° F.) and the solution should be injected at once. Salvarsan Nairium. — A third preparation has been produced by Ehrlich under the name of salvarsan natrium, or sodiiun salvar- san. This drug, which has not yet been placed upon the market, is said to combine the intensive action of the old salvarsan with the solubility and ease of preparation of neosalvarsan. 1 Miinchen. med. Wchnschr., 1913, Ix, p. 1309. H- C / \ -c c- 1 1 -H H- 1 1 -c c- \ / c 1 OH -NHzNaCl 224 TREATMENT It is produced by allowing sodium hydroxide to act upon sal- varsan, thus forming the di-sodium salt, which is then precipitated by proper reagents. The following represents the structural formula : As As ,1 I ". C / \ H— C C— H NaCl.NH2C C— H \ / C OH Dose. — The dose of salvarsan when first used was 0.3 gram, but was soon increased to 0.6 gram as the average amount admin- istered. Neosalvarsan is recommended by the manufacturers in doses not to exceed 0.9 gram, while an average of 0.6 to 0.75 gram for men and 0.45 to 0.6 gram in women is advised. Some workers, however, have administered as large doses as 1.2 grams of salvarsan and 1.8 grams of neosalvarsan. The tendency nowadays is to return to the smaller doses, and the author rarely gives a dose of over 0.4 gram of salvarsan or 0.6 gram of neosalvarsan. The rule usually followed is to administer salvarsan in doses of 0.006 gram per kilo- gram of body weight. Thus, a man of average weight, about 60 kilograms (150 pounds), should receive 0.35 gram. Clinical experi- ence has shown that such doses are fully as potent as the larger ones. Ehrlich's ideal of therapia magna sterilisans has not been realized, as in the majority of cases more than one dose of salvarsan is necessary. Technic of Injection. — Salvarsan or neosalvarsan for subcuta- neous or intramuscular injection after preparation should be placed in an all-glass syringe of sufficient capacity, to which is attached a needle of about 20-guage. The usual site of the sub- cutaneous injection is the back between the scapulae, and the needle should be pointed downward. Intramuscular injections usually are made in the gluteal region at the upper border of the muscles. The nefedle should be inserted deeply into the muscle arid the injection slowly made, the point of the needle being moved from time to time to ensure a greater distribution of the drug. The site of injection for both the subcutaneous and intramuscular methods should be painted with iodin before injection and should be massaged afterward. A great many forms of apparatus for the intravenous injection SPECIFIC TREATMENT 225 of these drugs, both depending upon air pressure and upon gravity, have been devised and placed upon the market. The Carey apparatus (Fig. 50) is a good example of the air-press- ure instruments, but to the author's mind the gravity instruments are much superior. The simplest form of the gravity type of apparatus is shown in Fig. 51, and consists of a single graduate cylinder, tapering to the end to which is attached a piece of rubber tubing 50 to 60 cm. in length, to the lower end of which in turn is attached a needle of suitable gauge. A glass observation tube may be placed between the needle and the rubber tubing. Owing to the marked toxic effect of salvarsan, and to a less extent of neosalvarsan on the perivascular tissues when these drugs are allowed to escape into them during intravenous injection, it is very desirable to have some arrangment to overcome this danger. Fig. 50. — Carey apparatus for intravenous administration of salvarsan. In the early days of salvarsan injection many workers made it a routine procedure to dissect out a vein in the arm before inserting the needle, some even ligating the vein and inserting a cannula. This practice, however, has fallen into disuse, except in very rare instances when the veins are so small or so obscure that successful venipuncture otherwise is impossible. In the past three years -the author has found this procedure necessary but once. With the single cylinder and rubber tubing the danger of allow- ing the drug to escape into the perivascular tissues may be over- come either by inserting the needle detached from the tube a successful venipuncture being indicated by the flow of blood through the needle, attaching the tube and allowing the drug to flow, or by placing 25 to 30 c.c. of normal salt solution in the cylinder, making the puncture and allowing the salt solution to flow. If the solution flows freely and there is no puffing of the tissues around 15 226 TREATMENT the needle, the latter may be considered as correctly inserted. The salvarsan then is poured into the cylinder and permitted to flow into the vein. If the glass observation tube is used between the needle and the rubber tubing, usually there will be a visible back flow of blood when the needle is properly inserted, after which the solution may be allowed to flow. Fig. 51. — Simple apparatus for administration of salvarsan. The salvarsan should be washed out of the cylinder and rubber tubing by pouring 50 to 100 c.c. of salt solution into the cylinder when but a few cubic centimeters of the drug remain and allowing it to run for a few seconds. The main objections to these methods are that when the needle is inserted disconnected there is some danger of contamination in making the connection, also some danger of embolism from clotted blood. When the glass observa- SPECIFIC TREATMENT 227 tion tube is used a back flow of blood is not always seen. And finally, with either method an assistant is necessary. In order to overcome all of these objections the author has devised the apparatus shown in Figs. 52 and 53. Fig. 52.— Author's apparatus for administration of salvarsan. This consists of a stand {A) adjustable for height, two glass burettes {B and C) of 250 c.c. capacity. Rubber tubmg connects the burettes to a glass Y ( D), the thb-d arm of which is connected with a specially devised three-way cock (F) by means of 50 to bO cm. of rubber tubing and a glass observation tube {E). A Luer 228 TREATMENT needle is attached directly to the opposite side of the three-way cock, and the third opening consists of an arm running at right angles so constructed as to allow the direct connection of a glass observation tube (G). To the latter is attached a small test-tube (H) by means of adhesive plaster. When ready for use the salvarsan is placed in burette B and nor- mal salt solution in burette C, the air is expelled from the apparatus by allowing salt solution t-o run through it, and the lever of the stop- cock is turned so that there is a direct connection between the needle and the test-tube ( H) . The stop-cock of burette C is turned so that the salt solution will flow, while the stop-cock of burette B is turned so that the salvarsan will not flow. The patient lies on an operating table and extends the arm on an arm rest. The region of the elbow is painted with iodin or rubbed thoroughly with alcohol, a tourniquet placed around the arm and the patient is told to open and close the hand a few times, which usually will cause the veins to stand out so prominently that they may be seen or at least palpated. Fig. 53. — Detail of three-way cock of author's apparatus. The needle is then inserted in the direction of the blood stream, a successful venipuncture being indicated by the flow of blood into the test-tube. The skin over the vein may be infiltrated with a little novocain solution, using a very fine hypodermic needle. This reduces the pain of inserting the salvarsan needle practically to nil and is very desirable, especially in nervous individuals. The salvarsan needle should be very sharp with a short bevel. The tourniquet is then loosened and the lever of the stop-cock (F) so turned that there is a direct connection between the needle and the observation tube (E) . If the point of the needle is well within the lumen of the vein the salt solution will be seen to flow freely and there will be no puffing of the tissues around the needle. The salt solution is then cut off by turning the stop-cock of burette C and the salvarsan permitted to flow by turning the stop-cock of burette B. When a sufficient quantity of salvarsan has run from the burette the stop-cocks are reversed and the salt solution per- SPECIFIC TREATMENT 229 mitted to run for a few seconds to allow the salvarsan to be washed from the apparatus. If the entire amount of salvarsan m the burette is to be administered, it is permitted to run until the air is seen in the glass Y, when the stop-cocks are reversed. By this method only a mini- mal quantity of salvarsan is wasted. The salt solution is not cut off imtil the needle is withdrawn, which is done with a quick jerk. The patient is in- structed to raise his arm for a few minutes, a piece of cotton or gauze is applied until the bleeding ceases, and the needle puncture covered with a drop of collodion or a piece of ad- hesive plaster. With this apparatus and using the dilution recommended, i. e., 0.1 gram to each 10 c.c, it is possible to ad- minister fom- doses of 0.5 gram in twenty to thirty minutes without as- sistance. A fiu-ther advantage of the author's apparatus is that the blood which flows into the test-tube when the needle is inserted into the vein may be kept for the Wassermann test, which it is desirable to have performed frequently during the coiU"se of treat- ment. For the injection of neosalvarsan in concentrated solution the author'^ em- ploys two 20 c.c. Luer s\Tinges and the same stop-cock described above. Fig. 54 shows the method of connec- tion, and is almost self-explanatory, salt solution being used in one s\Tinge and neosalvarsan in the other. The advantage of using this stop-cock rather than those with rubber con- nections is that the entire apparatus is solid and the operation can be performed in a minimal time without assistance. Administraiion by Enferoch/sw. — A nimiber of investigators have administered salvarsan and neosalvarsan by enteroclysis with more or less favorable residts. Oulmann and WoUheim- Fig. 5-1:. — ^Author's apparatus for adruinistration of neosalvar- san in concentrated solution. ^ Thompson: Jour. Cut. Dis., 1915, xxxiii. p. 631. - Jour. Am. Med. Assn., 1913, Ixi, p. S67. 230 ■ TREATMENT report the use of this method thirty-seven times in thirty cases, five with neosalvarsan and thirty-two with salvarsan. These workers dissolve the drug in exactly 240 c.c. of water and allow it to flow into the bowel through a rectal tube at the rate of one drop per second, thus taking one hour for the treatment. ■ After their experience Oulmann and Wollheim reach the following conclu- sions : 1. The administration of salvarsan and neosalvarsan by entero- clysis has a place in therapeutics. 2. In general it ought not to replace the intravenous method, because it is possible that in passing through the intestinal mucous membrane or the liver after absorption some of the salvarsan may be changed chemically and in that way its therapeutic effect may be less per unit of dosage. 3. It should be used in children in preference to other methods. 4. It should be the method of choice when the intravenous method is not feasible. 5. The subject is worthy of further study to determine the exact place of this method in the administration of salvarsan and neosalvarsan. Advantages of Various Methods of Injection. — Most writers on the subject are agreed that the subcutaneous injection of salvarsan and neosalvarsan should not be carried out. Wechselmann,i on the contrary, is very insistent that this is the method of choice in administering neosalvarsan, stating that with the concentrated solution he employs the pain, as a rule, is very slight and that in one thousand injections he has never seen necrosis result. The intramuscular injections which at first were extensively employed have been abandoned very largely owing to the intense pain which usually follows and the necrosis which sometimes results. In recent years the oily preparations of salvarsan for intramus- cular injection have been exploited quite extensively by certain pharmaceutical houses, but these are not to be recommended, owing to the danger of oxidation as well as the pain and abscess formation which sometimes occur. To the author's mind the intravenous method is the one of choice in all cases. The pain is practically nil, especially if the skin is anesthetized with novocain as outlined above, and the technic of injection may be mastered with a very little practice. Indications. — In a word, it may be said that salvarsan and neo- salvarsan are indicated in all cases of active syphilis. They are, however, especially indicated in severe cases and in such cases as do not do well under mercurial treatment. 1 Milnchen. med. Wchnschr., 1913, Ix, p. 1309. SPECIFIC TREATMENT 231 Contraindications.^ — The number of contraindications to the administration of salvarsan has gradually narrowed. At first many conditions were considered contraindications, such as marked debilitated conditions, whether due to syphilis or not, tuberculosis, nephritis, cardiac and arterial disturbances, syphilitic involvement of the nervous system, especially optic atrophy, pregnancy, high blood-pressure, etc. Some of these conditions must still be considered as contraindi- cations while others must be looked upon as partial contraindi- cations, that is, as requiring special care in treating. Debilitated conditions should not be considered as contraindi- cations to the use of salvarsan, as this drug exerts a tonic effect, and naturally if the condition be due to syphilis the injection of salvarsan will be expected to cause improvement. It has repeatedly been shown that tuberculous individuals with syphilis often are benefited materially by the use of salvarsan. Of course in advanced tuberculosis when a cure is without the range of possibility salvarsan should not be administered except for the purpose of curing syphilitic symptoms. Nephritis of any type formerly was considered a contraindication to the administration of salvarsan. If it can be shown that the nephritis is due to the syphilis, the administration of the drug cer- tainly is indicated. If, on the other hand, the nephritis cannot be shown to be due to the syphilis, salvarsan should be administered only with great caution. Not only should the urine be examined for albumin and casts, but the phenolsulphonephthalein functional test should be applied both before and after administering the remedy, and the initial dose should be very small. Patients with marked cardiac lesions, with decompensation, irregular pulse, and dyspnea, if shown not to be due to syphilis, should not receive salvarsan. If, however, the condition is shown to be due to the syphilis or there is doubt concerning it, the drug should be administered, but with caution and in small dosage. Marked aortic aneurysm, even if due to syphilis, will not be benefited by the use of salvarsan, but if the condition is not far advanced the drug should not be withheld. Syphilitic involvement of the nervous system should no longer be considered a contraindication to the administration of salvarsan, although the possibility of a Herxheimer reaction should be considered. (See page 237.) Pregnancy and a high blood-pressure also are no longer to be considered as contraindications, although in both conditions the dosage should be small and administered with caution. 1 The remarks concerning the contraindications to salvarsan apply as well to neo- salvarsan. 232 TREATMENT Preparation of Patients. — Salvarsan or neosalvarsan should not be administered on a full stomach. The patient therefore should be instructed to eat a light dinner the evening before the injection and little or no breakfast the following morning. The bowels should be moved by a saline or other mild cathartic. It need only be mentioned that a thorough physical examination should be made of each patient and a urinalysis including a phenolsulphone- phthalein test, performed before the administration of salvarsan. After-care of Patient. — It is not necessary for the patient to go to the hospital for the injection of salvarsan, as in the majority of cases it may be administered with perfect safety in the office. The patient should, however, return to his home as quickly as possible after the injection and remain quiet during the remainder of the day. It is not necessary to retire unless he is inclined to do so. The diet should be light during the remainder of the day, and individuals who are inclined to constipation should receive a mild laxative. In certain cases of syphilis, such as marked cutaneous lesions, severe visceral involvement, and syphilis of the nervous system, it usually is advisable to administer the drug in the hospital or in the patient's home. The urine of the patient should always be examined the morning following the injection. Action of Salvarsan. — The injection literally of millions of doses of salvarsan has proved beyond a doubt the beneficial effect of this drug upon the lesions of syphilis. Chancres, the syphilodermata, and the syphilomycodermata heal with startling rapidity, the treponemata sometimes disap- pearing from the lesions within twelve to twenty-four hours, while the symptoms of visceral syphilis and syphilis of the nervous system usually diminish and may disappear altogether following its use. The mode of action of salvarsan has been described very clearly by Ehrlich,^ who states that while it has been thought by some that the action of the drug is that of a stimulant to the formation of antibodies which in turn attack the treponemata, such is not the case, but that the salvarsan acts directly upon the organisms through the agency of the so-called chemoreceptors. Salvarsan also undoubtedly has a tonic effect upon the body, as it has been administered with favorable results in anemic conditions not due to syphilis. Untoward Effects. — Numerous phenomena ranging all the way from slight indisposition to death occur with more or less frequency following the administration of salvarsan, and as the drug may be 1 Lancet, 1913, clxxxv, p. 445. SPECIFIC TREATMENT 233 given, and often is, without any manifestations whatsoever, all will be considered under the heading of Untoward Effects. The local reaction which usually follows the subcutaneous and intramuscular injection of salvarsan varies from slight soreness with induration to intense pain, only controlled by morphin, necrosis, and abscess formation. It has been shown that the necrosis and abscesses, sometimes at least, are not due to infection, as the contents are found sterile, but to the direct action of the drug on the tissues. It is, of course, possible that the technic of injection be so poor that microorgan- isms are introduced with the salvarsan and abscess formation result. One such case came under the notice of the author during the sum- mer of 1911. The patient, a prostitute, had been injected intra- gluteally with salvarsan prepared in the physician's office and car- ried several city blocks before injection. When seen by the author, three days later, each buttock was markedly inflamed, red and swollen, and exceedingly tender, presenting a yellowish spot at the point of injection. After painting the buttocks with iodin an incision about 1 cm. long was made in each and several ounces of thick, creamy pus evacuated, which showed the presence of Staphylococcus aureus. The sterile abscesses and necroses which sometimes are seen following the subcutaneous and intramuscular injection of salvarsan may occur within a few days after injection, or they may not make their appearance until weeks later. A patient recently seen by the author through the courtesy of one of his colleagues came to him two weeks following the intra- gluteal injection of 0.6 gram of salvarsan into the left buttock, show- ing an area of necrosis 6 cm. in diameter but without suppuration. (Fig. 55.) It often happens, in fact it was the rule with the majority of cases of intramuscular injections made by the author, that while no abscess formation or necrosis takes place a tender induration about the size of a walnut is formed and persists in some cases for months. If during intravenous injection of salvarsan the operator has the misfortune to allow the drug to escape into the perivascular tissues a local reaction, depending in severity upon the amount of the drug escaping, will result. If only a few drops are deposited in the perivascular tissues, usually nothing more than a painful area and black-and-blue discoloration will follow, which will last for a few days. If, however, the drug escapes in considerable quantity, reactions similar to those following the intramuscular injection, with necrosis and sloughing may be observed. The author recently has had such a case under his care. This patient, a woman, aged thirty-eight years, had received an injection of 234 TREATMENT salvarsan ten days previous, at which time, in order to find a vein, the physician had made an incision about 3 cm. long at the bend of the elbow. Fig. 5.5. — Necrosis of buttock following intramuscular injection of salvarsan. The vein was located and the needle inserted. It, however, according to the patient, became dislodged twice during the injec- tion and the salvarsan was permitted to flow into the open wound. When seen by the author a large sloughing, ulcerative area 5 cm. long by 3 cm. broad and 8 or 10 mm. deep, was observed (Fig. 56). This healed in about six weeks, leaving an ugly scar. Fig. 56. -Ulceration following intravenous injection of salvarsan with escape of fluid into perivascular tissues. Certain general reactions also more or less regularly follow the administration of salvarsan, especially by the intravenous method. Probably the most frequent of these is headache. This headache may, however, be due more to the nervous condition of the patient SPECIFIC TREATMENT 235 than to the action of the^ drug. It may be present before, during, or after the injection, and is most frequent in individuals receiving their first treatment. There is no doubt that headache does some- times occur as a result of the action of the drug itself. Further in certain cases of cerebral syphilis in which headache is an almost constant symptom there may be an increase of the pain following the injection of salvarsan. This may be due to an exaggeration of the syphilitic process, and is not observed for twelve to twenty-four hours, or it may be due to the same causes which operate with the injection of salvarsan in cases in which there is no cerebral involvement. Nausea sometihies is observed following the administration of salvarsan, and usually is due to the action of the drug, although in certain individuals it may b^ a purely psychic phenomenon. As a rule it passes away in a few hours without ti-eatment, and nearly always can be relieved by placing cold towels on the throat and forehead or by allowing the patient to hold a small piece of ice in the mouth. A little hot water administered every ten minutes sometimes will relieve the condition. Vomiting also may occur as an after-effect of the administra- tion of salvarsan, although it is not so frequent as it formerly was. As a rule it is of short duration and needs no treatment. It may, however, be so severe as to require the use of morphin. This should be administered in |-grain dose hypodermically. A looseness of the bowels following the injection of salvarsan is sometimes noted. This has been ascribed by some workers to the liberation of an endotoxin from the destruction of treponemata. With this theory the author does not agree, as it rarely is noted if the bowels have been emptied previous to the injection, and is as frequently noted in mild cases as in severe ones. As a rule this looseness of the bowels does not need treatment, but if continuous may be controlled by bismuth, opium, or sometimes by an enema. In the early days of the intravenous injection of salvarsan a severe chill, followed by a distinct rise in temperature, even to 40.5° or 41° C. (105° to 106° F.), often occurred. This was shown, in the majority of cases, to be due to the use of old distilled water, and since the adoption of freshly distilled water for the preparation of the salvarsan these reactions have become less frequent. That such reactions occasionally do occur, however, even with the most careful technic is attested by all who have had any con- siderable experience in the intravenous administration of salvarsan. The cause of these reactions is more or less a moot point, some workers believing that they are due to the liberation of endotoxins from the destruction of the treponemata, while others affirm that they are drug reactions. 236 " TREATMENT Wechselmann^ states that it seems possible that some of the deaths of infants injected with salvarsan are due to the rapid dissolution of enormous numbers of treponemata. Swift^ says " In florid syphilis one frequently sees a fever and gen- eral malaise following the first injection of salvarsan. This picture is probably due to the setting free of some toxic substances from the spirochete." Martin^ is very insistent that these reactions are due to the liberation of endotoxins from the killed organisms, and considers the rise in temperature, even of a fraction of a degree, as indicative of the destruction of treponemata and that diagnostic importance can be placed upon this reaction. The author has seen a few very marked reactions follow the injection of salvarsan in severe cases of syphilis when the technic of preparation was perfect. On the other hand, he has seen it administered in moderately severe cases of syphilis with no reac- tion whatsoever, and when the clinical results were all that could be desired. He has therefore reached the conclusion that the vast majority of such reactions are due to the salvarsan, although in some cases he is inclined to believe the reaction may be due to the liberation of endotoxins from the treponemata. That diagnostic importance can be attached to the reaction he does not believe. Nephritis occasionally has followed the administration of salvar- san, but it is doubtful if a perfectly healthy kidney is ever very seriously damaged by this drug. A small amount of albumin and a few hyalin casts sometimes are found in the urine, especially if there has been a severe systemic reaction, and such findings should indicate the greatest care in subsequent treatment. Cyanosis and edema of the face rarely are seen following the injection of salvarsan. Levan* reports a case in which transient collapse occurred in a middle-aged patient following the intravenous administration of 0.3 gram of salvarsan. The injection was followed at once by cyanosis and nausea, while the face swelled enormously and the tongue became so large it could not be protruded between the lips. Intense headache and retching also were present. All the symptoms except swelling of the face subsided in twenty min- utes, while by the next morning nothing was left but edema of the eyelids. The pulse and temperature remained normal through- out the attack. Exanthemata of greater or lesser extent sometimes follow the administration of salvarsan. The usual type of eruption is morbil- liform or scarlatiniform, and, as a rule, appears from two to forty- 1 The Treatment of Syphilis with Salvarsan, New York, 1911, p. 19. 2 Jour. Am. Med. Assn., 1912, lix, p. 1236. » South. Med. Jour., 1915, viii, p. 458. 4 Med. Klin., 1911, vii, p. 849. SPECIFIC TREATMENT 237 eight hours following the injection. It may, however, be delayed and not appear for a week or ten days. These eruptions in the vast majority of cases undoubtedly are purely drug reactions, although it is possible that the liberation of endotoxins may in some cases be responsible to a greater or lesser degree. There usually is a rise in temperature even to 40° or 40.5° C. (104° to 105° F.), while other symptoms, such as diarrhea, polydipsia, and occasionally nausea and vomiting, may occur. Marked pruritus and some edema also usually are present. The treatment of these eruptions consists of thorough elimination, the use of a light diet, stimulants where indicated, and the local applications of some such ointment as zinc stearate. In one case seen by the author a scarlatiniform rash covering the entire body appeared three days after the injection of 0.6 gram of salvarsan. This injection was the fifth this patient had received. Following the fourth injection one week previous a slight eruption resembling miliaria, which condition it was con- sidered, appeared and lasted two or three days. The rash follow- ing the fifth injection was accompanied by intense pruritus and a temperature of 38.5° C. (101° F.), and lasted for nearly three weeks, disappearing with marked desquamation. The so-called Jarisch-Herxheimer reaction consists of an aggra- vation of the pathological process in luetic tissues following the use of specific treatment. It is seen more frequently following salvarsan and neosalvarsan than following mercury. The reaction is noted in skin lesions, in lesions of the mucous membranes, and in lesions of the viscera and nervous tissue. In the syphilodermata and the syphilomycodermata the reaction manifests itself by a redness, more or less pain, edema and sometimes fever. Gummata are swollen and may ulcerate. Visceral lesions act in a similar manner. If the kidneys are involved, there will be an increase in the amount of albumin and casts present in the urine. Liver involvement will result in an inflammatory reaction of the bile ducts with more or less marked symptoms of bile obstruc- tion, such as yellow conjunctivae, clay-colored stools, and bile pigments in the urine. In cases of syphilis of the nervous system the Herxheimer reaction is manifested with various symptoms depending upon the location of the pathological process. In cerebral syphilis the reaction usually is manifested by an intense headache. If, however, gum- mata exist, the reaction may be manifested by an exaggeration of the focal symptoms and paralysis. In tabes the reaction usually consists of intense pains due to involvement of the posterior spinal roots, which appear from one-half to one hour following the injec- 238 TREATMENT tion, and may last for twenty-four to forty-eight hours. These pains may be so severe as to require full doses of morphin, although it has been noted that they sometimes are stopped by the injection of another and smaller dose of salvarsan. When a cranial nerve which passes through a bony canal is involved in the syphilitic process, and is the seat of a Herxheimer reaction, the swelling of the nerve will produce symptoms depending upon the nerve involved. For example, if the seventh nerve is involved as it passes through the aqueduct of Fallopius, a facial paralysis will follow. Numerous theories have been advanced to account for the Herx- heimer reaction, the best known of which are that it is due to the liberation of endotoxins from the treponemata and that it is due to insufficient dosage. This latter theory was proposed by Ehrlich, who believed that instead of the treponemata being completely killed they are stimulated to increased activity and multiplication. The provocative Wassermann reaction described in the chapter on Laboratory Diagnosis should be considered as an evidence of the Herxheimer reaction. Salvarsan Fatalities. — Soon after the introduction of salvarsan it was learned that death might follow its use, and there sprang up a fear of it in the minds of the laity as well as in the minds of some physicians which it has been hard to dispel. Probably, how- ever, as Schmitt^ pointed out in 1914 in an analysis of the 274 deaths reported up to that time, in a large proportion of cases reported as salvarsan fatalities there is no connection between the drug and the death. The deaths which can be considered as due to the use of salvarsan have been ascribed to various causes. Probably, however, the majority have been due to faulty technic. The author has personal knowledge of but two deaths following salvarsan, one of which was due to embolism. The physician, after inserting the needle into one of the veins at the elbow and finding that the blood did not flow freely, attempted to open the lumen of the needle by passing a wire through it. Undoubtedly a blood-clot- was pushed out of the needle into the vein, as the patient died before the dose could be administered. Other errors of technic which may result in death which may be mentioned are inadequate antisepsis, air embolism, embolism from cotton fibers, from filtering the drug through cotton, and faulty preparation of the drug for injection. As pointed out above, Wechselmann considers it at least possible that the deaths in infants following the injection of salvarsan may be due to the liberation of endotoxins from the killed treponemata. 1 Miinchen. med. Wchnschr., 1914, Ixi, p. 1399. SPECIFIC TREATMENT 239 Other investigators have thought that this might account for part of the deaths in adults. Wechselmann^ considers that some deaths following the injection of salvarsan are due to the fact that the kidneys have been injured by previous mercurial treatment and thus are unable to eliminate the salvarsan. Death following an injection other than the first, especially the second, has been ascribed to an anaphylactic phenomenon. The second death of which the author has personal knowledge occurred in the practice of one of his colleagues following the administration of the second dose. Albumin and casts had been found in the urine following the first dose, and some hours after the injection of the fatal dose the patient fainted when attempting to go to the toilet. There was complete suppression of the urine, and the patient died in convulsions on the third day. Too large doses of the drug with too short intervals between them, thus resulting in arsenical poisoning, have been thought to be responsible for some salvarsan fatalities. Friiwald^ cites 29 cases of death following the injection of neo- salvarsan, and asserts that 15 undoubtedly were due to the drug. In these cases the symptoms were those of a toxic myelitis or encephalitis. One personal case belonged to the latter class. A girl, aged eighteen years, healthy except for an early syphilitic eruption of the face, mouth, and genitals, received an intravenous injection of 0.75 gram of neosalvarsan dissolved in 2 c.c. of distilled water. The dose was repeated in five days and on the seventh day the patient became unconscious and died in twelve hours. Brandenburg^ reports the case of a robust man, aged thirty-eight years who showed no symptoms of syphilis four years after a thor- ough mercurial treatment. The Wassermann reaction was negative and his wife and children were healthy. Nevertheless, he thought he had better have a dose of salvarsan as a prophylactic, and 0.5 gram was administered intravenously. Nausea, vomiting, and diarrhea occurred at once and the patient died in convulsions the fourth day following. The Fate of Salvarsan in the Body. — Wechselmann* states that in the organs of a patient dying from intercurrent disease fourteen days after the injection of salvarsan no arsenic could be demon- strated, although in the gluteus muscle into which the injection had been made arsenic was demonstrated in considerable quantity. In another case dying thirty-six days after injection about 0.01 1 The Pathogenesis of Salvarsan Fatalities, St. Louis, 1913. 2 Med. Klin., 1914, x, p. 1052. 3 Ibid., 1913, ix, p. 751. ^ The Treatment of Syphilis with Salvarsan, New York, 1911, p. 86. 240 TREATMENT gram of arsenic was found in the gluteus muscle. According to Wechselmann, following the intramuscular injection of salvarsan arsenic has been demonstrated in the blood on the second day, while it could not be detected on the fourteenth day. During the intravenous injection of salvarsan, blood withdrawn from the other arm can be shown to contain arsenic. The arsenic of salvarsan is excreted through the urine and feces, and its presence has been demonstrated in the urine as early as twenty-five minutes following the subcutaneous method of injection, and even before the injection is completed when the intravenous method is employed. The length of time that arsenic can be found in the urine following the injection of salvarsan will depend upon the method of injection, the dosage, and the condition of the kidneys. Thus, according to Wechselmann,^ the urine of a paretic having received 0.3 gram of salvarsan subcutaneously showed traces of arsenic on the eleventh and twelfth days following injection, while on the thirteenth day it could not be demonstrated. On the other hand, of twenty-five vigorous syphilitics each receiving 0.3 gram subcutaneously but few showed arsenic in the urine on the fifth day, while by the tenth day the urine of all was free from arsenic. Administered intravenously the drug is eliminated much more rapidl}^ and completely, as the urine is found to be negative on the third or fourth day following the injection of 0.3 gram. The elimi- nation through the intestine is slower than through the urine. Following intramuscular injection arsenic may be demonstrated in the feces as late as the tenth day, but usually is no longer present after the fifth or sixth day following intravenous injection. Kaplan^ states that some writers have found arsenic in the feces even after four weeks, while Finger reports a case in which the drug could be demonstrated nine months after a single injection of salvarsan. Comparative Value of Mercury and Salvarsan. — A great deal has been written concerning the relative values of mercury and salvar- san in the treatment of syphilis, and opinions vary greatly. Even after five years of successful salvarsan therapy there are a few physicians who cling to mercury and discredit entirely the newer specific. And, on the other hand, after four hundred years or more of mercury treatment of syphilis there are some who claim that it is not a specific for this disease and pin their faith exclusively to salvarsan. Of these Wechselmann^ uses salvarsan exclusively 1 The Treatment of Syphilis with Salvarsan, New York, 1911, p. 84. 2 Serology of Nervous and Mental Diseases, Philadelphia and London, 1914, p. 235. 3 The Pathogenesis of Salvarsan Fatalities, St. Louis, 1913, p. 143. SPECIFIC TREATMENT 241 because he considers it more efficient than mercury and less danger- ous except when given following that drug. Martin^ believes that mercury never kills the treponemata but merely forces them to retire and lie dormant, while salvarsan actually destroys the infecting organisms. Between this extreme view and that of the exclusive mercury supporters most syphilologists steer a middle course, consider both remedies as true treponemacides and use both in the treatment of syphilis. Even Ehrlich^ himself says : " On the other hand, however, the greater power of resistance of certain parasites has to be taken into account, and this is a purely chemical question which can only be solved by chemical means. The road leading to its solution which promises the best results is that of combined therapy. . . . (Combined therapy is best carried out with therapeutic agents which attack entirely different chemoreceptors in the parasites.) . . . A further advance of combined therapy is that under the influence of arsenic, which naturally would be a very great obstacle in con- nection with further treatment, it is apparently greatly diminished." There is plenty of clinical evidence to show that mercury can cure the lesions of syphilis and that these lesions often never return nor do other manifestations of syphilis appear, the individual living to a ripe old age apparently free from syphilis. In the case of salvarsan there is also clinical evidence to show that the lesions of syphilis disappear under it use, that in many cases they have not returned and other manifestations of syphilis have not occurred; in other words, a clinical cure has resulted. These facts are so well known that the quoting of statistics would be superfluous. It is, however, the consensus of opinion of the majority of syphilolo- gists that salvarsan is more potent than mercury and that most of the lesions of syphilis clear up more rapidly under the arsenic preparation than under the mercury. The time since the intro- duction of salvarsan has been so comparatively short, however, and the fact that relapses sometimes do occur makes the drawing of definite conclusions from clinical evidence alone impossible. It is therefore necessary to turn to the laboratory for evidence. Fox^ compiled the records of twenty-one observers, including 1634 cases, most of which had been treated thoroughly with inunc- tions or injections of mercury and in all stages of the disease, finding 64.8 per cent, giving negative Wassermann reactions. Noguchi* reviewed the work of several investigators concerning 1 Jour. South. Med. Assn., 1915, viii, p. 458. 2 Lancet, 1913, clxxxv, p. 445. 3 Jour. Am. Med. Assn., 1912, lix, p. 1243. ^ Serum Diagnosis of Syphilis, second edition, Philadelphia and London, 1911, p. 136. 16 242 TREATMENT the influence of mercury upon the Wassermann reaction. He quotes Citron as finding 81 per cent, of cases of syphilis positive before treatment and 65 per cent, positive after treatment. In 57 of his cases, about half the total, but one course of treatment was given. Bruck and Stern found 81.5 per cent, of 173 untreated cases gave positive reactions, while only 28 per cent, of treated cases reacted positively. Blaschko reported 45 to 52 cases of manifest syphilis, which before treatment gave positive reactions, were found negative after treatment. Of 211 cases studied by Hoehne, which before treatment reacted positively to the Wassermann, 56 per cent, became negative follow- ing mercurial therapy. In 5 cases the reaction was still positive after 11 to 12 injections of mercury salicylate over a period of two months. According to Lesser 30 inunctions of mercury will cause a positive Wassermann reaction to become negative in about 35 per cent, of cases, while 12 injections of an insoluble mercury preparation and 25 injections of a soluble preparation will have the same effect. Boas states that out of 82 cases with positive reactions 76 became negative following a course of injections over two or three months. Matson and Reasoner^ found that in cases of not over one year's standing the Wassermann reaction became negative on an average in slightly over two months under intramuscular injections of the red iodide of mercury. In 3 cases treated with inunctions negative reactions were obtained in slightly less time. These authors, however, consider that in a large series of cases the time for negativating the Wassermann with inunctions would be about the same as with the injections. They also found that mercury administered by mouth required a longer period of time to cause a positive Wassermann to become negative. In marked contrast to the above-mentioned findings are the reports of Craig^ and Nelson and Anderson.^ The former gives the following table concering the Wassermann reaction following mercurial treatment by mouth: Method of treatment. Time of treatment. No. of cases. Character of reaction.* Internal . 9 months 17 + + 8 + +- 7 2 Internal 1 year 26 16 8 2 Internal 2 years 17 7 9 1 Internal 3 years 8 3 4 1 1 Jour. Am. Med. Assn., 1911, Ivii, p. 1670. 2 Bull. No. 3, War Department, Surgeon-General's Office, Washington, 1913, p. 96. 3 Jour. Am. Med. Assn., 1915, Ixv, p. 1905. * A + + reaction indicates complete inhibition of hemolysis. SPECIFIC TREATMENT 243 Of 18 cases having received from 7 to 30 injections of gray oil 5 gave a + reaction and the remainder + + reactions. The latter authors report 50 cases, all giving strongly positive Wassermann reactions on at least two occasions before treatment, who received from 7 to 23 injections each of 100 mg. (1| grains of mercury salicylate administered as often as possible without caus- ing salivation. Each patient had a monthly Wassermann reaction performed, and while some showed occasional weakly positive reac- tions and even negative ones, all remained strongly positive at the end of the treatment. It is hard to account for the marked discrepancies in the findings of these different observers. The author has had comparatively little experience with the administration of mercury alone in the treatment of syphilis and none with mercury salicylate alone, so he cannot offer personal evidence concerning the latter drug. He has, however, treated a few cases both by intramuscular and intravenous injections of soluble preparations of mercury without other treatment in which positive reactions were changed to negative. Of 8 cases showing strongly positive Wassermann reactions before treatment 4 showed negative reactions one week following the pro- duction of symptoms of ptyalism by intravenous injections of mercurialized serum. One case (ulcerating gummatous syphilo- dermata) remained strongly positive in spite of enough mercur- ialized serum to produce mild symptoms of ptyalism. The three other cases did not report for Wassermann tests following their mercurial treatment. Of 18 cases giving positive Wassermann reactions before treatment by intramuscular injections of mercury succinimide, only 6 com- pleted their courses and of these, 4 showed negative Wassermann reactions one week following the production of symptoms of ptyalism, 1 a strongly positive reaction and 1 a weakly positive reaction. Of 40 cases with 4-plus Wassermann reactions receiving intra- muscular injections of mercury benzoate only 10 cases took treat- ment for three weeks or more. Of these 10 cases, 8 showed nega- tive tests after from 19 to 36 injections of 0.02 gram of the benzoate. The 2 other cases received 22 and 35 injections, respectively, and the Wasserm.ann reaction of each remained strongly positive. Of 19 cases with strongly positive Wassermann reactions receiving intravenous injections of mercury benzoate only 5 took treatment for three weeks or more. All of these 5 cases gave negative tests after 18 to 35 injections of 0.01 to 0.02 gram of the benzoate. One case was still strongly positive after 18 injections, but subsequently becam.e negative after 14 more injections. In another case the Wassermann was reduced from a 4-plus to a 2-plus by 21 injections, and from a 2-plus to a negative by 14 more injections. 244 TREATMENT All of these cases receiving mercury alone were charity patients from the Free Clinic of the Government Bath House and were unable to pay for salvarsan owing to the increase in price since the beginning of the European War. They represented nearly all types of cases including chancres, syphilodermata and the so-called latent cases. One case reported through the courtesy of Dr. William H. Dead- erick is worthy of mention. This patient showed no manifest symp- toms of syphilis but gave a history of chancre 7 years before followed by treatment by mouth for 7 or 8 months with no specific treatment since. His blood showed a 4-plus Wassermann reaction in the author's laboratory on August 10, 1915. From that date till Novem- ber 28, 1915, he received daily injections of mercury biniodide in doses of 0.005 to 0.01 gram without the production of ptyalism at which time his Wassermann reaction was entirely negative and was still negative on December 7, 1915, on December 22, 1915, and again on April 1, 1916. Numerous other cases which have been treated with both mer- cury and salvarsan have showed reduction in the Wassermann following the mercury but before the administration of the salvarsan and have later become entirely negative. In regard to the effect of salvarsan upon the Wassermann reaction Fox^ compiled the results obtained by thirteen observers in 987 cases treated by salvarsan, finding 47.4 per cent, gave negative Wassermann reactions. The results of different observers, however, were found to vary from 8.8 per cent, to 92.3 per cent, of negatives. Heidingsfeld^ reported 524 cases treated with salvarsan or neosalvarsan or both in which 74.8 per cent, showed clinical and laboratory recovery. Of these 326 were treated solely with salvar- san, and showed 74.14 per cent, recoveries, and 198 were treated solely with neosalvarsan, with only 67.67 per cent, recoveries. It is interesting to note that 37 cases which failed under salvarsan therapy proceeded to apparent recovery when neosalvarsan was administered and 19 cases in which neosalvarsan had failed to cure, recovered under salvarsan. In this connection Nelson and Haines^ state it is their belief that neosalvarsan should not be given in the proportion of 3 to 2 of salvarsan as usually stated, but that it should be given in the proportion of 6 or 8 to 2. This is in accord with the author's expe- rience as he has found neosalvarsan greatly inferior to the older drug, both in the effect on the clinical symptoms of syphilis and in the effect on the Wassermann reaction. 1 Jour. Am. Med. Assn., 1912, lix, p. 1243. 2 Urologic and Cutaneous Review, 1914, xviii, p. 236. 3 Jour. Am. Med. Assn., 1914, Ixii, p. 989. SPECIFIC TREATMENT 245 Noguchi^ reports a very complete serological investigation of 102 cases treated with salvarsan, of which more than half were under observation for more than three months while the remainder were injected only four weeks before the report was rnade. A quantative determination of the syphilitic antibody content was carried out in each case, the blood being examined before the injection of salvarsan and one day, three days, one week, two weeks, four weeks, six weeks, eight weeks, etc., after the injection. It was found that 30 cases became entirely negative, in 24 the serum was found to contain less than 1 antibody unit, while the remaining 48 cases still contained more than 1 antibody unit, thus giving strong positive reactions. It was further found that the reduction of the Wassermann varied somewhat with the stage of the disease, thus the reaction became negative in 40 per cent, of the so-called primary cases, in 37 per cent, of the secondary, in 35 per cent, of the tertiary, in 33 per cent, of the latent, in 14 per cent, of the hereditary and in 50 per cent, of the incipient tabes cases, with an average of 33.7 per cent, of all cases. In regard to the length of time required for a positive Wasser- mann to become negative following treatment with salvarsan the following table is given by Noguchi: 1 week. 2 weeks. 3 weeks. 4 weeks. 5 weeks. 6 weeks. 7 weeks. Total. Primary syphilis . 1 1 2 1 5 Secondary syphilis . 3 5 3 2 1 14 Tertiary syphiHs . 2 3 4 2 11 Latent syphihs . . 2 2 Hereditary syphilis . 1 1 Cerebrospinal syphilis Tabes 1 1 3 10 11 5 4 1 34 Craig^ has made an exhaustive study of the effect of treatment upon the Wassermann reaction in 500 cases and reaches the follow- ing conclusions: 1. The best results, as regards the disappearance of the reaction, are obtained in the treatment of patients in the primary stage of syphilis, and the poorest in the treatment of those in the tertiary stage. 2. The reaction, in our experience, has disappeared most fre- quently during the second, third, and fourth weeks after treatment with salvarsan. 3. The reaction disappears most rapidly in patients treated during the primary stage. 1 Serum Diagnosis of Syphilis, second edition, Philadelphia and London, 1911, p. 146. 2 BuU. No. 3, War Department, Surgeon-General's Office, Washington, 1913, p. 97. 246 TREATMENT 4. The prognosis, as regards the disappearance of the reaction, is most favorable in those patients giving a plus-minus reaction and least so in those giving a double-plus reaction. 5. As regards the method of administration of salvarsan, the best results have been obtained for intramuscular injections, and the poorest from intravenous injections. However, in justice to the latter method, it should be stated that a vast majority of the cases were given only one intravenous injection. 6. The data would appear to indicate that at least three or four intravenous injections of salvarsan are necessary in order to cause the disappearance of the reaction in from 70 to 80 per cent, of patients, patients. 7. The complement-fixation reaction disappears more rapidly after the intravenous administration of salvarsan than after the intramuscular injection. 8. A larger proportion of negative results were obtained in patients previously treated with mercury than in those not so treated, but the time of disappearance of the reaction was little affected. 9. The great superiority of salvarsan over mercury, as a specific remedy, was shown in the rapid disappearance of the reaction, after one or two injections of the drug, in patients previously treated for one, two, or even three years with mercurials, and in whom the reaction was still positive. It will be seen from the above that while there is no doubt as to the superiority in some respects of salvarsan over mercury in the treatment of syphilis, the latter drug certainly has a place in the therapy of this disease and should be used in practically all cases. A word may be said here concerning the effect upon the Wasser- mann reaction of the treatment of syphilis by sodium cacodylate. Heidingsf eld^ reports that 22 cases out of 50, which before treatment showed positive Wassermann reactions, became negative under the deep intramuscular injections of this drug twice weekly for thirty to sixty days. lodin.— "According to Lang^ iodin was used in the treatment of syphilis soon after its discovery in 1811 or 1812. Power^ states that it was first used in the form of burnt sponge in the treatment of venereal ulcers of the throat until, in 1821, iodin was substituted by Martini. In the same year Biett employed iodin with mercury in the treatment of syphilodermata and in 1831 Lugol published the cure of so-called tertiary syphilis treated with iodin alone. Most authorities ascribe the first use of potassium iodide in the 1 Jour. Am. Med. Assn., 1913, Ixx, p. 1598. 2 Steadmann: Twentieth Century Practice of Medicine, New York, 1899, xviii, p. 345. 3 System of Syphilis, London, 1909, ii, p. 242. SPECIFIC TREATMENT 247 treatment of syphilis to William Wallace who lectured upon its use in Dublin in 1S3G. Power/ however, states that this salt was used in England as early as 1831 by Williams. Nevertheless it was Ricord^ who really popu- larized the use of potassium iodide and taught that it was in his tertiary stage of the disease that the drug exerted its greatest influence. Other preparations of iodin which have been employed are the similar salts sodium, ammonium, strontium and rubidium iodide, iodoform, iothion and iodol and the proprietary compounds tiodin and iodipin. Methods of Administering Iodin. — The most frequently employed method of administering the iodides is by mouth. The potassium salt is the one most often used, except in certain cases when it is not well tolerated when one of the other salts sometimes is employed. It has been claimed that the rubidium iodide is better borne by the stomach. Potassium iodide may be administered in the so-called saturated solution. That is, 100 grams of the salt should be dissolved in a sufficient quantity of water to make 100 c.c. Thus: Kali iodidi 100.0 AquEB destillat . . . q. s. ad. 100.0 It will be seen that each cubic centimeter will contain 1 gram and each drop, 1 grain. The author usually prescribes it in 10-drop doses t. i. d., one hour after meals in half a glass of water, milk, tea or other similar vehicle, the dose to be increased each day by 5 drops until symp- toms of iodism appear. The patient should secure a graduate for measuring the doses and as the dose increases should be instructed to increase the amount of the diluent. The reason for prescribing the drug one hour after meals is that it is too irritating to the gastric mucosa to be prescribed on an empty stomach and if given immediately after meals will act upon the starch in the food, which in one hour will have been converted into sugar. Potassium iodide also may be administered in pill form but is more poisonous and is not to be recommended. The addition of ammonium chloride to potassium iodide has been said to increase its efficiency and the two drugs sometimes are prescribed together. Potassium iodide frequently is prescribed according to the formula of Ricord as follows: I^ — Kali iodidi 4.0 Syrupi corticis aurantii 250.0 M. et Sig. — Tablespoonful t. i. d. 1 System of Syphilis, London, 1909, ii, p. 242. 2 A Treatise on the Venereal Disease, Philadelphia, 1859, p. 503. 248 TREATMENT This disguises the taste and is said to eHminate the griping which sometimes follows the use of potassium iodide. The iodides also may be administered by hypodermic injection. The usual method is to administer the potassium salt in 50 per cent, solution in doses of 0.25 to 0.5 gram (4 to 8 grains). The pain which sometimes follows usually may be overcome by adding a little codein to the solution. The intravenous injection of potassium iodide has been prac- tised by several investigators. Doevenspeck^ administered it in this manner, using a 5 per cent, solution and injecting 2 c.c. daily. Wernig^ reports the intravenous injection of sodium iodide in doses of 10 to 30 grains in the treatment of syphilis with very satis- factory results. The iodides may also be administered by enema, and this method is to be recommended in some cases when the stomach does not tolerate the drug well. When administered per rectum the bowels should first be emptied by a plain hot-water enema following which the iodide should be injected in 5.15-gram doses (Ij to 3f drams) dissolved in 200 c.c. (6 ounces) of peptonized milk, to which should be added a few drops of laudanum. Iodoform sometimes has been substituted for potassium iodide and given either in pill form or hypodermically. This drug, however, has practically been dropped from the therapy of syphilis, except as a local application to specific lesions. lothion has been employed as an inunction quite extensively by some workers as a means of introducing iodin into the system, lothion, the chemical name of which is diiodohydroryyroimn, is a yellow, oily fluid containing 80 per cent, of iodin. It is nearly insol- uble in water but is readily soluble in alcohol, ether, chloroform, benzol and glycerin. It may be used for inunctions either pure, dissolved in alcohol or as an ointment. lodol or tetraiodipyrrol, a substitution derivative of pyrrol, is a light grayish-brown powder. It has been administered internally in the place of potassium iodide in doses of 0.13-0.3 gram (2-5 grains) and is said to be very slightly toxic. Tiodin is a proprietary preparation of iodin and sulphur con- taining, according to its manufacturers, 47 per cent, of the former. It is administered internally or by subcutaneous injection. lodipin, another proprietary preparation of iodin, is obtained by the action of iodin chloride on sesame oil. It is a yellow, oily liquid and is placed upon the market in two strengths containing respectively 10 and 25 per cent, of iodin. The 10 per cent, solution is administered by mouth in doses of 4 to 30 c.c. (1 dram to 1 ounce) . 1 Therap. d. Gegenw., 1905, xlvi, p. 676. 2 Jour. Am. Med. Assn., 1908, i, p. 609. SPECIFIC TREATMENT 249 The 25 per cent, solution is administered either internally in doses of 1 to 2 c.c. (15 to 30 minims), subcutaneously in doses of 2 to 20 c.c. {\ to 5 drams) or by rectum in doses of 6 to 10 c.c. (1^ to 2\ drams). lodipin is said to be less toxic than potassium iodide when admin- istered internally and when given subcutaneously is not irritating and is painless. While the majority of individuals who cannot tolerate a consider- able amount of potassium iodide also cannot tolerate greater doses of any of the other iodin preparations, this is not always the case. It is therefore well when symptoms of iodin poisoning are observed with comparatively small doses of potassium iodide to try with great caution one of the other preparations. It has been suggested that owing to the probable different rates of absorption of the various iodin salts it might be well to prescribe the three, sodium, potassium and strontium together, thus giving to the blood stream a more continuous flow of the iodin ion than is obtained with the administration of one salt alone. Therapeutic Effects. — The view that iodin is a true treponemacide is held by but few syphilographers at the present time. Nichols^ has shown that in experimental syphilis in rabbits the largest toler- ated dose, 0.03 gram of potassium iodide per kilo of body weight administered intravenously, has no effect upon the treponemata. In one rabbit with scrotal chancre, however, which received 0.1 gram of potassium iodide per kilo of body weight intramuscularly the treponemata disappeared in eight days and the lesion healed in ten days. In experimental work with monkeys Neisser^ has shown that it is possible to prevent syphilis as well as to cure it with doses of 7 to 8 grams. However, in man there is abundant clinical evidence to show that the administration of potassium iodide has little or no effect on chancre, adenopathy and other early lesions of syphilis, neither does it affect the Wassermann reaction by changing a positive to a nega- tive. Its effect on the luetin reaction has been discussed in the chapter on Laboratory Diagnosis. On the other hand, the use of this drug later in the course of the disease, especially with gummata, usually is attended with favorable results. The disappearance of gummata occurs without previous swelling in contrast to the action of salvarsan. While it undoubtedly is true that gummata are "absorbed" more quickly under treatment with potassium iodide than without it, as Power^ states, the term absorption is used merely for convenience, as the manner of the action of the drug is unknown. Power quotes 1 Jour. Exp. Med., 1911, xiv, p. 196. 2 Arb. a. d. k. Gsndhtsamte, 1910, xxxvi, p. 653. 3 System of Syphilis, London, 1909, ii, p. 241. 250 TREATMENT French as believing that potassium iodide acts "by its power of removing the barricades of nascent fibrous tissue in which the syphiUtic virus is ensconced. It therefore permits the leukocytes bathed in plasma and containing an opsonin to enter. The syphilitic microbe is thus taken up or attenuated, and this explains the lessened anemia of the patient." It formerly was thought that potassium iodide administered fol- lowing a course of mercury by a process of chemical selection united with the mercury and carried it out of the body. It is true that potassium iodide stimulates secretion and excretion and in this manner probably assists in the elimination of mercury. Some of the action of potassium iodide has been ascribed to its stimulating effect on the thyroid, increasing oxidation and general metabolism thus increasing the ability of the body to oxidize and eliminate both the infecting organism and its products. Untoward Effects. — The administration of iodin when pushed to the physiological limit is accompanied by certain symptoms known as iodism. It formerly was thought by many that syphilitics possessed a peculiar tolerance for the drug and that its administration in large dosage without the production of iodism was quite strong evidence of luetic infection. This theory, however, has been disproven as some syphilitics certainly are very intolerant to iodin, and some non-syphilitics are able to stand enormous doses without iodism. Usually the first symptom of iodism to appear is a metafile taste aptly described by Keyes^ as if a copper cent were in the mouth. This taste, however, is noticed by many even after a single dose has been administered and long before other symptoms of iodism appear. The most frequent, and usually the earliest symptom of iodism with the exception of the metallic taste, is a coryza, the so-called coryza iodica. This may be mild with sneezing, sensation of obstruc- tion in the nose and excessive secretion of mucous and be considered as a "cold in the head" or it may be severe with marked swelling of the mucous membrane of the nose, lacrimation, pain in the frontal sinuses, fever and even prostration. The severe types of coryza usually follow the administration of the first few doses of the drug, sometimes even the first dose, and may be considered as evidence of an idiosyncrasy. Gastro-intestinal disturbances often follow the administration of potassium iodide and vary from slight "indigestion" with heartburn and loss of appetite to severe gastro-enteritis with nausea, colicky pains in the abdomen and diarrhea. Various dermatological lesions occasionally are observed as symp- toms of iodism. The most frequent type is a papulopustular erup- 1 Syphilis, New York and London, 1908, p. 193. SPECIFIC TREATMENT 251 tion, the so-called iodide acne which very much resembles acne vulgaris. It occurs chiefly upon the face, forehead and back. The lesions consist of an infiltrated base which may or may not be sur- mounted with a focus of pus. Not infrequently several lesions become confluent. Less often erythema, eczema and herpes are noted and rarely vesicles, bulke and nodules may be produced. Sometimes pustules may develop which pass on to a crustaceous stage. Aside from these inflammatory skin lesions the administra- tion of the iodides may produce a purpura. Other symptoms of iodism which sometimes are seen are acute pains in the chest, cough, and dyspnea. These symptoms are due to edema of the upper air passages. There may be edema of the face which if confined, to this area is not serious. Edema of the upper air passages, however, has been known to cause death. Iodide salivation may occur, due to the action of the iodin on the salivary glands which may become markedly swollen. The saliva- tion is never as severe as mercurial salivation and is not accompanied by the marked lesions of the mouth seen in the latter condition. The prevention of iodism consists of administering the drug care- fully and being alert for the first untoward symptoms. The urine should be examined daily for evidence of the excretion of iodin, in which it may be detected in a few minutes after ingestion. A simple test for iodin in the urine consists of mixing 2 c.c. each of the urine and pure hydrochloric acid and adding a few drops of chloroform. The presence of iodin is indicated by a pink coloration of the chloro- form upon settling to the bottom of the tube following its inversion two or three times. The failure to detect iodin in the urine would indicate that the drug was not being eliminated and place the physician on his guard for symptoms of iodism. It is often true that if mild symptoms of iodism, such as slight coryza, appear after a few doses of an iodin preparation that the careful continuance of the drug will not increase the symptoms, and, on the other hand, they may disappear not to reappear until a very much greater amount of the iodin has been administered. The addition of a small amount of belladonna (0.01 gram (^ grain) to each dose) to the preparation of iodin will sometimes prevent symptoms of iodism. Arsenic administered with the iodides also tends to prevent iodism. The treatment of iodism naturally depends upon its severity. As stated, mild symptoms of iodism may disappear even under the continuance of the drug and many of the more severe symptoms may require no other treatment than the withdrawal of the iodin. Belladonna or atropine for the coryza, adrenalin for edema, and local treatment of the dermatological lesions as indicated should be used. 252 TREATMENT Elimination of lodin. — lodin is quickly absorbed and rapidly eliminated. It has been found in all the secretions and excretions of the body, the urine, the tears, the milk, the saliva, the perspiration. It is, however, mainly excreted by the kidneys. The time required for its elimination from the body, as stated by different authors, varies between wide limits. The following from the work of Rountree, Fitz and Geraghty^ shows the amount of potassium iodide ingested and the time required for complete elimination according to various authors : Author. Amount ingested. Time of elimination. Geisler 0.6 gram 25 hours Roux 0.5" 30 hours Studeni 0.1 " 30 to 36 hours Anten 0.5 " 40 hours Schlayer and Takayasu ...0.5" 48 hours Monokow 0.5 " 48 hours Mixed Treatment. — The so-called mixed treatment, that is, the administration of mercury and potassium iodide in the same solution, has little to recommend it. In the first place the use of mercury by mouth is not desirable for the reasons pointed out above, and in the second place potassium iodide should usually be administered in increasing doses. There is no reason, however, why the two drugs should not be administered at the same time. SYMPTOMATIC AND SPECIAL TREATMENT. While there is more or less similarity in the general and specific treatment of all cases of syphilis, there will be some difference depend- ing upon the portions of the body which are mainly affected and in certain cases treatment especially directed to certain lesions or organs is necessary. Chancre. — Numerous syphilographers have advocated the so-called abortion of syphilis by cauterizing or excising the chancre. Hunter^ probably was the first to undertake these procedures but did not consider them as absolutely certain preventatives of constitutional syphilis, although he did think that in a large per- centage of cases they were successful. However, in the light of modern knowledge of the infecting organism such procedures would seem, in the majority of cases at least, to be unjustifiable. A chancre of the lining mucous membrane of the prepuce which causes phimosis usually necessitates circumcision in order that a correct diagnosis may be reached. That syphilis may sometimes be aborted when no other symptoms but chancre exist by the institution of energetic specific treatment is 1 Arch. Int. Med;, 1913, xi, p. 121. 2 A Treatise on the Venereal Disease, Philadelphia, 1859, p. 318. SYMPTOMATIC AND SPECIAL TREATMENT 253 undoubted. The first essential, however, must be a correct diagnosis, that is, the finding of the Treponema palhdum in the secretion from the chancre. Following this specific medication should begin atonce. The local treatment of chancre is, as a rule, extremely simple, con- sisting, in uncomplicated genital chancres, of washing three or four times a day with warm boric acid solution, weak bichloride solution (1 to 5000) or potassium permanganate solution (1 to 4000). Fol- lowing this the lesion should be dusted with aristol or some similar dusting powder, and covered with a piece of sterile gauze. When healing begins or if crusts form, calomel ointment (10 per cent.) or hectine (20 per cent.) should be applied. Chancre of the urethra may be cauterized through an endoscope or it may be treated simply by irrigating the urethra twice daily with bichloride solution or potassium permanganate solution. Urethral suppositories of calomel or iodiform may be inserted. Chancre of the cervix and vagina may be treated by douches of boric acid and applying mercurial ointment on tampons or supposi- tories. Rectal chancres are best treated with suppositories of calomel or iodoform. Chancres of the lips and tongue should be washed with an aqueous solution of bichloride (1 to 6000) or painted with an ethereal solution of the same (1 to 20). Tonsillar chancres may also be painted with the ethereal solution of bichloride or a gargle or spray of the aqueous solution. Other extragenital chancres should be treated in a similar manner to genital chancres. Chancre complicated by chancroid, the so-called mixed sore, should be treated as if the syphilitic infection did not exist, that is, some form of cautery should be employed. The author has found the following procedure very satisfactory: The parts are first thor- oughly cleansed with warm water and dried, after which the lesions are "ringed" with vaseline. Cocaine crystals are next applied to the sore and removed with sterile water after remaining in contact two or three minutes. Pure carbolic acid is next applied with a cotton pledget on an applicator and after remaining a minute or two pure nitric acid is applied by means of a glass rod and allowed to remain in contact two or three minutes when the excess is removed with a pledget of cotton and a dry dressing of aristol applied. Phagedenic chancre should be treated by cautery with chromic acid, or the actual cautery. In the majority of cases general anes- thesia is necessary, as the cauterization must be thorough to be effective. Following the cautery the lesion should be dressed with an antiseptic solution and when the slough which forms is removed dusting powders such as aristol or iodoform may be applied. 254 TREATMENT Lymphatic Glands. — The adenitis following chancre as a rule requires no local treatment. If complicated by pyogenic infection, the painting of the skin over the gland with tincture of iodin may suffice, but if suppuration exists it may be necessary to incise the gland, currette and apply a dressing of aristol. The adenitis occurring later in the course of the disease needs no local treatment. Cutaneous Lesions. — No local treatment of the m.acular syphilo- dermata is necessary. The same may be said of the majority of the papular eruptions. The palmar and plantar syphilodermata, how- ever, should receive applications of an ointment such as the official unguentum hydrargyri nitratis. The author has found bichloride col- lodion painted on these lesions very satisfactory. The following formula from Lang^ may be used : I^ — Hydrarg. chlor. corros 0.05-0.2 (gr. f-iij) Collodii Aeth. sulph aa 10.0 (Siiss) 01. olivse 0.2 (miij) Moist papular lesions and condylomata should be washed once or twice daily with bichloride solution (1 to 4000) or carbolic acid solution (1 per cent.), dusted with aristol, calomel or salicylic acid, and covered with sterile gauze. The application of strong nitric acid followed by a dusting powder sometimes is beneficial. Pustular syphilodermata are best treated with daily mercurial vaporizations or mercurial baths. The method of administering mercury vapors has been described above. The mercurial baths should be prepared by adding 2 to 16 grams (^ to 4 drams) of the bichloride to 30 gallons of warm water and the patient should remain in the bath ten to fifteen minutes. Some absorption of the mercury is likely to occur, so the patient should be watched carefully for symptoms of ptyalism, especially if he is receiving mercury by some other method. The crusts of pustular syphilodermata may be softened with warm boric acid solution and removed. An ointment such as ammoniated mercury, oleate of mercury (5 to 10 per cent.) unguentum hydrargyrum, or resorcin (5 to 10 per cent.) should be applied on gauze twice daily. Nodular syphilodermata which have not ulcerated as a rule need no local treatment. When, however, ulceration has taken place the methods outlined for the pustular lesions are applicable. Gummata of the skin seen before ulceration also need no local treatment. It has been suggested that painting these lesions with iodin or the injecting of some mercurial or iodin preparation directly into the gumma or around it will aid in their resolution. These 1 Steadman: Twentieth Century Practice of Medicine, New York, 1899, xviii, p. 361. THE CURE OF SYPHILIS 255 procedures, however, have not been successful in the hands of the author. Ulcerating gummata of the skin may sometimes be treated suc- cessfully by the methods outlined above for the treatment of the pustular syphilodermata. These lesions, however, not infrequently are most refractory. In such cases cauterization with silver nitrate or even the actual cautery or the use of a curette may start the healing process. Chronic leg ulcers may be stimulated to healing by "nicking" the entire edge of the ulcer at intervals of 2 to 4 mm. with a pair of sharp scissors and by means of adhesive plaster strapping the edges back. Syphilis of the Appendages of the Skin. — In syphilitic alopecia local treatment is, as a rule, of little or no avail ; the condition gen- erally improving under the specifics. The scalp, however, should, be shampooed once or twice weekly following which a little vaseline should be well rubbed in. In onychia and paronychia the lesions should be kept scrupu- lously clean and washed twice daily with bichloride solution (1 to 2000) . Following this a mild mercurial ointment or dusting powder should be applied. Loose nails should be removed. Mucous Membranes. — The lesions of the mucous membranes as a rule require little or no local treatment beyond that of strict cleanliness. When occurring in the mouth the use of mouth washes and gargles such as potassium chlorate and tincture of myrrh several times daily is to be recommended. Rough places on the teeth should be removed, and, as stated above, the use of tobacco should be curtailed as much as possible. Very hot foods or those highly seasoned should be avoided, as in some cases they irritate and aggra- vate the condition. Severe lesions may be touched with a silver nitrate stick or a 5 to 10 per cent, solution every three or four days. THE CURE OF SYPHILIS. As a general rule, to which there are exceptions, it may be stated that the older the syphilis, the more difficult will be its cure, and as it is upon the specific treatment that we must rely for the cure of this disease, ordinarily more of such treatment must be administered in late cases than in early ones. The author urges all syphilitics, no matter at what time in the course of the disease they are seen to submit to a spinal puncture, so that if evidence of central nervous system involvement is found specific treatment may be directed toward it. In the author's practice as soon as chancre is diagnosed salvarsan is administered intravenously in dosage according to the patient's weight, that is, 0.006 gram per kilo. The following day either intra- 256 TREATMENT muscular or intravenous injections of mercury (usually the benzoate) are begun. These are continued until slight symptoms of ptyalism appear, or until the urine shows evidence of kidney irritation, the urine being examined daily. Salvarsan is administered weekly for four doses, the mercury being omitted on salvarsan days. Blood is collected for the Wassermann reaction at the time of the adminis- tration of each dose of salvarsan and if found positive at the fourth injection a fifth is given, and so on until it is found negative. If negative at the fourth injection, a fifth is not given. Local and general treatment are carried out as outlined above. Following the administration of the last dose of salvarsan one month is allowed to elapse without treatment, other than hygienic, when a Wassermann test is made. If this one is negative, three more tests are made six months, twelve months and eighteen months respectively later. If all of these are negative and no further symp- toms of syphilis have appeared at any time, the patient is considered as probably cured. However, in order to pass an absolutely positive opinion concerning the cure, the spinal fluid must be found normal on at least two occasions one year apart. If any of the Wassermann tests are found positive or any other symptoms of syphilis develop, the treatment is repeated. Berstein^ has suggested that all cases of syphilis, whether showing involvement of the central nervous system or not, should receive an intraspinal injection of salvarsanized serum as a prophylactic meas- ure to such involvement. The author considers such a procedure as entirely rational. The later manifestations of syphilis are treated specifically in a similar manner to the chancre, although as might be expected, two or more "courses" of mercury, often many, with four to six weeks' interval, and several more injections of salvarsan must be adminis- tered to effect a "cure." Potassium iodide also is used when gum- mata or arteritis are present. Local, symptomatic and special treat- ments are administered when indicated and will be discussed in Part II under the proper headings. The same standard for cure is required for all cases as is required when the chancre alone is present except those showing involvement of the central nervous system. (See page 355.) It is a well-known fact, however, that in certain cases of syphilis the Wassermann reaction remains positive in spite of the most thorough and long-continued treatment, although all clinical evi- dence of the disease has vanished. To the author's mind such cases cannot be considered as cured; they should frequently visit the physician for physical examination and should take periodic courses of treatment. 1 Jour. Am. Med. Assn., 1914, Ixii, p. 914. PART II. CHAPTER XI. SYPHILIS OF THE CIRCULATORY SYSTEM. HEART. Pathology. — Syphilis of the heart has long been recognized. All three layers, pericardium, endocardium and myocardium have been observed as the seat of the disease. Pericardium. — Syj^hilitic ijericarditis is of comparatively frequent occurrence and usually follows myocardial involvement. Gummata of the pericardium also are rarely primary but usually extend from the muscular tissue of the heart. Endocardium. — Syphilitic endocarditis resembles toxic endocar- ditis more than it does the infective form. The Treponema pallidum infiltrate the connective tissue of the endothelium, rather than grow on the surface as do bacteria. Here the organisms produce a chronic inflammation which results in more or less deformity. The aortic valve is most frequently affected, and when the mitral is involved the process is usually an extension from the aortic. Occasionally the entire endocardium may be involved. Gummata of the endocardium are sometimes observed and usually extend to the myocardium. Myocardium. — Warthin^ has made a very exhaustive study of syphilitic myocarditis, both of the congenital and the acquired types of the disease and considers both farencliymatous and interstitial involvement. LTnder the 'parenchymatous variety he describes: (1) the finding of large colonies of treponemata either in the tissue spaces or about the bloodvessels but showing no recognizable tissue change; (2) pale degeneration of the heart muscle which, he says, is probably^ to be interpreted as being of the nature of a serous atrophy or liquefaction necrosis; (3) fatty degeneration, which is often the only lesion associated with colonies of treponemata. It is a focal change seen macroscopically as yellowish pinhead spots, but aj-e often larger. Microscopically there is atrophy of the fibers which are filled with large fat droplets. This focal fatty degenera- 1 Am. Jour. Med. Sc, 1914, cxlvii, p. 667. 17 258 SYPHILIS OF THE CIRCULATORY SYSTEM tion may be followed by calcification; (4) simple atrophy of the muscle fibers may be associated with the treponemata. Under the interstitial changes Warthin noted: (1) Edema which consists of either pale, translucent and moist areas or of such a condition of the entire heart wall. Microscopically the muscle fibers are pushed apart, the reticulum fibrillated and containing fine granules and an increase of the number of wandering cells is noted. The apparently edematous areas are filled with treponemata and the presence of a mucus-like substance is more suggestive of myxedema. (2) Inter- stitial proliferation which may he the first recognizable lesion. It is always primarily vascular or perivascular. New vessels are pro- duced but are quickly obliterated by the proliferation of the endo- thelium. Treponemata are found in large numbers in the perivas- cular lymphatics. Later these areas may become fibroid and may be interpreted as non-caseating gumma when sharply localized. Clinical History. — Syphilitic pericarditis is rarely recognized clin- ically, although it not infrequently is observed at autopsy. The condition may be either acute or chronic and may occur at nearly any time during the course of the disease. The principle symptoms are precordial pain and distress, irregular and feeble cardiac action and dyspnea. A friction sound may or may not be present. As far as the author is aware pericarditis with effusion has not been observed. Endocarditis may occur early in the course of syphilis but gum- mata of the endocardium may develop late. The symptoms of endocarditis will depend upon the location and extent of the syphilitic process. As stated above, the aortic valve is most frequently affected and a stenosis is the usual result. In such cases there is generally a systolic murmur transmitted to the vessels of the neck. Aortic incompetence may, however, be observed. When the mitral valve alone is the seat of the pathology, which is rare, there is usually a murmur presystolic in time and not trans- mitted. Myocarditis is one of the most important of all syphilitic affections and undoubtedly is of frequent occurrence. It may be present early in the course of syphilis, and as pointed out above, treponemata may even be found' in the heart wall without any demonstrable tissue change. It is therefore easy to imagine syphilitic involvement of the heart without any clinical symptoms of the disease. However, when the process is extensive enough to cause tissue change the symptoms will be many and varied. Undoubtedly the most frequent symptom is dyspnea and it is most varied in degree, sometimes not being present except on unac- customed physical exertion and again may be so severe as to cause the patient marked distress. HEART 259 Other symptoms are precordial pain and tenderness, irregular cardiac action, cyanosis, decompensation and even heart-block. Following the latter condition the bundle of His has been found affected with gummata. Paroxysmal pain of an anginal character accompanied by a symp- tom of terror, ashy countenance and marked prostration has been described. Diagnosis. — Most frequently the patient with heart syphilis pre- sents himself to the physician with the complaint of symptoms referable to the heart but with no thought of syphilis. More rarely the involvement of the heart is discovered by the physician upon examining the patient who presents himself for treatment of syphilis of other portions of the body. The diagnosis of cardiac syphilis is seen from this to depend upon two factors, the diagnosis of heart disease and the recognition of the syphilitic etiology of the con- dition. Thus it is encumbent upon the internist to think of syphilis in all cases of disease of the heart and to recognize its presence or to exclude it from the etiology. Likewise the syphilologist must examine the heart most carefully and recognize its involvement in all cases of syphilis. The symptomatology of syphilis of the heart does not differ from the symptomatology of cardiac disease due to other causes. The diagnosis will therefore depend upon the history, which when nega- tive is of little value, the presence or absence of other manifestations of syphilis, the laboratory evidence and therapeutic tests. It must be understood that the presence of cardiac disease in an individual undoubtedly syphilitic, both clinically and from a laboratory stand- point, does not prove the heart condition to be due to syphilis. The improvement of the cardiac symptoms under antisyphilitic treat- ment will, however, be very strong presumptive evidence that such is the case. Prognosis. — It must be said that the prognosis, of syphilitic heart disease as with most syphilitic visceropathies, depends upon the date at which it is recognized and the extent of the process. How- ever, the fact remains that even extensive heart involvement with marked symptoms, including murmurs, sometimes yield in a remark- able manner to proper treatment. Probably the prognosis of syph- ilitic heart disease is more favorable in the vast majority of cases than is heart disease of other etiology. Nevertheless in all instances a guarded statement as to the outcome should be made and a too sanquine picture should not be painted until the result of specific therapy is noted. Treatment. — The treatment of syphilitic heart involvement con- sists of treating the heart and treating the syphilis. The latter of 260 SYPHILIS OF THE CIRCULATORY SYSTEM course consists of specific medication, and in the involvement of the heart early in the course of the disease usually is all that is necessary. Later when symptoms of cardiac involvement are marked treat- ment directed toward the condition of the heart is indicated. Most cases are best treated with rest in bed and such heart stimulants as strophanthus, digitalis, camphor, strychnine and adrenalin should be administered as indicated. Salvarsan should be administered in small doses when decompensation exists. f ARTERIES AND VEINS. Pathology. — Aorta. — The aorta when attacked by the Treponema pallidum presents certain changes which even grossly are fairly characteristic. While the ascending aorta and the arch are most frequently involved any portion may be the seat of the syphilitic pathology. Usually the process is quite circumscribed but may be diffuse. Syphilitic Aortitis. — Usually small pale gray, elevated patches varying in size from 5 mm. to 2 or 3 cm. in diameter are seen. On section they are observed to be of a grayish color, while beneath are opaque yellow streaks. Sometimes later in the disease the patches are much larger and may encircle the entire vessel. The surface is very irregular. The wall of the vessel is usually thinned and small bulgings are often seen. If the process is very extensive, diffuse dilatation or saccular aneurysm is observed. In very old cases atheroma may be present. Microscopically in the early cases the adventitia shows infiltration of round cells around the vasa vasorum. Minute new formed blood- vessels, surrounded by infiltrated small round cells, plasma cells and epithelioid cells are seen in the media. The endothelial cells of the intima are more or less proliferated. In the more advanced cases the infiltration around the vessels of the adventitia is very marked, while in the media are seen areas of coagulation necroses which are sur- rounded by small round cells and plasma cells and are in reality gummata. Giant cells are also usually seen. The endothelial cells of the intima are markedly proliferated. The elastic tissue is more or less destroyed, as seen by the use of Weigert's stain. Treponemata are found more or less plentifully scattered through the thickened intima. Darling and Clark^ have shown that the syphilitic process in the aorta may be so extensive as to occlude this vessel completely and to obliterate the lumen of some of its larger branches. Smaller Arteries. — The Treponema pallidum may attack either the adventitia or the intima of the smaller arteries or both may be affected at the same time. Thus the media may be involved from 1 Jour. Med. Research, 1915, xxvii, p. 1. ARTERIES AND VEINS 261 either or both sides. The process, as with that in the aorta, consists of a low grade of infiltration of the endothelial cells of the intima and there is narrowing or even complete occlusion of the lumen. Veins. — The adventitia of the veins is more frequently invaded by the Treponema pallidum than the intima, and periphlebitis fol- lows. When the intima is attacked a thrombophlebitis usually results. The process tends to progress along the course of the veins or to advance from one vein to another. The lumen of the vessel usually remains open, except in the smaller veins. Occasionally the veins may be the seat of gummata and in the case of superficial ones may appear as small reddened nodes along the course of the vein. Clinical History. — Aorta. — ^The symptoms of syphilis of the aorta will depend upon the severity of the pathological process. The involvement of the aorta by syphilis is usually described as occurring late in the course of the disease, but there is no doubt but that the treponemata early invade the blood stream and it is reasonable to infer that they early attack the aorta. In fact Brooks^ has reported a case of perforation of an aneurysm of the aorta before the skin eruption had fully appeared and another case with sufficient patho- logical change in the aorta to cause death within six months after infection. This early evidence of syphilitic involvement of the aorta is nevertheless rare and the length of time elapsing from the date of infection to the onset of symptoms is stated as varying from three to fifty-four years. The principal symptoms of syphilitic aortitis are pain, either pre- cordial or anginal, dyspnea, palpitation and tachycardia. The patient may be the subject of violent attacks of dyspnea which last from ten to fifteen minutes. The dyspnea is expiratory and is accom- panied by sibilant and crackling rales. There is also usually sweat- ing and cyanosis, while the blood-pressure may be markedly raised. When aneurysm follows syphilitic aortitis the symptoms will depend upon the location of the lesion. Fever of a mild degree is often an accompaniment of this condi- tion. Certain physical signs such as pulsation on palpation, areas of dulness on percussion, and murmurs on auscultation will be found depending upon the location and severity of the condition. Smaller Arteries and Veins. — ^The symptoms accompanying syphilis of the smaller arteries and veins will depend upon the ones affected and the extent of the process. If obliteration occurs in an artery supplying a comparatively small region and the conditions are favorable for the development of collateral circulation, there may be no symptoms. If, however, a terminal artery be affected or many arteries be involved, there will be diminished nutrition and necrosis. 1 Med. Rec, 1912, Ixxxi, p. 351. 262 SYPHILIS OF THE CIRCULATORY SYSTEMi Syphilitic phlebitis, if of the superficial veins, may cause swelling, pain and tenderness, and in certain cases edema. Diagnosis. — The diagnosis of syphilitic aortitis is, as a rule, com- paratively easy, although certain cases may present the greatest difficulty. Dyspnea, which is expiratory in character, with pain, either precordial or anginal, and aortic aneurysm, especially of the •ascending portion or arch as revealed by the .r-rays, occurring in an individual of middle life or younger, will be suspicious, even in the absence of positive history or other manifestations of syphilis. How- ever, the final diagnosis must rest upon laboratory procedures and therapeutic tests. Syphilitic arteritis and phlebitis cannot be diagnosed upon clinical evidence alone, but the indirect evidence of history, other manifes- tations of syphilis, positive laboratory findings and therapeutic tests will clear up the diagnosis in the majority of cases. Prognosis. — Aorta. — The prognosis of syphilitic aortitis is always bad, although this too will depend upon the time of its recognition and the extent of the process. In Longcope's^ series of 63 cases of syphilitic aortitis death occurred in 38, and in 34 of them was due directly to the syphilis, giving a mortality of 54 per cent. Of the 34 cases of death 8 died suddenly in an attack of angina pectoris or paroxysmal dyspnea and the remainder of cardiac failure. Smaller Arteries and Veins. The outcome of syphilitic involve- ment of smaller arteries and veins will depend upon the above-men- tioned features as well as upon the location of the vessels involved. Treatment. — Aorta. — Syphilitic aortitis should, as a rule, be treated in bed and aside from the specific treatment should receive stimu- lants as indicated. As with heart syphilis, salvarsan should be administered with caution and in small doses if decompensation exists. Smaller Arteries and Veins. — Syphilis of the smaller arteries and veins as a rule need no treatment other than specific and general. 1 Arch. Int. Med., 1913, ii, p. 15. CHAPTER XII. SYPHILIS OF THE RESPIRATORY TRACT. LARYNX. Pathology. — The syphilitic lesions which attack the mucous membrane of the larynx have been described in Part I in the chap- ter on Clinical History. Gummata of the deeper structures of the larynx are of comparatively frequent occurrence. Thus, the peri- chondrium of the laryngeal cartilages may be involved followed by necrosis. Clinical History. — The involvement of the larynx by the syphilo- mycodermata will produce symptoms depending upon the extent of the process. There is usually more or less hoarseness which may increase to aphonia and there may or may not be coughing, Gummata of the deeper structures of the larynx may cause edema and marked dyspnea and may ulcerate, causing great deformity upon healing due to cicatricial contraction. Diagnosis. — The diagnosis of the syphilitic lesions of the larynx occurring early in the course of the disease is usually attended with little or no difficulty, owing to the usual coexistence of syphiloder- mata or lesions of the mucous membranes of the mouth, throat, etc. If these are not present and the history of chancre is not obtained, a diagnosis of syphilis may not be made, although the Wassermann test at this time is usually positive. Gummata seen before ulceration are scarcely to be mistaken for any other condition. Ulcerating gummata of the larynx may, how- ever, be mistaken for tuberculosis or carcinoma. In tuberculosis there is more cough, expectoration and greater difficulty of swallow- ing than in syphilis. The ulceration of tuberculosis is also more superficial and diffuse than syphilitic ulceration and is accompanied by more pain. The progress of tuberculous ulceration is not so rapid, as a rule, as syphilis. Further, the demonstration of tubercle bacilli, either by stained smears or by animal inoculation can usually be accomplished in tubercular laryngitis. It must, however, be remembered that syphilis and tuberculosis of this region not infrequently coexist. Carcinoma of the larynx should be differentiated from gumma by the fact that in carcinoma there is more hemorrhage than in gumma, the progress of carcinoma is more rapid and the breath 264 SYPHILIS OF THE RESPIRATORY TRACT is more foul. The final diagnosis of syphilitic laryngitis will, however, depend upon the positive laboratory evidence and the improvement of the condition under specific therapy. Prognosis. — The prognosis of the healing of syphilomycodermata of the larynx is the same as that of the syphilomycodermata else- where. There may, however, be permanent injury to the voice, depending upon the severity and extent of the process following the healing of these lesions. Not infrequently singers find that their ability to sing has been greatly impaired or entirely lost following syphilis of the larynx. The prognosis of gummata of the deeper structures of the larynx is most grave. The danger of edema of the glottis must be thought of and deformity and more or less stenosis will follow the healing of ulcerating gummata. Treatment. — The local treatment of laryngitis due to the syphilo- mycodermata consists of insufflations of calomel or iodol, steam inhalations, mild alkaline sprays and applications of weak solutions of silver nitrate or argyrol. Rest of the voice is also desirable. When ulcerating gummata exist local cleansing with irrigations and swabs and the application of stronger solutions of silver nitrate are indicated. The local edematous membrane which sometimes is present should be punctured, while abscesses should be incised. In severe cases of edema and dyspnea tracheotomy may be necessary. The cica- tricial deformities and obstructions sometimes following the healing of syphilis of the larynx may be relieved by incisions and resections performed with the aid of the laryngoscope, followed by the use of dilators. Of course specific medication and general treatment must be employed, TRACHEA AND BRONCHI Pathology. — Syphilitic lesions of the trachea and bronchi are rather rare and are usual 'y extensions from the larynx or lungs. Papular lesions alone or in association with similar conditions in the mouth are occasionally observed. Gummata,, either diffuse or circumscribed, and encroaching upon the lumen of the tubes have also been described. Clinical History. — In syphilis of the trachea and bronchi the symp- toms will depend upon the extent and severity of the condition. If very extensive and ulceration is present, a tickling sensation will be felt in the throat which gives rise to a cough. A mucopurulent secretion accompanied by rales and occasionally pain behind the sternum will be observed. There may be narrowing of the trachea with dyspnea. THE LUNGS 265 Gummaia may ulcerate and perforate into the esophagus or one of the large bloodvessels. Diagnosis. — The diagnosis of syphilis of the trachea and bronchi will depend upon the recognition of lesions of these regions by physical examination, tracheoscopy and bronchoscopy, and the differentiation of tuberculosis; the latter, as a rule, may be accom- plished by the usual laboratory tests, and the administration of specific remedies. Prognosis. — The prognosis of syphilis of the trachea and bronchi depends upon the location and extent of the lesions. If diagnosed before ulceration has taken place, healing may occur with little or no stenosis. If, however, ulceration has taken place, more or less stenosis is bound to follow and the prognosis becomes correspond- ingly grave. The situation is rendered more serious if the lesion is low down in the trachea or in the bronchi, when death may occur from asphyxiation or from complications in the lungs. According to Conner^ in Vierling's list of 46 cases of syphilis of the trachea and bronchi deaths occurred in 39, while of Conner's own series of 80 cases there were 58 deaths, thus giving a mortality for the 128 cases, or 76 per cent. The causes of death in the 58 fatal cases of Conner's series were as follows: 19 from some form of pneumonia, 2 of these being due to the inhalation of food particles after perforation of the esophagus; 11 from a paroxysmal suffo- cative attack; 4 from sudden profuse hemorrhage from perforation of one of the large bloodvessels. In most of the remaining cases death was due to gradual exhaustion and gradual cardiac failure, while in a few cases it was due to syphilis of other parts of the body or intercurrent disease. Treatment. — ^Vigorous antisyphilitic therapy is indicated in syphilis of the trachea and bronchi. In administering the iodides the tendency of the latter drugs to cause edema of the mucous membrane of these regions must be remembered. Inhalations of mercurial vapors may also be used. Stricture of the trachea and bronchi sometimes may necessitate the use of dilators while dyspnea due to stricture of the trachea in its upper portion may be relieved by tracheotomy. Following the tracheotomy the stricture may be dilated by passing instru- ments through the wound. THE LUNGS. Pathology. — Syphilis of the lung is considered rare by most syphilographers, but undoubtedly numerous cases of this condition 1 Am. Jour. Med. Sc, 1903, cxxvi, p. 57. 266 SYPHILIS OF THE RESPIRATORY TRACT have been diagnosed pulmonary tuberculosis. Osier and Gibson' state that of twenty-five hundred autopsies at Johns Hopkins Hospital only twelve showed lesions of the lungs believed to be syphilitic. Two types of syphilis of the lung are usually described, diffuse interstitial fibrosis and gummata. The former condition consists of more or less marked cellular infiltration, usually starting in the interstitial connective tissue and the walls of the arteries and bronchi. There is also hyperplasia of connective tissue and swelling and desquamation of the epithelium of the alveoli. The process is found more especially in the hilus of the lung. It may be general and cause fibrosis and shrinkage of large portions of the lungs or it may be confined to comparatively small areas. It is usually unilateral but may be found in both lungs. Gummata of the lung occur as nodules varying in size from one or two millimeters to several centimeters and are usually quite numerous. When seen in their earlier stages they are grayish red or grayish white and surrounded by an area of congestion. Later they may become soft, necrosed and opaque and are usually walled off by connective tissue, or they may rupture into a bronchus. Instead of necrosis a fibrosis may trke place. Microscopically there is nothing in the gummata of the lungs to distinguish them from gummata of other regions. As far as the author is aware treponemata have not been demon- strated in the pulmonary lesions of acquired syphilis, but there is every reason to believe that they are present. However, according to Osier and Gibson,^ Buchanan found them in the sputum of a patient with undoubted pulmonary syphilis. Osier and Gibson^ describe a syphilitic phthisis consisting of formation of fibrous tissue, gummata, and pneumonic affections leading to cavitation and bronchiectasis. Clinical History. — Although syphilis of the lung is comparatively rarely found at autopsy, it is of more frequent occurrence than the autopsy records would seem to indicate. The difficulty in distin- guishing between syphilis and tuberculosis postmortem may in a measure account for this. The condition may develop at nearly any time during the course of the disease but is usually a late manifestation, being, as a rule, observed from three to ten years following the infection. The symptomatology of syphilis of the lung, will vary with the extent and nature of the process. > Power and Murphy: System of Syphilis, London, 1909, iii, p. 15. 2 Ibid., p. 24. 3 Ibid., p. 19. PLEURA 267 Diffuse interstitial fibrosis of the lung will sometimes cause symp- toms markedly resembling pulmonary tuberculosis. The most frequent symptom is cough, which may be mild or severe. The sputum is usually mucopurulent in character and may be scanty or profuse. It may contain elastic tissue and may be tinged with blood. Marked hemoptysis sometimes occurs. There may be chills in the afternoon followed by more or less fever, the temperature sometimes reaching 41° C. (106° F.) or over, as in a case reported by Roussel.^ The temperature may also become subnormal. Night-sweats are not found in pulmonary syphilis, as a rule, but do sometimes occur and may be of a drenching character. There is usually more or less l6ss of weight, sometimes extreme cachexia, but the patient may be well nourished. Depending upon the area involved there will be dulness, increased vocal fremitis, broncho- vesicular breathing and rales. Gummaia of the lung may or may not give rise to physical signs and symptoms, depending upon their size and location. The most frequently noted symptom is a cough, usually of trivial character. The physical signs of consolidation, dulness, increased vocal fre- mitus, rales, etc., may be present if the gummata are large or numerous. Diagnosis. — Syphilis of the lungs must be differentiated from pulmonary tuberculosis. In syphilis night-sweats are infrequent and cachexia is not so marked as in tuberculosis. The final diagnosis, however, must be made upon the absence of tubercle bacilli from the sputum, perhaps the finding of the Treponema pallidum, positive Wassermann or luetin test and the improvement of the condition under specific therapy Prognosis. — Syphilis of the lungs is always of grave import, but the prognosis will depend upon the extent of the involvement. Marked improvement and cure sometimes follow even extensive pulmonary syphilis. Treatment. — Aside from specific and general treatment the inhala- tion of mercurial vapors is indicated in pulmonary syphilis. Other treatment is symptomatic. PLEURA. Syphilitic involvement of the lung usually leads to thickening of the pleurae. Gummata of the pleurae have been described by Lancereaux.^ 1 New York Med. Jour., 1913, xcviii, p. 600. 2 Traite de la Syphilis, 1873, p. 326. CHAPTER XIII. SYPHILIS OF THE G ASTRO-INTESTINAL TRACT. THE MOUTH AND PHARYNX. Pathology. — The pathology of the lesions of the* mucous mem- brane of the mouth, pharynx and lips has been described in Part I, but aside from those conditions the muscles of the tongue and lips may be the seat of syphilitic infiltration, causing more or less swell- ing and deformity. Gummata of the tongue, hard and soft palates and walls of the pharynx are sometimes observed. Clinical History. — The symptoms accompanying syphilis of the mouth and pharynx will depend upon the extent of the process. There may be more or less burning, difficulty in eating and talking, or it may even be impossible to carry out these functions. Gummata of the hard palate often break down, causing perfora- tion into the nasal cavity, while gummata of the soft palate and uvula not infrequently cause destruction of these tissues. Gummata of the posterior wall of the pharynx may ulcerate and cause grave complications, such as involvement of the cervical vertebrae, hemorrhage from eroded vessels, and such marked deformities as to cause eating to be most difficult. These manifestations as a rule occur late in the course of the disease, but Long^ reports a case of perforation of the velum two months after the chancre. Diagnosis. — The diagnosis of the syphilomycodermata of the mouth and pharynx has been sufficiently discussed under the diag- nosis of these lesions in Part I. The diagnosis of gummata of these regions as a rule presents little difficulty, but should rest upon the history, and laboratory findings. If, however, these are negative and a diagnosis of cancer, tuberculosis or actinomycosis cannot be made specific therapy should be given a trial, when improvement would indicate that the condition is syphilitic Prognosis. — The prognosis of the syphilomycodermata of the mouth and pharynx has been discussed in Part I. The prognosis ef gummata of these regions depends upon the stage of the process. If seen early before marked ulceration has occurred, the prognosis 1 Twentieth Century Medicine, New York, 1899, xviii, p. 104. THE ESOPHAGUS 269 should be good, and even if the process has become quite extensive it may be arrested, although cicatrization may result and cause marked deformity. Treatment. — The treatment of syphilis of the mouth and phar^'nx, aside from the specific and general treatment consists of the use of mouth washes and gargles and the surgical removal of sloughing tissue. THE ESOPHAGUS. Pathology. — Syphilis of the esophagus has been considered a rather rare condition, but Wile^ after reviewing the literature and reporting an additional case seen in his practice considers it prob- ably not so rare as might be assumed from the meager literature on the subject. According to this writer, superficial erosions and ulcers such as found in the mouth and pharynx during the early course of the disease have not been described in the esophagus. However, he thinks that they may occur. The process described is a gummatous one, located in the submucosa. Here, either under treatment or spontaneously, involution by fatty degeneration may occur. , Usually without treatment and sometimes in spite of the same, early ulceration takes place. Healing of the ulcers leaves a scar and marked tendency to contraction and resulting stenosis; or instead of localized scarring and contraction there may be a diffuse process which involves the entire circumference of the esophagus for a greater part of its length with resulting contraction, almost completely closing the liunen and preventing the passage of solid food. Clinical History. — Syphilis of the esophagus will yield symptoms dependent upon the extent of the process. There is more or less difficulty in swallowing, at first probably noticed only on swal- lowing solids, but later liquids will also cause difficulty. Pain may or may not be present, but is usually noticed only on swallow- ing. There is generally more or less anemia and cachexia due, in part perhaps, to the general syphilitic infection, but probably more to the inability to swallow sufficient food. Diagnosis. — Syphilis of the esophagus may present considerable difficulty of diagnosis and must be differentiated from carcinoma, spastic stenosis and pressure on the esophagus by tumors of the mediastinum. Carcinoma, as a rule, occurs later in life than s;yT)hilis, is of more rapid development, causes more cachexia, usually is more painful, more frequently provokes emesis and hematemesis and is more common in the lower portion of the esophagus than the upper. 1 Am. Jour. Med. Sc, 1914, cxl\'iii, p. 180. 270 SYPHILIS OF THE GASTRO-INTESTINAL TRACT The location and extent of the lesion is determined by the a;-rays, while the Wassermann and luetin tests are valuable in establishing the presence or absence of syphilis. Prognosis. — The prognosis of syphilis of the esophagus will depend upon the extent of the process. If it is recognized before ulceration has taken place, the latter may not occur if specific medication is administered. However, if ulcers have formed, and they may form even in spite of the most vigorous treatment, their healing will result in scarring with contraction and more or less stenosis. Treatment. — Following the healing of syphilitic lesions of the esophagus, which in favorable cases will occur under specific therapy, the esophagus should be sounded carefully and if contrac- tion exists, should gradually be dilated with esophageal bougies. THE STOMACH AND INTESTINES. Pathology. — Until comparatively recent years syphilis of the stomach was considered a rare condition. However, it is now recog- nized as a not uncommon occurrence and numerous papers on the subject have appeared. According to Osier and Gibson^ acute syphilitic gastritis has been described, but they state that little is known concerning the anatomy of the condition. These authors further state that Virchow first described chronic syphilitic gastritis. Other pathological changes, as seen in syphilis of the stomach, are gummata and diffuse infiltration of the stomach wall. Gummata usually start in the submucosa, the process later involving the other coats. The gummata may break down and form ulcers, and the ulcers upon healing produce cicatrices and perhaps stenosis. The ulcer may perforate the stomach wall, causing peritonitis. Diffuse syphilitic infiltration of the stomach wall has been noted rarely and causes more or less thickening. Microscopically syphilis of the stomach shows cellular infiltra- tion, especially around the bloodvessels, which are more or less thickened by hyperplasia of the endothelial cells. Treponemata were not found in the cases reported by Curtis^ and McNeiP and as far as the author is aware have not been demonstrated in gastric syphilis. Syphilis of the intestine presents pathological appearances similar to those observed in the stomach. Duodenal syphilis may extend from the stomach. Rectal syphilis is more frequently observed than is syphilis of other portions of the gastro-intestinal canal. The rectum may be the seat of the chancre. Condylomata and papules are also found 1 Power and Murphy: System of Syphilis, London, 1909, iii, p. 37. 2 Jour. Am. Med. Assn., 1909, Hi, p. 1159. ^ Ibid., 1914, Ixiv, p. 430. THE STOMACH AND INTESTINES 271 here. Gummata, however, are the most frequent syphiHtic lesions of the rectum. The process begins in the submucosa and usually leads to marked ulceration. In severe cases the mucosa may be destroyed for a distance of 10 to 12 centimeters above the anus. Later the ulceration leads to cicatrization with stricture of the rectum. Perirectal gummata may disintegrate and form fistulse into the rectum, vagina or perineum. Clinical History. — Syphilitic gastritis is found early in the course of the disease, usually during the first year, and presents no symp- toms differing from those found in other forms of chronic gastritis. There is more or less pain, belching, achylia, loss of weight, etc. Gummata of the stomach will cause symptoms depending upon their size, location and condition. If a gumma of considerable size be present, it may be palpated. Dyspeptic symptoms are also usually present. The tumors may be situated at the pyloris and may cause stenosis with the resulting symptoms of dilatation, stagnation, etc. Ulcerating gumma which is the most frequent syphilitic lesion of the stomach usually causes symptoms very closely resembling ulcer of the stomach due to other causes than syphilis. There is usually more or less pain after eating, and there may or may not be vomiting. Hemorrhage is frequent, while diminished or absent hydrochloric acid is noted. Syphilis of the intestines is rare and its recognition before death is rarer. Marked diarrhea which will not yield to the ordinary remedies, the stools being thin and watery and containing blood and pus, may be noted. Deep palpitation over the affected portion of the intestinal canal will elicit pain. Ulcerating gummata of the intestines may lead to stenosis. Rectal syphilis, as stated above, is more frequently observed than syphilis of other portions of the intestinal canal. Syphilis of this region may give rise to no symptoms or there may be marked pain on defecation, proctorrhea, tenesmus, incontinence of feces or stricture. Diagnosis. — The diagnosis of gastritis occurring early in the course of syphilis, especially in the absence of other manifestations of the disease, may be attended with the utmost difficulty. If, however, there is any suspicion that the condition is syphilitic, and when the great prevalence of syphilis is considered, such a suspicion should be entertained in practically all cases in which other etiology is not evident, a Wassermann test should be performed, which if positive would indicate antisyphilitic treatment, and improvement of the gastric symptoms would confirm the diagnosis. Gumma of the stomach may be mistaken for simple ulcer or gastric carcinoma, and in some cases a positive diagnosis cannot be made. The pain of ulcerating gumma is, as a rule, not so severe or regular 272 SYPHILIS OF THE GASTRO-INTESTINAL TRACT as that observed in simyle ulcer and is not so dependent upon the ingestion of food. Hemorrhage also, while sometimes noted, does not occur as often as in simple ulcer and is not so severe. Diminu- tion or absence of hydrochloric acid is the rule in syphilis, while in simple ulcer hyperchlorhydria is more frequent. In gastric carcinoma the development of the condition is more rapid, the hemorrhage is more frequent, emaciation more marked and pain and vomiting more constant than in syphilis. The .T-ray picture may be very similar in both conditions, marked deformity of the stomach or stenosis of the pyloris being seen. The gastric analysis is also very similar except that lactic acid is not so fre- quently found in syphilis as in carcinoma. Finally, the diagnosis of gastric syphilis must rest upon laboratory findings and therapeutic tests. The diagnosis of syphilis of the intestines is usually most difficult. Marked diarrhea which does not yield to the ordinary remedies, with thin and watery stools and containing blood and pus should be suspicious. It must, however, be differentiated from amebic dysentery and the diarrhea of 'pellagra. In amebic dysentery the finding of the Ameba histolytica and in pellagra the usual presence of other manifestations of the disease, the typical eruption, stoma- titis, etc., will, as a rule, serve to establish a diagnosis of these con- ditions. A positive Wassermann or luetin test with improvement of the symptoms under specific therapy will confirm the diagnosis of syphilis. Stenosis of the intestine due to syphilis may be recognized by the a;-rays, and by positive laboratory findings. Gumma of the rectum must be differentiated from carcinoma, and may usually be accomplished by the history, the laboratory findings (Wassermann-luetin tissue examination) and therapeutic tests. Prognosis. — The prognosis of early syphilitic gastritis is good, as under specific therapy its cure is usually rapid. * The outlook of syphilitic gummata of the stomach is not so good, especially if located at the pyloris and ulceration has taken place, as upon healing, more or less cicatrization will take place and perhaps stenosis. The outcome of syphilis of the intestines is similar to that of syphilis of the stomach and a similar prognosis may be given. Treatment.^ — It has been suggested that in syphilis of the stomach and intestines mercury should be administered, by mouth for its local effect as well as for its constitutional effect. If this is done, mercury should also be administered carefully by intramuscular or intravenous injection and salvarsan intravenously. Aside from the specific medication the diet should be regulated according to THE STOMACH AND INTESTINES 273 the condition. In syphilitic gastritis the diet should be non- irritating and such articles of food as cabbage, smoked meats, goose, duck, animal fats, acids, pastries and cold drinks should be forbidden. In ulcerating gumma of the stomach the diet should also be non- irritating and the food should leave the stomach as quickly as possible. It should consist mainly of liquid and semisolid articles. The treatment of chancre of the rectum has been discussed above. Rectal gummata may be treated in a similar manner. 18 CHAPTER XIV. SYPHILIS OF THE LIVER, GALI^BLADDER, SPLEEN AND PANCREAS. THE LIVER. Pathology. — Acute yellow atrophy of the liver has been observed during the course of syphiHs and considerable controversy has arisen concerning the responsibility of the Treponema pallidum in this condition, some observers contending that the administration of antisyphilitic remedies produces the condition and not the syphilis per se. But as Buschke^ has shown that acute yellow atrophy may develop in untreated syphilitics, and that the condition may improve upon the institution of proper therapy, it seems that there is little doubt of the occasional role of the organism of syphilis in this condition. Syphilitic cirrhosis may occur in association with gumma of the liver or independently. The liver is usually smaller than normal when gummata are not present, while on section bands of sclerotic tissue are observed between the lobules. The process is usually observed in a more or less limited portion of the liver and generally leads to necrosis and inflammatory infiltration. Microscopically the cells are seen to be necrotic and undergoing fatty degeneration and amyloid change may also be present. Gummata of the liver vary in size from 1 or 2gpim. to immense tumors which may be mistaken for malignant growths. Cirrhosis is generally associated with this condition. The microscopic picture of gummata of the liver does not differ materially from gummata observed elsewhere. Treponemata can usually be demonstrated. Perihepatitis may occur as a localized condition or as a thickening of the entire capsule or the liver. It generally follows syphilitic involvement in the liver but may precede it. Clinical History. — Icterus is a comparatively frequent symptom of early syphilis and occurs, usually developing suddenly, most frequently about the sixth week following the infection. Several theories have been advanced to account for it. It has been thought to be due to enlargement of the lymphatic glands of the portal vein, to a catarrhal condition of the bile duct, to duodenal catarrh and to the direct action of the treponemata on the liver. The 1 Berl. klin. Wchnschr., 1910, Ixvii, p. 238, THE LIVER 275 latter theory is probably correct. The condition may or may not be accompanied by enlargement of the liver with pain and tender- ness. Fever is usually present, the urine contains bile and the feces are more or less clay-colored. The jaundice may disappear spontaneously in three or four weeks or it maj^ persist for months if treatment is not instituted. Acute yelloio atrophy is a grave and always fatal, but fortunately rare, seciiiel of the early icterus of syphilis. The condition may, however, be primary, that is, other symptoms may develop before the jaundice. The symptoms are the same as those noted in acute yellow atrophy due to other causes, namely, headache, tachycardia, insomnia, "coffee grounds" vomit, tarry stools, hemorrhages Fig. 57. — Treponema pallida iu liver. Levaditi's stain. from the mucous membranes, and into the skin, convulsions, coma and death. The liver diminishes rapidly in size. The urine is decreased in amount and contains bile, albumin, casts, mucin and tyrosin. Cirrhosis of the liver due to syphilis is, as a rule, a late manifes- tation, occurring from three to ten or more years after infection and is not infrequent. The symptoms are similar to those seen in non-luetic cirrhosis. Sometimes the first symptom noticed is an abnormal "appetite and thirst. This may be followed by gastro- intestinal symptoms such as pain after eating, belching, constipation, etc. Jaundice usually occurs early and may be very marked. The urine is scanty, contains bile and the feces are generally clay-colored. Vomiting is a rather frequent symptom. There may be acites and 276 SYPHILIS OF THE LIVER, GALL-BLADDER pleural effusion sometimes occurs. More or less cachexia usually exists. The liver may be either atrophic or hypertrophic, smooth or nodular. Gummata of the liver will produce symptoms varying with the size of the tumors and their location. They may be single or multiple and if located on the surface of the liver usually may be palpated. Diagnosis. — The icterus occurring early in the course of syphilis is usually an accompaniment of cutaneous manifestations and may be diagnosed from them or by laboratory procedures. If the icterus occurs as the only symptom, the diagnosis may not be made, although syphilis should be thought of if no other cause of the icterus is found. Laboratory procedures will in the majority of such cases clear up the diagnosis. Acute yellow atrophy due to syphilis must be diagnosed from the history, the presence of other manifestations of syphilis, laboratory procedures and postmortem findings. The differential diagnosis of syphilitic cirrhosis from that due to alcohol may be exceedingly difficult. The history, the presence or absence of other symptoms or lesions of syphilis, the Wassermann and luetin tests and therapeutic procedures may enable the physician to make a correct diagnosis. Howevel, it must be remembered that syphilis and alcoholism are very frequently associated. The Wassermann test on the acetic fluid has been found positive in these conditions. Gummata of the liver may resemble carcinoma and present some difficulty of diagnosis. The following are the main points of differentiation : Gumma. Carcinoma. 1. History of syphilis. 1. None. 2. Perhaps presence of other syphil- 2. None. itic manifestations. 3. Nodules do not increase much in 3. Nodules increase rapids size. 4. Usually no pain. 4. Pain usually present. 5. Usually spleen enlarged. .5. Spleen normal. 6. Usually in middle life or younger. 6. Usually past middle life. 7. Little cachexia. 7. Marked cachexia. 8. Wassermann or luetin usually posi- 8. Negative. tive. 9. Improvement under specific ther- 9. No improvement. apy. Prognosis. — The prognosis of the icterus occurring early in the course of the disease is exceedingly good, as it usually disappears spontaneously in three or four weeks even without treatment, while under specific medication it clears up in a remarkable manner. THE SPLEEN 277 Acute yellow atrophy either of syphilitic or non-syphihtic origin is always a fatal disease, death, as a rule, taking place within a week or ten days after the onset of symptoms. Syphilitic cirrhosis is, as a rule, of grave import, although under vigorous antisyphilitic treatment improvement or even cure may be noted. The same may be said of gummata of the liver, although the prognosis of this condition depends to a large extent upon the number, the size and location of the gummata. Treatment. — The early icterus of syphilis will require no treatment but specifics, while the treatment of acute yellow atrophy is entirely symptomatic. When acites or pleural effusion occurs in cirrhosis of the liver due to syphilis the fluids should be removed by aspiration, otherwise the treatment consists of specific medication and general measures. Rest in bed should be insisted upon. Gummata of the liver require no other treatment than specific and general. THE GALL-BLADDER. No mention of syphilis of the gall-bladder in the acquired form of the disease can be found in the literature. (See page 386.) THE SPLEEN. Pathology. — Syphilitic enlargement of the spleen is quite frequently noted in the early course of the disease, but usually the organ returns to its normal size upon the disappearance of the more acute symptoms. Diffuse hyperplasia of the spleen later in the course of syphilis with thickening of the reticulum and trabeculse is sometimes observed. Amyloid change has been noted in cases of long standing. Gummata of the spleen are rather rare and vary markedly in size and number. Sometimes being miliary and very numerous and at other times are single and attain a size which render them readily palpable. Treponemata may usually be demonstrated, especially in the walls of the arteries. Clinical History. — Syphilitic involvement of the spleen is often accompanied by involvement of other organs, so symptoms referable to this organ may be obscure. It usually occurs early, sometimes before the syphilodermata are manifest, and, as Wile and Elliott^ have pointed out, probably represents the earliest visceropathy. The spleen may be markedly enlarged, palpable and sometimes movable. Tenderness may or may not be noted and it may be either hard or soft. According to Osier and Gibson^ a leukocytosis sug- gestive of leukemia may be present. 1 Am. Jour. Med. Sc, 1915, cl, p. 512. 2 Power and Murphy: System of Syphilis, London, 1909, iii, p. 69. 278 SYPHILIS OF THE LIVER, GALL-BLADDER Diagnosis. — There is nothing in the symptomatology of syphiHs of the spleen which may be regarded as pathognomonic. The diagnosis of the involvement of this organ therefore must rest upon indirect evidence, history, other manifestations of syphilis, laboratory findings and therapeutic tests. Prognosis. — The prognosis of the sj'philitic involvement of the spleen early in the course of the disease is good, as most cases readily return to normal upon the institution of specific treatment. The outlook of the later syphilitic disease of the spleen is not quite so favorable. Treatment. — In splenic syphilis no other treatment than specific and general is indicated. THE PANCREAS. Pathology. — Syphilis of the pancreas was formerly considered a rare condition, but Warthin and Wilson^ state that in 39 cases of old latent syphilis the pancreas was not found normal in a single one. The pathological condition found was an interacinar and interlobular fibrosis with disappearance of the islands of Langerhans through fibrosis. There was also atrophy with compensatory hypertrophy, regenerative new formation of acini, and infiltration of lymphocytes and plasma cells. The condition is said by these authors to be essentially a "patchy" one, the tail and body of the organ being more frequently involved than the head, except in the most severe cases when nearly the entire gland may be affected . Tre- ponemata were found in the active inflammatory areas of one case. Gummata of the pancreas have also been described. Clinical History .^ — Syphilis of the pancreas certainly is rarely recog- nized clinically. The symptoms of syphilitic pancreatitis are epi- gastric pain, tenderness, fatty diarrhea, cachexia and glycosuria. Gummata of the head of the pancreas may cause obstructive jaundice, while pressure of a gumma on the inferior vena cava may produce edema of the lower extremities. Gummata may also some- times be palpated. Diagnosis. — The diagnosis of syphilitic pancreatitis must rest upon the symptoms of pancreatic disease as outlined above as well as upon the histor}^, other manifestations of syphilis or positive laboratory evidence of its presence. Prognosis. — The prognosis of syphilitic pancreatitis is grave but will depend upon the date of its recognition and its extent. Treatment.— The treatment of syphilis of the pancreas aside from the specific and general treatment of syphilis consists of a careful regulation of the diet (the restriction of carbohydrates) and perhaps the use of carbonated waters and pancreatin. lAm. Jour. Med. Sc, 1916, clii, p. 157. CHAPTER XV. SYPHILIS OF THE BREAST, THYROID, THYMUS, ADRENALS AND PITUITARY" BODY. THE BREAST. Pathology. — Chancre of the breast has been referred to in Part I in the chapter on Chnical History. Diffuse syphilitic infiltration and circumscribed gummata have also been observed, the former being the rarer of the two conditions. They are, as a rule, late manifestations of the disease, although diffuse infiltration has been noted early and the subcutaneous tissue as well as the glandular structure may be attacked. Gummata may be single but usually are multiple, while one or both breasts may be involved. Clinical History. — Syphilitic mastitis may cause no other symptom than swelling of the gland which may become half again as large as normal and may be discovered only accidentally. Pain and tenderness may or may not be present but usually are. The skin over the breast usually is not discolored, but is smooth and the gland is hard and firm. Gummata of the breast occur as lumps varying greatly in size. As a rule they are more or less tender. If left untreated they may break down and ulcerate through the skin, and upon healing form cicatrices, the skin being adherent to the deeper structures. Diagnosis. — Syphilitic mastitis must be differentiated from mastitis due to other causes, and can usually be accomplished by the history, the presence of other syphilitic manifestations, positive laboratory evidence and therapeutic tests. The diagnosis of gummata before ulceration has taken place will also depend upon the indirect evidence above mentioned or the tumor may be removed for microscopic examination. Ulcerating gummata may be mistaken for carcinoma, but the age of the patient, the history, and laboratory tests should make the diagnosis clear. Prognosis. — ^The prognosis of diffuse syphilitic infiltration of the breast is probably better than that of mastitis due to other causes as it usually yields to specific therapy. Gummata also, as a rule, are rather amenable to treatment although, as stated above, upon healing cicatrices may form, causing adhesions of the skin to the deeper structures. Treatment. — No treatment but specific and general is indicated in syphilitic mastitis. Ulcerating gummata will require surgical dressings. 280 SYPHILIS OF THE BREAST, THYROID, THYMUS THE THYROID GLAND. Pathology. — Reimers^ is said to have observed that half the cases of early syphilis show enlargement of the thyroid. Davis,2 in 1910, reported a case of gumma of the thyroid and reviewed the literature, finding only ten other cases diagnosed histologically. Clinical History. — Davis states that gummata of the thyroid may cause severe dyspnea by pressure on the trachea and by inducing an edema of the larynx. This may also interfere with deglutition. Interference with the function of the thyroid may cause myxedema. Symptoms of exophthalmic goiter also may occur. The nerve trunks of the neck may be involved, causing disturbance of their functions. Gummata of small size may cause no symptoms but the enlargement. In Davis's own case the patient gave a history of syphilis five years previous to admission to the hospital. At the time of admission the patient complained of hoarseness, great inspiratory dyspnea and pain on swallowing. This condition had lasted for four months with frequent exacerbations in which the dyspnea was so great that the patient became cyanosed. Tracheotomy was performed eight days after admission but without relief, death following twelve hours later. Diagnosis. — The diagnosis of syphilis of the thyroid can only be made by the history, evidences of syphilis of other regions, labora- tory findings, including histological examination, and therapeutic tests. Prognosis. — As stated above Davis's patient died twelve hours after tracheotomy. Of the seven other cases of gummata of the thyroid in acquired syphilis which were confirmed by histological examination and reviewed by Davis, three died and four recovered under specific medication, while eight cases reviewed by Davis which were diagnosed only clinically recovered under specific treatment. Treatment. — The treatment of syphilis of the thyroid, aside from specific and general measures, is symptomatic. Tracheotomy may be necessary on account of the dyspnea. THE THYMUS GLAND. Syphilis of the thymus is an exceedingly rare condition, especially in the acquired form of the disease. The condition as it occurs in congenital syphilis will be described in Part III. 1 Osier and Gibson: In Power and Murphy's System of Syphilis, London, 1909, iii, p. 14. 2 Arch. Int. Med., 1910, v, p. 47. THE PITUITARY BODY 281 THE ADRENALS. Involvement of the adrenals is rare in acquired syphilis. However, patients dying of Addison's disease are sometimes found to have gummata of these glands. Sezary^ has reported a case in which some of the symptoms of Addison's syndrome were observed and in which at autopsy numerous treponemata were found in the cortex of the adrenals. The author has seen a case of Addison's disease in which a definite history of syphilis and a four-plus Wasser- mann reaction were obtained. Syphilitic involvement of the adrenals without the symptoms of Addison's disease cannot be diagnosed clinically, although syphilis of the adrenals might well be suspected in cases of Addison's disease and laboratory procedures instituted to determine its presence. Addison's disease, whether of syphilitic etiology or not, is always a fatal disease, so treatment would be of no avail, and should there- fore be symptomatic. THE PITUITARY BODY. Syphilis of the hypophysis is an exceedingly rare condition. Hektoen,2 in 1896, reviewed the literature and reported a gumma of this body. Gushing^ reports a case in which there had been polyuria, poly- dipsia and glycosuria, although no acetone bodies were present. The diagnosis of diabetis mellitus was made, and under diabetic diet the patient improved. Less than a year later the condition recurred with intense frontal headache, vertigo, and vomiting. The patient then became very drowsy, irrational and disoriented; developed Cheyne-Stokes respiration, projectile vomiting, thick speech, static ataxia, tremor, incoordination of movements, etc., and died. The necropsy revealed a syphiloma, large enough to be distinctly seen by the naked eye on section, involving the anterior and intermediate lobes of the pituitary body. The diagnosis of syphilis of the hypophysis would be extremely difficult during life. Cases of glycosuria, especially if the acetone bodies are not present, should perhaps be looked upon with suspicion and a Wassermann test made. In cases of glycosuria in which the Was- sermann is positive it might be well to institute specific treatment. In certain cases of acromegaly, gigantism and infantilism a Wasser- mann test might be of service. 1 Gaz. d. Hop., 1914, Ixxxvii, p. 1317. 2 Tr. Chicago Path. Soc, 1897, ii, p. 129. 3 The Pituitary Body and its Disorders, Philadelphia and London, 1912, p. 263. CHAPTER XVI. SYPHILIS OF THE GENITO-URINARY ORGANS. THE PENIS. Syphilitic affections of the mucous membrane of the penis, have been described in Part I in the chapter on CHnical History. The body of the penis may also be the seat of gummata, and sj^ihihtic inflammation of the corpora cavernosum has been described. Gummata of the body of the penis may be single or multiple and vary from one or two millimeters to one centimeter or more in diameter. They are usually painless and may be discovered acci- dentally. They may soften and ulcerate either into the urethra or on the surface. The diagnosis is, as a rule, easy as gummata of this region are scarcely to be mistaken for any other condition, especially if labora- tory tests are applied. Gummata of the body of the penis if recognized early usually will disappear under specific therapy without leaving any serious after-effects. If, however, an early diagnosis is not made and vigorous treatment instituted, ulceration may take place either into the urethra or onto the surface which upon healing will form cicatrices and more or less deformity. Sometimes the process is so extensive as to destroy the entire penis. THE TESTICLE. Pathology. — Syphilis of the testicle occurs in two forms, as a diffuse orchitis or epididj^mitis or gummata. In either case the process usually begins in the testicle and later involves the epididymus. Diffuse syphilitic orchitis presents on section delicate bands of connective tissue of a whitish color and extending from the rete to the tunica albuginea. Microscopically, the intertubular stroma is seen to contain a few leukocytes and is greatly thickened by the deposit of new connective tissue, while a,trophy and hyaline change are seen in the tubules. Hypertrophy of the endothelium of the arteries is also observed. Gummata of the testicle occur as firm nodules enclosed in fibrous tissue. These may coalesce, forming a large mass which may break down and ulcerate. (See Fig. 58.) THE TESTICLE 283 Clinical History. — Syphilis of the testicle is of frequent occurrence and may be found as early as two or three months after infection although, as a rule, it is a late manifestation. The diffuse syphilitic orchitis causes a swelling of the gland which is usually uniform and painless but may be tender. The development of the condition is slow and may only be recognized accidentally. The epididymis may or may not be involved. If it is involved, it is usually secondary. Hydrocele is sometimes observed. Fig. 58. — Gumma of testicle. Gummata of the testicle also give rise to little or no pain. These tumors vary in size from two or three millimeters to several centi- meters. While the condition is usually unilateral it may be bilateral. There will be diminution in the sexual desire and even complete impotence, depending upon the extent of the lesion. Diagnosis. — Diffuse syphilitic orchitis must be differentiated from traumatic orchitis, and from gonorrheal orchitis. In traumatic orchitis there is history of injury, and the development of the swelling is rapid with pain, tenderness and redness of the skin. Gonorrheal orchitis usually is to be distinguished by the history of recent gonorrheal urethritis or its presence, by the more acute course, or by the complement-fixation test for gonorrhea and the Wassermann test and by therapeutic procedures. Gummata of the testicle may be mistaken for tuberculosis or carcinoma. Tuberculosis is more frequently found in the epididymis, is more often associated with suppuration, causes more cachexia, and tubercle bacilli may be found in the discharge. However, the 284 SYPHILIS OF THE GEN I TO-URINARY ORGANS diagnosis may have to rest upon laboratory evidence and thera- peutic tests. In carcinoma there is enlargement of the lymph glands, and section of the growth will show the typical picture of carcinoma, while in gumma of the testicle there is usually no lymphatic enlarge- ment, sections will not show the picture of carcinoma and syphilitic laboratory tests will generally be positive. Furthermore, upon the administration of specific remedies there will usually be improve- ment of the condition. Prognosis. — The prognosis of the healing of syphilitic involvement of the testicle is good but the prognosis of the function of the organs depends upon the extent and severity of the process. Treatment. — Syphilis of the testicle as a rule needs no special treatment other than wearing a suspensory bandage. If hydrocele exists, the fluid should be removed by aspiration. Ulcerating gum- mata should be treated antiseptically and if the involvement is very extensive it may be necessary to remove the testicle. THE PROSTATE. Pathology. — Syphilitic prostatitis is a most rare condition. Cook^ in 1912 reported a case of gumma of the prostate and reviewed the literature, finding mention of but six cases. Rush^ in 1913 reported an additional case. Clinical History. — The symptoms of syphilis of this gland are similar to those observed in non-luetic prostatitis and depend upon the extent of the condition. In Cook's case there was painful urination, sensation of fulness in the perineum, becoming painful on defecation, if constipated, and following coitus, slight, thin, sticky, brownish discharge, increased on pressure of prostate which was enlarged so that the size could not be determined, and of the consistency of a hard rubber ball. Diagnosis. — Syphilitic involvement of the prostate must be differentiated from simple hypertrophy, gonorrheal prostatitis and carcinoma, and should be accomplished by the history, the presence of other syphilitic manifestations, laboratory procedures and specific therapy. Prognosis. — Syphilis of the prostate is so rare that little data as to its prognosis are available. In Cook's case a very greatly enlarged prostate returned to normal size after the administration of specific remedies. Treatment. — ^Aside from the general and specific treatment of syphilis of the prostate, light prostatic massage may be of benefit and in case of suppuration prostatectomy may be advisable. 1 Interstate Med. Jour., 1912, xix, p. 980. 2 Med. Rec, 1913, Ixxxiv, p. 1028. THE CERVIX 285 THE SEMINAL VESICLES. Power^ states that no trustworthy evidence of syphihtic involve- ment of these organs has been recorded. THE VAGINA. Chancre of the vagina has been discussed in Part I in the chapter on CHnical History. That the vagina may be the seat of the syphilomycodermata has also been pointed out. Gellhorn and Ehrenfest" in an exhaustive monograph on syphilis of the internal genitals of the female state that these lesions are very rare in the vagina, but do occur hi the macular, papular and gummatous types. The macular eruption is the most rare and may occur either as isolated reddivsh spots or as a diffuse eruption. The papular syphilomycoderm is more frequently seen in the vagina than the macular. Both the eroded and ulcerative forms of the papular eruption have been observed and do not differ from these lesions seen elsewhere. According to the above-mentioned authors Oppen- heim states that the hypertrophic or vegetating papular lesion is excessively rare in the vagina. The gummatous syphilomycoderm, according to Gellhorn and Ehrenfest, is very rarely seen in the vagina except as a continuation of a gumma from adjacent regions. It is sometimes seen, however, as an ulcer which may lead to fistulse and strictures. None of the syphilomycodermata of the vagina presents characteristic symptoms and therefore these lesions are only recognized by examination with a speculum. THE CERVIX. Chancre of the cervix has been described in Part I. According to Gellhorn and Ehrenfest it is the most frequent of all the syphilitic lesions of the internal genitalia in the female. The other syphilitic lesions observed on the cervix consist of macular, papular and gummatous syphilomycodermata. The first two types have been but infrequently described. Gellhorn and Ehrenfest in their monograph have added eight cases to the literature. According to these authors the macular eruption occurs as small circular areas which become eroded. They may be single or multiple and several may coalesce, forming larger areas. Treponemata are very abundant, which accounts for their great infectivity. The papular lesion which is more common usually consists of very 1 System of Syphilis, London, 1909, ii, p. 145. 2 Am. Jour. Obst., 1916, Ixxiii, p. 864. 286 SYPHILIS OF THE GENITO-URINARY ORGANS small elevations, but large papules may occur through the blending of several smaller ones. These lesions rarely develop into the vegetating type but the more frequent sequel is an ulceration. Gellhorn and Ehrenfest state that these ulcerations show a char- acteristic color which is not found in any non-specific affections. This color consists of a yellow or whitish yellow which is obviously due to fatty degeneration of the superficial cell layers. An undertone of red or pink is observed in the yellow and is distributed as dots or fine lines which is thought to represent many newly formed and dilated capillaries. The macular and papular lesions which have not ulcerated give rise to no distinctive symptoms but when ulceration has taken place there is usually a profuse yellowish discharge. The gummatous syphilomycoderm occurring on the cervix is more common than the other types. These lesions usually ulcerate and may extend to the vagina or into the cervical canal. The usual color is a yellow but it may vary from whitish or dirty gray to a dark red or purple. There is usually no pain but bleeding and a yellowish discharge are common. Gellhorn and Ehrenfest mention the following characteristic features of the syphilomycodermata of the cervix: 1. Specific ulcers, as a rule, produce very little secretion; only extensive tertiary ulcers or necrotic gummata cause a pathological discharge. 2. There is no pain either spontaneous or on touch, 3. Luetic lesions are frequently at some distance from the external OS, which hardly ever occurs in non-specific ulcerations of the cervix. 4. Syphilitic ulcers are characterized by their sharp outline. 5. Syphilitic ulcers are usually covered with a film-like deposit which may be wiped off easily and exhibits a characteristic fatty luster. 6. Syphilitic ulcers show very little if any inflammatory reaction of the surrounding mucosa. Diagnosis. — In making a diagnosis of chancre of the cervix an examination should be made for treponemata. If they are not found, the Wassermann test should be performed at frequent intervals (every two or three days) until positive or until it is certain the condition is not syphilitic. The diagnosis of the macular and papular lesions is generally easy owing to the usual presence of other manifestations of the disease such as syphilodermata, and the Wassermann is usually positive. The diagnosis of the gummatous lesions is not always so easy, as there may not be other manifestations of the disease and the Wassermann may be negative. The provocative Wassermann in THE UTERUS 287 such cases is of value, while the removal of a portion of the growth for microscopic examination and the results of specific therapy should clinch the diagnosis. The gummatous lesion of the cervix may resemble carcinoma, as in one of the cases reported by Gellhorn and Ehrenfest, in which a cauliflower growth the size of a child's fist and occupying the entire cervix was observed. This was differentiated from carcinoma only by microscopic examination, as the Wassermann was negative and in spite of specific therapy the patient died from malignant syphilis. Treatment. — No other treatment than specific and palliative is indicated in syphilis of the cervix, as ordinarily these lesions are amenable to proper therapy. THE UTERUS. Although chancre of the endometrium has not been observed it is conceded as possible for the treponemata to enter at the cervical canal and a chancre develop on this tissue. Gellhorn and Ehrenfest state that no conclusive evidence of involvement of the endometrium in the so-called secondary stage of the disease has been published, although Franceschini agrees with Chearleoni, Fasola, and others who claim that leucorrhea, uterine neuralgia and dysmenorrhea may be produced by such lesions. An endometritis occurring late in the course of the disease and depending upon a gummatous condition of the endometrium has been described by numerous writers. Marshall^ states that in endo- metritis due to ulcerating gummata there is a mucopurulent dis- charge and hemorrhage. This writer, however, does not mention any personal observations nor does he quote from the observations of others. Gellhorn and Ehrenfest^ have pointed out that the only well-authenticated case of gummatous endometritis described in the literature was reported by Hoffmann. In this case the patient was admitted to the hospital with chronic sepsis two months following the delivery of living twins. She died four weeks later and at autopsy the entire surface of the endome- trium was involved with gummatous tissue several centimeters in thickness and extending deeply into the myometrium. Gummata of the myometrium have been described by several writers, but Gellhorn and Ehrenfest after a critical review of all of the available reported cases reach the conclusion that the evidence is not sufficient " on which to base the pathology of this condition or to attempt a classification of its various types." These authors 1 Syphilology and Venereal Diseases, New York, 1906, p. 180. 2 Am. Jour. Obst., 1916, Ixxiii, p. 864. 288 SYPHILIS OF THE GENITO-URINARY ORGANS further state that there is even a greater paucity of facts concerning the "characteristic sclerosis" of the myometrium. Letulle is quoted as having found a typical endophlebitis in the veins of the sub- mucosa, while Morisani found an endarteritis. All other cases are based upon improvement of irregular hemorrhages under antiluetic treatment. THE FALLOPIAN TUBES. That the Fallopian tubes may be the seat of the syphilitic process is within the range of possibility, but Gellhorn and Ehrenfest con- sider that none of the cases so far reported will bear the scrutiny of modern knowledge. Even the case of Bouchard and Lepine, which is quoted by all writers on the subject, they consider as not con- clusive. In this case both tubes of a woman, aged forty years, were found at autopsy to be thickened to the size of the finger with oblit- eration of the lumen. On section three gummata the size of a hazel- nut, soft and of a reddish color, were found in each tube. Micro- scopic examination of sections were made and described, but the description does not correspond to the findings considered character- istic by modern observers. The diagnosis is based upon similar tumors found in the liver and brain and a rarefying osteitis of the right clavicle. «; THE OVARIES. Numerous writers have described both the pathology and clinical history of syphilitic oophoritis. The work of Lancereaux^ is prob- ably most frequently quoted. This writer describes two cases. The first case is that of a woman, aged thirty-three years, who was admitted to the hospital with manifestations of syphilis of the nervous system and a history of syphilis ten years previously. At autopsy adhesions were found between the uterus, ovary, and the surrounding parts. One of the ovaries contained a white induration which occurred in patches. In the other case the diagnosis of gumma of the ovaries was made from the fact that two tumors the size of an egg were found in the region of the ovaries, which rapidly decreased in size under potassium iodide. Marshall^ states that the symptoms of syphilitic gvaritis are not distinctive, apart from other signs of syphilis. He continues that there may be pain and tenderness in the region of the ovary, but that the chief sign is menorrhagia in the earlier stages, followed by intermittent metrorrhagia. Gellhorn and Ehrenfest,^ after critically reviewing all of the avail- able literature, reach the following conclusions : 1 Traite de la Syphilis, Paris, 1868, i. p. 286. 2 Syphilology and Venereal Disease, New York, 1906, p. 180. 3 Am. Jour. Obst., 1916, Ixxiii, p. 864. THE URETHRA 289 "Various changes in the ovaries (simple enlargement, syphilitic oophoritis, tertiary sclerosis of the ovary, ovarian gumma) have been described as typical expressions of the secondary and tertiary stages of luetic infection, but in no instance (with the possible ex- ception of Hoffmann's case^) has positive proof been furnished that such alterations are actually due to a local luetic process. The fact that in some syphilitic patients an amenorrhea or, more commonly, a metrorrhagia disappears after specific medication, can- not be accepted as evidence of a syphilitic ovarian lesion. Spiro- chseta have as yet not been demonstrated in the ovaries of adults." THE URETHRA. Chancre of the urethra has been discussed in Part I in the chapter on Clinical History. The urethra is also occasionally the seat of gummata. Dey and Kirby-Smith,^ in 1915, reported two cases and reviewed the literature. In both of their cases ulceration was observed. Gumma of the urethra may occur either primarily or as an ex- tension from the corpora cavernosa. There is more or less enlarge- ment of the penis while ulceration is usually present and a thin serosanguinolent discharge is found. If this condition remains untreated, a fistula may be formed or it may become phagedenic. Gumma of the urethra must be differentiated from gonorrheal urethritis and chancre of the urethra. In the former condition the discharge is more purulent and contains gonococci, while in the latter condition there will be history of exposure, and probably inguinal adenitis, instead of a history of other manifestations of syphilis and probably no adenitis. The Wassermann or luetin tests are more frequently positive in gumma than in chancre and of course are negative in gonorrhea. If seen before marked ulceration has taken place, gummata of the urethra usually disappear under specific medication. If, however, ulceration or phagedena has occurred it may be most refractory, and even upon healing marked deformity may result. Treatment. — Ordinarily no other treatment than specific and general is indicated, but if ulceration is marked injections of bichlo- ride of mercury (1 to 4000) may be used, and if fistula or phagedena exist, surgical dressings should be applied. 1 This is the case quoted under syphilis of the endometrium in which in addition to the gummatous endometritis the right tube and ovary were transformed into a gummatous mass. 2 South. Med. Jour., 1913, vi, p. 20. 19 290 SYPHILIS OF THE GENITO-URINARY ORGANS THE BLADDER. Syphilis of the bladder is apparently exceedingly rare. Simons^ reported a case of probable syphilitic ulcer of the bladder. In this case hypogastric pain, dull and dragging in character, at first inter- mittent but later continuous, was noted. The pain was increased when the bladder was even moderately distended with urine, so that urine was voided about every hour during the day and five or six times at night. The urine was clear, amber, acid, and without sediment, except a moderate number of white cells. Cystoscopy revealed in the region just behind the trigone several round ulcers with clear-cut edges and about twice the size of tl\e normal ureteral orifice. The right ureteral orifice was irregular, due to the proximity of a large, irregular, ulcerated patch adjoining it on its lateral aspect. Just mesial to the right ureteral orifice and in the trigone a very small reddened spot, resembling a tubercle that had not ulcerated, was seen. After passing from observation, six weeks later, there was a marked exacerbation of the condition, especially the hypogastric pain, while the urine showed both red and white blood cells. At this time cystoscopy revealed the entire trigone and a small part of the post-trigone region raw, angry, red, and markedly injected, but with no distinct ulcerations present. Diagnosis. — The diagnosis of syphilis of the bladder can only be made by the symptoms of bladder disturbance, urinalysis, cysto- scopy, the history of syphilis, or the presence of other manifestations of the disease, positivejaboratory tests and the improvement of the condition under specific therapy. Prognosis. — The prognosis should, as a rule, be good if recognized before the process has progressed too far. The great danger is the perforation of the bladder wall by ulceration. In Simons's case complete apparent recovery, both symptomatically and anatom- ically, followed specific medication. Treatment. — ^The treatment of syphilis of the bladder should con- sist of vigorous specific treatment with rest in bed. Irrigations with bichloride solution (1 to 4000) should be employed. Syphilitic ulcers which do not readily heal under specific medication and irrigations might be touched with silver nitrate by means of an operating cystoscope. THE URETER. According to Osier and Gibson,^ Hadden has described an un- doubted case of syphilitic involvement of the ureter. Most other syphilographers are silent on the subject. 1 Jour. Am. Med. Assn., 1913, Ix, p. 1943. 2 Power and Murphy: System of Syphilis, London, 1909, iii, p. 79. THE KIDNEY 291 THE KIDNEY. Pathology. — All types of nephritis with syphilis as the cause, as well as gummata of the kidney, have been described. During the early course of the disease, especially when the cutaneous lesions are most manifest, disease of the kidney is of quite frequent occur- rence. This, however, is usually rather mild in character, being in all probability due to the toxins generated and not to the trepone- mata per se. However, acute and chronic nephritis may develop, and while there is nothing distinctive of syphilis in the anatomical picture, and treponemata have not been demonstrated in the kid- neys in acquired syphilis, there seems no doubt but that the con- dition is, sometimes at least, directly due to the action of these organisms. Amyloid kidney is also sometimes observed as a consequence of syphilis. Gummata of the kidney, while exceedingly rare, do occur and vary in size from 1 or 2 mms. to 1 cm. or more. They are usually multiple, and appear as pale yellow nodules. Bowlby^ has reported a case of diffuse gummatous infiltration. Clinical History. — Disease of the kidney occurring early in the course of syphilis is manifest by small amounts of albumin and a few hyaline and granular casts, and is usually mild in character. It may, however, become severe in type and present the clinical picture of acute nephritis, developing suddenly, usually with severe pains in the lumbar region, anorexia, fever, and perhaps nausea and vomit- ing. There is more or less edema of the face, legs, and scrotum. The urine is scanty, highly colored, of a low specific gravity, and contains enormous quantities of albumin (in one personal case 32 grams per liter), and many tube casts of various kinds. In the most severe cases there may be anuria and early development of coma. Munk' has recently described a type of syphilitic kidney disease which he considers more degenerative than inflammatory, occurring early in the course of the disease and more frequently in women than in men. It is characterized by a marked anemia, more or less edema, malaise and weakness, dyspnea, occasional headache, rarely vomiting, and little or no fever. The urine is decreased in amount, the twenty-four-hour quantity varying from 300 to 1200 c.c. It is, however, normal in color and reaction, but with high specific gravity, and an albumin content as high as 2.8 per cent. Microscopically, a few red cells, many white cells, cylindrical epithelium, and hyaline casts are seen. However, the feature to which Munk particularly calls attention is the presence of lipoids observed as fine droplets or 1 Tr. Path. Soc, London, 1897, xlciii, p. 128. 2 Dermat. Ztschr., 1914, xxi, p. 591. 292 SYPHILIS OF THE GEN I TO-URINARY ORGANS in packets, either in the epithehal cells or in the casts, which are doubl}^ refractive through a Nicols polariscope. Under the ordinary microscope these droplets resemble neutral fat globules, but when examined with the polariscope show a dark central cross separating four bright peripheral quadrants. While Munk found these lipoids in the urine of several nephritics of non-1 uetic origin they were more abundant in syphilitic nephritis. Stengel and Austin^ have reported similar findings, and in experi- mental uranium nephritis in rabbits and chromate nephritis in a dog secured negative results. Chronic nephritis is of comparatively infrequent, occurrence and is usually seen from three to ten years following the syphilitic infection. It may, however, occur earlier. In one case seen by the author albumin was found in the urine eighteen months following the appearance of the chancre. The symptoms will depend upon whether interstitial or parenchymatous nephritis exists. In the former case it is characterized by polyuria, small amounts of al- bumin, few hyaline casts, little or no edema, but high blood-pressure. In parenchymatous nephritis the urine is scanty, of high specific gravity, contains more or less albumin, and usually many hyaline and granular casts. There is usually edema, and the blood-pressure is increased. Amyloid kidney is also of late occurrence in syphilis, and is char- acterized by a large amount of albumin in the urine, which is usually diminished in quantity, but may be increased. There is generally more or less anemia and edema of the face and legs. The blood- pressure is normal or low. Gummata of the kidney occur late in the course of the disease and will cause symptoms depending upon their size and location. They may sometimes cause symptoms resembling renal calculus. Occa- sionally they develop to such a size that they are palpable. Diagnosis. — Acute syphilitic nephritis is to be distinguished from acute nephritis of other etiology, according to Osier and Gibson,^ first, by the fact that the amount of urine in syphilitic nephritis is not lessened to the same extent as in other forms with the same amount of albumin; second, in proportion to the amount of albumin casts are rare; third, the general type of the disease affects the patient, as a rule, less than the other types. To these features, however, must be added the history of syphilis or other evidence of it, positive laboratory findings, and in some cases improvement with specific treatment. The diagnosis of chronic syijhilitic 7iephritis may be most difficult but it seems to the author that if all nephritics were examined for 1 Am. Jour. Med. Sc, 1915, cvlix, p. 12. 2 Power and Murphy: System of Syphilis, London, 1908, iii, p. 74. THE KIDNEY 293 syphilis, both chnically and by laboratory methods, more cases of syphilitic nephritis would be found. Of course other evidences of syphilis and positive laboratory tests would not be absolute proof that the nephritis was luetic, but the improvement of the condition under carefully administered specifics would be strong presumptive evidence that such is the case. Gummata of the kidney must be distinguished from malignancy and from renal calculus. A diagnosis of malignancy of the kidney has been made on the clinical findings and operation performed, when the true nature of the condition was found to be syphilitic. Such mistakes in the majority of cases at least, would not occur if all patients with kidney tumors were subjected to careful laboratory tests for syphilis. Renal calculus can usually be recognized by the a"-rays. Prognosis. — The early involvement of the kidney by the syphilitic process when but a small amount of albumin and few casts are present, as a rule, readily yields to specific therapy. However, when the process assumes an acute type with all the symptoms of acute nephritis the outlook must be considered most grave. Other forms of syphilis of the kidney (chronic nephritis, amyloid kidney, gum- mata) present a more favorable outlook, although, as with syphilis of the heart, the prognosis should be reserved until the effect of antisyphilitic medication be noted. Treatment. — As with syphilis of the heart so with kidney syphilis, the treatment should be twofold, that is, directed toward the syphilis and toward the kidney condition. In the slight nephritis occurring early in the course of syphilis speciJ&cs and general treatment alone are indicated. Specifics, however, must be administered with extreme caution in all nephritic conditions; the urine being examined for albumin and casts as well as the phenolsulphonephthalein test performed at frequent intervals. In the more severe types of syphilitic nephritis rest in bed is imperative. Diuretics, such as digitalis and potassium citrate, as well as cathartics, should be administered. Hot packs to promote diaphoresis should be applied, especially in acute cases. The diet should be nourishing, and consist largely of carbohydrates. CHAPTER XVII. SYPHILIS OF THE BONES, JOINTS, BURSiE, TENDONS AND MUSCLES. THE BONES. Pathology. — Syphilitic involvement of the bones consists of periostitis, osteitis and osteomyelitis. Periostitis may either be localized or diffuse. In the localized variety the process may extend inward and involve the bone proper or outward, forming an ulcer of the skin. In the diffuse variety of periostitis, which is a rarer condition, considerable swelling is seen, although it is usually greater at one end. The periostium may separate from the bones, and spicules of bone may be formed from the ossifying periostium. The process begins with a hyperemia followed by a swelling consisting of a network of new connective- tissue fibers with an infiltration of lymphocytes. As the connective tissue arises from osteal cells a certain number are differentiated into bone cells and osteophytes are formed. Gummatous involvement of the periosteum may occur but it usually is followed by extension to the bone itself. Osteitis occurs either in circumscribed localities or may be diffuse, affecting the entire bone. At first there is usually a thickening or sclerosis of the bone which may continue as such but generally absorption takes place and there is not only loss of the new formed osseous deposits but also of the sound bone. The Haversian canals become enlarged by the absorption of the bony tissue around them, and adjacent canals may unite forming irregular spaces. The process may progress until large portions of the bone are destroyed. At times the sclerotic condition persists and the bone becomes exceedingly hard, resembling ivory. The process of infiltration may take place on the surface of the bone beneath the periosteum when outgrowths or exostoses are formed. When the process encroaches on the bloodvessels cutting off the blood supply necrosis results. Gummatous involvement of bone proper takes place as foci varying in size from 1 mm. to 1 or 2 cm. If the gummata are not very large, complete absorption may take place. However, if absorp- tion is incomplete, a portion of the gumma may remain as a caseous mass and the process may extend as an osteitis, causing more or THE BONES 295 less destruction of bone. As a result of the osteitis the bone may become very fragile and fractures result from light trauma or even muscular contraction. Osteomyelitis. — When the syphilitic process first invades the medulla of the bones the term osteomyelitis is applied. This is usually in the form of a gummatous process, and the gummata may become encapsulated and bony tumors result or they may break down and either perforate the bone proper or find an outlet through the joint. The process may be extensive, causing a thick- ening of the entire bone, or it may be confined to a single small gumma. Fig. 59. — Extensive osteitis of bones of skull. The bones may be attacked by the Treponema pallidum as an extension from the soft tissues, from gummata of the skin or mucous membranes or with the bones of the skull from meningeal in- volvement. Clinical History. — While it is usually stated that the bones which are nearest the surface of the body are most frequently attacked by syphilis and although lesions of these bones are more easily recognized clinically, since the introduction of the .r-rays it has been observed that other bones are rather frequently involved. 293 SYPHILIS OF THE BONES, JOINTS, BURS^ Periostitis may occur very early in the course of the disease, according to Swediaur as quoted by Townsend/ as early as the fifth day following the appearance of the chancre, but it usually Fig. 60. -Syphilitic periostitis and osteitis of cranial, bones showing numerous points of absorption. makes its appearance between the sixth and ninth months and is often much later. Periostitis is undoubtedly the cause of the so-, called osteocopic pains which occur early in the course of syphilis often before the appearance of the skin lesions. These pains are, 1 Morrow: System of Genito-urinary Diseases, Syphilology and Dermatology, New York, 1898, ii, p. 274. THE BONES 297 as a rule, nocturnal and are more frequently found in women than in men. Often there are no objective symptoms, although when the periostitis is severe and localized there will be a more or less elastic swelling having no very definite shape. The skin may be somewhat reddened and movable when superficial bones are attacked. When the process extends outward the skin may be involved and an ulcer produced. Fig. 61. — Osteitis of humeri. Osteitis and osteomyelitis usually occur between the second and third years following the chancre but the gummatous type may appear much later. The symptoms accompanying osteitis and osteomyelitis depend upon the severity of the process and consist of aching pains, tenderness, swelling and symptoms especially associated with the bone affected. Thus if one of the long bones of the lower limb be involved, limping will be observed, or there may be simply a sense of heaviness in the limb. If exostoses are formed, they may often be visible as nodules under the skin or they may be palpable. The rarefication of the bone may lead to spontaneous fracture as mentioned above. 298 SYPHILIS OF THE BONES, JOINTS, BURSM When the bones of the skull are the seat of the syphilitic process the periosteum is usually first attacked and subsequently either the internal or external table or both may become affected. When the bone substance is involved there may be more or less loss of sub- FiG. 62. — Syphilitic osteoperiostitis of ulna (note slight involvement of radius). stance. Occasionally this occurs in the form of rings or semicircles suggestive of the annular papular syphiloderm. Syphilis of the bones of the skull will cause headache, and tender spots can gener- ally be found. Often there will be considerable bulging and the THE BONES 299 process may extend inward, causing compression of the brain with severe headache and other marked symptoms depending upon the location. The usual outcome of syphilitic involvement of the bones of the face is degeneration and loss of substance, and often most gruesome appearances result from destruction of these bones. The so-called saddle nose is not infrequently the result of this involvement. (Fig. 63). Fig. 63. — Saddle nose. The sternum is very frequently the seat of exostoses, as are the long bones, especially the tibia, but they present no unusual features. Syphilis of the ribs may cause severe pain which may simulate pleurisy or intercostal neuralgia. The vertebrae are rarely attacked by the syphilitic process. Hunt,^ in 1914, stated that only 100 authentic cases, of which 4 were his, had been reported up to that time. Whitney and Baldwin,^ in 1915, in 100 unselected cases of undoubted syphilis found 3 cases of gumma of the spine. The process is most frequently found in the cervical region, though it may occur in any portion of the spinal column. All types of syphilitic bone involvement are found. The symptoms are pain, tenderness, rigidity, and deformity. It is sometimes possible to palpate exostoses, especially in the cervical region and the process may be revealed by the .r-rays. 1 Am. Jour. Med. Sc, 1914, cxlviii, p. 164. 2 Jour. Am. Med. Assn., 1915, Ixv, p. 1989. 300 SYPHILIS OF THE BONES, JOINTS, BURSM When the bones of the fingers and toes are attacked by periostitis or osteomyehtis the term syphilitic dactylitis is appHed. The term is also used to designate syphiUtic involvement of the subcutaneous connective tissue and the fibrous structures of the joints of the fingers. The onset of the condition is usually slow and is first observed as a swelling of the affected member. One or more of Fig. 64. — Syphilitic osteitis with necrosis of superior maxillary, hard palate, and tubinates. the digits may be attacked, the fingers being more frequently the seat of the process than the toes, and usually the joints sooner or later become involved. The condition may persist for a considerable length of time and finally be absorbed or the gummatous deposit may become soft and be discharged through a sinus. The bone may be left shortened or lengthened or it may resume its normal size. THE BONES 301 If necrosis occurs, there will be more or less deformity. As with affections of the bones in general syphilitic dactylitis is usually a comparatively late manifestation, occurring, as a rule, from five to fifteen years after the chancre, but it has been noted as early as the second year. Diagnosis. — The so-called osteocopic pains which occur early in the course of syphilis and which are undoubtedly due to invasion of the periosteum by the Treponema pallidum may be mistaken for rheumatism or neuralgia. The usual presence of other manifesta- tions of syphilis or of positive laboratory evidence will make the diagnosis easy in most cases. When these are lacking the fact that the pain generally is worse at night will be suspicious, but this would scarcely be sufficient for a positive diagnosis. The later diffuse periostitis may be mistaken for sarcoma, but an .T-ray plate will reveal the fact that the bone is uniformly enlarged throughout its entire circumference, while in sarcoma the enlarge- ment is on one side only. Osteitis and periostitis of syphilitic origin must be distinguished from non-syphilitic conditions. Tnherculosis is a more destructive process than syphilis and rarely attacks the shaft of the bone. It is also characterized by wasting of the muscles in the vicinity of the affected bone, is more painful, and shows less thickening of the periosteum than syphilis, although there may be considerable edema of the connective tissue. The .r-ray picture is also hazy with loss of bone detail. Carcinoma is, as a rule, secondary to soft tissue involvement elsewhere, is essentially a destructive process and most frequently attacks the ends of the long bones. Osteitis deformans, as well as syphilis, shows a thickened cortex and bowing. The .r-ray revels that the entire shaft is involved in the former condition. Suppurative osteomyelitis is accompanied by more or less fever and leukocytosis and the pain is not more severe at night as it usually is with syphilis. The .r-rays show the process of destruction and repair going on at the same time, with thickened new bone which is irregular in outline and may contain areas of much lessened density. The pain of syphilis of the ribs may simulate pleurisy or intercostal neuralgia. Pleurisy may be differentiated by the cough, fever and the physical signs. The use of the a:-rays may reveal the nature of the process, although it usually is necessary to resort to laboratory procedures. Syphilitic dactylitis, as a rule, presents little difficulty of diagnosis. The ;r-rays show in the earlier stages that the condition is confined to the shaft of the bone, although later the epiphyses may be 302 SYPHILIS OF THE BONES, JOINTS, BURSM involved. The differentiation from tuberculosis is usually easy in that the syphilitic process appears to veil the bone with several layers of periosteal overgrowth, while in tuberculosis the medullary portion is involved and a necrotic area formed. Finally it must be said that the diagnosis of syphilis of the bone should rest more upon the history, the presence or absence of con- comitant syphilitic lesions and the laboratory findings, than upon the clinical evidence found in the bones themselves. It must be admitted, however, that the Wassermann reaction is sometimes negative in well-marked cases of bone syphilis, and the diagnosis may have to rest on the time-honored therapeutic test. Prognosis. — The prognosis of syphilitic bone disease depends entirely upon the location and extent of the process. The perios- titis occurring early in the course of syphilis is usually very amenable to treatment. Osteitis and osteomyelitis also, as a rule, yield to specifics, although if exostoses are formed their absorption, as a rule, will not occur. The best that can be hoped for is to stop the process. Syphilis of the bones of the skull is to be looked upon with grave concern, owing to the danger of extension of the process to the meninges. However, if diagnosed in time such involvement should yield to antisyphilitic treatment. As stated above when the bones of the face are attacked there is usually marked degeneration and loss of substance. Naturally the best possible outcome of such a condition is the stopping of the process. Syphilitic involvement of the vertebrae is of grave import, owing to the danger of extension to the meninges of the cord. However, if the condition is diagnosed before the process has become very extensive the prognosis should be good, and complete recovery should occur under vigorous antisyphilitic treatment. Dactylitis due to syphilis, in the majority of cases even after the process has existed for some time, is peculiarly amenable to specifics. Treatment. — The treatment of syphilis of the bones, if recognized before ulceration through the skin or mucous membrane occurs, usually need consist of nothing but specific and general measures. The so-called osteocopic pains due to periostitis early in the course of the disease have been found to yield remarkably to potassium iodide. The pain of the later periostitis, osteitis and osteomyelitis may be so severe that surgical interference is indicated. The perios- teum should be incised, or if this does not suffice, the bone should be trephined. If suppuration of a gumma of bone has occurred and an abscess formed, it should be freely opened, curetted and treated with antiseptic solution. THE JOINTS 303 Spontaneous fractures and separation of the epiphysis from the diaphysis should be treated as any other fracture, although union sometimes is most difficult to obtain. When necrosis of bone has occurred and sequestra have formed they should be removed with great care and antiseptic solutions used. If exostoses are formed which press upon important structures and they do not decrease in size under specific therapy, they should be removed. When the syphilitic process attacks the outer table of the bones of the skull and necrosis has occurred, the diseased portion should be removed. If evidence goes to show that the inner table is affected and the meninges are not involved, the diseased portion of bone should be allowed to remain as long as possible so that the dura mater may become thickened and thus become better able to take the place of the bone. Following the healing of the lesion the diseased portion of bone may be replaced by a silver plate or a leather cover may be worn. When the bones of the face are attacked and sloughing occurs, as it usually does, the diseased portions of bone should be removed. Great care should, however, be exercised that the process does not extend to the meninges. Following the removal of the bone the parts should be thoroughly irrigated with an antiseptic solution and dressings applied. After healing certain of the deformities such as saddle nose may be at least partially overcome by plastic surgery. This consists of the use of inert substances such as wood, metal, rubber and paraffin, or the use of living tissues, bone from some other portion of the patient's body, such as parts of the tibia, bone from some other individual and animal bone. Syphilis of the vertebral column will require special treatment depending upon its extent. Such appliances as plaster jackets and similar supports may be indicated. Syphilitic dactylitis, as a rule, needs no other treatment than specific and general. An incision is rarely justifiable, although if softening occurs and a sinus is formed, the diseased bone should be removed and the part dressed antiseptically. THE JOINTS. Pathology. — That the joints of the body may be aft'ected by syphilis was maintained by Peter Martyr as early as 1498. The condition was denied by Hunter, and Ricord, while admitting that the joints of syphilitics were sometimes diseased, considered the process a complication. Richef^ was, however, the first accurately 1 Memoires de I'Acad. de med., Paris, 1853, xvii, p. 249. 304 SYPHILIS OF THE BONES, JOINTS, BURSM to describe luetic joint disease and termed it syphilitic white swell- ing. Since his time numerous syphilographers have written of joint infections, and several varieties have been described. Simple arthralgia in which little or no pathological change is observed has been described by most investigators. This condition will be dealt with more fully in the section on Clinical History. Fig. 65. — Syphilitic arthritis of ankle-joint. Acute synovitis may occur comparatively early in the course of the disease, usually within the first or second year. The synovial membrane is thickened and the tissues surrounding the joint are more or less edematous. Chronic synovitis may follow the acute form or it may develop some years later. In this condition there is considerable swelling of the joint due to effusion, in fact a chronic hydrarthrosis exists. Gummatous affections of the joints may occur secondarily to such conditions of the bones as mentioned above and an osteo-arthritis result or the gummata may originate in the synovial membrane. The infiltration occurs in the tissues beneath the endothelium of THE JOINTS 305 the synovial membrane and is usually diffuse but may occur as small nodules. The cartilages of the joint and the bones usually remain unaffected, however, the syphilitic process may spread to the surrounding tissues. Charcot's joint is a condition observed late in the course of syphilis, either with tabes dorsalis or as a precursor of that malady. The capsule of the joint is dilated, often ruptured and may be entirely destroyed. The synovial membrane is rough, thick and often adherent to the surrounding parts. In old cases it may be absent. The synovial fluid is usually thin and clear but may rarely be bloody or purulent. At first it is found in large quantity escaping through the ruptured capsule and infiltrating the surrounding tissues, causing considerable swelling. Particles of bone and detritis are Charcot joint. (Jelliffe and White.) often floating in it. There is either erosion of the ends of the bones and joint surfaces with considerable reduction in their size, or more rarely, hypertrophy. Clinical History. — Syphilis of the joints certainly is more frequent than it formerly was considered. Whitney^ found involvement of the joints in 15.2 per cent, of 544 syphilitics. Simph arthralgia, referred to above, in which little or no patho- logical change can be demonstrated in the joint occurs rather early in the course of syphilis, often before any cutaneous lesions are manifest, but is more frequently seen as an accompaniment of those lesions. The pain has been described as resembling the so-called "growing pains" of the young and may be worse at night. One or 1 Jour. Am. Med. Assn., 1915, Ixv, p. 1986. 20 306 SYPHILIS OF THE BONES, JOINTS, BURSM more joints may be affected and the condition is prone to disappear without treatment and often recurs. Acute synovitis, as stated above, may occur comparatively early in the course of syphilis, usually within the first or second year. There is generally pain on either marked flexion or extension of the joint, although motion within certain limits may be painless. The joint is swollen and local heat is observed. There is occasion- ally redness of the skin over the joint and fluctuation may be demon- strated.' Usually more than one joint is involved and the large ones, knee, shoulder, elbow, wrist or rarely the hip are most fre- quently the seat of the process. The condition generally lasts one or two weeks and is followed by a return to normal or by a chronic synovitis. Chronic Synovitis. — In this condition there is generally marked swelling with effusion, and fluctuation. Little pain is present while movement is not greatly impaired. The knee is the most frequently affected joint and the process is usually bilateral. The condition may last for months, and if complete resolution does not occur ankylosis may result. Guvimatovs affections of the joints are found late in the course of the disease. The symptoms will depend upon the extent of the involvement. Pain may or may not be intense and even in quite severe cases movement may be little hindered. There is usually more or less effusion. The knee is also the most frequently affected joint in this condition, but contrary to the chronic synovitis the process is generally unilateral. Whitney and Baldwin^ have pointed out the frequency of involvement of the joints of the spine in syphilis. These investigators found of 100 unselected syphilitics only 26 with perfectly normal spines, 6 more were considered as doubtful. Of the remaining 68 cases all but 4 had a type of spinal abnormality which is considered more or less • characteristic of syphilis. The synovia of the spinal joints is attacked which at first causes loss of motion from spasm but later, as the process becomes less acute, motion is limited by the formation of adhesions and even complete fixation occurs. These adhesions are unaffected by anti- syphilitic treatment but may be broken up by forcible manipula- tion. There is usually a characteristic deformity, whether the condition is due to spasm or adhesions. This is either a slight prominence of the spines, a flattened area or a shallow depression, and depends upon the location of the involvement. However, it is suggested that a second factor may be operative, namely, that if the intervertebral joints are involved a flexor spasm may predomi- 1 Jour. Am. Med. Assn., 1915, Ixv, p. 1989. THE JOINTS 307 nate while an extensor spasm is more frequent if the articulations of the laminae are the seat of the pathology. One characteristic of the condition is that, as a rule, only a limited number of vertebrae, usually six to eight, are affected, although sometimes the whole dorsal area or even the entire spine is involved. Pain, as a rule, is not severe even in active cases and in the synovial form the x-ray is negative. Another striking characteristic of these conditions is a hypotonicity of the ligaments and muscles of the uninvolved portions of the spine, the sacro-iliac joints and the hips. Thus in patients with localized stiffness as well as in those with general stiffness many were able to touch the floor with their fingers while keeping the knees stiff. While some were able to place their palms on the floor and two or three could bend their elbows while still keeping their knees stiff. This hypotonicity with localized stiffness in the spine is considered by Whitney and Baldwin as almost pathognomonic of syphilis. Charcot's Joint. — As stated above, Charcot's joint is either an accompaniment or precursor of tabes dorsalis. There is usually the history of an injury, as with a patient of the author who fell from a table, his weight falling on his right hand with the arm extended. However, the frequency of this condition in syringo- myelia leads to the conclusion that it is due to the spinal lesion with the injury as the exciting cause. The first symptom is usually an .abnormal range of motion. This is followed by marked swelling, with no redness or tenderness, and pain is slight or absent. While the large joints are usually affected, no joint is exempt. Nearly complete resolution may occur or the condition may go on until, as Church and Peterson^ remark, "Old tabetic joints present, merely a bag of bone fragments where articulations were formerly located." Diagnosis. — The simple arthralgia occurring early in the course of syphilis should present no difficulty of diagnosis, as it is usually an accompaniment of the cutaneous lesions. If, as sometimes happens, arthralgia is noted before he appearance of any ■ utaneous lesions, and a chancre is not found, the diagnosis may be impos- sible, as no pathological change is demonstrable, and, as a rule, the laboratory tests are negative. The acuts synovitis of syphilis may be mistaken for acute articular rheumatism but the usual absence of fever, and acid sweats will be suspicious, even without a history of chancre or the presence of other syphilitic manifestations. This condition may also be mis- taken for gonorrheal arthritis, but the history of gonorrheal ure- thritis or its presence in chronic form, and the fact that the gonor- 1 Nervous and Mental Diseases, Philadelphia and London, 1911. p. 446. 308 SYPHILIS OF THE BONES, JOINTS, BURS^ rheal arthritis is more acute and painful than the syphihtic condition, will usually serve as diagnostic points. The complement-fixation test for gonorrhea as well as the Wassermann test may also be of value, although it must be remembered that syphilis and gonorrhea are not infrequently associated in the same individual and that either disease alone or both may be the cause of the joint affection. The chronic synovitis of syphilis may be diagnosed as rheumatoid arthritis, but the latter condition is more chronic, there is more bony deformity and there is grating of the joint which is absent in syphilis. Gummatous affections of the joints must be differentiated from tuberculosis. In the latter condition the pain is greater, the process more rapid, while there is a general thickening of the synovial membrane instead of the usual gummatous nodules seen in the syphilitic disease. Charcot's joint can usually be diagnosed by the abnormal range of motion, the marked swelling without redness or tenderness, the slight or absent pain and the usual presence of other symptoms of tabes. The same remarks may be made concerning syphilitic joint disease in general as were made concerning bone syphilis, namely, that the history, the presence or absence of concomitant syphilitic lesions, the laboratory findings and the therapeutic tests are of more importance in diagnosis than the clinical evidence in the joints themselves. With the joints of the spine it must be remembered, as pointed out above, that localized stiffness with hypotonicity of the liga- ments and muscles of the uninvolved portions as well as of those of the sacro-iliac joints and the hip is considered as almost pathog- nomonic of s^qDhilis. However, the majority of these cases will yield positive results upon laboratory investigation. Prognosis. — A favorable prognosis of syphilitic joint involvement will depend upon an early diagnosis. If the condition is diagnosed before adhesions have formed or destruction has taken place, the prognosis for complete restitution under specific medication is good. If, however, adhesions have formed or marked destruction occurred, the prognosis for complete recovery is bad, although, as a rule, the process may be arrested. The prognosis of Charcot's joint is always bad, although even in this serious condition if the tabetic process can be halted, the arthropathy may also not progress. Treatment. — No other treatment than specific and general is indicated in syphilitic joint disease, as a rule, although if there is much pain, the joint should be at rest and analgesics may be necessary. THE TENDONS 309 When there is much effusion it may be desirable to drain off the synovial fluid by opening the joint. The most rigid aseptic pre- cautions should, of course, be observed. The adhesions of syphilis of the spinial joints may be broken up by forcible manipulations. The treatment of Charcot's joint consists of palliative measures. THE BURS^. Syphilis of the bursse is a rare condition, although it has been recognized since the days of Hunter. Verneuil,^ in 1873, described the condition as occurring early in the course of the disease and soon afterward showed that gummata are occasionally found in the bursse. In 1876 Keyes^ published a list of fourteen cases. Churchman,^ in 1909, reviewed the literature and reported a case. The bursitis of early syphilis may or may not be associated with arthritis. There is considerable swelling and redness of the skin while fluctuation may be noticed. It is usually accompanied by other manifestations of syphilis and occurs at a time when the Wassermann test is positive. It is generally transitory and readily yields to specific therapy. Gummata of the bursse usually occur from the second to the eighth year but have been observed as late as twenty-eight years following the chancre (Keyes). This condition may be primary or it may occur as an extension from the surrounding tissues. The bursse of the knee are the most frequently involved. There is a nodular infiltration and more or less fluid is found. The course is slow and insidious and if left untreated may extend to the sub- cutaneous tissues and skin. Pain is usually slight, although there may be some tenderness. The diagnosis must rest upon the history, the finding of other manifestations of syphilis, and positive laboratory evidence. If the Wassermann and luetin tests are negative a portion of the tumor should be removed for microscopic examination. Gummata of the bursse as well as the earlier syphilitic bursitis usually yield to specific medication, and need no other treatment, except, perhaps, rest in bed. THE TENDONS. Syphilitic affections of the tendons and their sheaths are of infrequent occurrence. The process may at first attack the tendon 1 Gaz. hebd. de medeciniB et de chirurgie, 1873, 2 S, x, p. 22, 2 Am. Jour. Med. Sc, 1876, Ixxi, p. 349. 3 Ibid., 1909, cxxxviii, p. 371. 310 SYPHILIS OF THE BONES, JOINTS, BURSAS or the sheath alone but soon both become involved. Serous inflammation of the sheath with effusion is rarely seen during the first year of the disease and later a gummatous condition is sometimes observed. The. former condition is always painful but readily disappears under specific treatment. The usual outcome of the rare gummatous involvement of the tendon is extension to the surrounding tissues and ulceration. Gummatous infiltration may lead to thickening and perhaps even to calcification. THE MUSCLES. Myalgia similar to the arthralgia mentioned above, and in which no pathological change of the muscles can be detached, is often seen early in the course of syphilis, sometimes even when the chancre is the only lesion present. The pain may be very slight, resembling a soreness of the muscle or be so severe that analgesics will be required. The pain may be worse at night. Points of tender- ness are usually found in the affected muscle, and motion generally aggravates the pain. No redness or swelling is observed. The muscles of the thighs and legs are most frequently affected, although the muscles of the arms and back are often involved. Such condi- tions are most difficult of diagnosis if other signs and symptoms of syphilis are not present. They yield readily to specific medication. Interstitial myositis is an exceedingly rare condition and consists of infiltration of the connective tissue and degeneration of the muscle fibers. It usually occurs within two years after infection, and there is a gradual increase in the size of the muscle without pain, and without increase in the hardness. No redness nor tender- ness is observed. Contracture soon develops and the joint to which the muscle is attached becomes fixed. The process is most frequently found in the biceps and gastrocnemius but has been observed in the pectoralis major,- trapezius and other muscles. It is usually unilateral. Gummata of the muscles is not such a rare condition and may be localized or diffuse. The anatomical picture does not differ from gummata of other regions. They generally occur between the third and fifth years of the disease. If the condition is localized, nodular swelling may be observed or if diffuse there will be general enlarge- ment. There is practically no pain or tenderness. The muscles may become adherent to the surrounding tissues, causing more or less loss of function. Often the process spreads and involves the subcutaneous tissues and skin, forming an ulcer. Calcification or ossification may occur. Gummata may be found in practically any muscle of the body and one or more may be involved. They must be differentiated from other tumors, mainly sarcomata. This THE MUSCLES 311 can, of course, be accomplished by section of the growth, or in most cases by the indirect evidence of history, etc. Koehler's case, as reported by Lang,^ must be thought of. In this case actinomycosis of the muscles was incorrectly diagnosed as gummatous. Prognosis. — The prognosis of syphihs of the muscles is good, espe- cially if diagnosed early. Treatment. — It has been suggested that local inunctions of mer- cury over syphilitic muscles is desirable. This, however, probably is of little or no value and the treatment, aside from the specific and general, is rest in bed with light massage of the affected muscles and hot packs. ' Steadman: Twentieth Century Praotioe of Medicine, New York, 1S99, xviii, p. 211. CHAPTER XVIII. SYPHILIS OF THE NERVOUS SYSTEM. History. — As early as 1497 Leoniceno^ in his treatise on syphilis pointed out that the internal organs were often involved and that paralysis sometimes followed. Other writers who followed him expressed similar views. Nevertheless, John Hunter^ combated the theory of syphilis of the internal organs and in this way, as well as by his theory of the unity of syphilis and gonorrhea, set back the knowledge of syphilis many decades. However, in 1834 Lallemond'' showed conclusively that the brain and meninges were sometimes affected with syphilis. While numerous contributions concerning syphilis of the nervous system followed the work of Lallemond, it was left for Virchow* to describe accurately the pathological anatomy of gummata of these tissues. The next important article dealing with syphilis of the nervous system was published by Heubner,^ in 1874, and described the syphilitic involvement of the cerebral arteries. Since the time of Heubner much has been added to the knowledge of syphilis of the nervous system and no other name stands out more prominently than that of Fournier.'^ He it was, who first connected tabes dorsaJis with syphilis and later he supported the same theory in regard to paresis. It was not, however, until 1913 that Noguchi and Moore,'^ by the discovery of the Treponema pallidum in the brains of paretics and the spinal cord of a tabetic, showed conclu- sively that these conditions are truly syphilitic, and the terms "para- and metasyphilitic are no longer tenable. Pathology. — It has long been customary to divide, both anatomic- ally and clinically, the syphilitic affections of the nervous system into so-called cerebrospinal syphilis, including gummata, endarteritis and meningitis, the parasyphilitic diseases, paresis, tabes and tabo- paresis, and the affections of the peripheral nerves. However, since the epoch-making work Noguchi and Moore and further since Dun- 1 Libellus de epidemia quam Itali morbum gallicum vocant vulgo brossulas, Venice, 1497. 2 A Treatise on the Venereal Diseases, Philadelphia, 1859, p. 410. ^ Recherches anatomo-pathologique sur I'Encephale, Paris, 1834, t, iii. 4 Virchows Arch. f. path. Anat., 1858, xv, p. 229. 5 Die luetische Erkrankung der Hirnarterien, etc., Leipsig, 1874. 6 De I'Ataxie locomotrice d'origine syphilitique, Paris, 1876. 7 Jour. Exper. Med., 1913, xvii, p. 232. PATHOLOGY 313 lap^ has pointed out that certain cases exist that may be termed border-line cases which anatomically may be interpreted as belong- ing to either group, it seems best to consider the pathology of the central nervous system under the following headings : 1. Meninges. 2. Arteries. 3. Brain Substance. 4. Cord Substance. 5. Nerves. It must be understood, however, that the majority of the cases will show more than one pathological condition, for example, it is hard to conceive of a basic meningitis in which the circle of Willis is not more or less affected by an arteritis. Meninges. — That the meninges may be the seat of syphilitic involvement early in the course of the disease has been deduced both by clinical evidence and by lumbar puncture. No one, how- ever, as far as the author is aware, has described the pathological anatomy in early syphilitic involvement of the meninges. Later in the course of the disease meningitis may occur as a diffuse inflam- matory process, or as a gummatous condition. It may involve all three of the enveloping coats of the brain and spinal cord. It may originate in the bones or periosteum and later affect the meninges or the meninges may primarily be involved. The diffuse inflammatory meningitis is characterized by an exuda- tion of endothelial cells and polymorphonuclear leukocytes and the formation of fibrin. There is generally a marked infiltration of lymphocytes, and giant cells are usually observed, while trepone- mata are more or less abundant. It is probable that this is the type of meningitis which exists when the meninges are involved early in the course of the disease. Gummatous meningitis, which usuall}^ complicates the inflamma- tory type may be either a diffuse process or consist of circumscribed nodules of varying size. Any one of the membranes may be affected alone, but it is usual for all to be involved. The gummatous menin- gitis usually is associated with a fibrous hyperplastic condition in which the dura may be several times thicker than normal. The leptomeninges usually are adherent, thickened and contain gum- matous deposits either diffuse or circumscribed. Circumscribed gummata of the meninges vary in size from one millimeter to several centimeters and may be found in any location. They usually appear in the fresh state as grayish-red nodules but may be of a yellowish tint. The most frequent seat of both the circumscribed and diffuse type 1 Am. Jour. Insan., 1913, Ixix, p. 1045. 314 SYPHILIS OF THE NERVOUS SYSTEM of gummatous meningitis is the base of the brain and from here it may involve the cranial nerves, extend down the meninges of the cord and affect the spinal nerves. On the base, the region of the chiasm and interpeduncular space are most often affected. The convexity of the brain is also usually involved and rarely may be the sole seat of the pathology. The meninges of the cord alone may be invaded by the syphilitic process. The most frequent location seems to be the cervical region, while it is most often observed on the posterior surface of the cord. However, the condition may completely surround the cord like a collar. The lumbar region is very rarely affected alone. Arteries. — Arteritis probably is the most constant syphilitic manifestation in the central nervous system, as the arteries are almost always found more or less involved with all other types of pathological lesion. In fact the arteries may be the starting-point of other types of syphilis of the nervous system. The arteries of the base of the brain are the most frequently involved. They are thick- ened and tough, due to the infiltration of the adventitia and the hyperplasia of the endothelial cells of the intima. This hyperplasia may be so extensive as to produce complete obliteration. This obliteration of the vessels may lead to encephalomalacia. Rupture of the cerebral arteries with or without aneurysm, followed by sec- ondary hemorrhage is of frequent occurrence. Arteritis of the vessels of the spinal cord with obliteration will lead to myelitis. Treponemata have occasionally been demonstrated in the arteries of the brain. Aside from the specific process in the arteries themselves they may become diseased, due to compression of gummata in the perivascular tissues. The veins of the central nervous system, as well as those of other localities, may also be the seat of syphilitic inflammation. Brain Substance. — Syphilis of the brain substance occurs in two types (jummatous formation and diffuse infiltration of the gray matter with treponemata. Gummata of the brain usually occur in the gray matter, but may be found in any locality, and while they generally originate in the meninges and spread to the cortex they may begin in the brain sub- stance itself. They are usually multiple, of irregular outline, and, if situated near the surface, are generally associated with a diffuse meningitis. Upon section a gumma in the fresh state presents a yellowish, dense mass in the centre, which is surrounded by a grayish zone which varies in consistency and which in turn is surrounded by a reddish area. Microscopically, the central portion is seen to be a necrotic mass, which may contain giant cells, the other cells being indistinguishable, while the periphery is composed of granulation PATHOLOGY 315 and fibrous tissue. Trepoiiemata rarely have been demonstrated in cerebral gummata. Uhle and Mackinney^ have reported the finding of the organisms in such lesions. Diffuse infiltration of the gray matter of the brain, especially the cerebrum, with treponemata results in little immediate injury. However, a proliferation of the glia cells slowly occurs with atrophy and disappearance of the ganglion cells and more or less resulting sclerosis. Tl)is is the pathological picture observed in paresis, to which are added other abnormal findings such as meningitis, endar- teritis, etc. The treponemata are found in groups or singly among Fig. 67. — Base of paretic brain. the nerve cells and neuroglia fibers. They may sometimes be observed to have become partially inserted in the nerve cell. Cord Substance. — The pathological findings in syphilis of the substance of the spinal cord are similar to those found in the brain. Gummata of the cord may occur in any locality and usually origi- nate in the meninges but very rarely arise in the substance of the cord. The macroscopic and microscopic pictures differ in no way from gummata of the brain. Myelitis due to occlusion of the bloodvessels of the cord usually is found in the gray substance. In 1 Proc. Path. Soc, PhUadelphia (N. S.), 1906, ix, p. 195. 316 SYPHILIS OF THE NERVOUS SYSTEM rare instances the lesion may involve the entire cross-section. It is almost always associated with meningitis, and is followed by ascend- ing and descending degenerations. Both grossly and microscopically syphilitic myelitis differs but little from that due to other causes. Fig. -Treponema pallidum in the brain of a paretic. (Moore.) There is congestion of the bloodvessels with rupture of some of them and hemorrhage into the gray matter. The ganglion cells are dis- torted with broken processes and are more or less destroyed, some of them completely so. CLINICAL HISTORY 317 Diffuse infiltration of the spinal cord, especially the posterior columns with treponemata, produces changes similar to those obser\'ed in the brain, and these changes, plus other pathological conditions, as meningitis, constitute the anatomical picture of tahes dorsal is. Noguchi^ has been able to demonstrate the Treponema pallidum in the posterior column of the dorsal portion of the spinal cord in tabes. When there is an infiltration of the treponemata into the gray matter of the brain as well as into the cord with the resultant changes, the condition is described as taboparesis. Nerves. — The nerves may be affected by syphilis either directly or indirectly. When directly affected the process is usually an extension from the meninges to the nerve roots. The interstitial substance is infiltrated with granulation tissue which slowly is changed into more or less dense fibrous tissue. Endarteritis of the nutrient vessels causing interference with the circulation is often observed. Marked degeneration follows these changes. A Gum- matous process of the nerves occasionally is observed and presents either a diffuse thickening or circumscribed nodules, like beads on a string. Indirectly the nerves may be affected by pressure either of a gumma or by periosteal thickening as they pass through a bony canal. Clinical History. — It has been pointed out above that while certain changes in one tissue of the nervous system, such as the meninges, may dominate the pathological picture, the process is usually not limited to one tissue but that others are more or less involved. Therefore, as would be expected, the clinical signs and symptoms are, as a rule, not limited to those produced by involvement of one tissue, although such symptoms may be most prominent. Meninges. — That the meninges may be involved in the syphilitic process early in the course of the disease was pointed out above. The earliest date following infection at which involvement of the central nervous system has been noted in the case reported by Read,- in which marked symptoms were present two weeks after the appear- ance of the chancre. Several other investigators have reported cases of syphilis in which the chancre was present, but no cutaneous manifestations had appeared in which either clinical symptoms or spinal puncture or both revealed involvement of the central nervous system. Wechselmann^ found positive evidence of involvement of the central nervous system in the spinal fluid of 6 such cases, while in only 3 were there any clinical symptoms present. 1 Jour. Cut. Dis., 1913. xxxi, p. 543. ^ XJrologic and Cut. Rev., 1915, xix, p. 75. 2 Deutsch. med. Wchnschr., 1912, xxxviii, p. 1446. 318 SYPHILIS OF THE NERVOUS SYSTEM FrankeP reported 2 cases in both of which the spinal fluid was negative and clinical symptoms of central nervous involvement were absent. Altmann and Dryfus^ found the spinal fluids of 2 out of 8 cases positive. Leopold* examined 16 cases in which the chancre was the only evidence of syphilis. In 6 there were clinical signs as well as posi- tive findings in the spinal fluid, showing that the central nervous system was affected. Wile and Stokes* reported 6 cases which were observed during the so-called second incubation period, that is, before any skin mani- festations had appeared. Neurological examinations as well as examinations of the fundus oculi and the eighth nerve were made on all cases. Lumbar puncture was made on all but 1. These investi- gators found both clinical and spinal fluid evidence of involvement of the central nervous system in 4 of the cases. One case showed slight clinical evidence with a normal spinal fluid, while 1 case, the only one which had had treatment, showed only a beginning arteriosclerosis and slight involvement of the eighth nerve, lumbar puncture having been unsuccessful. The author has examined for evidence of involvement of the central nervous system but 5 cases of cliancre in which no cutaneous manifestation was present. Of these 5 only 1 would consent to lumbar puncture. The following is a summary of the cases : Case 1. — A. S., male, aged twenty-six years; laborer. Family and past history negative. Small papular chancre of glans developed three weeks after exposure. Was seen two weeks after appearance of lesion. Had had no treatment but "salve." Adenopathy local only. Many treponemata demonstrated by dark-field illumination. Lower tendon reflexes slightly exaggerated. Ankle-clonus, Babinski and Romberg negative. Pupils regular in outline, equal in size and react normally to light and accommodation. Slight retinitis in both eyes. Spinal fluid showed no apparent increase' in pressure; three lymphocytes per cubic millimeter, negative globulin (author's modi- fication of Noguchi's butyric acid test), negative Wassermann; negative Lange colloidal gold test ; Wassermann dn blood -| — | — 1- . Case 2. — L. R., male, aged twenty-three years; cowboy. Family and past history negative. Unable to determine incubation period, as had been exposed numerous times during the month previous to appearance of large indurated chancre of balanopreputial fold. Was 1 Ztschr. f. ges. Neurol, u. Psychiat., 1912, ix, p. 1. 2 Munchen. med. Wchnschr., 1913, Ix, pp. 464, 530. 3 Dermat. u. Syph., 1914, cxx, p. 101. 4 Jour. Am. Med. Assn., 1915, Ixiv, p. 979. CLINICAL HISTORY 319 seen one week after appearance of lesion. Adenopathy sliglit and local only. Many treponemata demonstrated by dark-field illumi- nation. All neurological tests negative, as well as a normal fundus oculi observed. Lumbar puncture refused. Wassermann on blood negative. Case 3. — H. R., male, aged thirty-two years; carpenter. Family and past history negative. Chancre of lower lip appeared two weeks after exposure. Was seen three weeks after appearance of lesion. Enlargement of submaxillary glands. Few treponemata demon- strated by dark-field illumination. Lower tendon reflexes slightly exaggerated. Ankle-clonus and Babinski negative. Slight positive Romberg. Pupils equal in size, regular in outline but react some- what sluggishly to Hght and accommodation. Retinitis in both eyes. Lumbar puncture refused. Wassermann on blood -\ — | — |-. Case 4. — J. C, male, aged nineteen years; dishwasher. Family and past history negative. Papule developed on balanopreputial fold sixteen days after exposure. Was seen five weeks after appear- ance of lesion. Ulcerating chancre on balanopreputial fold with marked inguinal adenopathy. Treponemata could not be demon- strated by dark-field illumination. Neurological examination nega- tive, except for slight exaggerated lower tendon refiexes and posi- tive Romberg. Fundus oculi normal. Lumbar puncture refused. Wassermann on blood -\ — | — | — h • Case 5. — J. A., male, aged nineteen years; student. Family and past history negative. Eleven days after intercourse noticed slight burning of urethra on urination, which was followed the next day by a slight "whitish" discharge. A physiciapi was consulted who irrigated the urethra with potassium permanganate solution and gave him another solution for self-injection. There was no improve- ment; in fact, the condition grew worse. He consulted the author three weeks later and an examination revealed the following : There was a marked edema of the prepuce with phimosis and a copious purulent discharge. Gonococci could not be demonstrated. An indurated area about 1 cm. in diameter could be plainly felt on the under surface of the penis near the frenum. The inguinal glands on both sides were markedly enlarged. No other glandular enlarge- ment could be detected. The neurological examination revealed the lower tendon reflexes markedly exaggerated, the knee-jerks being explosive in character. Upper tendon reflexes slightly exaggerated. Ankle-clonus negative. Romberg negative. Pupillary reflexes normal. Ophthalmoscopic examination of the right eye showed the retina normal except at the border of the disk corresponding to the lower nasal side, where a distinct swelling was noted. The vessels were seen to dip and a part were completely hidden as they passed onto the disk. The border of the disk was obliterated to the extent 320 SYPHILIS OF THE NERVOUS SYSTEM of the swelling, that is, about one-fifth. The left eye showed a normal retina. At the lower margin of the disk there was a cloudi- ness which hid the border. There was no swelling present. Lumbar puncture was refused. Wassermann on the blood + + + +•.. Numerous investigators have reported the involvement of the nervous system slightly later in the course of the disease, that is, during the early active cutaneous manifestations. Wile and Stokes^ go so far as to state "that in all probability every case of syphilis which reaches the secondary period has more or less involvement of the cerebrospinal axis." Ravaut^ reported 67 per cent, involved. Ellis^ reported 6 cases of early syphilitic meningitis. Swift and Ellis^ found 36 per cent, affected. Wile and Stokes^ reported the apparent involvement of 66.7 per cent, of a series of 36 cases, while Fordyce^ found less than 20 per cent, with involvement of the central nervous system. Of 31 cases of early active cutaneous lesions, that is, during the first year of the disease, which have come under the observation of the author, and have been examined neurologically, 9, or 30 per cent., have shown some positive evidence of involvement of the central nervous system. No spinal fluid examinations were made, and such symptoms as headache, while probably due to involvement of the meninges, were not considered positive evidence. Syphilitic meningitis may also occur late in the course of the disease; in fact, Ricord classified syphilis of the nervous system with his so-called tertiary manifestations. The symptoms of syphilitic meningitis of the brain will depend upon the location of the involvement, although it cannot always be determined from the symptoms whether the convexity or base is involved or whether both locations are the seat of the pathological process. Base. — Headache is the most frequent symptom of specific menin- gitis of the base of the brain. It is present in practically all cases and may be the only s}Tnptom observed for a very long time. It is usually paroxysmal in character and is described as boring, split- ting, stabbing, throbbing. Between the severe paroxysms there may be a dull ache. Not infrequently there may be severe pain deep in the orbits of the eyes and sometimes the headache is localized upon the forehead or over the eyes. Vertigo and even reeling and stagger- ing are often noted. 1 Jour. Am. Med. Assn., 1915, Ixiv, p. 979. 2 Presse med., 1912, xx, p. 181. 3 Jour. Am. Med. Assn., 1912, lix, p. 1263. * Forschheimer : Therapeutics of Internal Diseases, New York and London, 1914, V, p. 401. 5 Jour. Cut. Dis., 1914, xxxii, p. 607. 6 Am. Jour. Med. Sc, 1915, cxlix, p. 781. CLINICAL HISTORY 321 Vomiting, which often occurs without food in the stomach, is a very frequent symptom, although not a constant one, and may precede all other symptoms. The temperature is usually normal, but may be slightly elevated. A very high temperature may be considered a complication. Polydipsia and polyuria are rpther common symptoms, while diabetes mellitus has been observed. The psychic symptoms vary greatly. The most frequent condi- tion is one of stupor from which the patient may be aroused tem- porarily. There may be a purposeless motor delirium. More or less complex acts may be performed on command, although the urine and feces may be passed in bed. There is usually loss of memory, especially for recent events, and a disorientation for time and place. There may be more or less periods of excitement or there may be marked depression with suicidal tendency. Conscious- ness may last for a long time, followed by the sudden appearance of coma and death. General convulsions of an epileptiform type are often observed or there may be partial or unilateral convulsions. The cranial nerves are usually more or less affected. The result- ing conditions will be described under Syphilis of the Nerves. Convexity. — When the meninges of the convexity of the brain are involved, as with the base, the most constant symptom is head- ache. However, in this condition, while the headache may be severe and diffuse, although it may be dull, there is usually also a definite severe pain localized in some particular spot. Most authors state that this is worse at night, although this is not always the case. There is usually localized tenderness on pressure and percussion and a difference in the percussion note may be observed. The psychic state is usually one of progressive dementia. There is loss of memory with apathy; delirium, however, may exist. Neurological symptoms will depend upon the exact location and severity of the process. There may be cortical convulsions which may be general and indistinguishable from idiopathic epilepsy or they may be confined to one extremity or even to a part of one, such as the finger. Gummata of the meninges will cause symptoms depending upon their size and location. There will be more or less increase of intra- cranial pressure with symptoms of tumor, vomiting, choked disk, vertigo, slow pulse and stupor. There may also be focal symptoms pointing to the location of the lesion or lesions such as monoplegia, hemiplegia or Jacksonian epilepsy. Meningitis of the Cord. — The meninges of the cord alone may be involved in the syphilitic process, although it is more usual for men- ingitis of the brain to coexist. The symptoms of specific meningitis of the cord consist of stiffness and pains in the neck, back and 21 322 SYPHILIS OF THE NERVOUS SYSTEM sacrum. These pains may be severe but are not always so. Pains radiating in the arms and legs and trunk are often noted. There may be numbness and tingling sensations, areas of paresthesia and hyperesthesia are often found. The so-called girdle pain is very frequent. The back is usually more or less rigid and there are spots along the spine which are tender to percussion. Kernig's sign is often present. The superficial and deep reflexes are exagger- ated. If the meningeal exudate be extensive, symptoms of compres- sion myelitis will develop. Arteries. — It has been pointed out above that syphilitic arteritis and meningitis usually occur together, although the clinical and pathological picture may be dominated by the more extensive involvement of one or the other. Syphilitic arteritis occurs as early as the third or fourth month after infection, but is usually a later manifestation, being observed from the third to the tenth year and often very much later. The symptoms of syphilitic arteritis of the central nervous sys- tem will naturally depend upon the location of the arteries affected and the extent of the process. When the brain arteries are involved monoplegia and hemiplegia are very frequent and the first sjinptom may be an apoplectic attack, although there may be such prodromal symptoms as headache, which is usually not so severe as in menin- gitis, dizziness, insomnia, loss or impairment of memory, lack of ambition, irritability, inability to concentrate on mental effort, etc. All these symptoms are explainable by the pathology, although they may occur in other conditions. There may be transient motor disturbances such as slight clonic contractions of the extremities or there may be transient paralyses. The onset of a hemiplegia may be quite sudden with varying symptoms of apoplexy such as giddiness, nausea, stupor and even complete loss of consciousness. Sometimes there are convulsions. If the attack is slight, it is usually transitory in character. Often the condition is that of a monoplegia, the symptoms depending upon the location of the trouble. Not infrequently there may be an aphasia, usually motor in character, either appearing as the only symptom or in combination with a monoplegia or a hemi- plegia. Marked involvement of the basilar artery will cause symptoms of pons affection, and is usually fatal. Disturbances of sensation are rare. Quite often the pupils show anomolies, being irregular in outline of different size and reacting sluggishly or not at all to light. Homonymous hemianopsia due to involvement of the posterior cerebral artery, thus affecting the optic radiations and calcarine region of the occipital lobe, is occasionally found. • CLINICAL HISTORY 323 Affections of the arteries of the spinal cord will cause more or less myelitis, the symptoms of which will be described later. Brain Substance. — Gummata of the brain substance are rather rare and will produce symptoms of brain tumor depending upon the location, number and size. Paresis. — The clinical picture called paresis or dementia para- lytica is now known to be a syphilitic condition due to the diffuse infiltration of the gray matter of the brain with treponemata, with the resulting changes, and the old saying "no syphilis no paresis" is proven to be true. And while there are certain cases which both anatomically and clinically may be difficult or impos- sible of classification, as a rule the picture in paresis is of sufficient clearness to make it unmistakable. The date of onset of paresis in respect to the syphilitic infection is in a large percentage of cases difficult to determine, but it is usually a late occurrence, developing, as a rule, from ten to fifteen years after the chancre. The earliest development of paresis which the author has seen was five years after contracting syphilis. Kraep- elin^ cites a case occurring three years after infection and states that Oliver reported a case developing forty-four years following infection. The symptoms of paresis are varied and complex and may be divided into mental, neurological and general. Mental Symptoms. — The psychic phenomena of paresis may be said to be represented by a peculiar mental failing, at times asso- ciated with a delusional trend, changes in mood, and periods of excitement and depression. One of the earliest evidences of on-coming paresis is a change in moral tone. Not only may the model husband and father, the " pillar of the church" fall from his high moral plane, be heard to utter oaths, seek lewd companions and revel in licentiousness, but on the other hand, the roue often becomes highly moral, seeks religion, or, as in a case of the author's, actually becomes a minister and seeks to save sinners. There is usually an early absent-mindedness, an inattention, and failure to grasp details of every-day life. Often in a general conver- sation there is a failure to hear questions asked and sometimes answers are given to questions directed to others. The ability to concentrate is lost early in the disease, the will- power is weakened, and there is a lack of decision, the patient may be irresolute or he may be unusually headstrong. He often makes serious business blunders. Initiative is lost and he can easily be influenced, readily falling a prey to the business shark. Often great business enterprises are planned which may even be started. 1 General Paresis, New York, 1913, p. 169. 324 SYPHILIS OF THE NERVOUS SYSTEM Ability to understand subtle or witty conversation is early lost, and remarks concerning the paretic can often be made in his pres- ence without his comprehension. One of the early symptoms is often a tendency to tire easily, both physically and mentally. The paretic soon begins to be careless of his personal appearance, often going unshaven for days. There is scarcely ever any insight into his condition. Early in the course of the disease there may be an understanding of the seriousness of the disorder and the probable fate. Occasionally such understanding will drive the individual to suicide. A change of disposition is an early symptom. An excitability develops, he becomes easily angered and often completely loses his temper, flying into a rage at the slightest provocation. He loses all pleasure in mental activities, has no fear of danger, and over- whelming misfortune does not appall him. Sooner or later a grandiose condition develops. He forces him- self into prominence and in conversations becomes boastful. Delu- sions of grandeur are expressed, he is endowed with great power, is president, a king, or even God, himself. These delusions are usually not fixed and can be changed by suggestion. Later the excitability disappears and his mood corresponds to his delusions, being happy with his delusions of grandeur and depressed with those of a sor- rowful nature. Rapid changes of mood from hilarity to tears and back again are brought about by the most trival causes, and are very character- istic. Sense illusions and hallucinations are rare. A gradual loss of acquired knowledge is seen and is characterized by the longest retentions of those thought associations with which he is most familiar. Thus, the mathematician will retain a knowledge of arithmetic longer than the laborer. The entire catalogue of proprieties may be outraged, the patient attending to the calls of nature regardless of his surroundings. He often will indulge in masturbation in the presence of others. Loss of memory occurs early in the course of the disease, and a disorientation for time is observed. He cannot tell the season of the year, even though snow be on the ground or leaves be on the trees. He may be able to give the date of his birth but fail to tell his age. Evasive answers are frequently given to questions. Lapses of memory are often filled in by imagination. He draws upon his dreams and stories he has read to fill in the space of his delusions. Following a paretic convulsion he may have lost all memory of recent happenings, not recalling even his attendants. Occasionally upon sufficient questioning the paretic can recall past events fairly well. Inability to do so may be due partially to lack of compre- hension and upon suggestion may be overcome. CLINICAL HISTORY 325 There is more or less clouding of consciousness which develops gradually, and the paretic seems to live in a dream state. Toward the last consciousness is entirely lost and nothing passes beyond the threshold. Catalepsy of a transitory character is frequent, also echolalia, echopraxia and verbigeration are noted. Often there is a marked resistiveness such as mutism, refusal of food and retention of urine and feces. Toward the end there is a complete suspension of mental processes, the patient becomes nothing but a body which breathes, passes urine and feces involuntarily, and in which the heart beats, and to which death is a blessed relief. Fig. 69. — Group of typical paretics; (Note varying expressions.) Neurological Symytomsi — Of all the sym.ptoms of paresis the so-called neurological ones are the most character'stic, and are of most importance. A severe headache which may be the only symp- tom present for a long time is of very frequent occurrence. It is generally of a dull, heavy character, as if an iron band were com- pressing the brain. The frontal region is usually most severely affected. The countenance of a paretic is generally more of less changed; it lacks expression, is flabby with a flatness of the nasolabial folds, which, however, may be unilateral only, while silly, almost idiotic, expressions are often seen. Fibrillary tremors of the facial muscles are common. Motor symptoms are always present and are of the greatest importance. There is little or no loss of muscular power except a general weakness following a paretic convulsion and an increasing paralysis diminishes it. There is early seen a loss of ability to make several movements in quick succession, like opening the mouth. 326 SYPHILIS OF THE NERVOUS SYSTEM protruding the tongue and wrinkling the forehead. The performance of single movements is slow and clumsy, while the carrying out of more complicated muscular effort early becomes an impossibility. The general carriage of the paretic soon becomes lax and the gait is shuffling, unsteady, and with a wide base. A spastic gait is also often seen. The protrusion of the tongue is usually awkward and jerky, often accompanied by movements of the eyes and muscles of the face. It very frequently deviates to one side or the other and a fine fibrillary tremor is seen. The most striking motor disturbances, however, are the paretic convulsions. These convulsions are variously stated as occurring in from 30 to 90 per cent, of cases. They are probably more frequent in men than in women, and usually occur after the disease has become well established or they may be noted as one of the earliest symptoms. No macroscopic change can be found to account for them but they are probably due to congestive conditions or cir- cumscribed edemata of the cortex. Certain prodromal symptoms are generally noted, such as more marked dulness, increased clumsiness of movement, or even uncon- sciousness. The patient frequently is seen to lean far to one side, finally sinking to the floor when the convulsions begin. Usually simple rhythmical twitchings are observed, although jerking, pitch- ing movements are not rare. Often there are merely twitchings of the face muscles with nystagmus, later spreading to other muscles of the body. Sometimes only small groups of muscles are affected such as those of the arm, the attack being repeated, perhaps with slight variations as many as one hundred times in twenty-four hours, with stupor between attacks. A form of attack which occasionally is seen resembles an apoplectic seizure, whfle sudden death is not infrequent. One feature of the paretic attacks is their usual transitory character. The recovery from the attack generall}^ is gradual and may terminate in an excited state. There is almost always a decrease in the mental capacity following the convulsions. The sense organs often show a hypersensitiveness in the beginning of the disease which later disappears, the senses usually being dull. Word-deafness, asymbolia and inability to recognize substances by the sense of smell are often noticed. The sense of touch is usually abnormal. At first there may be sensations of itching, burning, tingling and may be the only symp- toms present for a long time. Later in the course of the disease a marked lessening of the pain sense is noted. Often the paretic may receive severe burns due to his insensibility to pain and the self-infliction of wounds by biting, tearing the skin with the finger-nails, etc., is not rare. CLINICAL HISTORY 327 The internal organs share in the hypaigesia and the paretic may be the victim of severe diseases of the stomach, gall-bladder, etc., without discomfort. The voice of a paretic early loses its natural quality, due to paralysis of the vocal cords, and is more or less monot- onous or tremulous. Changes in speech are of the utmost importance and consist of aphasia and difficulties in articulation. Aphasia is fre- quent following a paretic convulsion, though it is usually transitory. Paraphasia is also very frequent and may be present for a long time. The syllables of words are often changed, one being left out or repeated. Those who have been acquainted with more than one language often jumble the words of different languages together. Inability to articulate correctly is very frequent, and difficult words or phrases are incorrectly pronounced. Thus Theosiphus is called Teosipus. While the patient is usually unconscious of his error, he may attempt to excuse it. The writing of a paretic presents irregularities which are com- parable to his speech defects. Letters and syllables are misplaced, repeated and omitted. Little or no attention is paid to spacing, while the writing often runs off the page. In the later stages of the disease complete agraphia is seen. Attempts to write may be made, but after making a few scrawling lines or simply a blotch on the paper he gives up with some excuse. Pupillary disturbances are noted early in the course of the disease and are usually most striking. The most characteristic change is a distortion of the outline of one or both pupils. The opening may be eccentrically located, elliptical or flattened. One or both pupils may be pin-point in size or widely dilated. Irregularity in size is very frequent. The reaction to light is very often lost, while the reaction to accommodation is also sometimes absent. Failure to react to accommodation without loss of light reaction is occasionally observed . Disturbances of superficial and deep reflexes are generally seen in paresis. As a rule the knee-jerks are markedly exaggerated, some- times differing on the two sides, while ankle-clonus is very frequent. The Achilles, jaw, elbow and wrist reflexes also usually are exag- gerated, while the cremasteric reflex and Babinski's sign are, as a rule, positive. In a certain percentage of cases, variously estimated from 16 to 30, the knee-jerks are diminished or absent. They may later become exaggerated. Toward the end of the disease marked rigidity of the muscles with contracture is noted. These contractures are of a most severe type almost the entire musculature of the body participating in the process until neither the limbs nor the head can be moved. General Symptoms. — The general appearance of a paretic is that of senility with wrinkled skin, gray and falling hair, tremors, etc. 328 SYPHILIS OF THE NERVOUS SYSTEM At first, especially during the excited stage, there is a loss in weight, which is soon followed by an increase, while in the terminal stages there is marked emaciation. The appetite, which is diminished at first, is usually voracious later, although in spite of this, owing to the marked altered metabolism, there is, as noted above, loss of weight. As a rule there is no increase in the temperature in paresis, except during a convulsion, but toward the end a subnormal condition is generally observed. Certain trophic disturbances, such as bed-sores, which are very prone to occur in the terminal stages, herpes, hema- tomata of the ear, etc., are often seen. A striking feature of paresis is the frequency of fractures. This undoubtedly is due to a greater fragility of the bones, and often leads to false accusations of attendants. The sexual strength of the paretic, which is often increased in the beginning of the disease and may in part account for his leud con- duct, is later dminished and finally entirely lost. Bladder symptoms, both paralysis of the sphincter with inconti- nence and retention, are noted. The condition of the bowels is often most distressing, there often being at first constipation with impaction and distention, while later there is incontinence of feces. The whole picture of paresis in the terminal stages, both mental and physical, is one of the most repulsive in all the field of medicine. Cord Substance. — Gummata of the cord are exceedingly rare and may originate either in the meninges or in the substance of the cord itself. The symptoms produced will depend upon their location and size. The myelitis following syphilitic arteritis is most frequently found in the dorsal region. Among the first symptoms noted, in fact often the first symptom, is disturbance of the bladder function, either incontinence or retention. Other symptoms are paresthesias, para- plegia, usually spastic, disturbances of sensation, either in all of the sensations or in part of them. Not infrequently the temperature sense is the only one not disturbed. As a rule the deep reflexes are increased, while the superficial reflexes may be increased or dimin- ished. Babinski's sign is usualy positive. When the lumbar region is involved there is a flacid paralysis of the legs with abolishment of both superflcial and deep reflexes. Bladder symptoms and disturbances of sensation are similar to those in dorsal involvement. Bed-sores are very frequent. Involvement of the cervical region is marked by motor and sensory disturbances in all four extremities with perhaps atrophy of the m^uscles of the arms. When the lower segments of the cervical and the upper segments of the dorsal regions are involved there may be afi'ections of the sympathetic with contraction of the pupil of the CLINICAL HISTORY 329 involved side, enopthalmus and suppression of perspiration of one- half of the face. Tabes Dorsalis. — Tabes dorsalis or locomotor ataxia, as is paresis, is now known to be a true syphilitic disease and as such deserves most careful consideration. This condition, as a rule, develops somewhat earlier than paresis, being seen most frequently between the fifth and tenth years follow- ing the syphilitic infection, but has been observed as early as ten months after the chancre and as late as thirty-five years. As a rule tabes is of very insidious onset and is extremely slow in its progress, its course occupying ten, twenty or even thirty years. On the other hand, however, the onset of tabes may be abrupt and it may run its course to a fatal termination in two or three years. The symptoms of tabes are in the aggregate quite constant, while the individual symptoms vary within a wide range. They may be described under the following heads: Sensory, motor, visual, audi- tory, reflex, visceral, including the bones, joints and muscles, and trophic. Sensory symptoms are both subjective and objective, the former being in the majority of cases the earliest symptoms of the disease. The subjective sensory symptoms consist of pains of varying loca- tion and intensity, the most characteristic ones being the so-called lightning or lancinating pains, and certain paresthesias. The light- ning pains are most frequently noted in the lower extremities, often beginning in the great toe and being mistaken for gout. They may, however, be felt in the face, arms or trunk. They are described by the patient as most excruciating in character. Their duration varies from a few minutes to several hours or even days and can be relieved only by morphin. There is usually no correspondence of the pain with the distribution of the nerve, although the pain may sometimes simulate sciatica. These pains may recur with rather startling regularity in the same location, and if beginning early in the course of the disease they may disappear later, while if they are not ob- served early they may not occur at all. It has also been noted that severe pains occurring early are, as a rule, followed by a prolonged course of the disease. Other pains of a less severe nature but more permanent are noted. The chief of these is the so-called girdle pain which the patient de- scribes as the sensation of a tight belt around the body. It generally is narrow in extent, may be located at any level of the trunk, but is sometimes described as feeling like an iron jacket. A similar pain on the arms or legs is often noted, and described as feeling like a tight bracelet or a tightly wound rope on the extremity. These pains may last for long periods of time, even years, and may disappear only to recur at a later period. 330 SYPHILIS OF THE NERVOUS SYSTEM The pains referable to the various viscera will be described later. Certain jMresthesias such as numbness, formication, tingling, prickling, the sensation of walking on velvet, as if cold water were running over the body, the feeling of cobwebs on the skin, etc., are often observed. The so-called Hutchinson mask, the sensation of the face being covered with a mask or cobweb is not rare. Of the objective sensory symptoms the most frequent is analgesia which affects the cutaneous surface, and also the bones, joints and muscles. Severe injuries, burns, cuts, bruises and even fractures and dislocations are unaccompanied by pain. Analgesia of the cuta- neous surface is found in areas which have a tendency on the trunk and extremities to bilateral distribution, while on the head the dis- tribution is usually unilateral. On the upper extremities the most frequently affected areas are the fingers and ulnar border of the forearm. The sole of the foot, the heel, the toes and the inner sur- faces of the thighs are the favorite locations of the analgesia in the lower extremities. On the trunk the areas most often affected are over the pectoral regions, the umbilicus, the inguinal regions and the shoulders. The areas of analgesia are often marked by borders of hyperesthesia. The patient is frequently unaware of his affliction until it is demonstrated to him, and shows great surprise when a pin is stuck deeply into his body without pain. Areas of hyperalgesia are also common but are less symmetrically located and less frequent. Not only may the areas be more sensi- tive to such pains as the prick of a needle but may be hyperalgesic to heat and cold. Often these areas are the seat of the lightning pains and appear during the crises. Anesthetic areas are very frequently observed in tabes. The most typical is the so-called tabetic cuirass, which is an area encircling the trunk, usually three or four inches broad, but sometimes occupying the entire length of the trunk and often associated with the girdle pain. Other areas of anesthesia are sometimes found on the inner surfaces of the arms and forearms, the ulnar margins of the hands, the outer margins of the feet, the outer sides of the legs, the anterior and internal surfaces of the thighs and in the perineum. Not infrequently there are alterations in the pain and tactile sense, the individual being unable to tell the nature of a pain, perhaps calling a pin prick a pinch. The pain sense may also be retarded, the prick of a pin being felt as a touch immediately and later (three to ten seconds) felt 3,3 pain. A striking symptom in some cases is an impairment of stereognosis , the patient being unable to distinguish by the sense of touch such objects as a key or a coin. Motor symptoms in tabes consist of ataxia, which may be more than that of locomotion, involuntary movements, and paralyses. CLINICAL HISTORY 331 The ataxia is not, as a rule, an early symptom of tabes, usually developing after sensory symptoms have been present for some time. The ataxia, however, may be the first symptom to call the attention of the patient or the physician to the true nature of the condition. It is usually a gradual development, the patient first noting that he has difficulty in ascending or descending steps or walking in the dark. He soon also finds it difficult to stand with the feet close together without swaying (Romberg's sign). Before long a change Fig. 70. ait. (Note hyperextension of knee.) in gait is noted, the feet being placed on the ground differently, and he walks with a wide base and finds a cane of assistance. Gradually it is noticed that the feet are raised too high, are placed too far for- ward and are stamped down suddenly. Later standing, even with support, becomes impossible, the feet slipping out in front of him. Ability properly to control movements of the feet and legs while lying in bed becomes lost, the patient throwing the foot wide of the mark when told to touch some object with it. Ataxia of the upper extremities may not occur, may follow much later that of the lower extremities and may in rare instances occur first. This is noticable in such movements as writing and grasping articles. 332 > SYPHILIS OF THE NERVOUS SYSTEM The involuntary movements of tabes consist mainly of jerking move- ments of the hmbs or portions of the hmbs as a thumb or finger, and are of comparative frequency. They may occur early in the course of the disease or they may be a later manifestation. They may occur while the patient is asleep or while he is awake and are usually uniform for each individual. The ijaralyses found in tabes consist of monoplegias, hemiplegia and paraplegia, paralysis of the tongue and larynx, facial paralysis and ptosis. These paralyses are due to organic and vascular changes in the cerebrum and cord. They are of comparatively infrequent occurrence and may be transitory or permanent. Visual Symytoms. — Ptosis has been mentioned as one of the symptoms of tabes and paralyses of the muscles of the eyeball also occur, the external rectus being most often affected. Anomalies of pupillary reaction are found in the vast majority of tabetics. Of these the so-called Argyll-Robertson pupil is the most important. This phenomenon, which consists of a loss of light reflex, while the reaction to accommodation remains intact, is found in from 50 to 70 per cent, of cases. It is usually bilateral but may be unilateral. Other pupillary disturbances are inequality, pin-point size, increase in size, irregularity in outline, loss of accommodation and absolute iridoplegia. Sluggishnes>: of the pupils with slight irregularity in outline or inequalities are very early symptoms of tabes, while the other pupillary disturbances are, as a rule, of later occurrence. Optic atrophy occurs in a small percentage of cases and is, as a rule, of early development, the resulting defect in vision or blindness often being the first symptom to lead the patient to the phj'^sician. Auditory Symi^toms. — According to Murpurgo^ auditory defects are found at some time during the course of the disease in 80 per cent, of tabetics. These consist of recurring sounds like the ringing of bells, rushing water, whistles, musical sounds, etc. and impairment of hearing. The sounds are due to affections of the cochlear branch of the auditory nerve, while the impairment of hearing may be due to degeneration of the auditory nerve or to abnormalities in the middle or external ear. Reflex Symptoms. — Diminished or absent deep reflexes, especially the knee-jerk, is one of the earliest and most frequent symptoms of tabes. It is usually bilateral but may be confined to one side. The superficial reflexes may or may not be disturbed. Visceral Symptoms. — The most important and frequent of the visceral symptoms are those referable to the stomach. The so- called gastric crises, which are of sudden onset, may occur very early 1 Ar9h. f. Ohrenheilk., 1890. CLINICAL HISTORY 333 in the course of tabes, in fact, may be the only symptom observed, the patient being treated for other types of gastric disorder. Pain is the most conspicuous feature of these attacks, is located in the epigastrium, just beneath the xiphoid cartilage, and may radiate in all directions. It is most excruciating in character, often being so severe as to cause unconsciousness. Vomiting also occurs, the attacks being frequent and uncontrollable. It may or may not be accompanied by straining. It occurs regardless of the presence of food in the stomach, although the ingestion of even a very small quantity of food or water during a crisis is followed by its immediate ejection. The vomitus following the first ejection of whatever undigested food is present is soon seen to consist mainly of gastric mucous, later mixed with bile, and if the vomiting is long continued, may contain blood. It has been shown that in the beginning of the attacks a hyper- acidity exists, due to an increase in hydrochloric and lactic acids, which is diminished throughout the attack. The gastric crisis may last for an hour or for days or even weeks, and is accompanied by marked prostration, the patient appearing as if suffering from shock. They may end as abruptly as they began with a cessation of pain and a desire for food. One crisis may be the only one experi- enced during the course of the disease but, as a rule, they are repeated, sometimes daily, but usually only at intervals of several weeks or months. They may diminish in frequency and severity as the dis- ease progresses or they may be so severe as to cause death. Intestinal crises are of rather rare occurrence, are characterized by marked diarrhea but without pain. Constipation also may occur. Rectal crises are more frequent and are accompanied by most intolerable tenesmus, and the passage of small amounts of bloody mucous. The bladder is the seat of some of the earliest and most constant symptoms of tabes. The usual condition is one of difficulty in start- ing urination or of incontinence. Vesical tenesmus of a most dis- tressing character is also sometimes noted. Nephritic crises have been described, but may be due to true renal colic. The genital organs are very frequently affected in tabes. Diminu- tion of the sexual appetite and even impotence are observed in about 50 per cent, of the cases and is sometimes preceded by an excessive sexual appetite. Impotence may occur very early in the course of the disease or may only appear as a late manifestation. Diminution or loss of the cremasteric reflex and the so-called virile reflex usually accompany impotence in tabes. The testicle is sometimes the seat of analgesia and is often accompanied by atrophy of the organs. Clitoris crises may occur in females. 334 SYPHILIS OF THE NERVOUS SYSTEM Laryngeal crises occur quite frequently and consist of spasms of the laryngeal muscles. The symptoms are noisy inspiration and expiration with cough and usually more or less dyspnea and pain. The hones are very frequently the seat of spontaneous fracture due to a rarefication and decalcification. The most frequently fractured bones are the femur, the tibia and fibula and the ulna and radius, although any of the long bones may easily be broken. The bones develop this condition early in the course of the disease and spontaneous fractures may occur before any symptoms of tabes have been noticed or they may occur later. The Joints. — The so-called Charcot's joint, which sometimes occurs in tabes, has been described in the section on joint affections. (See pages 305 and 307.) The muscles in tabes usually show more or less hypotonus which corresponds to the ataxia of the limbs. It is readily appreciated by the ease with which overextension of the elbows, knees and ankles, and the flexion of the hip and abduction of the thighs may be produced. The muscles of tabetics also in some cases present an atrophy, the onset of which is very insidious and which may occur early in the course of the disease. The most frequent seats are the foot and leg muscles and the small muscles of the hands and the forearm. The resulting deformities, such as eqninovarus, are due to the atony and not to contracture. The wasting and flaccidity of the muscles observed late in the course of the disease is to be dis- tinguished from this atrophy. The troyhic symptoms of tabes consist mainly of certain cutaneous lesions such as herpes zoster, trophic dermatoses, hyperidrosis, anidrosis and hypertrophies of the epidermis of the extremities, and are of more or less rare occurrence So-called ferf orating ulcer is more frequently found, especially on the foot. It begins as a callous spot on the sole which is followed by deep ulceration and is very refractory to treatment. Decubitus is noted only in the terminal stages of the disease. Taboparesis, as the name implies, is a combination of tabes dorsalis and general paralysis. While tabetic symptoms may develop in an individual suffering with paresis it is more frequent for the symptoms of general paralysis to develop in a tabetic. Nerves. — Syphilis of the cranial nerves is, as a rule, an extension from a basilar meningitis. Any of the cranial nerves may be attacked singly, or, which is more frequent, several that are in close anatomical relation become involved together. The resulting symp- toms wil naturally depend upon the nerves affected, thus, the involvement of the optic nerve will cause more or less disturbance of vision, even blindness, choked disk, etc., while involvement of the oculomotor, which is probably the most frequently affected of DIAGNOSIS 335 the cranial nerves, will cause paralysis of the ocular muscles sup- plied by this nerve. Neuralgias due to syphilis are of comparatively frequent occur- rence, usually being observed early during the course of the disease^ but may be late manifestations. The trifacial, the sciatic, the cer- vical and brachial plexes, and the intercostals are most often involved. Syphilitic neuritis and jwlyneuritis are rarely observed and the symptoms do not differ from the symptoms seen in these conditions due to other causes. Diagnosis. — The diagnosis of syphilis of the nervous system can in many cases be made with considerable certainty upon clinical evidence alone, but to the author's mind such a diagnosis is rarely justifiable without the evidence of laboratory procedures, especially the examination of the spinal fluid. In certain cases of tabes and paresis in the terminal stages, however, the spinal fluid may be entirely negative to laboratory tests, in which cases the diagnosis must rest upon the history and clinical evidence. Meninges. — Syphilitic meningitis must be differentiated from meningitis due to other etiological factors, especially that due to the tubercle bacillus and the Diplococcus intracellularis. This can, as a rule, be accomplished by the more acute course of the tubercular and epidemic forms of meningitis, as well as the presence of fever which is rarely seen in the syphilitic form. However, in most cases it is necessary to resort to lumbar puncture and examination of the spinal fluid to determine the true nature of the affection. Arteries. — Syphilitic arteritis of the brain with the resulting encephalitis, which is usually accompanied by more or less meningitis, causes symptoms which may be mistaken for a variety of conditions. The most important of these is paresis and in some cases the differ- ential diagnosis may be most difficult. The usual insidious onset of paresis, the progressive dementia and paralysis, the complete alteration of personality and disorientation will in the majority of cases serve to distinguish this disease from the more acute, irregular course of syphilitic arteritis. Nevertheless the diagnosis of syphilitic arteritis to the exclusion of paresis should not be made without recourse to examination of the spinal fluid. (See Chapter VIL) Even with this evidence a diagnosis may sometimes be impos- sible and the final verdict must rest upon an observation of a con- siderable period of time and the effects of specific therapy. Syphilitic arteritis of the central nervous system must also be differentiated from arteriosclerosis, uremic poisoning, viultiple sclerosis, hysteria, and chronic alcoholism. Arteriosclerosis usually occurs later in life than specific arteritis but the clinical picture may be so similar that only laboratory evidence can clear the diagnosis. 336 SYPHILIS OF THE NERVOUS SYSTEM Uremic poisoning is accompanied by disease of the kidneys, which will be manifest by examination of the urine. Multiple sclerosis may be manifested by symptoms resembling syphilitic arteritis and the two conditions sometimes can be differ- entiated only by laboratory procedures. Hysteria, especially if it occurs in a syphilitic, may present difficulties of diagnosis which can be cleared up only by lumbar puncture and spinal fluid examination. In chronic alcoholism evidences of the recent ingestion of this drug are usually observed, and after its eft'ects have had time to wear off the true nature of the condition will, as a rule, be manifest. However, more or less lasting symptoms may be present and the resort to laboratory procedures may be necessary. Brain Substance. — Gummata of the brain substance cannot be differentiated from non-syphilitic tumors upon clinical evidence alone. The history may be of value and laboratory procedures should be instituted. The Wassermann test upon the blood may or may not be positive, and too much reliance should not be placed upon it, as it is possible for a non-luetic tumor of the brain to develop in an individual suffering from syphilis, but without central nervous system involvement. If the gumma is deeply embedded in the brain substance, the spinal fluid will, as r. rule, yield negative results, although the Wassermann test may be positive. The final diagnosis may have to rest upon the result of specific therapy, although even this may be of no avail, as not all gummata yield to treatment. Paresis. — In the majority of cases of general paralysis the clinical picture is quite characteristic and when positive laboratory evidence is added to this, especially the gold chloride test, mistakes should rarely be made. In no other syphilitic condition are laboratory procedures of more importance and to the author's mind a diagnosis of paresis should rarely be made without them. Certainly such a diagnosis should never be made upon psychic symptoms alone. As stated above, encephalitis due to syphilitic involvement of the arteries of the brain may simulate paresis and the differential diagnosis has been discussed. The mental symptoms of paresis may be mistaken for many other abnormal psychic states such as manic-depressive insanity, paranoia, hysteria, senile dementia, alcoholic deterioration, etc., and often a correct diagnosis can only be reached by resort to spinal puncture. The paretic convulsion must be differentiated from epilepsy and convulsions due to uremic poisoning and diabetes. In epilepsy the history of seizures for years before mental symp- toms began will, as a rule, serve to distinguish it from paresis, while an examination of the urine in uremic poisoning and in diabetes will, as a rule, clear up the diagnosis. DIAGNOSIS 337 Cord Substance. — Gummata of the spinal cord, though rare, are to be differentiated from other tumors of non-specific origin. The history and a positive Wassermann reaction upon the spinal fluid will clear up the diagnosis. A history of lues cannot by any means always be obtained and the Wassermann may be negative (see page 156), so that the final diagnosis may of necessity rest upon a therapeutic test. Even this test may prove negative, as gummata of the cord as well as gummata of the brain do not always yield to specific therapy. Myelitis due to syphilitic involvement presents no symptoms which are pathognomonic and which may not occur in non-luetic spinal cord disease. The main conditions which must be differ- entiated from syphilitic myelitis are spinal neurasthenia, tumors, multiple sclerosis, hysteria and myelitis due to compression from tubercular caries of the vertebrce, and while the history may be of value the diagnosis must, as a rule, rest upon laboratory evidence, especially lumbar puncture, and therapeutic procedures. Tabes Dorsalis. — The diagnosis of a fully developed case of tabes dorsalis rarely presents much difficulty, but in the early course of the disease before ataxia has developed it may be confused with many other conditions. The various visceral crises and the light- ning and girdle pains are quite frequently ascribed to other causes, especially if 'occurring before other symptoms. This fact but serves to emphasize the importance of a thorough examination of all patients presenting themselves for diagnosis, as very early in the course of tabes pupillary anomalies and disturbances of reflexes will be found. Behr^ emphasizes the fact that pupillary disturbance, especially only partial failure of the iris to contract to light, may be found even years before other symptoms. He states that this some- times cannot be detected without the use of the ophthalmoscope. The repetition of a gastric or other crisis or of the lightning or girdle pains should at once arouse suspicion. Later in the course of tabes the most important disease from which it is to be differentiated is multiple neuritis. In the latter condition, the more rapid development, the absence of the Argyll- Robertson pupil, girdle pains and laboratory evidence of syphilis, as well as a history of some toxic condition such as diphtheria, typhoid, lead poisoning or aleoholism will serve to establish a diagnosis. It must be remembered that there is a certain small percentage of cases of tabes, according to Kaplan,^ 7 per cent., in which all laboratory evidence of syphilis is negative. In these cases the diag- nosis must rest upon the history and clinical evidence. 1 Med. Klin., 1914. x, p. 1842. 2 Serology of Nervous and Mental Diseases, Philadelphia and London, 1914, p. 136. 22 338 SYPHILIS OF THE NERVOUS SYSTEM Tahoparesw. — The diagnosis of taboparesis depends upon the same factors as the diagnosis of tabes and paresis occurring separately. It is sometimes extremely difficult in cases which are frankly tabetic to determine whether or not a condition of involvement of the brain substance also exists. The obtaining of a typical paretic curve in the colloidal gold test would be very significant. Nerves. — There is nothing characteristic in syphilitic involve- ment of the nerves and the diagnosis must rest upon the history, evidence of syphilis of other localities, laboratory procedures and the result of specific therapy. Prognosis. — The prognosis of syphilis of the nervous system was formerly almost always bad, but with the institution of more modern therapy the outlook is much less gloomy than heretofore. The importance of early diagnosis of syphilitic involvement of the nervous system must be emphasized. As with all syphilis, so especially with syphilis of the nervous system, the earlier the condition is recognized, the better will be the prognosis. It may be said, however, that where there has been actual destruction of ner- vous tissue no hope of regeneration can be entertained, that the best which can be expected is to stop the advance of the process. Meninges. — The prognosis of complete recovery from the syphilitic meningitis seen early in the course of the disease probably is better than that of any other syphilitic condition of the nervous system. With the institution of vigorous antisyphilitic treatment most cases become normal both clinically and from a laboratory standpoint in a surprisingly short time. Syphilitic meningitis occurring later in the course of the disease, during the second or third year, is more serious, although even this meningitis may be completely cured by proper therapy. Meningitis of the convexity is more refractory to treatment than basilar men- ingitis. This is especially true if the basilar meningitis is limited to one side of the brain. Syphilitic meningitis of the spinal cord is also quite amenable to treatment. Arteries. — The prognosis of syphilitic arteritis is worse than that of meningitis. The earlier the condition is recognized, however, the better will be the prognosis. If the diagnosis is made before the arteries have become obliterated, intensive antisyphilitic treat- ment may arrest the process and the patient return to normal. If, however, obliteration has taken place and destruction of nerve tissue has occurred, the best that can be hoped for is to stop the advance of the disease. The symptoms depending upon destruc- tion of tissue will remain, although to a certain extent the lost functions may be taken over by the normal portions of central nervous system. Involvement of the basilar artery is almost always fatal. PROGNOSIS 339 Brain Substance. — Gummata of the brain substance quite frequently yield to antisyphilitic treatment; however, some cases are most refractory. In these cases surgical interference has been tried with some measure of success. Paresis. — The prognosis in paresis is the most gloomy of all syphilitic processes, and even since the establishment of the direct etiological relationship of the Treponema pallida to this condition and the advent of modern methods of treatment few cases of com- plete recovery have been reported and most of these are open to some doubt as to the correctness of the diagnosis. Nevertheless this unfavorable outlook should not deter the physician from car- rying out all the therapeutic means at his disposal, with the hope that the process may be arrested. The fact must not be lost sight of, however, that remissions, even of several years' duration, have been observed and must not be mistaken for cure. In the majority of cases, however, remissions, if occurring at all, are of short duration and the disease goes on to a rather speedy fatal termination. According to Kraepelin^ nearly one-half of all cases die in the course of the first two years. This author tabulates the year of the disease in which deaths occurred in 224 cases as follows : 1st 2d 3d 4th 5th 6th 7th 8th 9th 10th 14th 51 63 52 41 22 4 5 2 2 1 1 Of 104 cases of paresis at the Arkansas State Hospital for Nervous Diseases, the majority of whom were observed by the author, 48 are living at the present time, (1915) with residence in the institution as follows: Less than one year 29 Between one and two years 15 Between two and three years 4 Of the 56 who are dead, 19 died during the first three months of residence in the hospital, 8 during the second three months, 5 during the third three months, 3 during the fourth three months, 16 during the second year, 4 during the third year, and 1 during the fourth year. Cord. — Gummata of the substance of the cord may yield to anti- syphilitic remedies, or if these fail, surgical intervention may bring results. The myelitu following arteritis of the cord is usually most refractory to treatment, the majority of cases going on to a fatal termination. Usually the most that can be hoped for is to arrest the process. 1 General Paresis, New York, 1913, p. 99. 340 SYPHILIS OF THE NERVOUS SYSTEM Tabes Dorsalis. — Since the institution of modern methods of treatment the prognosis in tabes has become more hopeful and even cases of long standing may yield in a remarkable manner. It must be said, however, that those cases which are early recog- nized and show the greatest activity of the syphilitic process, that is, those with positive laboratory findings are the most amenable to treatment. Cases in which marked degeneration has taken place, cannot, of course, be restored to normal but the process may be stopped, and at least the subjective symptoms, the lightning pains and crises may be relieved. This in itself constitutes a distinct victory, as probably no suffering in all the field of human ills is more intense. It must be remembered that many cases of tabes progress to a certain stage, the process halting even without treatment and remaining stationary for long periods of time, even years. Taboparesis. — The prognosis of taboparesis is most grave, as practically all cases go on to a fatal termination. It has been noted that sometimes when tabetic symptoms develop in a paretic the mental condition improves, and on the other hand, when paretic symptoms occur in a tabetic there may be a diminution of the ataxia. Nerves. — The prognosis of syphilitic involvement of the cranial nerves, which occurs in association with specific basilar meningitis, is practically the same as the prognosis of the meningitis, although if degeneration has taken place the outlook is very unfavorable. Syphilitic neuralgia, especially that occurring early in the course of the disease, is very amenable to treatment, most cases quickly being cured upon the administration of specifics. The prognosis of neuritis and polyneuritis will depend upon the extent of the process and the prognosis of the syphilis itself. Mortality. — Mott^ gives the following table regarding the mor- tality of cerebral syphilis: Fournier. Hjellmann. Naunyn. Cured i i 24 probable Improved J 5 49 t Death ....... e - 2 ^ 10 (treatment no influence) The mortality of 148 cases of cerebral, spinal, and cerebrospinal syphilis seen by Nonne^ is shown in the following table : Died . . 16 cases = 10.8 per cent \ ^^ ^^^^^ ^ 3^^ ^^^^ Unimproved . 30 cases = 20 . 3 per cent. J Improved . 30 cases =20.3 per cent. \ g cases =68.9 per cent. Recovered . 72 cases = 48 . 6 per cent. J 1 Power and Murphy: System of Syphilis, London, 1909, iv, p. 482. 2 Syphilis and the Nervous System, Philadelphia and London, 1913, p. 163. TREATMENT 341 According to Hoppe, as quoted by Kraepelin/ 32.8 per cent, of paretic men and 18.5 per cent, of paretic women die during convul- sions, whicli may occur at nearly any time during the course of the disease. Pneumonia, following the aspiration of food or saliva, especially during convulsions, is the most common cause of death. Septicemia and fat embolism from bed-sores, pyelitis or cystitis also not infrequently cause death. Some paretics die from suffo- cation during vomiting or stuffing their mouths with food and aspirating a portion into the larynx, and finally in those who escape the dangers described, death from cardiac failure terminates a severe marasmus. Treatment. — Syphilis of the nervous system is caused by the same organism that causes syphilis of other portions of the body, never- theless the treatment of syphilis of the nervous system presents problems which differ in many respects from the treatment of other syphilitic involvement. The ideal which it is desirable to attain in the treatment of any case of syphilis is completely to rid the body of the invading organisms and to restore to normal the portions of the body involved. In the case of syphilis of the nervous system this may be undertaken by the administration of specific remedies by the ordinary methods as in any case of syphilis with the hope that these remedies will be carried to and destroy the organisms, and by the direct administration of specifics to the parts involved. To these may be added certain general measures as outlined for the treatment of all syphilis, and symptomatic treatment. All cases of syphilis of the nervous system should be most vigorously treated with specifics in the same manner as syphilis of any other portion of the body. Added to this, in cases of involvement of the cerebro- spinal axis, specific medication directly administered to the parts involved should be undertaken. Probably the first investigator to treat syphilis of the nervous system by intraspinal injection was Schachmann,^ who, in 1901, treated 4 cases by the injection 1 c.c. of a 1 per cent, solution of mercury benzoate. One case of syphilitic myelitis is reported in detail. This patient received twenty-three injections in twenty- five days, showing marked improvement. The first injection caused restlessness, slight rise in temperature and insomnia, but by the fifth injection no untoward symptoms were ob- served. Karsley, according to Smith,^ in 1910, advocated intraspinal irrigations with mercuric chloride solution for syphilis of the nervous system. 1 General Paresis, New York, 1913, p. 100. 2 Bull, de la Soc. med. des hop. de Paris, October 24, 1901. 3 Jour. Am. Med. Assn., 1915, Ixiv, p. 1563. 342 SYPHILIS OF THE NERVOUS SYSTEM The work of Swift and Ellis^ on the intraspinal injection of salvarsanized serum, however, was the first to arouse any consider- able attention, and since the publication of their investigations numerous workers have applied their method and it has stimulated others into devising similar procedures, so that today intraspinal treatments and intracranial have taken a permanent place in the therapy of syphilis of the nervous system. The method of Swift and Ellis consists of administering a large dose of salvarsan or neosalvarsan intravenously, and one hour after administration to withdraw by venipuncture 40 c.c. of blood. This is allowed to clot, after which it is centrifugalized and the clear serum pipetted off. The next day 12 c.c. of the serum are diluted with 18 c.c. of normal salt solution which make a 40 per cent, solu- tion. This is heated in the water-bath at 56° C. for half an hour, after which it is injected intraspinally by gravity following the withdrawal by lumbar puncture of a sufficient quantity of spinal fluid to reduce the pressure to 30 mm. Wechselmann,^ in 1913, reported the intraspinal injection of neosalvarsan into two paretics and also into two children with congenital syphilis, without any injurious effects. Marinesco^ injected thirteen patients intraspinally with neosal- varsan, each receiving 5 mg. in 4 c.c. of solution. Severe unpleasant symptoms appeared immediately in ten of them, while eight devel- oped permanent bladder disturbance. This author also reports the intraspinal injections of serum from patients with so-called secondary syphilis following treatment with salvarsan. In these cases some beneficial results were noted. Robertson'* treated paretics with intraspinal injections of serum of patients with secondary syphilis withdrawn on the third day after the intravenous injection of salvarsan. Serum from the patients themselves one hour after the intravenous injection of salvarsan also was used. Marie and Levaditi^ treated paretics with intraspinal injections of neosalvarsan in doses of 0.005 to 0.04 gram. Wile^ advocated the technic of Ravaut which he describes as follows: A 6 per cent, solution of neosalvarsan, which is hypertonic, is employed. Each drop contains 3 mg. of the drug and is prepared by dissolving the contents of a 0.3 gram ampule of neosalvarsan in 5 c.c. of sterile freshly distilled water. The dose to be admin- 1 New York Med. Jour., 1912, xcvi, p. 53. 2 Deutsch. Med. Wchnschr., 1912, xxxviii, p. 1446. 3 Ztschr. f. diatet. u. physik. Therap., 1913, xvii, p. 194. * Edinburgh Med. Jour., 1913, x, p. 428. s Bull, et mem. Soc. M6d. d. h6p. de Paris, 1913, Series 3, xxxvi, p. 675. * Jour. Am. Med. Assn., 1914, Ixii, p. 1165. TREATMENT 343 istered, which varies from 3 to 12 mg. (1 to 4 drops), is placed in a syringe accurately graduated in drops. A spinal puncture is performed with a needle into which the syringe fits and after a few drops of spinal fluid have escaped the syringe is attached and the fluid allowed to flow into the syringe barrel where it mixes with the neosalvarsan. The fluid and drug are now forced into the spinal canal by gentle pressure on the plunger of the syringe. Slight suction is then made with the plunger to withdraw a small amount of fluid and wash out the needle, following which it is reinjected and the needle withdrawn. The patient is then placed in the Trendel- enburg position in which he remains for one hour. Fig. 71. — Method of intraspinal injection. A distinct advance in the preparation of salvarsanized serum for intraspinal injection has been proposed by Ogilvie.^ His method consists of withdrawing about 50 c.c. of blood from the patient without previous intravenous treatment. This is centrifugalized immediately at a high rate of speed which throws the fibrin and cellular elements down, and the serum is pipetted off. To 15 c.c. of this is directly added the salvarsan in the dose which is to be used. The salvarsan is prepared as for intravenous injection with freshly distilled and boiled water, the total quantity being made up so that each 40 c.c. contains 0.1 gram of the drug or each c.c, 0.25 mg. Ogilvie cautions against adding an excess of sodium hydroxide when preparing the salvarsan solution. He also states 1 Jour. Am. Med. Assn., 1914, Ixiii, p. 1936. 344 SYPHILIS OF THE NERVOUS SYSTEM that the temperature of the salvarsan and the serum should be the same when the two are mixed. The dose recommended by Ogilvie is from 0.25 to 0.5 mg. for repeated injections, although he has given as high as 4 mg. After adding the salvarsan and gently shaking to thoroughly mix the two the serum is placed in a thermostat at 37° C. for forty-five minutes, then in a thermostat at 56° C. for thirty minutes. Ogilvie insists that it should be administered as soon as possible after preparation and under no circumstances should it be injected if more than three hours old. Wile^ recently has modified his technic for intraspinal medica- tion, employing salvarsan instead of neosal-varsan. His method is to attach the barrel of a 40 c.c. Luer syringe to the spinal puncture needle after a successful puncture by means of about eight inches of rubber tubing. About 10 c.c. of the spinal fluid are allowed to flow into the barrel of the syringe by lowering the latter below the level of the puncture site. The salvarsan is a freshly prepared, neutralized solution of 0.1 gram in 30 c.c. of water and the amount used 0.1 c.c. (approximately 2 drops), corresponding to I mg., is carefully dropped into the barrel of the syringe and stirred into the fluid by means of a sterile glass rod. The salvarsanized fluid is now allowed to flow into the spinal canal by gravity by raising the barrel of the syringe above the level of the puncture site. Byrnes^ suggested the intraspinal injection of mercurialized serum prepared from human blood serum by adding a solution of bichloride of mercury in a manner similar to that described for the prepara- tion of mercurialized serum for intravenous injection. This is used in doses of 0.0013 gram (5^0- grain) to 0.0026 gram {-jq grain) and is administered by gravity. Recently a similar preparation prepared from horse serum has been placed upon the market and has given satisfactory results in the hands of the author, although he prefers to prepare the serum himself from human blood. Intracranial injection of specifics in the treatment of syphilis of the nervous system has been practised by several workers. Wardner^ treated five patients by intracranial injection of salvar- sanized serum prepared after the technic of Swift and Ellis. The patient is prepared for operation, anesthetized with ether, and a trephine hole bored as nearly as possible over the precentral gyrus. When the dura is exposed 20 c.c. of spinal fluid are withdrawn by lumbar puncture. This relieves the tension which is noted in the dura and permits the respiratory pulsations of the membrane to be plainly seen. By means of a 30 c.c. Luer syringe and an 1 Jour. Lab. and Clin. Med., 1915, i, p. 119. 2 Jour. Am. Med. Assn., 1914, Ixiii, p. 2182. ' Am. Jour. Insan., 1915, Ixxi, p. 459. TREATMENT 345 ordinary small caliber salvarsan needle, bent upon itself at about a quarter of an inch from the point, connected by about 18 inches of rubber tubing, 30 c.c. of the previously prepared salvarsanized serum are injected subdurally by gravity. Wardner states that the trephine opening should be not less than 2 cm. in diameter for the safe introduction of the needle. Hamill^ reports two cases treated by the intracranial injection of neosalvarsan. A lumbar puncture is performed and about 6 c.c. of spinal fluid withdrawn. Following this a Neisser-Polock puncture is made 8 cm. above the orbital arch, 2.5 mg. are care- fully weighed out, dissolved in 5 c.c. of spinal fluid and injected subdurally through the cranial puncture, one-half on either side. Hammond and Sharpe^ recently have reported the intraventric- ular injection of salvarsanized serum and neosalvarsan in paretics. Their technic is as follows: The patient is etherized and a small skin flap, slightly larger than the trephine used is made a little in front of the bregma and 2.5 cm. from the sagittal sinus. A button of bone 1.5 cm. in diameter is removed and an incision made in the dura. A blunt slender canula is introduced at a point free from underlying vessels and passed downward and a little backward into the lateral ventricle. The head of the table is lowered, and from 10 to 20 c.c. of fluid allowed to escape. The head of the table is then raised and the serum allowed to flow slowly into the ventricle by gravity from a funnel through a rubber tube attached to the canula, after which the canula is removed and the scalp wound sutured. In subsequent injections a general anesthetic is not re- quired as the brain is not sensitive and the scalp may be opened over the trephine opening under novocaine. The rationale of the subdural treatment oi syphilis of the cere- brospinal axis is, of course, to bring the specific drug into as direct contact as possible with the tissues involved. Certain syphilographers have objected to the treatment on the ground that it is not necessary, that the salvarsan or neosalvarsan reaches these areas as readily following intravenous administration as following subdural injection. The majority of investigators, however, have shown that the spinal fluid following intravenous administration of the arsenicals contains little or no arsenic. Lorenz,^ working with sodium cacodylate, found that the spinal fluid contained no arsenic following the intravenous administra- tion of small doses. With doses of 1 gram, however, traces of arsenic were found in the spinal fluid one hour after administration. 1 Illinois Med. Jour., 1915, xxvii, p. 204. 2 Jour. Am. Med. Assn., 1915, Ixv, p. 2147. 3 Med. Rec, 1912, Ixxii, p. 185. 346 SYPHILIS OF THE NERVOUS SYSTEM Camp^ administered 0.6 gram of salvarsan intravenously and performed spinal puncture at varying periods from 15 minutes to 40 hours after injection. In only one instance was arsenic found in the spinal fluid. This was in a case of so-called secondary syphilis, in which the spinal puncture was performed 15 hours after the injection of the salvarsan. Engman, Buhman, Gorham, and Davis^ performed spinal punc- ture on four paretics, withdrawing 10 c.c. of spinal fluid immediately, after which a full dose of neosalvarsan was administered intra- venously. In two of the cases spinal puncture was performed again in 48 hours and in the other two in 98 hours. The examination of the fluids for the presence of arsenic by the Gutzeit and Marsh tests were negative in all cases. Sicard and Bloch^ were unable to find arsenic in the spinal fluid of patients following either the intramuscular or subcutaneous administration of 0.4 gram of salvarsan. However, traces of arsenic were found in the spinal fluid of one patient two hours after the intravenous administration of 0.4 gram of salvarsan. Hall'^ administered neosalvarsan intravenously to five patients, performing spinal puncture one and a half hours, six hours, and twenty-four hours following injection without finding arsenic in the spinal fluid. Salvarsan was injected intravenously into six patients, the spinal fluid showing arsenic only in two cases after twenty-four hours. Swift^ states that with the pooled fluids up to 100 c.c. withdrawn the day following the intravenous injection of salvarsan almost uniformly negative results were obtained, and that when arsenic was found it was in such small quantities it could not be estimated. Contrary to the above-mentioned observations, Benedict^ found from an analysis of four specimens of spinal fluid withdrawn twenty- four hours following the intravenous injection of 0.4 gram of sal- varsan, free arsenic in "about one-sixth to one-tenth the concen- tration in the whole blood." As Swiff pertinently remarks in view of the negative results obtained by most investigators, these findings are hard to explain, unless in Benedict's case the permeability of the meninges and choroid plexus was markedly impaired by the syphilitic process. Further evidence that solutions injected subcutaneously and into the blood stream do not reach the tissues of the cerebrospinal axis nearly as readily as when injected subdurally is furnished by 1 Jour. Nervous and Mental Diseases, 1912, xxxix, p. 809. 2 Jour. Am. Med. Assn., 1913, lix, p. 735. 3 Bull. et. mem. Soe. med. d. hop de Paris, 1911, 3 S., xxxi, p. 664. 4 Jour. Am. Med. Assn., 1915, Ixiv, p. 1384. 'Ibid., 1915, Ixv, p. 209. * Cited by Sachs, Strauss and Kaliski, Am. Jour. Med. Sc, 1914, cxlviii, p. 693. •^Jour. Am. Med. Assn., 1915, Ixiv, p. 1384. TREATMENT 347 Woolsey.^ His investigations also show the rationale of intra- cranial injections in certain cases. This worker found that repeated subcutaneous injections of trypan blue over a period of several days and intensely staining all other tissues of the body failed to reach the central nervous system except in exceedingly small quan- tities. Intra-arterial injections resulted in intense generalized blue color of the other tissues which was in marked contrast to the creamy whiteness of the central nervous system with only slight tinting of the cranial dura and ventricular plexus. Injections into the jugular vein were always followed by intense staining of the tissues with the exception of the central nervous system. On the other hand, subarachnoid lumbar injections of trypan blue resulted in marked staining of the meninges of the cord up to the level of the cervical enlargement above which the intensity of the staining diminished to the foramen magnum, while the cranial meninges showed a distinct deep blue, in places they also showed many areas hardly more deeply stained than in the intravascular injections. The substance of the cord to a depth of ^ to 1 mm. below the surface was stained a distinct blue, while the brain substance showed no such staining. Campbell has shown that when trypan blue is injected subdurally through a trephine hole above the tentorium cerebelli the cerebral cortex as well as the whole cerebrospinal axis is stained, and that when injected through lumbar puncture only the cord and brain stem are stained, while the cortex cerebri remains unstained. He therefore concludes that there is a slight flow of the spinal fluid from the brain toward the spinal canal and that an ebb and flow occurs in the fluid between the subarachnoid space in the base of the cranium and the spinal subarachnoid space depending upon the variations in the quantity of the intracranial blood. Certain syphilographers, who have found fault with the Swift- Ellis method of treatment have based their objections upon the low arsenic content of the blood serum withdrawn at the specified time following the intravenous injection of salvarsan. Thus, Sachs, Strauss and Kaliski^ state that Benedict was able to find but 0.00004 gram to 0.0001 gram of metallic arsenic in 20 c.c. of whole blood forty-five minutes after injection. As Swift'* has pointed out, however, this represents from 0.12 to 0.3 mg. of salvarsan which corresponds rather closely to his figures which averaged 0.016 mg. per c.c. of serum, and is approxi- mately the amount recommended by Ogilvie^ as safe for repeated 1 Jour. Nervous and Mental Diseases, 1915, xlii, p. 477. 2 Brit. Med. Jour., 1914, ii, p. 577. 3 Am. Jour. Med. Sc, 1914, cxlviii, p. 693. * Jour. Am. Med. Assn., 1915, Ixiv, p. 1384. ^ ibid., 1914, Ixiii, p. 1936. 348 SYPHILIS OF THE NERVOUS SYSTEM injection according to his method. The higher figure also is approxi- mately the amount recommended by Wile.^ The objection to the use of serum salvarsanized in vivo is not, therefore, found in its low arsenic content, but in the variable amount of arsenic present. It has been suggested that the favorable results obtained in the treatment of syphilis of the nervous system by the method of Swift and Ellis might be due to other factors than the arsenic content of the serum. For example, it has been thought that the injection of the serum rendered the meninges more permeable so that the sal- varsan circulating in the blood was enabled to reach the tissues of the nervous system more readily. Stillman and Swift^ have shown, however, that such is not the case. It has also been stated that the presence of the salvarsan in the patient's body for a period of time may cause the formation of certain unknown substances which are present in the serum and act favorably upon the syphilitic process. It is for this reason that Ogilvie^ incubates the serum at body tem- perature for forty-five minutes. In consideration of any therapeutic measure, however, two factors, aside from its rationale, must be taken into account, namely, its practical value and its untoward effects if any occur. The efficacy of subdural injections of specifics in the treatment of syphilis of the cerebrospinal axis is attested by numerous investigators; in fact, with very few exceptions all workers who have reported upon the use of this method of treatment have commented favorably. Swift and Ellis* report in detail 10 cases (8 of tabes and 2 of cerebrospinal syphilis) in which marked improvement was noted following intra- spinal treatment according to their technic. Swift^ later summarized the results of the treatment of 34 tabetics, 3 paretics, and 2 tabo- paretics. Of the 34 tabetics, in whom observation extended over at least one year, 3 received intraspinal treatment alone, while the remainder received intravenous treatment as well. In 25 cases, or 73 per cent, negative Wassermann reactions were obtained with 1 c.c. of spinal fluid, while in 14 of these cases the reaction was negative with 2 c.c. In 8 cases the Wassermann was negative with 1 c.c. and positive with 2 c.c. A number showed negative reactions for from one and a half to two and a half years. Two of the 3 paretics treated died, while the third who responded well both clinically and biologically while under treatment relapsed twice when treat- ment was discontinued. The 2 taboparetics responded only slightly and relapsed when treatment was stopped. 1 Jour. Lab. and Clin. Med., 1915, i, p. 119. 2 Jour. Exper. Med., 1915, xxii, p. 286. 3 Jour. Am. Med. Assn., 1914, Ixiii, p. 1936. / "Arch. Int. Med., 1913, xii, p. 331. s Jour. Am. Med. Assn., 1915, Ixiv, p. 1384. TREATMENT 349 Wile^ reported in detail 15 cases treated by the Ravaut method. Of these 2 died, 7 were markedly improved, both subjectively and in the objective findings in the spinal fluid; 3 paretics who received only a single injection showed no improvement, 1 showed improve- ment after a single injection followed by relapse and no subsequent treatment: While his cases are too few to draw any but tentative conclusions from his experience, it would seem that cases with cerebrospinal syphilis, other than tabes or paresis, show much more improvement than when one or both of the latter conditions are present. Ogilvie- in his original communication states that in all cases treated by his method there was biological improvement and in the majority a concomitant clinical improvement. He, however, states that it was too early to draw definite conclusions as to the permanency of the results. In a later paper Ogilivie^ summarizes the results of the treatment of 15 cases, in 13 of which there was a complete disappearance of all subjective manifestations, while the objective signs showed more or less improvement for an average period of one year. One showed moderate improvement only, while 1 failed utterly to respond to the treatment. Wile* reports the result of the treatment of 15 cases by his method, using salvarsan, in all but 2 of which definite objective improvement was noted in the spinal fluid, and a very marked improvement in the subjective symptoms in the majority of cases. Three cases passed from observation but in the remaining 12, relapses did not occur. The most marked results were obtained in early brain and cord syphilis, although in tabes encouraging results were noted. Byrnes^ treated 32 cases of syphilis of the nervous system with his mercurialized serum witTi very encouraging results, the most improvement being seen in tabes and meningomyelitis, although some cases of paresis were distinctly benefited. BjTnes does not give his results in detail but concludes that the mercurialized serum is equally, if not more, efficacious than salvarsanized serum. Numerous other workers have reported favorably upon the intraspinal treatment of syphilis of the nervous system. Paresis seems the most resistent to this type of treatment, which from the location of the organisms is to be expected, although some very encouraging results have been obtained in early cases of this condition. In contrast, however, to the almost brilliant results obtained by most investigators Sachs, Strauss and Kaliski^ state that the intra- 1 Jour. Am. Med. Assn., 1914, Ixiii, p. 137. 2 Ibid., p. 1936. 3 Med. Rec, 1915, Ixxxvii, p. 1062. * Jour. Am. Med. Assn., 1914, Ixiii. p. 137. s ibid., p. 2182. 6 Am. Jour. Med. Sc, 1914, cxlviii, p. 693. 350 SYPHILIS OF THE NERVOUS SYSTEM spinous treatment possesses no advantage over the intravenous. Such a statement is hard to understand, for, while the time has been too short since the introduction of this method to draw absolutely definite conclusions concerning the permanency of the improvement usually recorded, there is enough favorable evidence of its superiority over other methods to warrant its use in some form in all cases of syphilis of the cerebrospinal axis. The results of intracranial injections in syphilis of the nervous system have in some instances been more brilliant than those obtained by intraspinal injections. Wardner^ in the treatment of five cases of paresis by intracranial injections of salvarsanized serum reports complete remissions in two cases after two treatments, which have remained unchanged for one and two months repectively. One case after three treat- ments had a remission with slight impairment of apperception and judgment. Two cases showed no improvement after one injection. Hammond and Sharpe^ state that while two of their three patients injected intraventricularly showed "definite changes for the better a statement of the progress at this early date would be valueless." However, these writers by experiments with trypan blue have shown that the distribution of the dye in the cortex, following intraventricular injections is much more extensive than that following subdural injections either intracranially or intraspinally. The most suggestive result thus far obtained is found in the case of Gordon.^ This patient with syphilis of fifteen years' standing showed both cerebral and spinal symptoms which had resisted intravenous injections of salvarsan. Seven intraspinous injections of auto-salvarsanized serum relieved and finally removed the cord symptoms but had no effect on a most severe headache which was the most marked cerebral symptom. This headache, however, was relieved completely by the subdural intracranial injection of 30 c.c. of auto-salvarsanized serum following spinal puncture and the withdrawal of 30 c.c. of spinal fluid. After a period of four months, during which the patient reported regularly each week for inspection, no recurrence of pain was noted. Untoward Effects. — Certain untoward effects following intra- spinal medication have been reported. Thus Swift and Ellis'* state that frequently there is a certain amount of pain in the legs, commencing a few hours after the injection. This they state is noticed more often in tabetics than in patients with so-called cerebrospinal syphilis. More serious results, however, follow the Revaut technic and 1 Am. Jour. Insan., 1915, Ixxi, p. 459. 2 Jour. Am. Med. Assn., 1915, Ixv, p. 2147. ^ ibid., p. 154. 4 Arch. Int. Med., 1913, xii, p. 286. TREATMENT 351 such symptoms as pain in the legs and hips, nausea and vomiting and suppression of the urine frequently are noted. Gordon^ reports a case of tabes which previously had received an intraspinal injection after the method of Swift and Ellis with very gratifying results and no untoward effects, which one-half hour after the injection of 6 mg. of neosalvarsan by Revaut's method developed severe pains in the lower limbs, and during the same day vomiting which con- tinued for five days. Retention of urine and incontinence of feces developed and all symptoms continued without relief. On the fifth day small erythematous patches developed on the glans penis, scrotum and sacrum which soon became larger and distinctly gan- grenous and his condition gradually grew worse until he died. A most unfortunate accident occurred in the Los Angeles County Hospital in March, 1914,^ when eight deaths followed the intra- spinal injection of neosalvarsanized serum. The serum was pre- pared by adding freshly dissolved neosalvarsan in doses of 1, 2, and 3 mg. to 5 c.c. of serum and heating to 54° C. for half an hour. After remaining on ice for twenty-four hours they were injected intraspinally. The autopsy of one of the patients showed " a some- what congested spinal cord with marked distention of the blood- vessels and softening of the posterior columns." This unfortunate occurrence must have been due to changes in the neosalvarsan occur- ring during the time the serums remained on ice. Lewinsohn^ reports a severe and nearly fatal arrest of respiration occurring twenty-four hours following the intraspinal injection of 6 c.c. of a solution of 0.15 gram of neosalvarsan in 300 c.c. of saline. No more marked untoward symptoms have been reported fol- lowing the intraspinal injection of salvarsanized serum prepared after Ogilvie's method, or the mercurialized serum prepared after BjTues's method than following the intraspinal injection of the Swift and Ellis salvarsanized serum. In fact, Byrnes'* states that in general the reactions are not so severe. It was the severity of the reactions following the Ravaut technic which led Wile^ to discard this method and adopt the new one reported. Using the later technic Wile states that the only untoward symptom noted was a slight amount of darting pain for a few hours following injection which invariably disappeared in twenty-four hours. This was observed only in tabetics. The author used the Swift-Ellis method of intraspinal medication exclusively until the Byrnes method was described, which he adopted at once. Later the Ogilvie method was employed instead of the 1 Jour. Am. Med. Assn., 1914, Ixiii, p. 1851. 2 Ibid., 1914, Ixii, pp. 861 and 957. 3 Deutsch. med. Wchnschr., 1915, xli, p. 248. * Jour. Am. Med. Assn., 1914, Ixiii, p. 2182. 6 ,Jour. Lab. and Clin. Med., 1915, i, p. 119. 352 SYPHILIS OF THE NERVOUS SYSTEM Swift-Ellis method and recently the Wile technic of injection of salvarsan has been employed in a few cases. The only untoward symptoms observed in over two hundred injections have been slight pains in the legs and back, which usually were controlled by asperin. In one instance only was it necessary to administer morphin. A large percentage of the cases treated were paretics of the advanced hospital type which showed little or no improvement. A considerable number were tabes cases which came to Hot Springs for treatment and after one or two injections without marked clinical improvement refused further injections or went home. One case of syphilitic meningitis which the author has been able to follow consistently deserves mention. Case 1. — Male, aged thirty-two years, married; travelling sales- man. Contracted syphilis seven years ago. Treated with "mixed treatment" intermittently for two years. Nervous manifestations such as dizziness, weakness and numbness in the legs occurred in summer of 1913, at which time he received two doses of salvarsan intravenously followed by improvement. In January, 1914, the nervous symptoms returned, at which time there was difficulty of speaking and walking, slight retention of urine and also some loss of memory. On January 18, 1914, an examination showed the following: Right pupil dilated and irregular in outline, left pupil normal in size, both pupils react sluggishly to light and accom- modation. Eye-grounds normal. Lower tendon reflexes markedly exaggerated, ankle-clonus and Romberg sign positive. Blood: Wassermann, negative. Spinal fluid Wassermann + + + +. Cell count 99; globulin + +• This patient was thoroughly mercurialized with the succinimide and given potassium iodide until symptoms of iodism appeared, after which he received three intravenous injections of 0.6 gram of salvarsan ten days apart followed by intraspinal injections of sal- varsanized serum after the method of Swift and Ellis. Spinal fluid removed at the time of the last injection showed 26 cells per c.mm.; globulin +; Wassermann + +; while the clinical symptoms had improved remarkably. At this time the patient was forced to return to his home but reported again for treatment in June. The same course of treat- ment was carried out and the spinal fluid collected at the time of the third injection showed 12 cells per c.mm.; globulin — ; Wassermann -\ with 1 c.c. Again in September the same course of treatment was carried out and spinal fluid showed 6 cells per c.mm.; globulin ^; Wassermann — with 1 c.c. The blood Wassermann remained con- stantly negative. The clinical symptoms were completely cured TREATMENT 353 with the exception of a slight exaggeration of the lower tendon reflexes. In December, 1915, the patient showed no clinical symptoms of his former disease but refused spinal puncture. Other Treatment of Syphilis of the Nervous System. — In syphilis of the nervous system, as with syphilis of other regions of the body, other treatment than specific and general sometimes is indicated. In syphilitic meningitis the headache may require the coal-tar derivatives or it may be so severe as to require opiates, although it usually will yield to some form of specific medication. The treatment of syphilitic arteritis, aside from the administra- tion of specifics, consists of treating the symptoms. A hemiplegia occurring suddenly with symptoms of apoplexy should be treated with absolute rest, ice packs to the head and liquid diet. Massage, hydrotherapy and electricity may be used to advantage in treating the permanent paralysis. Gummata of the brain will require treatment other than specific according to the location, number and size and the symptoms produced. Numerous investigators have practised surgical pro- cedures on brain gummata with more or less success. If a certain diagnosis of brain gumma has been made and it does not yield to specific medication, and further, if the tumor is in an accessible location, surgery should be tried. The treatment of paresis other than specific and general must be symptomatic, and usually is best carried out in a hospital, especially if an excited mental state exists. Greatly excited paretics may require the continuous bath or the administration of sedatives. Careful watching to prevent injuries to the patient and others is necessary. Often the paretic will refuse food and tube feeding may become necessary, while, especially in the later stages, he will have to be cleansed frequently. The prevention of decubitus is sometimes difficult but frequent bathing, the use of alcohol and the care and cleanliness of the bed and changing the position of the patient frequently will in the majority of cases prevent this complication. The treatment of bed-sores in paretics after they have once formed is most difficult. The use of the continuous bath and the applica- tion of antiseptic powders may result in a cure. The paretic convulsion, according to Kemmler,^ should be treated by packing the head in ice and in severe seizures the administra- tion of amyl hydrate either per rectum or hypodermically. The results of gummata of the cord and myelitis will require symptomatic treatment. As far as the author is aware surgery has not been resorted to in the treatment of cord gummata. 1 Cited by Kraepelin: General Paresis, New York, 1913, p. 196. 23 354 SYPHILIS OF THE NERVOUS SYSTEM The treatment of tabes aside from the most vigorous antisyphilitic medication and general treatment consists of symptomatic measures and the attempt to restore lost coordination. The application of cautery and cold in various forms such as ice, douche, etc., to the spine have been advocated, but are of questionable value. The lightning and other pains of tabes sometimes are so severe as to require morphin, although hot and cold applications or the coal-tar derivatives may control them. Resection of the posterior roots of the seventh to the tenth dorsal nerves for the control of gastric crises has been successfully practised. Vesical weakness may sometimes be overcome by exercises which strengthen the pelvic floor, such as separating and adducting the knees against resistence while lying on the back as well as by massage of the perineal muscles. Cystitis must be guarded against and is best prevented by the administration of urotropin. Treatment of tabetic arthropathies is of little or no avail. Cer- tain supporting and fixation apparatus may be of service in enabling the patient to walk. In attempting to restore lost coordination certain exercises are of the utmost value. FrankeP describes two types of exercises, those performed by the patient in bed and those performed out of bed. In bed, flexing, extending, abducting and adducting the legs separately and together are practised. The attempt to place the heel of one foot on the great toe of the other and on the knee and permit it to travel slowly along the shin to the ankle is made. These exercises are attempted alternately with each leg both with open and closed eyes, and are performed many times with frequent rests and encouragement. The exercises performed out of bed consist of slowly seating in a chair and slowly rising with the heels close together and without the use of a cane, careful walking, stepping, placing of the feet, standing with the feet together, various movements of the arms, walking along a painted line on the floor, etc. The exercises must be progressively attempted and great perseverence is necessary. Fatigue, however, must be avoided. In the terminal stages decubitus should be prevented or, if it develops, should be treated as in paresis. Syphilitic neuralgia rarely needs any treatment but specifics, although analgesics may be necessary. The treatment of syphilitic neuritis and polyneuritis after the use of specific medication consists of the use of massage and electricity. Standard Treatment. — All cases showing syphilitic involvement of the cerebrospinal axis by examination of the spinal fiuid should 1 The Treatment of Tabetic Ataxia, Philadelphia, 1902. STANDARD TREATMENT 355 receive intraspinal injections as well as other vigorous specific treatment. The author usually uses the Ogilvie and Byrnes methods alternately at intervals of 7 to 10 days, in order to bring both specifics into contact with the treponemata. The Wile method certainly promises much on account of its simplicity and in all probability in the future will be the method of choice for the intraspinal administration of salvarsan. The intraspinal treatments should be continued until the spinal fluid becomes negative, or in the case of paretics, for eight or ten injections if no objective or subjective improvement is noted. If intraspinal treatments do not relieve cerebral symptoms, intra- cranial, either subdural or intraventricular, injections should be given a trial. No case of syphilis, from the chancre to paresis, should be given up until all means of treatment are exhausted. The standard for cure of a case of syphilis showing central nervous system involvement consists of a constantly negative spinal fluid as well as a negative blood Wassermann without any increase in symptoms for a period of at least two years following the last treatment. CHAPTER XIX. SYPHILIS OF THE EYE AND EAR. THE EYE. Pathology. — Eyelid. — Chancre of the eyelid has been discussed in Part I in the chapter on CUnical History. Nearly any of the syphilodermata may occur in this locality. Papular lesions have been observed on the palpebral conjunctivae. Gummata of the eyelids are of not infrequent occurrence but present no unusual features. Iris. — Syphilitic iritis is quite often seen, being the most common of all luetic conditions of the eye. The process is generally plastic in type, the iris being congested, thickened and of a grayish color. There is more or less injection of the anterior ciliary vessels and the anterior chamber contains a plastic exudate. Serous iritis is also sometimes noted, in which an exudate consisting of grayish spots on the lower half of Descemet's membrane is seen. In this type the ciliary injection is not so great. Synechia more frequently follows the plastic type than the serous type. Papules of the iris which correspond to the papular syphiloderm are sometimes seen on its pupilary border or on its anterior surface. They are usually single and about one millimeter in diameter, but may be multiple. The color varies from a reddish brown to a yellow. Gummata of the iris are of exceedingly rare occurrence. When found they vary from two to six millimeters in diameter and present no peculiarities not observed in gummata of other localities. Treponemata have been found in the aqueous in acute iritis. Ciliary Body. — Cyclitis is usually associated with iritis but may be observed alone. As with iritis it may be of plastic or serous type or gummata may originate in the ciliary body or involve it by extension from the iris. Cornea. — Syphilitic involvement of the cornea is rare in the acquired form of the disease but may occur as diffuse parenchyma- tous or interstitial keratitis in which there is a cloiidy opacity in the deeper layers of the cornea, as keratitis punctata, characterized by the deposit of grayish spots about one millimeter in diameter in the corneal parenchyma, or as gummatous infiltration. Sclera. — Syphilis may involve the sclera as a diffuse infiltra- tion or as circumscribed gummata. In the former there is thinning PLATE V Syphilitic Retinitis. (Norris and Oliver.) THE EYE 357 of the affected area while in the latter there is thickening. The process may be complicated by iritis or cyclitis. Choroid. — ^The choroid is rarely alone the seat of syphilis, as its involvement usually is observed as an extension from the ciliary body or in connection with retinitis. Syphilitic choroiditis is, how- ever, next to iritis, the most frequent luetic affection of the eye. As usually observed there are at first yellowish patches of exudate scattered over the choroid. Later they may become white, due to atrophy of the choroid and be surrounded by a zone of pigment. Gummata of the choroid have been described but are exceedingly rare. Fig. 72. — Syphilitic iritis and keratitis. Retina. — Retinitis of syphilitic origin may occur alone but is usually an extension from disease of the choroid. Several types are observed: First, a simple retinitis which is an inflammation of the superficial layers of the retina and in which there is hj^eremia of serous type and edema; second, an exudative retinitis, showing more or less deposit of yellowish exudate scattered over the retina; third, hemorrhagic retinitis, due to endarteritis and the formation of thrombi; and fourth, the so-called central recurring retinitis of von Graefe. The latter type is exceedingly rare and is characterized by the appearence of small, white punctate dots in the macula. Optic Nerve.- — The optic nerve may be the seat of the syphilitic process in its intra-orbital end as well as in its intracranial or intracerebral portion. Papillitis or inflammation of the intra-orbital 358 SYPHILIS OF THE EYE AND EAR end of the optic nerve is characterized by marked swelHng of the optic disk, more or less edema and cellular infiltration. Lacrimal Apparatus.— Syphilis of the lacrimal apparatus is usually due to an extension from adjacent structures but cases have been reported in which gummata were first observed in the lacrimal gland. Orbit. — ^The bones of the orbit may be the seat of the syphilitic process, but the pathological picture does not differ from that observed in other bones. Clinical History. — Eyelid. — Chancre of the eyelid as well as the various syphUodermata and syphilomycodermata present no features which are not found in these lesions in other localities. There will, however, be more or less deformity, depending upon the extent of the pathological process. Iris. — Syphilitic iritis is the most common of all luetic conditions of the eye. It usually occurs during the first year of the disease and may be present before the chancre has healed but sometimes is observed considerably later. There is nothing in the symptoma- tology pathognomonic of syphilis, as the same condition may be found in non-luetic iritis. It is characterized by marked ciliary injection, the vessels forming a zone around the corneal margin with more or less conjunctival congesaon, swelling of the iris, contraction, irregularity and sluggishness of the pupil due to pos- terior synechia, turbidity of the aqueous, occasional increased ten- sion of the eyeball, lacrimation, photophobia, interference with vision and pain. The latter symptom is usually not so severe as in non-luetic iritis. The serous type of syphilitic iritis is less frequently observed than the plastic type, the symptoms are less marked and the con- dition shows more tendency to become chronic. The serous type is also more frequently complicated by cyclitis or choroiditis. Gummatous iritis, which is an exceedingly rare condition, and occurs, as a rule, late in the course of syphilis, presents a clinical picture similar to that just described, with the addition of one or more gummata observed as distinct tumors varying in size from two to six millimeters in diameter and situated in or on the iris. Ciliary Body. — While the ciliary body is occasionally alone the seat of the syphilitic process, it usually is affected with the iris or choroid. The symptoms consist of tenderness in the ciliary region, deposits on Descemet's membrane, increased tension in the serous type and diminished in the plastic. Gummata when arising in the ciliary body usually extend to the choroid. The intra-ocular tension is usually diminished, sometimes markedly so. THE EYE 359 Cornea. — Syphilis of the cornea in the acquired form is a rare condition and is almost always observed late in the course of the disease. Diffuse pare7ichymatous or interstitial keratitis may begin either in the centre or at the margin and consists of a grayish opacity which soon spreads and involves the entire cornea, obscuring the iris. Deep-seated bloodvessels soon pervade more or less of the cornea, causing a yellowish-red discoloration. In uncomplicated cases the subjective symptoms of photophobia, lacrimation, pain and interference with vision are dependent upon the severity of the process, but are usually mild in character. The condition is, however, usually complicated by iritis, choroiditis, cyclitis and changes in the vitreous with the accompanying symptoms. Keratitis inm.ctata characterized by the deposit of small grayish spots in the corneal parenchyma produces no other symptom, there being no injection and the remainder of the cornea appearing normal. Gummata of the cornea is a most rare condition and will give rise to symptoms depending upon the extent of the process. Sclera. — Syphilis involving only the sclera is rare. The diffuse infiltration sometimes observed will cause a deep bluish-red injec- tion of the affected portion. It appears like a blotch of color rather than injected vessels. There is also usually conjunctival injection. More or less thinning with consequent bulging of the eyeball is observed. The process is usually bilateral and partial or complete blindness will result, depending upon the severity of the process. The subjective symptoms vary with the condition and consist of pain, usually of a dull, aching character, but sometimes boring, lacrimation and photophobia. Gummata of the sclera are exceedingly rare and vary in size from one or two millimeters to two or three centimeters in diameter. The larger gummata usually involve the ciliary body. They are generally hard and sensitive, while the conjunctival injection is marked. Subjectively there is more or less pain, photophobia and some interference with the mobility of the eyeball. Choroid. — Diffuse syphilitic choroiditis is usually associated with retinitis and occurs, as a rule, early in the course of the disease, generally during the first year. No external signs of the condition exist but the ophthalmoscope reveals at first yellowish patches of exudate scattered over the choroid, especially in the region of the macula, while the retinal vessels are seen to pass over them. Later there is absorption of exudate and atrophy of the choroid occurs in patches. These appear as white, irregularly shaped areas, the sclera showing through, and often marked with choroidal vessels, and more or less pigment. 360 SYPHILIS OF THE EYE AND EAR The subjective symptoms are disturbances of vision, consisting of diminution of acuteness, the appearance of spots, the distortion of objects and flashes of Ught before the eyes. Pain is absent in this condition. Gummata of the choroid is an exceedingly rare condition and is usually not recognized during life. Retina. — Syphilitic retinitis is quite common and usually occurs in association with choroiditis and often with iritis. It is generally found during the first or second years of the disease, but may occur later. Both eyes are usually involved but sometimes only one is affected. No external objective symptoms are found. In the simple form the ophthalmoscope reveals a hazy condition of the fundus, most marked around the disk, the margins of which are more or less indistinct. The veins are tortuous and dilated, while' the vessels are hidden in places by the edema. Occasionahy hemorrhages are seen. There is impairment of vision, contraction of the visual field, distorted vision and scotomata. In the exudative type of retinitis the fundus is indistinct, due, not only to swelling of the retina and disk, but also to fine dust- like opacities in the posterior portion of the vitreous which cause the disk to appear red and hazy. Scattered over the fundus, espe- cially in the region of the macula are seen grayish or white spots sometimes surrounded by pigment. There is diminution in the acuteness of vision, depending upon the severity of the process, night-blindness, flashes of light, distortion of vision, scotomata and contraction of the visual field. In hemorrhagic retinitis there is added to the signs and symptoms just mentioned numerous hemorrhages which may be superficial and appear flame-shaped or deep and roundly irregular. The central recurring retinitis of von Graefe,^ which is very rare, is at first characterized by small, white, punctate dots grouped in the macula, as well as by an opacity in the vicinity of the latter. There also is more or less disturbance of vision. The condition develops suddenly, lasts a few days and disappears but recurs in a few weeks. In subsequent attacks to the appearance of the punctate spots in the macula are added irregular white streaks radiating from the optic disk into the retina, generafly along the vessels, which may be elevated. Punctate spots are also scattered over the entire fundus. Optic Nerve. — Syphilitic papillitis is characterized by swelling of the disk, which is of a whitish or grayish color, is striated and often contains spots and hemorrhages. The margins are indis- tinguishable and the disk is only located by the convergence of the bloodvessels. The arteries are usually thin but may be of normal 1 Arch. f. Ophth., 1860, vii, p. 211. THE EYE 361 size, while the veins are distended and tortuous. The retina sur- rounding the disk is edematous, congested and white spots and hemorrhages are seen in it. There is more or less disturbance of vision, sometimes amounting to complete blindness, although often there is less disturbance than would be expected from the ophthal- moscopic picture. There may be hemianopsia or scotomata. Lacrimal Apparatus. — Gummata of the lacrimal gland have been described and cause symptoms depending upon the size of the gumma. Dacryocystitis not infrequently occurs, usually as an extension from other parts and causes an epiphora, and a sense of fulness in the region of the lacrimal sac. Orbit. — The bones of the orbit are rather rarely affected by syphilis and the symptoms will depend upon the extent and severity of the process. There is usually more or less pain and swelling and when a gumma is deeply situated in the orbit or is very large there will be exophthalmus, and marked fixity of the eyeball. Diagnosis. — Eyelid. — Chancre of the eyelid as well as the various syphilodermata and syphilomycodermata are to be diagnosed upon the same grounds as these lesions of other localities. Iris. — Syphilis is the most frequent etiological factor in iritis, so should be thought of in all cases. There is nothing in the clinical picture, however, which will differentiate it from iritis due to other causes except, perhaps, that the pain is not so pronounced as in some other forms. The diagnosis therefore must rest upon the his- tory, the finding of other evidences of syphilis (syphilodermata are usually present), positive laboratory tests and therapeutic measures. Ciliary Body. — Syphilis of the ciliary body is, as a rule, asso- ciated with syphilis of the iris or choroid, and its diagnosis will depend upon the same factors as the diagnosis of syphilis of those portions of the eye. Cornea. — Syphilitic keratitis is rare in the acquired form of the disease but syphilis is the most frequent etiological factor in inflam- mation of the cornea. It is, as a rule, complicated by iritis, choroid- itis, and cyclitis and its diagnosis will depend upon the indirect evidence of history, laboratory findings, etc. Sclera. — Syphilis of the sclera is also to be diagnosed by the history, presence of other manifestations of syphilis, positive Was- sermann or luetin tests, and improvement under antisyphilitic treatment. Gumma of the sclera, although exceedingly rare, must be differentiated from malignant growth and, as a rule, may be accomplished by the above factors. Tumors of the sclera occurring in the young would be against it being malignant. Choroid. — Syphilis is the cause of the majority of cases of choroiditis, so should always be thought of in all such cases. The 362 SYPHILIS OF THE EYE AND EAR ophthalmoscopic picture is usually quite characteristic, but a diag- nosis of syphilis of the choroid should rarely be made without corroborative evidence. Retina. — Syphilitic retinitis, as a rule, presents an ophthalmo- scopic picture which is scarcely to be mistaken for retinitis of other etiology, however, the findings in the eye-ground should be substan- tiated by the exclusion of other types of retinitis, such as albumin- uric and diabetic by the examination of the urine, by the history, the presence of other manifestations of syphilis, positive laboratory findings and in some cases the improvement of the condition under specific therapy. Optic Nerve. — There is nothing pathognomonic, either in the symptomatology or the ophthalmoscopic picture of syphilitic papil- litis, so its differentiation from papillitis due to other etiology must be accomplished by the diagnosis of the presence of syphilis in other portions of the body and perhaps by its improvement upon the administration of specific treatment. Lacrimal Apparatus. — Syphilis of the lacrimal apparatus, also, is not characteristic and its diagnosis can only be accomplished by indirect evidence. Orbit. — Syphilitic disease of the orbit is to be differentiated from tumors of various types and the presence of foreign bodies, and as with syphilis of the lacrimal apparatus, is only to be accom- plished by indirect evidence. Prognosis. — Iris. — The prognosis of the curing of syphilitic iritis is good but often the sequelae are most troublesome. In the milder cases, if posterior synechiae are formed, they may be broken down with atropine so that pupillary activity may be restored, although uveal pigment will, as a rule, be found on the anterior lens capsule. Sometimes when the process has been severe synechise are formed which cannot be overcome with atropine and permanent distor- tion of the pupil is seen. However, if the pupil is not so fixed that communication between the anterior and posterior chambers is closed, some sight will remain, although it will be more or less damaged. If the iris is so fixed that the communication is com- pletely closed, secondary glaucoma will develop with a bulging bombe iris, and, as a rule, blindness will result. Ciliary Body. — The prognosis of syphilitic cyclitis when exist- ing alone is good if recognized early and treatment is vigorously applied, although glaucoma may result. However, as cyclitis is usually associated with iritis or choroiditis the outcome will depend upon the outcome of the associated condition. Cornea. — Syphilitic keratitis is, as a rule, very amenable to treat- ment, and even in the most severe cases the opacity of the cornea may clear in a remackable manner, so that only the most careful THE EYE 363 examination will reveal the fact that it has been affected. This is not always the case, however, and more or less permanent opacity is often left. The prognosis as to sight must be guarded until the cornea has sufficiently cleared for an ophthalmoscopic examination to reveal the presence or absence of a choroiditis. Sclera. — The prognosis of syphilis of the sclera will depend upon the severity of the process, the mild cases recovering without serious permanent damage, the severe ones leaving more or less blindness. Choroid. — The prognosis of syphilitic choroiditis is always grave, although if the macula escapes some vision may remain. Retina. — Syphilitic retinitis must be considered a serious con- dition, yet if recognized early and antisyphilitic treatment vigor- ously pushed, the prognosis is fair, although at best there is usually some impairment of the vision. If neglected, syphilitic retinitis is often followed by disseminated choroiditis, pigmentary degenera- tion of the retina and optic atrophy. Optic Nerve. — The prognosis of syphilitic papillitis is bad, for although under specific treatment the process may subside, more or less permanent damage is left. Most severe cases develop optic atrophy, either partial or complete and the process may extend to the brain with even fatal consequences. Lacrimal Apparatus. — Syphilitic involvement of the lacrimal apparatus, if recognized early and vigorously treated, is usually followed by complete recovery. Orbit. — The prognosis of syphilitic disease of the orbit will depend upon the extent and severity of the process. Treatment. — All syphilitic involvement of the eye requires thorough and persistent specific medication as well as the general treatment outlined in Part I. Added to these most conditions should receive local treatment. Iris. — Atropine (1 per cent, solution) should be administered as soon as the diagnosis is reached. This drug causes mydriasis, puts the iris at rest, prevents the formation of adhesions and tends to break up those already formed. The atropine should be instilled every two hours at first until the pupil is dilated, then three or four times a day for a week or ten days after all injection has left. For the pain hot compresses are very beneficial. Leeches applied to the temple near the outer canthus act not only in relieving pain but in reducing the injection. The removal of 25 to 30 c.c. of blood with an artificial leech may readily be accomplished. The eye should be protected from light and in the beginning, at least, the patient should be placed in bed. Cornea. — In syphilitic keratitis it is also important to keep the pupil dilated with atropine throughout the course of the disease. The eye should be bathed with boric acid solution and protected 364 SYPHILIS OF THE EYE AND EAR from the light by a shade or smoked glasses. When the opacity begins to clear an ointment such as yellow oxide of mercury and calomel should be applied. Sclera. — As stated in the section on Clinical History, syphilis involving only the sclera is rare, therefore its treatment consists of treating the complicating conditions. The eye should obtain complete rest and hot bathing and atropine applied. Choroid and Retina. — Syphilitic disease of the choroid and retina usually are associated, and even when occurring alone the treatment is the same. In no other condition is vigorous and prompt antisyphilitic treatment more desirable. Atropine should be used locally and smoked glasses worn. Optic Nerve. — Papillitis requires no other treatment than specific and general measures, except the use of smoked glasses. Numerous workers have proposed the direct installation of anti- syphilitic remedies in the conjuctival sac in the various syphilitic diseases of the eye. Most of these measures have met with com- paratively little success. Lamb^ has advocated the use of salvar- sanized serum prepared after the method of Swift and Ellis^ for intraspinal medication. It is kept on ice in sealed ampules of 1 c.c. capacity and warmed to body temperature before using. Numerous types of cases have been treated, interstitial keratitis, iritis, gum- matous iritis, iridocyclitis, chorioretinitis and even optic atrophy. Lamb states that the results sometimes were so rapid as to be almost, startling. The author has employed this method of treatment in syphilitic iritis with very satisfactory results. Lacrimal Apparatus. — Dacryocystitis if seen early enough usually will clear up under specific medication, or at least with the installation of bichloride solution (1 to 5000) into the coujuctival sac. If it does not, surgical procedures may be necessary. The canaliculi should be opened and the lacrimal sac washed out with antiseptic and astringent solutions. If, in spite of this treat- ment, the process persists the lacrimal sac should be removed, and the cavity irrigated with antiseptic solutions until granulation occurs. THE EAR. Pathology. — Chancres of the auricle have been recorded, but as with those of the great toe and nose mentioned in Part I, are merely medical curiosities. Syphilodermata of the auricle and external auditory meatus are of comparatively frequent occurrence, condylomata being most often seen, while gummata have been reported. 1 Washington, Med. Ann., 1915, xiv, p. 69. 2 New York Med. Jour., 1912, xcvi, p. 53. THE EAR 365 The middle ear may be the seat of the syphiUtic process early m the course of the disease when the infection may extend from the nasopharynx through the Eustachian tube. Endarteritis of the mucous membrane and periostitis of the bony walls, as well as gummata are sometimes noted. In syphilitic involvement of the internal ear the pathological process consists of hyperplasia of connective tissue, especially of the periosteum and infiltration of small round cells. A serous labyrinthitis following a severe hyper- emia may occur and pus may be formed. Endarteritis and hemor- rhage into the cochlear nerve may occur, while gummata of the petrous portion of the temporal bone have been observed. Clinical History. — The chancres and syphilodermata found on the auricle and in the external auditory meatus present no features in themselves which are essentially different from these lesions in other localities. Condylomata of the external auditory meatus will produce a watery, offensive discharge and the swelling may com- pletely occlude the canal. More or less deafness will result and tinnitus is sometimes observed. When the middle ear is involved in the syphilitic process there will be more or less pain, which is worse at night, although at no time is it very severe, air conduction of sound is impaired, while bone conduction is normal and the membrani tympani shows evidence of exudate without congestion. Syphilitic involvement of the inner ear may occur very early in the course of the disease, according to Stein^ as early as one week following the appearance of the chancre. The usual time of its appearance, however, is between the sixth and twelfth months, but it may occur years later. The onset of the condition is' sudden and deafness develops rapidly, occasionally during one night. Usually the deafness is absolute, that is, the hearing of all tones is lost, but sometimes the higher tones are not heard, while the lower ones are. The condition is usually bilateral but is sometimes seen first in one ear, the other being affected soon after. Bone conduction is diminished from the beginning. There is usually tinnitus, the noises seeming to be high, such as ringing of small bells. Vertigo js frequent and sometimes pain deep in the ear is felt. Menier's syndrome is occasionally seen in syphilitic involvement of the internal ear. Diagnosis. — ^The diagnosis of chancre and syphilodermata on the auricle and in the external auditory meatus will depend upon the same factors as the diagnosis of these lesions of other localities. There is nothing in the clinical picture of syphilis of the middle 1 Annals of Otology, Rhinology and Laryngology, 1914, xxiii, p. 116. 366 SYPHILIS OF THE EYE AND EAR ear to distinguish it from middle-ear involvement of other causes, except, perhaps, the usual increase of the pain at night. The diag- nosis must depend upon the history, the presence of other syphilitic lesions or symptoms, positive laboratory tests and the response to antisyphilitic treatment. The same may be said concerning syphilis of the inner ear except, perhaps, in the case of Menier's syndrome due to syphilis which, according to Grey^ as stated by Stein, is characterized by but one attack, while if due to other causes there is likelihood of similar attacks. Prognosis. — The prognosis of chancre and the syphilodermata of the auricle and external auditory meatus differs in no respect from the prognosis of these lesions elsewhere. Syphilis of the middle and inner ear is more serious and partial or complete permanent deafness will result, depending upon the extent of the process, the time it is recognized and the treatment instituted. Treatment. — The treatment of chancre and the syphilodermata of the auricle and external auditory meatus is the same as the treat- ment of these lesions elsewhere. Syphilis of the middle and internal ear is to be treated solely by specifics and general measures, as loc«,l treatment is of no avail. The injection of pilocarpine has been recommended in these con- ditions but is of little or no value. PART III. CHAPTER XX. CONGENITAL SYPHILIS. NOMENCLATURE. Considerable uncertainty seems to exist in regard to the use of the terms congenital and hereditary syphihs. Sturgis^ states that hereditary syphihs may be divided into two varieties, congenital and hereditary, the difference being that in congenital syphilis the symptoms are present at birth and in hereditary syphilis they appear at a longer or shorter time after birth. Marshall states that congenital syphilis embraces all cases which show signs of syphilis at or soon after birth and that both cases infected during pregnancy and post-conceptional cases are included, and that hereditary syphilis applies to cases of infection of the ovum by maternal syphilis or of the ovum by spermatozoa of the father. StilP holds the same views as Marshall but states that while the differences mentioned exist it is inexpedient to use the different terms, as there is no clear evidence of any corresponding difference of course. This writer also suggests that the term "infantile syphilis" might be used to include also those cases of infection of the child during birth from lesions on the maternal genitals and those infected soon after birth by kissing, etc. It seems to the author that the term hereditary syphilis should be applied to all cases of syphilis developing in utero, and the term congenital syphilis should include all such cases as well as those contracted by the child during its passage through the birth canal. HISTORICAL. As pointed out in Part I, Buret affirms that hereditary syphilis was known to the Chinese centuries ago. This same writer^ states 1 Morrow: System of Genito-urinary Diseases, Syphilology, and Dermatology, New York, 1898, p. 603. 2 Syphilology and Venereal Disease, New York, 1906, p. 317. 3 System of Syphilis, London, 1908, i, p. 284. ■i Buret: Syphilis in the Middle Ages and in Modern Times, American edition, Philadelphia, 1895, p. 210. 368 CONGENITAL SYPHILIS that Almenar, in 1502, and Bethencourt, in 1526, considered " syphilis incurable, was inevitably transmitted to children and could even in these latter not show itself until adult life." Paracelsus,^ in 1529, stated that it was an hereditary disease and could be transmitted from father to child "Fit morbus hereditarius, et transit a patre ad filium." Most other writers following Paracelsus did not recognize this manner of infection until Fallopius^ wrote, in 1555, "You will see SDiall children born of infected women who suffer for the sins of their parents, and who are born in a simicooked condition." Rondelet,^ in 1689, wrote of syphilitic infection of children from nurses, but hinted only obscurely that syphilis in the parents might be responsible for "certain transmitted diseases in the children." Subsequently numerous investigators have written upon the subject of congenital syphilis and with it no other name is more prominently linked than that of Sir John Hutchinson (1828-1913), who probably is best known on account of his description of the notched, peg-shaped incisor teeth in congenital syphilis ("Hutchin- son teeth*"). ETIOLOGY. In discussing the etiology of congenital syphilis the question naturally arises as to whether the infection is due to a syphilitic father, a syphilitic mother or to both. Until comparatively recently most authorities were agreed that if either parent were infected a syphilitic child could result, that paternal infection was the most frequent and that if both parents were luetic the chances of syphi- litic offspring were increased. It was thought that the syphilitic virus could be carried in the spermatozoa and thus infect the ovum or that the fetus could be infected in utero from the semen. These, however, certainly are false premises, for although as pointed out in the chapter on Etiology of Acquired Syphilis, the semen in some cases of syphilis has been found to be infective for animals, this does not necessarily mean that the treponema is present in the spermatozoon. In fact from the relative sizes of the syphilitic organism and the spermatozoon, as well as the active motility of the former, it would seem to preclude such a possibility. Further, while it is admitted that the semen might in some cases carry the syphilitic organism to the ovum, although it is doubtful if this 1 Cited by Marshall: Syphilology and Venereal Disease, New York, 1906, p. 317. ^ Cited by Sturgis in Morrow's System of Genito-urinary Diseases, Syphilology, and Dermatology, New York, 1898, p. 604. 3 Cited by Still in Power and Murphy's System of Syphilis, London, 1908, i, p. 283. ^ Hutchinson: Brit. Med. Jour., 1861, p. 515. ETIOLOGY 369 could occur when the ovum is in the Fallopian tube, its usual loca- tion upon fecundation, it seems extremely improbable that the ovum could develop with even a single Treponema pallidum within it. In regard to the subsequent infection of the embryo or fetus in utero direct from the father, it need only be mentioned that the membranes at a very early date effectually close the uterine canal. From the above evidence it would seem that direct paternal infection is impossible. Congenital syphilis can therefore occur only through an infected mother, and this only after conception either by the carrying of the organisms by the blood through the placenta or by infection from a diseased placenta, or finally, by direct contact with syphilitic lesions of the genitals at the time of birth. The outcome of the conception of a syphilitic woman presents several possibilities, namely: 1. Infection of the embryo or fetus in utero or of the child at the time of birth; 2, the death of the embryo or fetus due to a markedly syphilitic placenta; 3, the transmission of certain unknown traits to the embryo which cause abnormal development, without actual infection by the Treponema pallidum occurring; and 4, the birth of a perfectly healthy child. What factor or factors serve as determining causes it is impossible to say. Of the first possibility several results may be seen, depending to a large extent upon the age of the embryo or fetus when infection takes place. If infection occurs very early, the development of the embryo usually will cease and abortion follow. Later infection may permit development to continue and a living but syphilitic, weak and puny child be born prematurely. This child may die directly following birth or soon after. The child may develop for some time, even to term, and stillbirth occur. A further possibility is the birth of a full-term child showing either marked or very slight manifesta- tions of syphilis or none at all but developing symptoms a few weeks later, or finally the so-called "syphilis hereditaria tarde" may occur, the syphilitic manifestations apparently not showing for months or even years after birth. These latter cases, however, must be looked upon with consider- able doubt, as in all probability earlier manifestations of the con- genital disease occurred and were unnoticed or they may have been cases of acquired syphilis with slight and unnoticed early mani- festations. The time at which the embryo or fetus may become infected will depend upon whether the mother is suffering with syphilis at the time of conception or is infected subsequently, and also upon 24 370 CONGENITAL SYPHILIS the severity of the disease in the mother. It is almost self-evident that if the mother is suffering with a marked treponemia at the time of conception the embryo soon will become infected. If, on the other hand, the syphilis of the mother is in a comparatively quiescent state with treponemata in the blood only in small number, if at all, the chances of infection are lessened. Formerly the dictum of Ricord, that only until the sixth month can the mother trans- mit syphilis acquired during pregnancy to the offspring, after which time they are safe, was religiously followed, but in recent years well- authenticated cases of the mother being infected in the eighth or even the ninth month of pregnancy and bearing syphilitic children have been reported. The second possibility of the conception of a syphilitic woman, the death of the fetus in utero, due to a diseased placenta is brought about, not by infection, but by lack of nutrition, and is followed by abortion. The third possibility, the transmission of certain traits to the child without causing infection with the organism of syphilis, may be as serious as the actual transmission of the disease. In such cases again the development of the embryo may be retarded, abortion or stillbirth may occur^ or the child may be premature or born at full term but with certain abnormalities of mind and body. Such a condition may also be brought about by a syphilitic father without the necessity of the mother having the disease, although in all probability it is more frequent when both parents are syphilitic. The pathogenesis of such a condition is not known. It may be that it is due to the toxins of the treponemata acting upon the spermato- zoon or ovum or both and so changing them chemically or physi- cally, or by lowering their vitality, that they fail to develop in a normal manner. It is, of course, possible that there may be a com- bination of the first and third possibilities, that is, a true syphilitic infection from the mother may be superimposed in utero upon the child which is already developing abnormally from the traits trans- mitted through the ovum 'or spermatozoon. The possibility of the conception of a syphilitic woman that she may bear a normal child needs no further comment but that such a child may follow or precede a syphilitic one. Secondary Etiological Factors. — ^That there are any secondary factors such as race, age, climate, etc., which have any bearing upon the etiology of congenital syphilis has not been shown. Moore^ found of 582 hospital admissions of negro infants and chil- dren, 52 or 8.9 per cent, were clinically suffering from hereditary syphilis, and of 225 white infants and children only 7 or 3.1 per 1 Southern Med. Jour., 1915, viii, p. 946. ETIOLOGY 371 cent, were syphilitic. This, however, does not prove that syphiHtic negroes are more prone to produce syphiHtic children than whites, but merely shows that syphilis is more prevalent in the negro race. Syphilis in the Third Generation. — ^That hereditary syphilitics may in turn produce syphilitic children is undoubted. Hutchinson^ expressed his disbelief in such an occurrence, although he cited a case of his own which was probably one of syphilis in the third generation. Numerous other syphilographers have written pro and con upon this subject but until the advent of the Wasser- mann reaction the evidence for neither side of the question was absolutely convincing. Glomset^ recently has reported two cases, one of which undoubt- edly was an instance of syphilis in the third generation, while the evidence in the other case is at least very suggestive. In the first case reported, Glomset states that the first born of a young couple was diagnosed syphilitic, clinically, by two physicians and by a positive Wassermann, and later died in spite of treatment. Both of the parents denied the possibility of infection but sub- mitted to Wassermann tests, the father's blood upon repeated examinations giving negative results and the mother's positive. Following this the mother in order to clear herself, brought an older sister and a younger brother for tests, both of which proved to be positive. Then the children brought their father for a Wasser- mann which was negative, but soon after, the man's wife, the grand- mother of the child originally seen, died from what was diagnosed gumma of the brain, and blood collected less than twenty minutes after death gave a positive reaction. 1 Steadman: Twentieth Century Practice of Medicine, New York, 1899, xviii, p. 395. 2 Jour. Am. Med. Assn., 1915, Ixv, p. 682. CHAPTER XXI. GENERAL PATHOLOGY AND CLINICAL HISTORY. In general it may be said that the pathological picture in con- genital syphilis is the same as in the acquired form, however, there are certain differences which must be described. The chancre, of course, is not present in congenital syphilis except where the child is infected in passing through the birth canal, and even if present may pass unnoticed. While all the other lesions of acquired syphilis may be duplicated in the congenital form, as a rule they are milder in type, though of more extensive distribution. Gummata in con- genital syphilis are comparatively rarely seen but connective-tissue production is marked in the various organs, especially in the liver, and is the result of a regenerative proliferation of the fibroblasts. Placenta. — While the placenta is composed partly of maternal and partly of fetal tissue, it is nevertheless a product of conception and therefore its affection with syphilis is discussed at this place. The syphilitic placenta is larger and heavier than normal, its weight sometimes being one-fourth to one-third that of the fetus, while the normal proportion is one-sixth. This increase in weight is caused by a hyperplasia of the chorionic villi, chiefly due to an increase in the connective tissue surrounding the bloodvessels which show endarteritis. Treponemata have been found by numerous investigators. The syphilitic placenta is more friable than the normal organ and is of a light red color, showing pale yellowish patches. It may be the seat of hemorrhages which cause a partial separation. The umbilical cord also may be the seat of the syphilitic process, the Treponema pallidum having been demonstrated numerous times. An endarteritis and even thrombosis may occur. Course of Congenital Syphilis. — As pointed out above, infants may be born with active manifestations of syphilis, or without such manifestations which develop within a few weeks, or finally the so-called syphilis hereditaria tarde may occur. The typical picture of an infant born with active syphilitic manifestations is a pitiable sight. It is small, weasened, thin and weak. The skin is wrinkled and flabby, has been described as of a cafe au lait color, and may be the seat of syphilodermata. The eyes are more or less sunken and inflamed and the general appear- ance has been likened to a "little old man." There is more or less PLACENTA 373 involvement of the mucous membrane of the nose, causing the so- called " snuffles," and the cry is hoarse, due to laryngeal involvement. There may also be pseudoparalysis, due to inflammation of one of the bones near the epiphysis or there may be various symptoms, due to involvement of the central nervous system. It is rare for such a marked picture to be observed in living infants but some of the symptoms may be present. On the other hand, it is more frequent for a syphilitic child to be born apparently normal. In a variable time, from a few days to several months, it begins to fall away and the various symptoms outlined above, snufHes, hoarse cry, syphilodermata, pseudo- paralysis, etc., may make their appearance. Miller,^ in an analysis of 1000 cases, states that the first symptoms developed during the first month in 64 per cent, (by weeks; first, 8.5 per cent., second, 13.8 per cent., third, 24 per cent., fourth 17.7 per cent.) and during the second month in 22 per cent. For a longer period than two months accurate observations were not made. In addition to these such symptoms as stomatitis, nephritis, enlarged spleen and liver, retinitis, iritis, various bone lesions, alopecia, etc., may make their appearance. If the patient recovers from these symptoms he may remain in apparent health for several years only to develop lesions which resemble the later manifestations of acquired syphilis, such as gummata of the skin or viscera, as well as certain lesions rarely seen in the acquired form of the disease. The most typical of these are interstitial keratitis and Hutchinson's teeth. In the so-called syphilis hereditaria tarde, symptoms apparently do not develop for years after birth, but in all probability they are present either at or soon after birth and are so slight as to pass unnoticed. Such symptoms as rhinitis or a rash may have existed and little or no attention given it, but it is entirely within the range of possibility that no outward manifestations are present and the viscera alone are affected. Finally, as pointed out above, the pos- sibility of acquired syphilis with slight early symptoms must be kept in mind. The year at which syphilis tarde is said to make its appearance most frequently is the twelfth, although it may appear earlier or in rare instances much later. Bellizzi^ reports a case in which appar- ently perfect health was enjoyed until the age of thirty-eight was reached, at which time cardiovascular disease with positive Was- sermann both on the blood and pleural effusion developed. Other cases of extremely late development of symptoms of con- genital syphilis have been reported, but only those which have carefully been followed from birth should be considered as authentic. 1 Jahrb. f. Kinderh., 1888, xxvii, p. 359. 2 Reforma med., 1915, xxxi, p. 174. 374 GENERAL PATHOLOGY AND CLINICAL HISTORY Lymphatic Glands. — That the lymphatic glands are affected by the Treponema pallidum in congenital syphilis as well as in the acquired type is well known, although most writers have little or nothing to say on the subject. The epitrochlear, inguinal and cervical are the glands most frequently involved, although any of the lymphatic glands of the body may be affected. The epitroch- lears are enlarged on one or both sides in from 80 to 90 per cent, of cases, while the inguinal and cervicals are less frequently involved. Enlargement of the various glands due to their proximity to ulcera- tive skin lesions is not rare. As a rule the glands are only moder- ately enlarged, rarely becoming larger than a bean, although the size of an ordinary marble may be attained. The pathological picture differs in no respect from that observed in acquired syphilis. Cutaneous Lesions. — Nearly all of the syphilodermata of the acquired disease may be duplicated in congenital syphilis, although they are usually somewhat modified and some types are less often observed, while the bullous syphiloderm is much more frequent than in acquired syphilis. Macular Syphiloderm. — An erythematous macular eruption is one of the most frequently observed of the syphilodermata of the con- genital type of the disease. The macules rarely are circumscribed, but more often are diffuse and usually are of a dull ham color, although a yellowish brown sometimes is observed. The true macular eruption is not elevated above the surrounding skin. The circumscribed macules are irregularly round in shape while the diffuse eruption occurs in large irregular blotches. The most fre- quent location is the genitocrural region, usually also involving the buttocks and sometimes passing down the thighs. The eruption not infrequently is seen on the face; the chin, upper lip and the area between the eyes and above the nose being the most frequent locations. The macular eruption occasionally is the first evidence of the disease, although, as a rule, it is accompanied by other symptoms such as snuffles. It is rarely or never seen at birth and usually makes its appearance during the first few weeks of life, but may be delayed two, three, or more months. When the borders of the lips and the cutaneous surface around the nostrils and around the eyes, where the action of the muscles keep the skin in motion, are attacked by the diffuse macular syphilo- derm fissures, rhagades are formed which may leave permanent scars and are very suggestive of congenital syphilis. This type of eruption is somewhat persistent, and even in spite of treatment new lesions may develop. In milder cases the eruption in a short time begins to fade and gradually disappears. The macular syphilodermata in congenital syphilis sometimes VESICULAR SYPHILODERM 375 must be differentiated from erythema intertrigo. The skin in the latter condition is of a lighter red color than the syphilitic eruption, and the color disappears on pressure, which it does not altogether do in syphilis, in which condition a yellowish tint to the skin is left. However, other evidences of congenital syphilis usually are present as well as positive laboratory jfindings. Papular Syphiloderm. — A true papular eruption without macules is exceedingly rare in congenital syphilis. When this type of lesion does occur it is nearly always as a recurrence, being observed, as a rule, between the sixth and twelfth months, although it may be^een as late as the third or fourth year. This type of eruption is of a brownish color and of a peculiar glossy appearance. The papules, which are always few in number, are sometimes scattered and sometimes occur in groups. The most frequent locations are the back of the neck, the back, the forehead and rarely on the arms and legs. They are usually most refractory to treatment. Moist papules around the anus, genitalia and in the the folds of the skin comparable to these lesions in acquired syphilis are not infrequent. Maculopapular Syphiloderm. — The so-called maculopapular erup- tion certainly is the most frequently observed of all the syphilo- dermata of the congenital form of the disease, and in quite a large percentage of cases is the first symptom of the disease to appear. Some of the eruptions are macular, some papular and some truly maculopapular. As with the macular eruptions, they may be circumscribed or diffuse, the latter being due to a confluence of several discrete lesions. The color, as a rule, is the typical dark red ham hue, although a lighter shade may be observed when the eruption is seen early. They are slightly elevated above the surrounding skin, and in size and shape resemble the macular eruptions. The lesions are distributed mainly on the lower limbs, the flexor surfaces of the arms, the neck, the chin and the face, although scarcely any portion of the body is exempt. The palms of the hands and the soles of the feet quite frequently are involved where the eruption appears thicker, tenser and of a lighter color. The date of the appearance of the eruption corresponds to that of the true macular type. As a rule the eruption disappears by absorption, although desquamation of these lesions is not uncommon, the skin sometimes peeling in large flakes. Vesicular Syphiloderm, — ^This type of eruption in congenital syphilis, as in the acquired form of the disease, is exceedingly rare and when it does occur usually is in association with a pustular or bullous eruption. Two cases have been reported by Grindon,^ 1 Jour. Cut. Dis., 1910, xxxviii, p. 284. 376 GENERAL PATHOLOGY AND CLINICAL HISTORY who briefly reviews the subject. One case sliowed many mihary and the other many pin-head-sized vesicles. Bullous Syphiloderm. — This lesion, often eroneously called syphi- litic pemphigus, which is the rarest of all skin lesions of acquired syphilis, is of comparatively frequent occurrence in the congen- ital type, being found by Miller^ in 25 per cent, of cases. The lesions usually are of large size, from 1 to 3 cm. in diameter. They are of a copper color, are seated either upon an ulcerated or eroded base and may be surrounded by an infiltrated copper-colored rim. As a rule they are flacid but they may be tense and contain a yellowish, cloudy fluid, often becoming purulent or bloody. The most frequent location of the bullous syphiloderm is upon the palms of the hands and the soles of the feet, to which locations it may be limited, or it may be found on nearly any portion of the body surface. This lesion is seen earlier than any of the other syphilodermata of congenital syphilis not infrequently developing in intra-uterine life and being present at birth. It may, however, not make its appearance for two or three to five or six weeks. The bullae, as a rule, soon burst, leaving an eroded or ulcerating surface which later may be covered by a greenish scab. On section the bullous syphiloderm is seen to be made up of two chambers containing fluid. First, the superficial layers of the epidermis are distended with a large amount of fluid between them and the rete Malpighii, and second the rete is detached in places by an accumu- lation of fluid between it and the papillary layer. Microscopically, a uniform inflammatory proliferation of the cells of the papillary layer is observed. This is seen to follow the bloodvessels. Num- erous investigators have reported the finding of treponemata both in the fluid of the blebs and in the papillary layer. The bullous syphiloderm must be distinguished from pemphigus. The latter condition rarely appears before the end of the second week of life, while the syphilitic lesion is common at birth or soon after. The syphilitic eruption, also, has a predilection for the palms of the hands, or the soles of the feet, which regions pemphigus rarely attacks. The contents of the syphilitic bullae soon become purulent, which does not occur with the blebs of pemphigus. With the syphilitic eruption other manifestations of syphilis also, as a rule, are present, although the final diagnosis may have to rest upon the finding of the treponemata in the lesions or other positive laboratory evidence. The pustular syphiloderm is a rare type in congenital syphilis and when pustules do occur they usually are the result of purulent change taking place in the vesicular or bullous lesions. Never- 1 Jahrb. f. Kinderh., 1888, xxvii, p. 359. BULLOUS SYPHILODERM 377 theless occasionally true pustules may be seen, especially around the mouth or anus, usually in association with the maculopapular Fig. 73. — Congenital syphilis showing papulopustular syphiloderm. (Holt.) eruption. Sometimes the contents of the pustule upon drying forms crusts very much resembling the rupia of acquired syphilis. 378 GENERAL PATHOLOGY AND CLINICAL HISTORY Nodular Syphiloderm. — This type of syphilitic eruption also is rare in the congenital form of the disease. When it does occur it is, as a rule, of late appearance, usually being seen as a recurrence several years after birth. It may, however, develop as early as the sixth month. This lesion differs in no respect from the same type of lesion in acquired syphilis. Fig. 74. — Chancre of lip with pustular syphiloderm in child. Gummatous Syphiloderm. — Gummata of the skin in congenital syphilis differ in no respect from these lesions in the acquired form of the disease. They are seen most frequently upon the front of the leg or on the face. In the latter location they may produce considerable destruction of tissue by ulcerating. The gummatous syphiloderm is rare in early congenital syphilis but is not infrequent later as a recurrence or as one of the symptoms of syphilis hereditaria tarde. GENERAL SYMPTOMS 379 Aside from the syphilodermata the skin in early congenital syphilis may present a wrinkled, paper-like appearance. Syphilis of the Appendages of the Skin. — ^Alopecia. — Alopecia may occm* in congenital syphilis as in acquired syphilis, although complete baldness is rare. The eyebrows may be attacked as well as the hair of the head. Alopecia may occur as an early symptom in association with the skin lesions or it may appear later and in syijhilis tarde it may be a prominent symptom. It must be borne in mind that not infrequently the first hair of the newborn falls out when no syphilis is present. StilP states that an unusually abundant crop of dark hair at birth or appearing soon after has been described as a symptom of congenital syphilis, and that this " syphilitic mop" or "wig" has been observed by him in 4 per cent, of his cases. Onychia.^ — Onychia occurs in congenital syphilis as a drying and shrivelling process. It has been suggested that the nail appears as if it had been pinched together laterally, with a high ridge in the centre resembling a claw. The nails of either the fingers or the toes may be involved and sometimes all the nails are affected. Paronychia. — Paronychia also may occur, the nail becoming loosened and detached. These conditions, as a rule, are manifestations of the first few months of the disease, but may be observed later in its course. Mucous Membranes. — Not all of the syphilomycodermata seen in acquired syphilis are found in the hereditary form but the erosive yapular lesions or mucous yatch not infrequently is observed in the mouth. Condylomata and ulcerative gummatous lesions also are not rare. The mucous patch and condylomata are types of early hereditary lesions, while gummata are of late appearance. The lesions differ in no respect from the similar lesions in acquired syphilis. Syphilitic involvement of the mucous membranes of the nose will be discussed under Syphilis of the Respiratory Tract. General Symptoms.^ — Temperature. — The more marked of the syphilodermata of congenital syphilis usually are accompanied by more or less fever. The temperature rarely rising above 39° C. (102° F.) and when the eruption is not severe may be subnormal. The jiulse rate may or may not be in proportion to the temperature, although it rarely reaches more than 110 to 120 beats per minute. Blood. — There is more or less anemia in practically all cases of congenital syphilis, especially is this true in early cases with active manifestations. Chiaravalloti^ examined the blood of 150 cases of varying ages and found that the hemoglobin varied from 12 to 75 per cent., with an average of 56.8 per cent., while the number 1 Power and Murphy: System of Syphilis, London, 1909, i, p. 303. 2 Pediatria, 1914, xxii, p. 881. 380 GENERAL PATHOLOGY AND CLINICAL HISTORY of erythrocytes was lower than normal. Marked variations in the differential leukocyte count were observed, though nothing char- acteristic was found. Hazen^ in an examination of but 5 cases of congenital syphilis states that such cases do not necessarily show a high lymphocyte count. Hochsinger^ states that aside from the diminution in the per- centage of hemoglobin and the number of erythrocytes observed in early congenital syphilis many normoblasts are observed as well as a leukocytocia which especially affects the myelocytes and eosinophiles. 1 Jour. Cut. Dis., 1913, xxxi, p. 618. 2 Pfaundler and Schlosemann : Diseases of Children, Philadelphia and London, 1912, ii, p. 534. CHAPTER XXII. REGIONAL SYPHILIS. SYPHILIS OF THE CIRCULATORY SYSTEM. Heart. — ^Warthin^ in an excellent study of 12 cases of congenital syphilis states that in the majority of early cases the heart was found large and dilated, in the others normal in size or smaller than normal. The heart muscle was usually pale or contained lighter areas, while the walls were generally thicker than normal. The muscle seemed moister, softer and more translucent than normal. In some hearts nothing pathological could be detected by the gross appearance. The older cases showed grossly, mitral endocarditis, with insufficiency, compensatory hypertrophy and dilatation, with no evidence of myocarditis until microscopic examinations were made. Microscopically, all the cases showed throughout the myocardium numerous or few light staining patches separating or replacing the muscle fibers and made up of a fibroblastic or myxomatous tissue. These contained a delicate granular or fibrillar reticulum in which were found numerous cells of lymphocyte or plasma-cell type, as well as numerous large epithelioid cells with abundant pink-staining granular protoplasm and pale nuclei. These latter cells presented various sizes and shapes as well as vacuolization, fragmentation and loss of nucleus. The heart-muscle fibers showed a peculiar pale coagulation degeneration or necrosis in the neighborhood of the fibroblastic proliferation. The protoplasm was seen to have lost its striations and its ability to take the eosin stain, while the nuclei were large and swollen and took the hematoxylin poorly. The smaller bloodvessels showed an epithelioid proliferation of their walls and often the lumina were filled with cells similar to those of the stroma. The larger vessels, both arteries and veins, showed varying degrees of thickening, especially in the intima and adventitia. Obliterating endarteritis was not common, in fact the interstitial changes were in all cases much more marked than the arterial changes. Stained by Levaditi's method the fibroblastic epithelioid areas of the heart wall were found crowded with treponemata. From the above evidence Warthin concludes that there exists not infrequently in congenital syphilis a characteristic form of 1 Am. Jour. Med. Sc, 1911, cxlii, p. 398. 382 REGIONAL SYPHILIS interstitial myocarditis due to the localization of colonies of Trepon- ema pallidum, which in some instances is the only evidence of the disease and sometimes cannot be recognized except by miicroscopic examination. Only in the older cases of Warthin's series were symp- toms of heart disease present and in them syphilis was not suspected. Arteries. — xiortitis with or without aneurysm has been noted in congenital syphilis and differs little, if at all, from that observed in the acquired type. Endarteritis and periarteritis of the smaller arteries also are observed. Veins. — The veins in congenital syphilitics seem to be peculiarly weak and dilatation of the superficial veins of the scalp often are noticed in young infants. Later in the course of . congenital syphilis varicose veins, especially of the legs, are common. These frequently lead to ulceration and the combination of syphilitic characteristics and those of varicose ulcers often is most refractory to treatment. SYPHILIS OF THE RESPIRATORY TRACT. Rhinitis is one of the most frequent affections in early congenital sj'philis. It is seen, as a rule, during the first three months of life and not infrequently has been observed on the first day of life. The most typical symptom of this condition is the so-called "snuffles" or snuffling respiration which describes the condition quite accurately. At first there is little or no discharge, there being merely an obstruction to the nasal passages due to swelling of the mucosa, especially of the inferior turbinate bone. Soon, however, a mucotis discharge makes its appearance which may become purulent, or even stained with blood, depending upon the severity of the process. This obstruction of the nasal passages makes nursing difficult and often the head is retracted in a position of opisthotonos to aid respiration. If the condition is left untreated and the process extends to the cartilage, bone ulceration and even necrosis may occur and marked deformities result. These deformities, however, are noted more frequently later in the course of the disease as a result of gummata. Such deformities as saddle- nose, perforated palate, etc., are seen and are comparable to similar deformities in acquired syphilis. Larynx. — Syphilitic laryngitis usually occurs in the congenital type of the disease as an accompaniment of rhinitis. It is not, how- ever, as frequent as the latter condition. The principle symptom is a hoarse, rasping cry which is very suggestive. Edema of the glottis due to laryngitis may cause marked dyspnea, while death may result from sudden spasm of the glottis. The process may be so severe as to cause ulceration and upon healing leave cicatrices which later may break down. Late in the course of congenital SYPHILIS OF THE GASTRO-INTESTINAL TRACT 383 syphilis the larynx may be the seat of gummata which will cause symptoms resembling those of similar conditions in the acquired form of the disease. Trachea and Bronchi. — Conner/ in a review of 128 cases of syphilis of the trachea and bronchi, found 10 cases in the congenital type of the disease. The lesions differed in no respect from those found in acquired syphilis. The symptoms produced are also similar. Lungs. — The most characteristic condition in the lungs in congenital syphilis is the so-called white pneumonia of Virchow, which consists of an increase in the size of the lung, the surface of which when cut is whitish, grayish or of a mottled red and gray appearance. Microscopically, there is thickening of the alveolar walls and an infiltration of the alveoli and smaller bronchi with inflammatory and epithelial cells, many showing fatty degenera- tion. Treponemata are found usually in large numbers along the walls of the capillaries and alveoli and sometimes within the inflam- matory cells filling the alveoli. One or both lungs may be affected or perhaps only one lobe of one lung. A more advanced stage of this type of pneumonia is more of an interstitial form. The lung is harder and tougher than normal. A round-cell infiltration of the intra-alveolar connective tissue is noted microscopically and there is increase in the number of small bloodvessels. Gummata of the lung are rare in congenital syphilis but when found differ in no respect from gummata in the acquired form. Most authorities state that involvement of the lung in congenital syphilis cannot be recognized during life, or at least that on account of the fact that these conditions so commonly are fatal they may be said to have no clinical manifestations. Still,^ however, cites several cases which lived a year or more and states that the condition is easily recognized, clinically, by the con- traction of one side of the thorax, signs of consolidation, bron- chiectasis and displacement of the heart toward the affected side. SYPHILIS OF THE GASTRO-INTESTINAL TRACT. Mouth. — The syphilomycodermata occurring in the mouth have been described above. When ulcerating gummata occur on the soft or hard palate perforation or even more serious deformity may occur. Teeth. — Congenital syphilis may affect the teeth in two ways, namely, by retarded eruption and by malformation. The milk teeth, as a rule, are not affected in congenital syphilis, although 1 Am. Jour. Med. Sc, 1903, cxxxvi, p. 57. ^ Power and Murphy: System of Syphilis, London, 1909, i, p. 297. 384 REGIONAL SYPHILIS they may decay earlier and more frequently than those of normal individuals. The permanent teeth, however, may show very striking abnor- malities. These abnormalities may consist of almost any malfor- mation in size, shape and position and are due to the influence of syphilis during the course of the development of the teeth. The most typical of these malformations are the so-called Hutchinson's teeth, first described by Sir Jonathan Hutchinson'^ in 1861. In such teeth there is a decided crescentic notching of the free border, the lateral angles are rounded, and the tooth tapers from above downward (peg-shaped) . The condition usually is symmetrical and the teeth most frequently affected are the upper central incisors, although the other incisors occasionally are involved. Rarely one tooth alone is affected. When the teeth first erupt the free border does not possess the crescentic shape but presents a rough saw-like edge which gradually wears away, leaving the typical notch. As the child grows older this in turn is worn away and the edge becomes more or less straight. Fig. 75. — Hutchinson's teeth in congenital syphilis. Other abnormalities of the teeth consist of transverse furrows of the incisors, widely separated teeth, micodentism, changes in type, for example, canines resembling incisors, and early and fre- quent decay. Not infrequently two or more types of abnormality may be present in one person. Hutchinson considered the type of deformity bearing his name to be pathognomonic of congenital syphilis, but such is not the case, as typical Hutchinson teeth occasionally are seen in other condi- tions where syphilis is absent. Any severe disease occurring before the eruption of the permanent teeth may cause these deformities, and on the other hand, the teeth of many congenital syphilitics do not show such changes. Esophagus, Stomach and Intestines. — Most syphilographers have paid scant attention to affections of these portions of the gastro- intestinal tract in congenital syphilis. Peyer's patches are occasion- i Brit. Med. Jour., 1861, p. 515. SYPHILIS OF THE GASTRO-INTESTINAL TRACT 385 ally the seat of the syphilitic process and the term syphilis annularis intestini has been applied, while Parrot^ is said to have described gummatous infiltration and ulceration of Peyer's patches. No description of the clinical manifestations of syphilis of these portions of the alimentary tract in congenital is available, but should such conditions be present they undoubtedly would present symptoms in every way comparable to the symptoms produced by involvement of these regions in the acquired type of the disease. In fact, it is well known that intestinal disturbances are quite frequent in congenital syphilis and it is well within the range of possibility that these may be due, partially at least, to lesions of these regions. Liver. — The liver is one of the most frequently affected organs in the body in congenital syphilis. In fact, this organ is found almost constantly involved in stillborn syphilitic infants. The reason for this undoubtedly is that it receives maternal blood direct by the umbilical vein. The liver usually is enlarged and hard with rounded edges. On section it is of a light yellow color, usually with many opaque white spots, which upon microscopic examination are found to be miliary gummata. There is a slight inflammatory exudation and marked proliferation of the connective-tissue cells due to the presence of the treponemata. The proliferation is due to efforts at regeneration and the connective tissue is most abundant where the treponemata are most numerous. The contraction of the collagen fibrils causes compression of the liver cells which results in atrophy. This condition occurring in utero may be followed by hydramnios due to obstruction of umbilical vein. In syphilitic involvement of the liver in late congenital syphilis the condition may resemble syphilitic cirrhosis in the acquired form. Perihepatitis and gummata also rarely are found. Quite marked involvement of this organ by the Treponema pallidum in congenital syphilis may be present without demon- strable symptoms. However, in a considerable percentage of cases enlargement may be detected. In the majority of instances this is slight but the liver may reach quite a large size and be distinctly palpable. Ascites does not occur in the early involvement of the liver in congenital syphilis, but later in the course of the disease a typical syphilitic cirrhosis with acites may occur with other symp- toms as in the acquired form. Jaundice also is exceedingly rare in early involvement of the liver in congenital syphilis. The symptoms associated with gum- mata of the liver differ in no respect from those observed with gummata in the acquired form of syphilis. 1 Cited by Marshall: Syphilology and Venereal Disease, New York, 1906, pi 360. 25 386 REGIONAL SYPHILIS Gall-bladder. — ^The only reference to syphilis of the gall-bladder found in the literature is the case of Beck^ in which the gall-bladder of an eight-months-old fetus was found affected. Spleen. — The spleen qtiite frequently is involved in early cases of congenital syphilis, and less often in the late cases. The usual condition is a slight enlargement due to round-cell infiltration and proliferation of the connective-tissue elements. The enlargement, however, may be marked so that the organ is distinctly palpable while tenderness may or may not be present. Numerous trepone- mata generally are found, especially in the walls of the arteries. Gummata of the spleen and amyloid degeneration also have been described in congenital syphilis. Pancreas. ^ — This organ rarely is affected in congenital syphilis, though perhaps more often than it is in the acquired form of the disease. The usual condition is a diffuse interstitial fibrosis. As far as the author is aware the Treponema pallidum has not been demonstrated in the pancreas of congenital syphilitics. While affections of the pancreas rarely may be found postmortem in congenital syphilis, no symptoms have been described during life referable to this organ. Marshall has suggested that syphilis of the pancreas may be the cause of diabetes occurring in children and adolescents. THE THYROID GLAND. Involvement of the thyroid in congenital syphilis is exceedingly rare. Davis^ quotes Demme as having observed children with gum- matous nodules in the thyroid, and Furst as having observed the case of a child born with a goitre of considerable size, which he thought was undoubtedly due to syphilis. Congenital syphilis of the thyroid may produce marked symp- toms of exophthalmic goitre, as in a case reported by Clark^ in which symptoms developed twenty-four years after birth. A positive Wassermann reaction was obtained in this case as well as in the mother of the patient and the symptoms disappeared under specific therapy. THE THYMUS GLAND. Syphilis of the thymus also is rare, but according to Adami^ gummata and diffuse fibroid induration have been observed. 1 Prag. med. Wchnschr., 1884, ix, p. 257. '^ Syphilology and Venereal Disease, New York, 1906, p. 359. 3 Arch. Int. Med., 1910, v, p. 47. 4 Jour. Am. Med. Assn., 1914, Ixiii, p. 1951. 6 Pathology, Philadelphia and New York, 1911, p. 732. THE GENITO-URINARY ORGANS 387 Hocksinger"^ states that the thymus may be so enlarged as to pro- duce stenosis of the trachea with stridor thymicus, but that the enlargement disappears under specific therapy. THE ADRENALS. After the liver and spleen the adrenals seem to be the organs most frequently involved in congenital syphilis. Symptoms refer- able to such involvement have not been described. It may be, however, that certain cases of Addison's disease are due to con- genital syphilis of the adrenals. THE GENITO-URINARY ORGANS. Testicles. — Syphilitic orchitis is not infrequent in congenital syphilis. It is most often found during infancy but has been observed in children and even in adult life. It usually is bilateral but may be unilateral. The epididymis rarely is involved and hydro- cele is uncommon. The condition usually is a diffuse inflammatory process, although gummata have been observed. Rarely the devel- opment of the testicles is arrested in utero, and infantilism results, the testicles being small and, as a rule, functionless. In syphilitic orchitis the testicle is enlarged, hard and sometimes tender, while gummata of the testicle may rarely break down and ulcerate. Uterus and Ovaries. — Actual involvement of the uterus in con- genital syphilis has not been observed as far as the author is aware, however, certain congenital abnormalities, such as uterus bicornis, etc., may indirectly be due to syphilis. That the ovaries of congenital syphilitics may be affected with syphilis is proven by the finding of the treponemata in these organs in a child of one year, by Levaditi and Sauvage,^ and in a fetus of seven months by Hoffman and Wolters.^ However, no symptoms referable to involve- ment of these organs in congenital syphilis have been described. Kidney. — Syphilitic nephritis, both acute and chronic, has been observed in congenital syphilis, and may occur at nearly any age. The condition usually is interstitial, although it may be parenchy- matous. During the active eruptive stage in infants acute neph- ritis is not infrequent, although it clears up quite readily under specific therapy. Treponemata have frequently been demonstrated in large numbers in the connective-tissue stroma of the kidney and 1 Pfaundler and Schlossmann: Diseases of Children, Philadelphia and London, 1912, p. 553. 2 Cited by Metchinkoff in Power and Murphy's System of Syphilis, London, 1908, i, p. 64. 3 Ibid. REGIONAL SYPHILIS in less numbers in the tubules and between the epithelial cells. Gummata of the kidney have not been observed in congenital syphilis. THE BONES. Involvement of the bones is quite frequent in congenital syphilis, and those bones which are preformed in cartilage are more often affected before birth, while those bones which are formed in mem- brane are attacked after birth. It seems that the syphilitic process is more prone to invade those portions of the bones in which growth is most active. It is, therefore, that the so-called osteochondritis of Wegner is the most frequent pathological process in the bones of congenital syphilitics. This lesion is found along the border zone between the epiphysis and diaphysis of the long bones, and is often erroneously termed epiphysitis. Normally in ossification in the long bones the border-line between the zones of calcification and ossification is straight or slightly curved, narrow and sharply defined. In the syphilitic lesion the border-line is broader and irregular. Various grades of severity of the process are observed. If the lesion be of moderate degree, a white or reddish-white zone, about 2 mm. in width, is seen between the cartilage and the new- formed spongy bone. This consists of calcified cartilage in which the rows of cartilage cells are more numerous than normal. When the lesion is more pronounced the zone of calcification is broader, more irregular and less sharply outlined against the zone of ossifi- cation. It also contains a greater number of cartilage cells than normal. The cartilage next to the zone of calcification is softer, contains numerous bloodvessels and sometimes small zones of con- nective-tissue calcification or irregular ossification. If the process is most severe the periosteum and perichondrium are thickened and the bone is found pouched out at the sides around the zones of calcification and ossification. The zone of calcification is white, irregular, hard and friable. This is mainly made up of irregular rows of degenerated and distorted cartilage cells which are surrounded by a calcified substance consisting of irregular masses of atypical bone tissue and bloodvessels which in turn are surrounded by cells of various shapes. Between this zone of calcification and the new-formed bone a grayish or grayish-yellow zone, irregular and from 2 to 4 mm. in thickness is seen. This is made up of vascular tissue, round and spindle-shaped cells and a homogeneous sub- stance, and forms a loose, easily detached connection between the diaphysis and the cartilage. Not infrequently different degrees of severity of the process are observed in the same individual. The most severe degree is found in the lower end of the femur, after which the lower ends of the tibia THE BONES 389 and fibula, the ulna and radius, the upper ends of the tibia, femur and ulna are affected most severely. The early or mild degrees of the osteochondritis, as a rule, cannot be recognized macroscopic-ally but are revealed by the microscope. The more severe processes are also revealed by the x-rays. Clinically, the osteochondritis if of a mild degree cannot be recog- nized. However, if the process is severe a swelling of the bone with more or less tenderness in the region of the epiphysis may be detected and the so-called pseudoparalysis of Parrot observed. This apparent paralysis is due to the pain. The condition usually is seen during the first three months, often very early and never later than the sixth month. It is observed, according to various authors in from 11 to 25 per cent, of cases. Later in the course of congenital syphilis a periostitis or osteitis may be noted and may occur in the long bones or in the bones of the face or skull. It may be a diffuse process and involve nearly the entire diaphysis or it may be noted in circumscribed areas. It usually starts in the solid bone and grows outward to the perios- teum and inward to the medulla. When the process breaks through the periosteum the soft tissues become involved and sinuses are formed. The affected bone is more or less changed in size and shape and nodides or exostoses may develop. Periostitis and osteitis will cause s\TQptoms depending upon the bone affected and the extent of the process. Pain, severe and per- sistent, especially at night, may be noticed. Probably the most frequently involved bone in congenital sj'philis is the tibia and when this bone is typically affected it constitutes an almost pathognomonic sign. The middle third of the diaphysis most often is involved, although the process may extend through- out the entire length of the bone. There is thickening, especially anteroposteriorly, giving the bone an appearance of being bent, the so-called "saber tibia." Subjective s\Tnptoms, as a rule, are slight or absent, although nocturnal pain and aching and some tenderness are occasionally complained of. The bones of the skull may be attacked and more or less deformity result. The so-called Parrot's nodes are protuberances or bosses due to diffuse periostitis. If the frontal bone alone is affected, the "OhTn- pian brow" will result, while if the parietal bones are affected as well, the " hot-cross-bun" deformity will exist. Craniotabes which consists of a thinning of the bones of the skull, is not a rare condition. It is due to pressure on the bone during development. Both of these affections have been ascribed to rickets and undoubtedly do occur in this condition but probably more fre- quently when associated with congenital syphilis. As a rule 390 REGIONAL SYPHILIS Parrot's nodes and craniotabes are early manifestations of the disease occurring within a few weeks to a few months after birth. Various cranial deformities, saddle-nose, perforated palate, etc., and of the pelvis may be the result of osteitis and periostitis. Gummata of the bone which is a very rare condition in con- genital syphilis will cause symptoms and results depending upon the bone or bones affected, and they differ in no respect from those of gummata in acquired syphilis. Dactylitis is unusual in congenital syphilis. It occurs, as a rule, during the first year and is exceedingly rare after the second year. The fingers are affected more frequently than the toes and occa- sionally the metacarpal bones are involved. The symptoms do not differ from those found in dactylitis of acquired syphilis. Graves^ has called attention to the frequent occurrence of the so-called scaphoid scapula in children of syphilitic parents, although also found when no syphilis exists. The chief characteristic of this condition is that the vertebral border below the spine of the scapula is concave instead of showing the normal convexity. THE JOINTS. Simple arthralgia in which no demonstrable lesion exists is seen in congenital syphilis as well as in the acquired type. It occurs, as a rule, early in the course of the disease and differs in no respect from that of acquired syphilis. Chronic synovitis with effusion and osteo-arthritis due to hyperos- tosis are of not infrequent occurrence and are characterized by their , slow development, chronic course, absence of pain, and slight limitation of movement. These conditions are of the later mani- festations of congenital syphilis occurring, as a rule, between the fifth and fifteenth years. The so-called syphilitic arthritis deformans of Fournier which is produced by osteophytic outgrowths from the epiphyses is charac- terized by the limitation of movement and even ankylosis, while more or less wasting of the muscles may occur. The usual date of the appearance of this type of arthropathy is between the fifth and twelfth years. The symptoms of Charcot's joint may occur in juvenile tabes and differ in no respect from the same condition in tabes due to acquired syphilis. THE BURS.ffi. From the scanty literature on the subject it would seem that syphilitic bursitis is exceedingly rare in the congenital form of the 1 Recent Studies in Syphilis, St. Louis, 1911, p. 118. THE TENDONS AND MUSCLES 391 disease. It is possible, however, that some of the cases reported as specific arthritis are in reaUty bursitis or at least that the bursse as well as the joints are affected. The only case of which the author is able to find record was reported by Coues^ in 1915. This case was a boy of thirteen years, who had always had "something the matter." Two months previous to being examined he had had trouble with his right elbow followng a fall. There was considerable swelling and disability which persisted for a time, then partially disappeared but again became worse until another fall occurred the day before. Follow- ing this there was a great deal of pain and disability. The examination showed a fairly well-nourished and developed boy, although rather undersized. There were no obvious signs of congenital syphilis. The right elbow was swollen, especially over the olecranon, while there was some tenderness over the external condyle. Motion was limited and painful. At a later examination two small pieces of bone were felt through the fluid of the olecranon bursa. Owing to the tenderness in the region of the external condyle it was supposed that there was a separation of the epiphysis or a fracture. The a;-rays, however, showed that the joint was normal. After five weeks as there was no improvement an operation was decided upon. At this time it was determined that cardiac dilata- tion and mitral insufficiency existed and a probable diagnosis of specific myocarditis was made. It was also determined that the shin bones were tender to pressure and the .r-rays revealed slight but definite periostitis of the tibia. The Wassermann test was negative. The bursse of the right elbow were opened under cocaine and a gummy, honey-like material was evacuated with a small amount of pus. Two small worm-eaten pieces of bone were removed from the cavity which did not connect with the joint. No microscopic examinations were made. Under specific therapy the elbow returned to normal and the heart condition improved. THE TENDONS AND MUSCLES. The author has been unable to find any reference in the litera- ture to involvement of the tendons and muscles in congenital syphilis with the exception of one case of gumma of the gastroc- nemius and four cases of gumma of the muscles of the tongue reported by Fournier.^ 1 Boston Med. and Surg. Jour., 1915, clxxiii, p. 18. 2 Cited by Hartley in Morrow's System, of Genito-urinary Diseases, Syphilology and Dermatology, New York, 1898, ii, p. 261. 392 REGIONAL SYPHILIS THE NERVOUS SYSTEM. Jonathan Hutchinson/ even so late as 1899, wrote that there was good reason to beUeve that involvement of the nervous system was very infrequent in congenital syphilis, and that it never occurred to him in a single instance to identify congenital syphilis with sufferers from tabes and general paralysis. Since that time abundant evidence has been brought forth proving the affection of the nervous system in congenital syphilis. Rumpf^ states that in 13 per cent, of all cases of hereditary syphilis there is involvement of the nervous system. All types of syphilis of the nervous system found in the acquired form may be seen in congenital syphilis, including arteritis, men- ingitis, syphilis of the brain substance (gummata and paresis), syphilis of the cord substance (gummata and tabes) and syphilis of the nerves. As a rule, however, various lesions are combined. Treponemata have been found in the meninges and walls of the bloodvessels of the brain in congenital syphilis by numerous investi- gators, but as far as the author is aware these organisms have not been demonstrated in the brains of juvenile paretics or the cords of juvenile tabetics. Certain malformations of the nervous system not seen in the acquired type of syphilis are observed in the congenital form. One of the most frequent of these is hydrocephalus. This condition is produced by an accumulation of fluid in the lateral ventricles and may be due to any condition which prevents the escape of the fluid and therefore is found in other conditions than syphilis. As pointed out above, certain abnormal infants sometimes are produced as the product of conception when one or both of the parents are syphilitic without actual infection of the fetus with the Treponema pallidum. Monsters of various types, especially those with gross abnormalities of the brain, and individuals with defec- tive mental development, morons, imbeciles, and idiots not infre- quently are observed. These abnormal infants also are found with positive evidences of syphilis. Involvement of the nervous system may occur in utero and still- birth follow or a living child may be born with manifestations of nervous-sytem involvement present or such manifestations may develop at almost any subsequent time. As stated above, all of the lesions of acquired syphilis of the nervous system are found in the congenital form of the disease, and 1 Steadman: Twentieth Century Practice of Medicine, New York, 1899, xviii, p. 394. 2 Cited by Nonne: Syphilis and the Nervous System, Philadelphia and London, 1913, p. 313. THE NERVOUS SYSTEM 393 even more frequently than in the former are two or more types of pathological picture observed. For example, an arteritis and a meningitis usually are associated. This is especially true of early involvement of the nervous system. It is therefore to be expected that the clinical course will present a mixed picture with varied and complex findings. However, the same symptoms as are observed in acquired syphilis are found in the congenital type, hemiplegias, paraplegias, reflex disturbances, headache, mental derangements, etc., although modified to a greater or lesser extent. Symptoms depending upon conditions not found in acquired syphilis also are observed. One of the most frequent of the early manifestations of involve- ment of the nervous system in congenital syphilis which is not seen in the acquired form is hydrocephalus. This condition may be observed at birth or it may not develop till puberty, however, the most frequent time of its appearance is when the child is between three and eleven months of age. Occasionally clinical symptoms are absent, but, as a rule, there is irritability, sleeplessness, kicking, screaming and movements of the hands and arms. Vomiting is not rare and retraction of the head often is observed. Nystagmus and irregular and fixed pupils are frequent. Spasticity and rigidity sometimes are present. The temperature is normal or only slightly raised. While juvenile paresis and juvenile tabes are similar to the same conditions observed in acquired syphilis they deserve special mention. Juvenile Paresis. — According to Kraepelin,^ the first case of juvenile paresis to be described was reported in 1877 by Clouston, since which time numerous cases have been observed. In the past year the author has seen two cases. Symptoms of the disease may begin as early as the fifth or sixth year, although, as a rule, the onset is somewhat later (seventh to twelfth year). Paresis due to congenital infection must now be regarded either as a recurrence or as a case of syphilis hereditaria tarde, as it has been noted following early manifestations of congenital syphilis and also when such symptoms were absent or overlooked. The child may or may not have appeared normal up to the time of the development of paretic symptoms, although, as a rule, there is a history of backwardness, both in physical and mental development. The clinical picture usually is one of dementia and formerly many cases undoubtedly were diagnosed as idiocy or imbecility, although as Kraepelin^ states, childish ideas of grandeur may 1 General Paresis, New York, 1913, p. 145. 2 ibid. 394 REGIONAL SYPHILIS occur. Convulsions usually of an epileptiform character are very frequent in juvenile paresis, often occurring daily or even many times daily. The course of this malady is, as a rule, protracted, lasting some- times, as in Kraepelin's^ case, as long as nine years. The following case observed by the author is quite typical: H. J., male, aged sixteen. (See Fig. 76.) Family History. — Mother died at age of thirty-six, cause unknown. Not known if father is living. One sister, aged twenty-five, living and married, but has no children. One sister died at age of two months, cause unknown. Twin brothers alive and said to be well at age of thirteen. Fig. 76. — Juvenile paretic showing slight notching of upper central incisors Personal History. — Patient said to have been nervous in school and did not learn rapidly. No history of diseases in childhood, and is said to have been well until four years ago when "eyes began troubling him." Present illness began about one year ago with extreme nervousness and loss of vision in left eye. Later he suffered with fainting spells followed by aphonia. In October, 1914, the patient received inunctions of mercury with improvement. Later, nervousness increased, with loss of memory, irritability and fits of uncontrollable temper. Examination. — April 10, 1915. Boy, apparently fifteen or six- teen years of age is well nourished, muscles are firm, but asthenic. 1 General paresis, New York, 1913, p. 145. THE NERVOUS SYSTEM 395 Facial expression is dull and expressionless. Heart, lungs and abdominal viscera apparently are normal. No luetic scars or aden- itis is present. Upper central incisors are slightly notched. There is slight convergent strabismus in left eye; nystagmus in both eyes. Both pupils irregular in outline and do not react to light. Left pupil reacts to accommodation. Upper tendon reflexes are normal. Lower tendon reflexes are markedly exaggerated. Ankle-clonus and Romberg sign are positive. Coarse tremor of hands and fingers and fibrillary tremor of tongue are noticed. Fig. 77. — Juvenile paresis in the emaciated stage. (Jelliffe and White.) Speech is slow and hesitating and articulation poor. Memory both for recent and remote events is poor. Fund of acquired knowledge is slight. Orientation for place and personality is not impaired. He could not tell the day of the week, although he said it was springtime. Laboratory Findings. — Wassermann on blood + + H — h • Was- sermann on spinal fluid -\ — h + +• Lymphocytes, 16 per c.mm. 396 REGIONAL SYPHILIS Globulin H — |-. Colloidal gold test, typical paretic curve. Luetin test negative. The patient was treated with mercury inunctions until slightly salivated and large doses of potassium iodide were administered. Intraspinal medication was refused and no further treatment was employed. The patient left Hot Springs in July, 1915, apparently in the same condition as when first seen. Juvenile tabes is a much more rare condition than juvenile paresis. The date of onset, as a rule, is earlier than in the latter condition, the first symptoms usually being observed between the fifth and tenth years, although cases developing as late as the twenty-fifth year have been reported. The symptoms dififer but little from those observed in tabes following acquired syphilitic infection. Mental Defectives. — Children of syphilitic parents presenting certain types of mental defect without obvious syphilitic lesions quite frequently are observed. Some of these show some evidence of syphilis, such as interstitial keratitis, rhagades, etc., and a larger number give positive laboratory evidence. However, a certain percentage of these mentally defective children, morons, imbeciles and idiots, while giving no evidence of actual infection with the Treponema pallidum undoubtedly owe their unfortunate condition to the "sins of their fathers." The diagnosis of the actual involvement of the nervous system with the Treponema pallidum in congenital syphilis will differ but little from that of acquired syphilis. Hydrocephalus due to syphilis must be differentiated from that due to other conditions and usually can be accomplished by the finding of other clinical manifestations of syphilis or by positive laboratory evidence. The determination of the role of syphilis in the etiology of such mental defectives as morons, imbeciles and idiots except where positive clinical or laboratory findings of syphilis exist will depend upon family evidence. The diagnosis of the mental condition is purely a psychiatric problem and is without the scope of the present volume. THE EYE. The eye is very frequently the seat of the syphilitic process in the congenital type of the disease. Iritis due to congenital syphilis differs in no respect from that seen in acquired syphilis, except, perhaps, that the process, as a rule, is not so severe. While usually developing during the first few months of extra-uterine life it may run its entire course within the uterus, the child being born with synechia of the iris. Iritis may also appear as a symptom of syphilis hereditaria tarde. PLATE VI Interstitial Keratitis. THE EAR 397 Cyclitis almost invariably is an accompaniment of iritis. Interstitial keratitis is much more frequently seen in congenital syphilis than in the acquired form. This condition with Hutchinson teeth and deafness without earache or otorrhea constitutes the so-called Hutchinson'' s triad, which when all are present is practi- cally pathognomonic of congenital syphilis. Interstitial keratitis while more frequent in the congenital form of syphilis differs in no respect from that seen in acquired syphilis, except, perhaps, that in the latter form of syphilis there is a greater tendency for the disease to remain unilateral, while in the former type it usually is bilateral. Both eyes, however, may not be affected simultaneously, although, as a rule, they are involved in rapid succession and both corneas are opaque at the same time. It is most frequently seen between the eighth and fifteenth years, although it has been noted as early as a few weeks after birth. Scleritis also is seen more frequently in congenital s\'philis than in acquired syphilis but presents no clinical differences. It is, as a rule, a late manifestation, usually being observed after puberty. Choroiditis and retinitis occur in the same types in congenital syphilis as are found in the acquired disease. They usually are early manifestations, being seen most frequently diu-ing the first year. Papillitis as a primary condition is rare in congenital s^'philis but more often is seen as an extension from the retina. It also is an early manifestation and the sjTiiptoms are similar to those observed in acquired syphilis. THE EAR. In early congenital s\"philis not infrequently there is an extension to the middle ear of the pathological processes in the nose and pharynx which results in an otorrhea. Later in the coiu-se of the disease, usually between the fifteenth and twentieth years, a rapidly advancing deafness may occur which probably is due to a similar process to that observed in the internal ear in deafness due to acquired s^-philis. There may be tinnitus but usually the deafness is the only s\Tnptom. Meniere's sjTidrome due to congenital s^'philis has also been observed. CHAPTER XXIII. DIAGNOSIS. The diagnosis of congenital syphilis depends upon the. history, clinical symptoms and laboratory findings, of the individual him- self and upon similar evidence in his parents and brothers and sisters, although, as with acquired syphilis, the diagnosis, occasion- ally must rest on the results of therapeutic measures. In the vast majority of cases it is impossible to establish a definite syphilitic history in the parents, especially in the mother, also it is comparatively infrequent that active manifestations of the dis- ease are present in the parents at the time of examination of the patient, although when possible such manifestations, as well as their residuals (scars, etc.) should be searched for. Of course positive evidence of syphilis in the father with absolute proof of its absence in the mother would be convincing that the child was not congenitally syphilitic. However, it may be said that absolutely certain evidence of the absence of syphilis in the mother would be hard to establish. The history of conceptions, both those previous to the one resulting in the child under consideration, as well as earlier and later ones should also be gone into, for with the mother of syphilitic children the sequence of sterility, abortions, stillbirths, live chil- dren with syphilitic manifestations and apparently normal children often may be established. If the mother shows any evidence of congenital syphilis herself, her family history should also be looked into. The history of brothers and sisters should be taken and they should also be examined carefully for evidences of the disease. The Wassermann test and perhaps the luetin should be made on all members of the family, and when iiidicated the provocative Wassermann and lumbar puncture with examination of the spinal fluid. Of course the establishing of syphilis in the mother or brothers and sisters of an individual does not of necessity mean that the individual himself is congenitally syphilitic, but in the presence of suspicious symptoms is very strong presumptive evidence. The evidence to be derived from the patient himself will of course vary with his age, as pointed out in the section on Clinical History. As a rule little or no difficulty will be encountered in arriving at a DIAGNOSIS 399 correct diagnosis of a case of congenital syphilis with active mani- festations at birth. The skin lesions, the snuffles, the hoarse cry as well as the emaciated condition and coffee color of the skin will in typical cases be convincing. Even in such well-marked cases a Wassermann test should be made as corroborative evidence but more as a guide to future treatment. In those cases, however, in which no symptoms are manifest at birth and in which they do not develop in a typical manner the diagnosis will be more difficult. The presence of enlarged lymphatic glands can be relied upon but little in the diagnosis of congenital syphilis, as they may become enlarged through many other causes. However, the absence of such enlargement may be of some value, as one or more of the epitrochlear glands are found enlarged in the early course of the disease in from 80 to 90 per cent, of cases and other glands quite frequently. Too much importance should not be placed upon the so-called "snuffles," as many other conditions than syphilis may cause this symptom. However, taken with other symptoms of syphilis the snuffling respiration may be of considerable value. The finding of treponemata in the secretion from the nose would, of course, be conclusive. Concerning the hoarse cry due to involvement of the larynx, prac- tically the same may be said. Taken alone it is of little or no value, with other symptoms it may be considered as one link in the chain of evidence. The finding of iritis in early infancy or childhood should at once cause the physician to be suspicious, as syphilis is the most frequent cause of this condition at these ages. In the absence of other syphilitic lesions, however, the diagnosis would have to rest on laboratory findings. While syphilis is by far the most frequent cause of interstitial keratitis, this condition should not be considered pathognomonic. Taken with other evidence of congenital syphilis, much reliance may be placed on it. However, the diagnosis should be confirmed by laboratory evidence. Rapidly advancing deafness observed between the fifteenth and twentieth years without otorrhea or earache, should be looked upon with grave suspicion and other evidence of syphilis, either clinical or laboratory, be searched for most diligently. Hutchinson's teeth when present are of some value in the diag- nosis but taken alone should in no case be considered as conclusive. The absence of this condition also should be considered as far from excluding syphilis, as but a comparatively small percentage of congenital syphilitics show the typical Hutchinson's teeth. 400 DIAGNOSIS The pseudoparalysis occurring in early congenital syphilis as a result of involvement of the long bones must sometimes be dis- tinguished from infantile paralysis, although the latter condition is rare at the early age, the former condition usually is observed. Other manifestations of syphilis nearly always are present, while the a;-rays will, as a rule, reveal the true condition. The so-called Parrot's nodes and craniotabes are of a certain value in the diagnosis of congenital syphilis, but in the absence of other manifestations are not conclusive. LABORATORY DIAGNOSIS. The most valuable laboratory procedure in congenital syphilis is the Wassermann reaction on the blood serum. Methods of collecting blood for this test have been described in the chapter on Laboratory Diagnosis in Part I. Authorities differ as to the value of the Wassermann test. Holt^ states that it is positive in practically 100 per cent, of untreated syphilitic infants and even in those who have received mercury, unless the treatment has been very thorough and protracted. Veeder and Jeans^ found 92.6 per cent, of 82 cases positive. No accurate statistics are available concerning the Wassermann reaction in syphilis hereditaria tarde but it is stated by most writers that the test is positive in practically all cases. Coues's case of syphilitic bursitis mentioned above should be kept in mind and in doubtful cases therapeutic tests applied. The luetin test is also of distinct value in congenital syphilis. Noguchi^ states that it is positive in 70 per cent, of cases and that one observer found it positive in 93 per cent. Brown* found 88 per cent, of 34 syphilitic infants gave positive luetin reactions and of 100 controls 96 gave definitely negative tests and 4 were doubtful. The tests on the spinal fluid are the same as those employed in the spinal fluid of patients suffering with acquired syphilis, and the results are the same, depending upon the type and extent of the involvement of the central nervous system. 1 Am. Jour. Dis. Child., 1913, vi, p. 166. 2 Ibid., 1916, xi, p. 177. 3 New York Med. Jour., 1914, c, p. 341. 4 Am. Jour. Dis. Child., 1913, vi, p. 172. PLATE V] Positive Luetin Reaction. Case of Congenital Syphilis. CHAPTER XXIV. PROGNOSIS, PROPHYLAXIS AND TREATMENT. The prognosis of congenital syphilis may be said in the main to be bad, although this statement must be qualified according to the age of the patient and the severity of the lesions and symptoms. Infants born with typical active manifestations of syphilis almost invariably succumb to the disease, while those in whom s\Tnptoms develop only after a few days to a few weeks stand a better chance of recovery under vigorous specific treatment. It has been stated that in the comparatively rare cases in which undoubted marked clinical symptoms of syphilis exist and the blood gives a negative Wassermann reaction, the prognosis is bad. Congenital syphilis developing active manifestations at puberty or later must also be considered of grave prognosis although some cases recover under proper therapy. Of the individual symptoms and lesions the bullous syphiloderm presents one of the most unfavorable prognoses. If, however, it does not occur for some time after birth and vigorous treatment is instituted recovery may follow. Involvement of the viscera in congenital syphilis renders the prognosis most unfavorable, although as pointed out above, there may be quite marked invasion of the heart by the treponemata without clinical manifestations. Jaun- dice occiu-ring in congenital syphilis, according to Coutts,^ usually constitutes an unfavorable prognosis, as most cases developing this symptom die. Of the eye symptoms interstitial keratitis usually presents a favorable prognosis, although some cases are most refractory. The prognosis of involvement of the nervous system in congenital syphilis is more unfavorable than such involvement in the acquired form of the disease, and most cases lead on to a fatal termination. According to both Mott^ and Watson^ the later in life juvenile paresis appears, the more rapidly fatal will be its course. Mortality. — The following table given by Sturgis^ shows the num- ber of births and deaths of syphilitic children in the Moscow Hospital from 1860 to 1870. 1 Cited by Still in Power and Murphy's System of Syphilis, London, 1909, i, p 360. 2 Ibid., p. 361. 3 Ibid. ^ Morrow: System of Genito-urinary Diseases, Syphilology and Dermatology, New York, 1898, ii, p. 631. 26 402 PROGNOSIS, PROPHYLAXIS AND TREATMENT Number of Percent- Number of Percen Years. children. Deaths. age. Years. children. Deaths. age. 1860 224 148 66 1866 165 124 70 1861 204 150 75 1867 174 131 69 1862 140 - 93 67 1868 208 152 73 1863 150 123 82 1869 184 116 63 1864 198 139 70 1870 184 118 65 1865 171 131 70 It will be seen that the highest percentage of deaths was 82 in 1863, and the lowest 63 in 1869. These percentages, however, must be too high and undoubtedly a certain number of congeni- tally syphilitic children were born without the condition being recognized. StilP states that in the families of 87 congenitally syphilitic children under treatment, there were 39 stillbirths, 36 miscarriages, and 25 deaths all attributable to congenital syphilis while of the 87 children themselves, 13 died while under observation. Post^ tabulated the mortality in 30 syphilitic famiHes in which there had been 168 pregnancies. These pregnancies resulted in 53 stillbirths and miscarriages, and 44 early deaths, a total of 97 or 57 per cent, lost, leaving 71 living children, of which 32 have been patients and 39 presumably healthy. PROPHYLAXIC. The most important factor in the prophylaxis of congenital syphilis is the preventation of the marriage of syphilitic individuals. This in a large measure could be accomplished as outlined above by the requirement of a clean bill of health in regard to syphilis before the issuance of a marriage license. If, however, syphilitics are married, the prevention of conception should be insisted upon until all evidence of syphilis is absent, that is, until the standard of cure proposed in Part II is complied with. This to the author's mind applies to the husband as well as to the wife, for he believes that a man may be infective until he is cured, although of course the chances of infection are much less when active manifestations are not present. Finally, if conception has taken place when either husband or wife is syphilitic the intensive treatment of the wife should be insisted upon even if she shows no manifestations of the disease. If this treatment is carried on, especially the adminis- tration of salvarsan throughout the course of pregnancy, the pre- vention of congenital syphilis can be accomplished in the vast majority of cases. It must be remembered, however, that salvarsan should be administered in pregnancy with caution, the kidneys being watched most carefully. 1 Power and Murphy: System of Syphilis, London, 1909, i, p, 359. 2 Boston Med. and Siffg. Jour., 1914, clxx, p. 113. TREATMENT 403 TREATMENT. The treatment of congenital syphilis is in the main the same as that of the acquired disease. The same principles are involved and the same methods employed, the only difference lying in the manner of application which must be modified to suit the indiyidual needs. General Treatment. — Hygienic. — The hygienic treatment of con- genital syphilis in infants consists of careful nursing with cleanli- ness, the frequent change of diapers and the free use of powder, as well as regularity of feeding and sleeping and plenty of fresh air. Dietetic. — With congenitally syphilitic infants the importance of breast-feeding is not to be overestimated. If, however, the child does not do well on breast-feeding the milk of the mother should be examined and if found unsuitable a syphilitic wet-mirse with suitable milk should be found if possible. This, however, usually is impossible, when modified cow's milk must be substituted. The hygienic and dietetic treatment of older children and of young adults with congenital syphilis does not differ materially from that of acquired syphilis. Specific Treatment. — The specific treatment of congenital syphilis consists of the administration of mercury, iodin and the arsenical s, but the methods of administration may have to be considerably modified. Mercury. — The most popular methods of administering mercury to infants are by the mouth and by the application to the body of cloths smeared with mercurial ointment. All of the preparations of mercury administered by mouth in acquired syphilis have been employed in congenital syphilis. The gray powder in doses of 0.03 to 0.06 gram (^ to 1 grain) three times a day is very satis- factory. This may be deposited on the child's tongue where it will readily be taken up or it may be administered in a little sweetened water or milk. In administering mercury by applying the ointment to the skin a cloth of suitable size is smeared with 4 to S grams (1 to 2 drams) of mercurial ointment or with a like amount of ointment and vaseline in the proportion of 1 to 1 and wound around the child's body, the ointment being applied to the back. This should be removed daily, the child bathed carefully and after renewing the ointment, reapplied. ^Mercurial baths have been employed as in acquired syphilis and may be useful in certain cases, but the child should be watched carefully for untoward effects. The intramuscular injection both of the soluble and insoluble preparations has been practised, but owing to the pain usually is 404 PROGNOSIS, PROPHYLAXIS AND TREATMENT impractical except in older children and adults. Certainly the use of the insoluble preparations has nothing to recommend it. The intravenous injection, especially of mercurialized serum, is of distinct value and is much to be preferred to intramuscular injections. Salvarsan and Neosaharsan. — The use of these drugs in congen- ital syphilis is very much to be recommended and the intravenous route is certainly the only one to be considered. Quite frequently, however, intravenous injections in infants is accomplished with considerable difficulty. When it is impossible to find a vein at the elbow the jugular vein may be employed, or better still, one of the veins of the scalp as recommended by Holt and Brown. ^ The method of procedure consists of securing the infant's arms in a sheet when the crying of the child and the hyperextention of the head will cause the veins to become distended and prominent, and either the posterior auricular or one of the branches of the tem- poral may be employed. The author uses the apparatus described for the intravenous injection of mercury and neosalvarsan (see Fig. 54), except that two 5 c.c. syringes are employed instead of the 20 c.c. ones. The use of small doses is to be recommended, as several deaths have occurred in infants following the injection of salvarsan. The same dosage should be employed in congenital syphilis as in the acquired form, that is 0.006 gram per kilogram of body weight. Thus, an infant weighing 4 kilos (8.8 pounds) should receive 0.024 gram of salvarsan. It is scarcely necessary to state that the same precautions in preparation and administration should be employed in congenital syphilis as in acquired syphilis. lodin in any form is rarely employed in early congenital syphilis and in the later course of the disease should be administered as in acquired syphilis. Symtomatic and Special Treatment. — Only such conditions as are not found in acquired syphilis or require treatment differing from similar conditions in the acquired form will be discussed under this head. From the symptomatic and special treatment of other conditions the chapter on Treatment of Acquired Syphilis should be consulted. Skin Lesions. — The bullous syphiloderm usually is the only skin lesion of congenital syphilis which needs local treatment. The blebs should be emptied of their contents and if the epidermis has become detached and ulceration exists, the lesions should be dressed with calomel and bismuth powder or with mercurial ointment diluted 1 to 4 with vaseline. 1 Am. Jour. Dis. Child., 191.3, vi, p. 174. TREATMENT 405 Mucous Membranes. — As infants cannot use mouth washes or gargles when lesions exist in the mouth it should be swabbed out with potassium chol orate solution several times a day or the lesions touched with a 5 to 10 per cent, silver nitrate solution. Rhinitis. — The local application of a 2 per cent, solution of silver nitrate to the nostrils will assist in controlling the snuffles. Still^ recommends the use of adrenalin solution (1 to 1000) in each nostril if other means fail to give relief. If ulceration exists, the nostrils should be anointed with ammoniated mercury or the yellow oxide of mercury. The Cure of Congenital Syphilis. — The same standard of cure of congenital syphilis is required as in acquired syphilis, although it must be said that the production of a complete clinical and biologi- cal cure is often much more difficult in the former condition than in the latter. This is especially true of syphilis hereditaria tarde. The treatment, however, should be continued at least periodically throughout the life of the patient as long as any evidence of active syphilis, either clinical or laboratory, is present. 1 Power and Murphy: System of Syphilis, London, 1909, i, p. 364. INDEX. AcNEiFORM syphiloderm, 84 Acute yellow atrophy, 274 Adenitis, time of development of, 67 Adrenals, syphilis of, 28 i Age and syphilis, 43 Aix-la-Chapelle, 189 Alopecia, complete, case of, 96 syphilitic, 95 clinical history of, 95 diagnosis of, 118 differentiation from alopecia areata, 119 from premature alopecia, 119 from senile alopecia, 119 prognosis of, 179 treatment of, 255 Amboceptor, preparation of, 143 preservation of, 146 Ancient times, syphilis in, 17 writings, Chinese, 18 Egyptian, 19 Grecian, 19 Hebrew, 19 Hindoo, 19 Japanese, 18 Roman, 20 Animal inoculation, 34 Anorexia in syphihs, 103 Antigen, 137 acetone insoluble lipoids, 139 alcoholic extracts, 138 cholesterinized, 138 Treponema palUdum, 140 Thompson's, 140 Wassermann's original, 137 Aorta, syphilis of, clinical history of, 261 diagnosis of, 262 pathology of, 260 prognosis of, 262 treatment of, 262 Appendages of skin, syphilis of, 95 Arkansas State Hospital, syphilis in, 27 Arsenic in treatment of syphilis, 211 Arteries of brain, syphilis of, clinical history of, 322 diagnosis of, 335 Arteries of brain, syphilis of, pa'hology of, 314 prognosis of, 338 of spinal cord, syphilis of, clinical history of, 328 diagnosis of, 335 pathology of, 323 prognosis f, 338 and veins, syphilis of, 260 Arteritis of nervous system, differentia- tion from arterio- sclerosis, 335 from chronic alco- hoHsm, 336 from hysteria, 336 from multiple sclero- sis, 336 from, paresis, 335 from uremic poison- ing, 336 Astruc, Jean, 23 Atoxyl, 212 B Berlin, syphilis in, 26 Bladder, syphihs of, 290 Blood picture in syphilis, 104 prognosis and, 180 pressure in syphihs, 104 of syphilitics, infectivity of, 36 Bones, syphihs of, clinical history of, 295 diagnosis of, 301 differentiation from carci- noma, 301 from osteitis deformans, 301 from sarcoma, 301 from suppurative osteo- myelitis, 301 from tuberculosis, 301 pathology of, 294 prognosis of, 302 treatment of, 302 Brain substance, syphihs of, clinical history of, 323 diagnosis of, 336 pathology of, 314 prognosis of, 339 408 INDEX Breast, syphilis of, 279 British Army, syphihs in, 27 Bronchi, syphihs of, 264 BuUous syphiloderm, dinical history of, 83 diagnosis of, 115 pathology of, 53 prognosis of, 179 Bursa?, syphilis of, 309 Butyric acid test, Noguchi's, 168 Kaplan's method, 169 Thompson' smodifi cation, 169 Calomel ointment as prophylactic, 184 Cerebrospinal fluid, 164 anatomy of, 164 chemical properties of, 164 complement-fixation with, 175 cytology of, 174 examination of, 168 proteins in, estimation of, 168 significance of increase of, 169 physical properties of, 164 physiology of, 164 reduction of Fehling's solu- tion, 175 Cervix, syphilis of, 285 Chancre, adenitis following, 66 of anus, 61 of breast, 64 differentiation from carci- noma, 110 from fissure, 110 from gumma, 110 of cervix, 60 differentiation from epithe- lioma, 109 clinical history of, 68 complications of, 65 development of, 58 eroded, 65 extragenital, clinical history of, 61 diagnosis of, 109 prognosis of, 178 prophylaxis of, 185 treatment of, 253 of eyelid, 64 diagnosis of, 110 of finger, 64 diagnosis of. 111 genital, 59 diagnosis of, 108 differentiation from chancre redux, 109 from chancroid, 108 from herpes, 109 from scabies, 109 Chancre, genital, differentiation from simple erosion, 108 of glans penis, 59 of groin, 61 histopathology of, 47 Hunterian, 65 of labia majora, 60 labial, 62 differentiation from epithe- lioma, 109 lingual, 64 differentiation from simple ulcer, 110 from tubercular ulcer, 110 location of, 59 of preputial orifice, 59 of prescrotal angle, 60 prognosis of, 177 of rectum, 61 redux, 65, 103 of scrotum, 60 of skin of penis, 59 of tonsil, 62 differentiation from abscess, 110 from cancer, 110 from diphtheria, 110 from gumma, 110 from simple angina, 110 from Vincent's angina, 110 treatment of, 252 ulcerating, 65 of urethra, 60 differentiation from gonor- rhea, 109 of urinary meatus, 59 of vagina, 60 varieties of, 65 Charcot's joint, 305, 307, 308 Cholesterinized antigens, 138 Choroid, syphilis of, clinical history of, 359 diagnosis of, 361 pathology of, 357 prognosis of, 363 treatment of, 364 Ciliary body, syphilis of, clinical history of, 358 diagnosis of, 361 pathology of, 356 prognosis of, 362 Cincinnati City Hospital, deaths from syphilis in, 28 Circulatory system, syphilis of, 257 Circumcision as a prophylactic of syphilis, 185 Cirrhosis, syphilitic, 274 Civil state and syphihs, 45 Civilization and syphilis, 45 Climate and syphilis, 45 Cobra venom test of Weil, 159 INDEX 409 Collargol in demonstrating trepone- mata, 126 CoUes' law, 42 Colloidal gold test, 169 preparation of reagent, 170 technic of, 171 value of, 173 Complement, collection of, 141 preservation of, 142 Comi)lcment-fixation tests, 130 Noguchi's method, 147 preparation of reagents, 134 principles of, 130 technic of, 134 theory of, 154 Thompson's method, 149 value of, 155 Wassermann's method of, 146 Condyloma. {See Vegetating Syphilo- derm.) Congenital syphUis, 367 adrenals in, 387 alopecia in, 379 arteries in, 382 blood in, 379 bones in, 388 bronchi in, 383 bullous syphiloderm in, 376 bursse in, 390 clinical history of, 372 diagnosis of, 398 laboratory, 400 ear in, 397 esophagus in, 384 etiology of, 368 eye in, 396 gall-bladder in, 386 gastro-mtestinal tract in, 383 genito-urinary organs in, 387 gummatous sj^philoderm in, 378 heart in, 381 historical, 367 intestines in, 384 joints in, 390 kidneys in, 387 larynx in, 382 late development of, 373 liver in, 385 lungs in, 383 lymphatic glands in, 374 macular syphiloderm in, 374 maculopapular syphiloderm in, 375 mortality in, 401 mouth in, 383 mucous membranes in, 379 muscles in, 391 in negroes, 370 nervous system in, 392 nodular syphiloderm in, 375 Congenital syphilis, nomenclature of, 367 onychia in, 379 ovaries in, 387 pancreas in, 386 papular syphiloderm in, 375 paresis in, 393 paronychia in, 379 pathology of, 372 prognosis of, 401 pro])hylaxis of, 402 pulse in, 379 pustular syphiloderm in, 376 respiratory tract in, 382 rhinitis in, 382 scaphoid scapula in, 390 secondary etiological factors of, 370 snuffles in, 382 spleen in, 386 stomach in, 384 symptoms in, 379 syphilodermata in, 374 tabes dorsalis in, 396 teeth in, 383 temperature in, 379 tendons in, 391 testicles in, 387 thymus in, 386 thyroid in, 386 trachea in, 383 treatment of, 403 uterus in, 387 veins in, 382 vesicular syphiloderm in, 375 Cornea, syphilis of, clinical history of, 359 diagnosis of, 361 pathology of, 356 prognosis of, 362 treatment of, 363 Corpuscle suspension, 146 Coryza iodica, 250 Craniotabes, 389 Cytoryctes luis, 32 Dactylitis, 300 Dark-field illumination, 123 Development and course of syphilis, 56 Direct contact, infection by, 40 Disse and Taguchi, diplococcus of, 32 Drinking cups, infection by, 41 Ear, syphilis of, 364 clinical history, 365 diagnosis of, 365 410 INDEX Ear, syphilis of, pathology of, 364 prognosis of, 366 treatment of, 366 Economic importance of syphilis, 27 Endocarditis, syphilitic, 258 Enzyme test, 160 Esophagus, syphUis of, 289 Etiology, 30 early views, 30 microbiology, 31 Extragenital chancre, 61 Eye, syphilis of, 356 clinical history of, 358 diagnosis of, 361 pathology of, 356 prognosis of, 362 treatment of, 363 Fallopian tubes, syphilis of, 288 FaUopio, Gabrille, 23 Fernal, John, 23 Folhcular syphiloderm, 73 Fowler's solution, 212 Fracastoro, 22 Frankel treatment of tabes, 354 G Gall-bladder, syphilis of, 277 Gastritis, syphilitic, 271 Gastro-intestinal tract, syphilis of, 268 Genito-urinary organs, syphilis of, 282 Geographical distribution of syphilis, 25 Giemsa's stain for treponemata, 126 Goldhorn's stain for treponemata, 127 Gray powder, 195 Gummata of bone, 294 of brain substance, clinical history of, 323 diagnosis of, 336 pathology of, 314 prognosis of, 338 surgery of, 353 of ciliary body, 358 of cornea, 359 of iris, 358 of liver, 274 differentiation from carci- noma, 276 of meninges, 313-321 of spinal cord, clinical history of, 328 diagnosis of, 337 pathology of, 315 prognosis of, 339 treatment of, 353 of stomach, 271 Gummatous syphiloderm, clinical his- tory of, 92 diagnosis of, 117 differentiation from abscess, 117 from chancre, 109 from chancroid, 117 from epithelioma, 118 from fibroid, 117 from lipoma, 117 from lupus, 118 from sarcoma, 117 from varicose ulcer, 118 histopathology of, 53 syphilomycoderm, clinical history of, 103 diagnosis of, 120 H "Hair cut," 58 syphilis of, 95 Heart, syphilis of, 257 Hecht- Weinberg reaction, 158 Herxheimer reaction, 237 Hoffmann, cultivation of Treponema pallidum by, 38 Hot springs of Arkansas, 189 Hunter, John, 23 Hutchinson teeth, 384 Hydrocephalus, 392 Hypophysis, syphilis of, 281 Icterus in syphilis, 274 Idiosyncrasy, 42 Immunity in syphilis, 42 India-ink method of demonstrating treponemata, 126 Indurated papule, 65 Intermediate contact, infection by, 41 Intracranial therapy, results of, 350 technic of, 344 Intraspinal therapy, 341 rational, 345 results of, 349 technic of, 344 untoward effects of, 350 Intraventricular therapy, results of, 350 technic of, 345 lodid acne, 250 lodin in syphilis, 246 administration of, 247 elimination of, 251 therapeutic effects of, 249 untoward effects of, 250 lodipin, 248 lodism, 250 Iodoform, 248 INDEX 411 lothion, 248 Iris, syphilis of, clinical history of, 358 diagnosis of, 361 pathology of, 356 prognosis of, 362 treatment of, 363 Jarisch-Herxheimer reaction, 237 Jenner's stain for treponemata, 127 Joint, Charcot's, 305, 307, 308 Joints, syphilis of, clinical history of, 305 diagnosis of, 307 differentiation from acute arti- cular rheumatism, 307 from gonorrheal arthritis, 307 from rheumatoid arthri- tis, 308 from tuberculosis, 308 pathology of, 303 prognosis of, 308 treatment of, 308 Joseph and Piorkowsky, bacillus of, 32 Juvenile paresis, 393 tabes, 396 K Keidel tube, 135 Kidney, syphilis of, clinical history of, 291 diagnosis of, 292 pathology of, 291 prognosis of, 293 treatment of, 293 Labial chancre, 62 Laboratory diagnosis, 122 Lacrimal apparatus, syphilis of, clini- cal history of, 361 diagnosis of, 362 pathology of, 358 prognosis of, 363 treatment of, 364 Landau's color test, 160 Lange colloidal gold test, 169 Larynx, syphilis of, 263 Leukocytes in syphilis, 105 Leukocytozoon syphilidis, 33 Leukoplakia, chnical liistory of, 102 diagnosis of, 120 differentiation from psoriasis, 120 prognosis of, 180 Lingual chancre, 64 Liver, syphilis of, clinical history of, 274 Liver, syphilis of, diagnosis of, 276 pathology of, 274 prognosis of, 276 treatment of, 277 Los Angeles County Hospital, deaths following intraspinal therapy in, 351 Luetin, 160 experimentation, 161 preparation of, 160 technic of injection of, 161 tjqaes of reaction of, 161 value of, 163 Lumbar puncture. {See Rachicentesis.) Lungs, syphilis of, 265 clinical history of, 266 diagnosis of, 267 pathology of, 265 prognosis of, 267 treatment of, 267 Lustgarten's bacillus, 31 Lymphatic glands, syphilis of, clinical history of, 66 diagnosis of, 111 diagnostic importance of, 111 gummata of, 68 pathology of, 48 prognosis of. 178 treatment of, 253 M McDonagh's leukocytozoon s>Tphilidis, 33 Macular syphiloderm, annular, clinical history of, 69 diagnosis of, 113 histopathology of, 50 pigmentary, clinical history of, 69 differentiation from chlo- asma, 113 from tinea versicolar, 113 from vitiligo, 113 roseolar, clinical history of, 68 diagnosis of, 112 differentiation from drug rashes, 113 from German measles, 113 from measles, 113 from tinea versicolar, 113 syphilomycoderm, clinical history of, 100 diagnosis of, 119 differentiation from aphthous sore, 120 from diphtheria, 120 from herpes, 120 412 INDEX Macular syphilomj^coderm, differen- tiation from mercurial ulcer, 120 Maculopapular sjqDhiloderm, 72 Malaise in S5^philis, 103 Marriage of sj'philitics, 180 Medieval times, SA'philis in, 20 Meniere's sj'^ndrome, 365 Meninges, sj^ihilis of, clinical history of, 317 diagnosis of, 335 differentiation from non-speci- fic meningitis, 335 pathology of, 313 Mercury, contraindications to, 206 effects on Wassermann, 241 fumigation, 198 history of use of, 194 injections, intramuscular, 198 comparative value of var- ious preparations of, 202 insoluble preparations of, 199 soluble preparations of, 200 technic of, 201 intravenous, 204 Nixon's method of, 205 inunctions of, 196 mouth administration of, 194 phj'siological action of, 207 plasters of, 197 precautions in administermg, 206 suppositories of, 205 untoward effects of, 208 value of, compared with salvarsan, 240 Metchnikoff, 24 Mixed sore, 65 treatment, 252 Modes of transmission of syphilis, 40 Mortality of syphilis, 182 Mouth, s3T3hihs of, 268 Mucous membranes. {See Syphilo- mycodermata.) patch. (See Papular Erosive Sj'^philomycoderm.) Mullens, cultivation of Treponema pal- hdum by, 38 JNIuscles, syphilLs of, 310 Myelitis, syphilitic, clinical historj^ of, 328 diagnosis of, 337 prognosis of, 339 Myocarditis, syphilitic, 258 N Ntuls. (See On3'chia and Paronj^chia.) Naples, epidemic of, 22 Neisser's paste, 185 Neosalvarsan, 222 Nerves, syphilis of, clinical history of, 334 diagnosis of, 338 pathology of, 317 prognosis of, 340 treatment of, 354 Nervous system, syphilis of, 312 clinical history of, 317 diagnosis of, 335 early involvement of, 317 history of, 312 mortality of, 340 pathology of, 312 prognosis of, 338 treatment of, • standard, 354 symptomatic, 353 Neuralgia, syphilitic, 335 Neuritis, syphihtic, 335 New World origin of syphilis, 21 New York City, syphilis in, 26 Nodular syphiloderm, clinical history of, 90 diagnosis of, 116 differentiation from acne rosacea, 117 from epithelioma, 116 from leprosy, 117 histopathology of, 53 Noguchi's method of cultivating Tre- ponema pallidum, 38 Nomenclature, 22 Nonne-Apelt test, 168 Nummular syphiloderm, 75 Occupation and syphilis, 45 Ogilvie treatment, results of, 349 technic of, 343 Old World, syphilis in, 17 Onychia, clinical history of, 98 diagnosis of, 119 differentiation from eczema, 119 from psoriasis, 119 prognosis of, 179 treatment of, 255 Optic nerve, syphilis of, clinical history of, 360 diagnosis of, 362 pathology of, 357 prognosis of, 363 treatment of, 364 Orbit, syphilis of, clinical history of, 361 diagnosis of, 362 pathology of, 358 prognosis of, 363 Ovaries, syphilis of, 288 INDEX 413 Palmar syphiloderm, clinical history of, 79 diagnosis of, 115 differentiation from dermatitis seborrheica, 115 from squamous eczema, 115 Pancreas, syphilis of, 278 Papular syphiloderm, annular, clinical history of, 76 differentiation from ery- thema multiforme, 114 from psoriasis, 114 from tinea circinata, 114 histopathology of, 51 clinical history of, 72 histopathology of, 50 lenticular, clinical history of, 74 diagnosis of, 114 miliary, clinical history of, 73 diagnosis of, 113 differentiation from acne, 114 from keratosis pila- ris, 113 from lichen planus, 113 scrofulosis, 113 from papular eczema, 114 from pityriasis rubra pilaris, 114 from psoriasis, 113 from scabies, 113 moist, clinical history of, 80 differentiation from ver- uca acuminata, 115 histopathology of, 51 syphilomycoderm, clinical history of, 101 diagnosis of, 120 Papulosquamous syphiloderm, clinical history of, 78 diagnosis of, 114 differentiation from psoriasis, 114 Parental infection, 369 Paresis, chnical history of, 323 diagnosis of, 336 mortahty of, 339 pathology of, 315 prognosis of, 339 symptoms of, bladder, 328 mental, 323 neurological, 325 Paretic brain substance, infectivity of, 36 Paretic convulsions, 326 treatment of, 353 Paris, syphilis in, 26 Paronychia, 179 clinical history of, 99 diagnosis of, 119 treatment of, 255 Parrot's nodes, 389 Penis, gummata of, 282 Perforating ulcer, 334 Pericarditis, syphilitic, 258 Perigenital chancres, 61 PharjTix, syphiUs of, 268 Pituitary body, syphilis of, 281 Placenta, syphilis of, 372 Plantar syphUoderm, clinical history of, 79 diagnosis of, 115 Pleocytosis, significance of, 175 Pleurse, sj^ihilis of, 267 Polydipsia in sj'philis, 104 Potassium iodide in syphilis, 246 methods of administering, 247 Precipitin tests, 159 Prehistoric times, syphilis in, 17 Prevalence of syphilis, 25 Primary stage of Ricord, 55 Prophylaxis, 184 and education, 186 and legislation, 187 personal measures, 184 pubUc measm-es, 185 Prostate, syphilis of, 284 Prostitution, regulation of, 185 Provocative Wassermann test, 157 Pulse in syphilis, 104 Pustular syphiloderm, accuminate, clinical history of, 84 diagnosis of, 115 histopathology^ of, 53 large flat, clinical history of, 86 diagnosis of, 116 histopathology^ of, 53 small flat, clinical history of, 85 diagnosis of, 116 histopathology of, 53 Pustulocrustaceous syphiloderm, 87 Quaternary stage of Foiu-nier, 55 R Rabbits, inoculation of, with s"\'philis, 35 Race and syphilis, 44 Rachicentesis, contraindications of, 165 414 INDEX Rachicentesis, indications of, 165 technic of, 165 untoward effects of, 168 Ravaut treatment, results of, 349 technic of, 342 Recurring or relapsing chancre, 65 Registration area, deaths from syphilis in, 28 Respiration in syphUis, 104 Respiratory tract, syphilis of, 263 Retina, syphilis of, clinical ' history of, 360 diagnosis of, 362 pathology of, 357 prognosis of, 363 treatment of, 364 Ricord, Phillippe, 23 Ricord's classification inadequate, 55 Rupia, clinical history of, 88 diagnosis of, 116 histopathology of, 53 Salvarsan, 215 action of, 232 after-care of patient, 232 chemical properties of, 217 contraindications for, 231 dosage of, 224 effect of, on Wassermann, 244 enteroclysis, 222 fatalities from, 238 fate of, in body, 239 history, of, 215 indications for, 230 intramuscularly, 219 intravenously, 220 natrium, 223 oily preparations of, 220 physical properties of, 217 preparation of patient for, 232 reactions following, 235 significance of, 236 subcutaneously, 219 technic of injections of, 224 untoward effects of, 232 value of, compared with mercury, 240 Scaphoid scapula, 390 Schereschewsky, cultivation of Trepo- nema pallidum by, 37 Sclera, syphilis of, clinical history of, 359 diagnosis of, 361 pathology of, 356 prognosis of, 363 treatment of, 364 Secondary etiological factors, 42 stage of Ricord, 55 Seminal vesicles, syphilis of, 285 Serpiginous nodular syphiloderm, 91 Serum, methods of obtaining from patients, 134 Sex and syphilis, 43 Siegel's cytoryctes luis, 32 "Snuffles" in congenital syphilis, 382 Soamin, 213 Social condition and syphilis, 45 Sodium cacodylate, 213 effect on Wassermann, 246 Spinal cord, gummata of, 337 syphilis of, clinical history, 328 diagnosis of, 337 pathology of, 315 prognosis of, 339 fluid. {See Cerebrospinal Fluid.) puncture. {See Rachicentesis.) Spleen, syphihs of, 277 Squamous papular syphiloderm, 51 Stomach and intestines, syphilis of, 270 Subconjunctival injections of salvarsan- ized serum, 364 Sucking, infection by, 41 Swift-Elhs treatment, 342 Synechia following iritis, 356 Syphilodermata, classification of, 49 diagnosis of, 112 histopathology of, 49 prognosis of, 178 treatment of, 254 Syphilomycodermata, classification of, 54 clinical history of, 100 diagnosis of, 119 histopathology of, 54 prognosis of, 180 treatment of, 255 Syphilis and marriage, 180 hereditaria tarde, 369 modes of transmission of, 40 Syphilitic fever, 104 and prognosis, 180 psoriasis, 78 Tabes dorsalis, anesthesia in, 330 Argyll-Robertson pupil in, 332 ataxia in, 331 bones in, 334 clinical history of, 329 clitoris crises in, 333 decubitus in, 334 diagnosis of, 337 genital organs in, 333 intestinal crises in, 333 involuntary movements in, 332 laryngeal crises in, 334 muscles in, 334 nephritic crises in, 333 paralysis in, 332 INDEX 415 Tabes dorsalis, pathology of, 317 perforating ulcer in, 334 prognosis of, 340 sexual appetite in, 333 symptoms of, auditory , 332 bladder, 333 motor, 330 reflex, 332 sensory, 329 trophic, 334 visual, 332 treatment of, symptomatic, 354 and paresis, less frequent in females, 44 Taboparesis, cUnical history of, 334 diagnosis of, 338 pathology of, 317 prognosis of, 340 Temperature in syphilis, 104 Tendons, syphilis of, 309 Tertiary stage of Ricord, 55 Testicle, syphilis of, 282 _ Third generation, syphilis in, 371 Thymus, syphilis of, 280 Thyroid, syphilis of, 280 Tiodine, 248 Toilets, infection by, 41 Towels, infection by, 41 Trachea, syphilis of, 264 Treatment of syphilis, 188 diatetic, 189 hydrotherapeutic, 189 hygienic, 188 specific, 194 symptomatic and special, 252 tonic, 194 Treponema palhdum, agglutination of, 37 biology of, 33 collection of material, 122 cultivation of, 37 Noguchi's method, 38 Zinnser's method, 40 demonstration of, 122 different strains of, 37 discovery of, 32 identification of, in pure cul- ture, 40 length of life on towels and glass, 41 location of, 34 morphology of, 33 in paretic brains, staining method, 129 Treponema pallidum, staining of smears of, 126 in tissue, 127 Tuiiercular sj^philoderm. {See Nodu- lar Syphiloderm.) Tuberculopustular syphiloderm, 91 Tuberculosquamous syphiloderm, 91 Umbilical cord, syphiUs of, 372 United States Army, syphilis in, 27 deaths from syphilis in, 28 syphilis in, Banks' estimation of, 26 Ureter, syphilis of, 290 Urethra, syphilis of, 289 Urethral chancre, 60 Uterus, syphilis of, 287 Vagina, syphilis of, 285 Vaginal chancre, 60 Varioliform syphiloderm, 84 Vegetating syphiloderm, clinical history of, 82 histopathology of, 51 syphilomycoderm, 102 Venarsen, 214 Vesicular syphiloderm, clinical history of, 82 diagnosis of, 115 histopathology of, 52 W Wassermann test in diseases other than syphilis, 157 and prognosis, 177 provocative, 157 technic of, 146 West Point cadets, syphilis among, 27 Wile treatment, results of, 349 technic of. 344 ZiNNSER, Hopkins and Gilbert, method of cultivating treponemata, 40 COLUMBIA UNIVERSITY LIBRARY 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 ar- rangement with the Librarian in charge. 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