ffCl5G ^3^ a C-4> 1; >- LECTURES ON THE MALARIAL FEVERS BY WILLIAM SYDNEY THAYER, M. D. ASSOCIATE PROFESSOR OF MEDICINE IN THE JOHNS HOPKINS UNIVERSITY NEW YORK D. APPLETON AND COMPANY 1897 Copyright, 1897, By D. APPLETON AND COMPANY. TO WILLIAM OSLER THESE PAGES ARE GRATEFULLY AND AFFECTIONATELY DEDICATED. Digitized by tine Internet Arciiive in 2010 witii funding from Open Knowledge Commons http://www.archive.org/details/lecturesonmalariOOthay CONTENTS. LECTURE 1. PARE Introductory remarks. — A brief history of the development of our knowledge concerning the pathogenic agent of the malarial fevers 1 LECTURE IL Methods of examination of the blood. — Description of the haeraocy- tozoa of malaria 34 LECTURE III. Description of the hffimocytozoa of malaria {continued). — General con- ditions under which the malarial fevers prevail .... 70 LECTURE IV. Clinical description of the malarial fevers. — Types of fever. — Period of incubation. — 1. The regularly intermittent fevers : {a) tertian fever; (6) quartan fever. 2. ^stivo-autumnal fevers ... 97 LECTURE V. Clinical description of the malarial fevers {continued). — Pernicious fevers. — Fevers with long intervals. — Combined infections. — Masked malarial infections. — The urine in malarial fever . . 145 LECTURE VL Seqnelfe and complications 183 LECTURE VII. Morbid anatomy. — Anatomical changes occurring in acute malarial in- fections. — Anatomical changes following repeated or chronic infec- tions. — Cirrhotic processes and malaria. — Malarial pigment . .311 V vi LECTURES ON THE MALARIAL FEVERS. LECTURE VIII. ■ PAGE General pathologj'. — General pathology of the main symptoms of malarial fever. — Infection with multiple groups of parasites. — Mechanism of defence. — Phagocytosis. — Spontaneous recovery . 245 LECTURE IX. Diagnosis. — Prognosis. — Treatment. — Prophylaxis .... 273 LIST OF ILLUSTRATIVE CIIAETS. CHART PAGE I. — Tertian Fever — Single Infection . . . . . .110 II. — Quotidian Fever — Double Tertian Infection . . . 114,115 III. — Tertian and Quotidian Fever — Double Tertian Infection Facing 116 IV. — Quotidian Fever — Double Tertian Infection .... 117 V. — Quotidian Fever — Double Tertian Infection . . . .118 VI. — Continued Fever due to Infection with Tertian Parasites 120, 121 VII.— Quartan Fever 123 VIII.— Double Quartan Fever .126 IX. — Quotidian Fever — Triple Quartan Infection . . . . 138 X. — ^stivo-autumnal Fever — Quotidian Paroxysms . . . 131 XI. — ^stivo-auturanal Fever . . . . . . . . 133 XII. — ^stivo-autumnal Fever 135 XIII.— ^stivo-autumnal Fever ........ 137 XIV.— ^stivo-autumnal Fever 138, 139 XV. — ^stivo-autumnal Infection — Remittent Fever . . 142, 143 XVI. — j3]]stivo-autumnal Fever — Remittent Fever — " Subcontinua Typhoidea" Facing 144 XVII. — Quotidian and Tertian Fever — Double Tertian Infection Facing 171 XVIIl. — Intermittent Fever — Gonorrhoeal Endocarditis . . . 273 XIX.— Influenza .275 I. — The Parasite of Tertian Fever .... Facing 313 II. — The Parasite of Quartan Fever .... Facing 314 III. — The Parasite of -33Istivo-autumnal Fever . . Facing 314 " Sono gia molti anni cK io porto opinions che le febhri i7itermittenti vengono prodotte da parasiti che ne rinnovano Vaccesso alV atto della loro ripro- duzione, la quale suceede piii o meno presto secondo le diverse loro specie." Rasori {1766-1837); conversation with Bassi. LECTURES ON THE MALARIAL FEVERS. LECTUKE I. Introductory remarks. — A brief history of the development of our knowl- edge concerning the pathogenic agent of the malarial fevers. In the following lectures I shall endeavor to place before you a summary of the present status of our knowledge con- cerning the malarial fevers. There are few diseases toward the comprehension of which greater advances have been made within the last fifteen or sixteen years, and yet it is surprising how slow the general medical public has been in appreciating the true significance and value of the results which have fol- lowed Laveran's discovery of the malarial parasite. Much of the work of recent years has gone to confirm the accurate observations of such men as Morton, Sydenham, Lancisi, and Torti. But since the clear descriptions of some of these early observers the term "malaria" has come to be applied in so loose a manner to so great a variety of different pathological conditions that it has been difficult for many physicians to realize that malarial fever is in fact a disease as sharply defined and as easily recognizable as pneumonia, pul- monary tuberculosis, or diphtheria. It is high time, however, that these facts should be under- stood and appreciated by all intelligent medical men, and I 2 LECTURES ON THE MALARIAL FEVERS. trust that in the following remarks I may succeed in convinc- ing you of the satisfactory basis on which these assertions are made. The malarial fevers have been described from the earliest times. They were, however, throughout the older writings, included without distinction among various other febrile pro- cesses, more especially typhus, typhoid, and relapsing fevers, and the different septic infections. It was not until some years after the introduction of quinine that Torti * succeeded in distinguishing among these fevers a special class which yielded to this drug. To the fevers yielding to quinine — fevers mainly characterized by their intermittence and more or less regular periodicity — the term " malarial " came to be applied. The anatomical distinction between malarial and typhoid fevers in particular — ^two diseases which are so frequently confounded — ^became definitely established early in this cen- tury through the discovery of the intestinal lesions in typhoid, and by the recognition of the association of melanosis of the organs with malarial fever. Chnically, the distinction of the malarial fevers from those of other nature by the so-called therapeutic test is, as we shall see from further consideration of the process, in the main reliable. To-day, however, in the light of our present knowledge, we are able to distinguish the malarial infections from other febrile processes, however similar their clinical manifestations may be, not only by their behavior under treatment with qui- nine, but also by the presence in the blood of the specific parasites discovered in 1880 by Laveran. Therapeut. spec, etc., 4to, Mutinse, 1712. INTRODUCTORY REMARKS. 3 Despite this fact, it is a melancholy truth that a large body of medical men in this country have scarcely passed beyond the limits reached by Hippocrates in their clinical ap- preciation of the continued fevers. The term "malaria" is used very commonly to describe any continued or irregular fever the nature of which is not wholly clear. And the term is applied indiscriminately not only to fevers but also to a variety of non-febrile conditions, most of which have no rela- tion to true malarial infection. This fact has greatly impaired the value of our statistics with regard to the continued fevers. A glance at the vital statistics of a few of the larger Eastern cities reveals a state of affairs which is little less than appalling. Thus in J^ew York city during the six years ending in 1890 the statistics show : Deaths from malarial fever 2,060, or 24-62 per 100,000 of average population. Deaths from typhoid fever 2,031, or 24*27 per 100,000 of average population. In Brooklyn for the same period of time there were : Deaths from malarial fever 1,413, or 32-62 per 100,000 of average population. Deaths from typhoid fever 1,002, or 23-13 per 100,000 of average population. During the same years there were reported in Balti- more : Deaths from malarial fever 934, or 41-51 per 100,000 of average population. Deaths from typhoid fever 904, or 40-lY per 100,000 of average population. It may be stated with certainty that these statistics are almost absolutely incorrect. 4 LECTURES ON THE MALARIAL FEVERS. Let us consider for a moment tlie condition of affairs in Baltimore. During a period of somewliat over seven years since the opening of the Johns Hopkins Hospital, two of the years being included among those during which the above- named census statistics were compiled, there were : Deaths from typhoid fever, 48. Deaths from malarial fever, 3. In other words, there was, in the hospital, a proportion of sixteen deaths from typhoid to every one of malarial fever, w^hile outside the deaths reported from malarial fever were in excess, the proportion being as 1-01 is to 1. It is probably safe to say that 90 per cent at least of these deaths reported as from malarial fever were due to some other cause — in most instances, probably, typhoid. If this be trae of Baltimore, which is situated in a malarious region where relatively severe infections are not altogether uncommon, what must we think of the condition of things in Brooklyn, for example, where only the milder forms of malaria prevail, the few fatal cases representing probably the occasional instances of pernicious fever brought from Panama and the tropics by incoming steamers ? The term " malaria," as it is now used, is unscientific and inexact, and leads to much confusion. Used, however, prop- erly, and better in a qualifying sense (as " the malarial fevers "), it distinguishes a class of fevers due to a specific micro-organ- ism, fevers which yield, always, to treatment by quinine ; to this class of diseases alone may the term be j^roperly applied. We have in this country been lamentably backward in fully appreciating the chnical value of the advances in our knowledge concerning this disease, which have followed Lave- ran's discovery of the parasite sixteen years ago. PATHOGENIC AGENT OF MALARIAL FEVERS. 5 THE PATHOGENIC AGENT OF THE MALARIAL FEVERS. The idea that the malarial fevers are of parasitic origin is very old. Varro (b. c. 118-29)* says: " Advertendura etiam si qua erunt loca palustria et propter easdem causas, et quod arescunt, crescunt animalia qusedam minuta, quae non possuiit ociili consequi, et per aera intus in corpus per os, ac nares perveniunt, atqne efficiunt difficiles morbos." Morton,t in the seventeenth century, maintained that the disease was engendered by marsh air. This air, charged with hetero- geneous poisonous particles, and the autumn season with cold mornings and evenings, were, accordmg to him, the causes of the malarial infection. This theory was accepted in 1716 by Lancisi,:|: and after- ward by Easori and a number of other observers. Lancisi behoved that the disease was due to animalcula arising from putrefactive processes in the vegetable matter of swampy districts ; these were inhaled and capable of entering the blood and multiplying there, thus giving rise to the patho- logical symptoms. This theory had many adherents ; indeed, at the beginning of this century the idea had become so gen- erally implanted in the pubhc mind that the supposititious ani- malcula had become known in Italy by the definite name of " serafici." Bassi* reports that Easori in a conversation expressed, himself as follows : " For many years I have held the opinion that the intermittent fevers are produced by parasites which * De Re Rustica, lib. i, cap. 12. t Pyretologia opera medica, 4to, Genevae, 1696. X De noxiis paludum eflauviis, lib. ii, Roma, 1717. * Discorsi suUa Natura e Cnra della Pellagra, etc.. Milano, tip. chinsi, 1846. deferred to by S. Calandruccio, " Agostino Bassi di Lodi, il foudatore della tcoria parasitaria, etc.," Catania, 1892, 70. Q LECTURES ON THE MALARIAL FEVERS. renew the. paroxysm by tlie act of their reproduction, which occurs more or less rapidly according to the variety of their species." Virey believed the disease to be due to infection with in- fusoria. Boudin * believed that the fever was caused by the inhalation of poisonous volatile principles given off by certain plants which grow in the marshes. In 1849 J. K. Mitchelljf of Philadelphia, suggested that the disease was due to spores which were found in large num- bers in marshy districts. The same idea was held by Muehry.:}: Lemaire * studied the vapor collected just above the sur- face of the marshes in Sologne, a malarious district. Finding that the air here contained a marked excess of micro-organisms of various sorts as compared with that in a neighboring healthy district, he inclined to the view that these lower organisms had a close causal connection with malarial fever. Bouchardat | believed that the process resulted from the inhalation of poisons produced by microscopical animalcula which flourished in the swamps. Later, in 1866, Salisbury ^ described small vegetable cells of the family of Falmella, which he asserted he found in the urine and sweat of patients with malarial fever. These he believed to be the pathogenic agent. His communications excited considerable interest and attention ; indeed, there are * Traite des fievres intennittentes, etc., Paris, 1842. \ On the Cryptogamous Origin of Malarious and Epidemic Fevers, Phil- adelphia, 1849. X Die geographischen Verhaltnisse der Krankheiten, etc., Leipzig and Heidelberg, 1856, pp. 124 et seq. * Corapt. rend, de I'Acad. des sc, se. du 17 aout, 1864, xlix, p. 317. II Annuaire de therapeutique, 1866, p. 299. ^ Amer. Jour. Med. Sci., January, 1866. PATHOGENIC AGENT OF MALARIAL FEVERS. 7 observers to-day wlio with singular blindness still cling to tbe wholly groundless supposition of Salisbury. His views were satisfactorily controverted by Wood * in 1868. BinZjf in 186Y, noted that the efficacy in malarial fever of quinine which he had shown to be an active protoplasmic poison, pointed to the possibility that the disease was due to infection with lower organisms. During the next ten years a considerable number of com- munications appeared in which various forms of vegetable life — mainly algae — were regarded as the causal element of the malarial fevers. Lanzi and Terrigi, in 1875, described bacteria which they believed to be the cause of the malarial infection. It remained, however, for Klebs and Tomassi Crudeli,:}: in 1879, to first excite a world-wide interest and a really ex- tensive belief in the bacterial origin of the malarial fevers. These observers found in the soil of malarious districts, cer- tain bacilli which they cultivated and injected into animals, convincing themselves that they were able to reproduce the symptoms of malarial fever. Their researches were carried on with enthusiasm by Schiavuzzi and others, and despite the fact that practically all other careful observers have failed to demonstrate any conclusive connection between these bacilli and malarial fever, the general belief in the validity of the conclusions of Klebs and Tomassi Crudeli was so strong, that within twelve months of the time of writing, an editorial article appeared in one of the leading English medical journals referring to the connection between the bacillus of * Amer. Jour. Med. Sci., 1868, vol. Ivi, p. 333. t (a) Centralbl. f . d. med. Wiss., Berlin, 1867, S. 808 ; (i) M. Sehultze's ArcMv t mikr. Anat., Bd. iii, S. 383, 1867. X Studien iiber die Ursaehe des Wechselfiebers und uber die Natur der Malaria, Arch. f. exp. Path. u. Pharmak., 1879, xi, 811. 8 LECTURES ON THE MALARIAL FEVERS. Klebs and Tomassi Crudeli and the malarial fevers as a settled fact. Let it be enongli, however, to say that rej)eated re- searches in this line have clearly demonstrated the fallacy of the original ideas of these observers. The parasite which is now generally recognized as the cause of the malarial fevei-s is not a bacterium, but belongs to the protozoa, and more closely to the class of sporozoa. Its further classification is not definitely settled; some of the theories concerning this question will be referred to later. These organisms live in the blood of the infected individual, attacking the red corpuscles, develoj^ing in their interior, accumulating dark pigment granules derived from the altered haemoglobin, and eventually destroying ihe red elements, from the surrounding shell of which they burst at the time of their sporulation. The parasites were discovered in 1880 by A. Laveran, a French army surgeon, who was pursuing a systematic study of the malarial fevers at his post at Constantine, in Algeria. As is so frequently the case in scientific discoveries, these bodies had been frequently seen, and indeed desciibed, years before they were recognized as parasites by Laveran. Thus, Meckel * in 1847, not only described pigment in the blood of a patient dead of malarial fever, but noted further that it was contained for the most part in round, ovoid, or spindle- shaped protoplasmic masses, which were, beyond a doubt, the malarial parasites. In the following year Yirchow f described and clearly pictured certain forms of the malarial organisms ; it must be said, however, that the parasitic nature of these bodies ap- pears never to have been suspected. * Zeitschrift fur Psychiatrie, 1847, 198. f Virchow's Archiv, 1849, ii, 587. PATHOGENIC AGENT OF MALAKIAL FEVERS. 9 It remained for Laveran to recognize the fact that these pigmented elements represented living parasites. This ob- server was stationed in 1879 in Algeria, where he took upon himself the task of investigating the malarial fevers. In I^^ovember, 1880, while studying the blood of a patient suffer- ing from malarial infection, his attention was attracted by one of these pigmented bodies from which there extended several actively motile filaments. The dancing of the pigment granules within and the active serpentine motion of the fila- ments were so striking as to convince the observer immedi- ately that he was looking upon an animate object. In the same month a preliminary communication was made to the Academy of Medicine in Paris ; * this was rapidly followed by a number of other communications. In 1881 Laveran published a small monograph f in which he described his observations at length. The bodies which he had noted were small, colorless, pigment-containing elements varying in size from one sixth that of a red blood-corpuscle to nearly an equal volume. The smallest contained but one or two fine, dark bits of pigment, while the larger, which were at times nearly the size of a leucocyte, contained numerous actively motile granules. These bodies he believed to be attached to the red corpuscle, at the expense of which they grew and accumulated pigment. He also noted larger bodies, crescentic or ovoid in form, eight or nine micromillimetres in length by three micromilli- metres in diameter, which were quite transparent and color- less, excepting for a group of rounded pigment granules lying near the middle, or more rarely collected toward one end of the body. Sometimes the granules were arranged in * Bull, de I'acad. de med. de Paris, se. du 23 Nov., 1880. t Nature parasitaire des accidents de I'impaludisme, etc., 8vo, Paris, 1881. 2 10 LECTURES ON THE MALARIAL FEVERS. the shape of a crown or wreath. At times the extremities of the crescentic bodies were comiected by a pale curved Hne, He noted, further, circular bodies about six micromilli- metres in diameter with a collection of rounded pigment granules in the middle arranged in the form of a ring or wreath. At times these bodies might be seen to become ex- tremely active, suddenly developing from three to four fine filaments with active serpentine motion, stretching out from the periphery. According to Laveran these pigmented bod- ies represent different stages in the existence of the para- site, the earlier forms being small cyst-like structures within which are contained the motile filaments which represent the organism at the stage of most perfect development. These observations were confirmed by another French army surgeon, Richard,* studying at Philippeville, in Algeria. He went a little further than Laveran in that he recognized the youngest form of the parasite as a small, clear, non- pigmented spot in the corpuscle, and, moreover, in that he described round forms of the parasite in which the pigment had collected toward the middle into a single clump, from which delicate radial striations might be seen extending out- ward. In a second publication f he differed from Laveran in asserting that the parasite develops within rather than upon the red corpuscle. During the first four years after Laveran's discovery the public remained almost entirely unconvinced, much more cre- dence being given to the work of Klebs and Tomassi Crudeli, which has been referred to above. In the meantime Marchiafava and Celli, studying in Italy, * Compt. rend, des se. de I'Acad. des sciences, 20 lev., 1883 ; also Gaz, med. de Far., 1882, 6 s., iv. 252. f Rev. scientifique, Par., 1883, 113. PATHOaBNIC AGENT OP MALARIAL FEVERS. H had observed and pictured the parasites, believing them to represent areas of degeneration within the red cells; it is, moreover, interesting to note that, despite the fact that Laveran visited Eome and demonstrated the parasite to one of these observers, they remained unconvinced until they themselves began the study of fresh specimens. In 1885, however, Marchiafava and Celh * began a series of most fruitful and valuable contributions upon this sub- ject. They described with great accuracy the small, non- pigmented forms of the parasite. They noted that these forms, which were especially frequent in the more severe Eoman fevers, were actively amoeboid when observed in the fresh blood. They proposed for the organism the unfortunately chosen term "plasmodium malarise." Biologically, the term Plas- modium has a perfectly well-recognized meaning ; it is ap- plied to large multinuclear masses of protoplasm. Such a structure is wholly different from the small hyaline amoeba of malaria, and the use of the term as applied to the latter body is injudicious and misleading. It is most desirable that this term, which is not yet too deeply implanted in medical usage, should be eradicated. Since 1885 all students who have had a proper oppor- tunity to investigate malarial blood have confirmed the obser- vations of Laveran in the main, and the diagnostic importance * (a) Arch, per le sc. raed., 1885, ix, No. 15 ; also, Fortschritte der Med., 1885, iii, No. 11, 14. (b) Fortschritte der Med., 1885, iii, No. 24, 787 ; also, Arch, per le sc. med., 1886 ; also, Arch. Ital. de Biol., 1887. (c) Bull. d. R. ace. med. d. Rom., 1887, 417. (d) Arch, per le sc. med., 1888, xii, 153 : also, Arch. Ital. de Biol., 1888 A., ix, f. 3. (e) Fortschr. der Med.. 1888. No. 16. (/) Arch, per le sc. med., 1890, xiv ; also, Arch. Ital. de Biol., 1890, 302. (g) Bull. d. R. ace. med. d. Rom., anno xvi, 1890, 287. {h) Arch, per le sc. med., xiv, 1890, 449. (i) Bull. d. R. ace. med. d. Rom., 1889-'90, f. ii. (J) Festschrift z. R. Virehow's 70. Geburtstag, iii, 1891. 12 LECTURES ON THE MALARIAL FEVERS. of the discovery of the parasite in tlie circulating blood is now generally recognized. In this country the earliest observations confirming those of the French students were made by Councilman and Abbott,* Sternberg, f Osier, :}: and James,* while valuable work has been done later by Dock, |! and others. In 1885, Golgi, of Pa via, made a great advance in the study of the malarial parasite by his investigations into the life history of the organisms observed in quartan fever.^ His studies led him to the conclusion that quartan fever depends upon a specific form of the parasite. The organism in its youngest stages is represented by a small, clear, hyaline body which lies within, and not, as Laveran had originally supposed, upon the red corpuscle. Within this corpuscle it grows, developing pigment granules at the expense of its host, which it gradually destroys. At the end of the cycle of existence the pigment granules collect toward the centre into a little clump or block, while delicate radial striations extend from this toward the periph- ery, forming a figure exactly similar to that described by Richard in 1882. These radial lines are but indications of fissures which later on appear in the substance of the parasite, until finally the central pigment block is surrounded by from six to twelve delicate leaflets, forming a Marguerite-like figure. * (a) Amer. Jour. Med. Sei., April, 1885. n. s., vol, Ixxxix, 416. {b) Transact, of the Assoc, of Amer. Phys., 1886, i, 90. (c) Med. News, Phil., 1887, i, 59-68. {d) Portschr. der Med., 1888, Nos. 12 and 13, 449, 500. + Medical Record, N. Y., May 1 and 8, 1886, 489, 517. X (a) Phil. Med. Times, 1886 ; also, British Med. Journal, 1887, i, 556. (ft) Medical News, Phil., April 13 and 20, 1889. (c) Johns Hopkins Hosp. Bull., 1889, i. 11. # Medical Record, N. Y., March 10. 1888, 269. II (a) Medical News. July 19. 1890, 59. {h) Fortschr. der Med., 1891. ix, 187. (fi) Mod. News, May 30 and June 6, 1891, 603, 628. ^ Arch, per le sc. med., x, 1886, 109 ; also. Arch. Ital. de Biol., viii, 1887. PATHOGENIC AGENT OF MALARIAL FEVERS. 13 Eventually these separate leaflets spring away from the central pigment collection and assume a round or ovoid shape, resembling in every way the small hyaline bodies which at the same time may be observed within other red cells. Golgi thus confirmed a suspicion which had been pre- viously expressed by Marchiafava and Celli that these Mar- guerite-like bodies represent parasites in the process of repro- duction. These investigations demonstrated clearly that the quartan parasites present in the blood are aggregated into enormous groups, all the members of which are approximately at the same stage of development and pass through their cycle of existence simultaneously. The length of this cycle of ex- istence is, in the quartan parasite, approximately seventy-two hours, so that in infections with a single group of organisms sporulation occurs every fourth day. By carefully comparing the stage of existence of the or- ganisms in the circulation with the clinical manifestations, Golgi discovered the remarkable fact that the malarial par - oxysm, always coincides ivith the sporulation of a group of parasites. Thus, in infections with a single group of the quartan organism a paroxysm occurs every fourth day. In his first publication, however, Golgi pointed out the fact that a group of parasites must first attain a certain size before it is capable of producing a paroxysm, and in a similar man- ner the severity of the paroxysm depends within certain limits upon the number of parasites present in the blood. It was also noted that often more than one group of the parasites may be present at the same time in the circulating blood. When this is the ease the several groups reach ma- turity almost invariably on successive days ; thus, if two groups be present, segmentation occurs on two successive 14 LECTURES ON THE MALARIAL FEVERS. days, with a day of intermission between ; when three groups are present, segmentation occurs daily. This observation was partially confirmed within a few months by Osier * in Philadelphia, In his earliest communication upon the quartan parasite Golgi mentioned the fact that in several cases of tertian fever he had observed organisms with certain characteristic devia- tions from the type already described ; this observation led him to suggest that possibly further study might show that tertian fever depended upon a different variety of parasite. He also noted that in none of these cases of quartan or tertian fever had he seen the crescentic bodies described by Laveran ; they were present, however, in one case of more or less irregular fever. This was shortly followed by an equally remarkable series of observations upon the blood in tertian fever,f resulting in the demonstration of a second variety of the parasite, mor- phologically and biologically distinctly separate from the quar- tan organism. This parasite also exists in the blood in enor- mous groups, all the members of which are nearly at the same stage of development ; here, however, the cycle of existence lasts approximately forty-eight instead of seventy-two hours. In tertian as in quartan infections, more than one group of the organism may be present, though more than two groups are rarely seen. When two groups are present sporulation occurs daily. These observations have been almost universally con- firmed. Among the more important communications are * Phil. Med. Times, ISSG-. f (a) Boll, med.-chirurg. di Pavia. 1886 ; also, Gaz. d. osp., 1886, No. 53, 419. (b) Arch, per le sc. med., 1889, xiii, 173; also, Fortschritte der Med., 1889, vii, 81 ; also, Arch. Ital. de Biol., 1890, xiv, f. i, ii. PATHOGENIC AGENT OP MALARIAL FEVERS. 15 those of Grassi and Feletti * in Sicily ; Antolisei,f Canalis,:}: Bastianelli and Bignami,* Patella, || Marchiafava and Celli,^ Terni and Giardina, ^ in Italy ; of Mannaberg, ;^ in Austria ; of Kamen,:|: in Germany; of Sakharov, | Titov,** Roma- novsky, f f Korolko H^l;. and Gotye,** in Russia ; of Remou- champs, || || in Holland ; of Jancso and Rosenberger,^^ in Hungary; of Osier, 0^ Dock, |;I; Koplik, :|;:|; Hewetson, and the author, || in this country. Further studies, however, have revealed yet another dis- * (a) Centralbl. f.'Bakt., 1890, vii, 396, 430; also, Riforma medica, 1890, No. 11, 62, and No. 50, 296; also, Arch. Ital. de Biol., 1890, 287-293. (b) Centralbl. f. Bakt., 1891, ix, 403, 429, 461. (c) Centralbl. f. Bakt., 1891, x, No. 14, 448. (d) Arch. Ital. di clin. raed., Milano, 1894, xxxiii, 207-265. t (a) Riforma medica, 1890, Nos. 12 and 13, pp. 68, 74. (b) Riforma medica. 1890, Nos. 26 and 27, Feb. 1 and 3, 152, 158. X Arch, per le sc. med., 1890, xiv, f. 1, No. 5, 73 ; also Fortschritte der Med., 1890, Nos. 8 and 9 ; also, Arch. Ital. de Biol., 1890, xiii, 263. « Riforma medica, 1890, Nos. 144-146, pp. 860, 866, 872. II Atti e rendiconti della ace. med.-chirurg. di Perugia, ii, 1890, 85. ^ Bull. d. R. ace. med. di Roma, xvi. May 4, 1890, 287. Arch. Ital. de Biol., 1891, 157. 1 Die Malaria Parasiten, Wien, 1893, 8vo ; also (English translation). The New Sydenham Society, vol. cl, London, 1894. $ (a) Beit rage z. path. Anat., etc., Jena, 1892, xi, H. 3, 375. (b) Beitrage z. path. Anat., etc., Jena, 1892, xii, 57-64. J Acts of the Imp. Acad, of Med. of the Caucasus, Tiflis, 1890, No. 50 (Russian) ; (ref.) Centralbl. f. Bakt., etc., 1890, ix, 16. ** Cent. f. Bakt., 1891, ix, 284. ft St. Petersburger med. Woch., 1891, Nos. 34 and 35. $t Vrach, 1891, No. 46 (Russian) : ref. in Centr. f. Bakt., 1892, xi, 512. ** Parazitie Laveran'a, 8°, Moskva, 1896 (Russian). II II Weekblad van het med. Tijdschr. voor Geneesk., December 16, 1893, No. 24, 849. ^ (a) Pest, med.-chir. Presse, 33. Jahr, March 1 and 8, 1896, Nos. 9 and 10, (6) Pest, med.-chir. Presse, 32. Jahr, No. 34, p. 794. (c) Deutsch. Arch. f. klin. Med., 1896, Bd. Ivii, p. 449. 0^ Op. cit. %% Op. cit. ii New York Med. Jour., 1893., 315 %% Johns Hopkins Hospital Reports, 1895, vol. v, p. 1. 16 LECTURES ON THE MALARIAL FEVERS. tinct form of tlie malarial parasite. Oolgi, in 1885,* called attention to the fact that in the blood of the one ease of irreg- ular fever which he examined there were found only tlie cres- centic and ovoid bodies of Laveran, forms which were not present in an}^ of his other cases. In view of this fact he suggested that these elements might represent a third type of the organism having a special cycle of existence differing from those already described. These organisms had also been described by both Laveran and Marchiafava and Celli, who found them ^^^tll much greater frequency than did Golgi. Marchiafava and Celli, f it will be remembered, found many cases in which the blood showed only small amoeboid hyaline bodies — their " plasmodia." Laveran and the Italian observers had, however, been working in districts where, at the height of the malarial season, a large proportion of the cases are of a very severe, more or less irregular or contin- uous type, while Golgi, in Pavia, met only with the milder, regularly intermittent forms of the disease. Thus it gradually became evident that there was a class of cases where the blood contained only the small hyaline amoeboid bodies with perhaps a few fine granules of pigment, associated, often, with the large ovoid and crescentic bodies of Laveran, while in some cases only the latter forms were to be found. Councilman,:}: in 1887, was the first to hint at the practical diagnostic value of this fact. He says : " The character of these bodies varies in different forms of the disease. Al- though they seem in rare cases to run into one another, still, in general, we can say that where the plasmodia inside the red corpuscles * are seen the patient has intermittent fever, * Op. cit. t Op. cit. X Op. cit. « He refers here to the large pigmented, probably tertian forms.— W. S. T. PATHOGENIC AGENT OP MALARIAL FEVERS. 17 and where the crescentic and elongated masses are found he has either some form of remittent fever or malarial cachexia. . . . We are not only enabled to diagnosticate the disease as such, but in most cases the particular form." In 1889, on the basis of observations of several cases with irregular symptoms, Golgi suggested the association of these parasites v/ith fevers with long intervals between the paroxysms. He believed that the cycle of development be- gan with small hyaline bodies and passed through the cres- centic and ovoid stages ; its duration was unusually long — lasting ten days or more. He was, however, unable to trace the entire life history of the parasite, having never seen sporulating forms, and advanced this idea merely as an hy- pothesis. In the fall of the same year, however, Marchiafava and Celli * and Canalis f almost simultaneously published articles describing the life history of the organism found in the severe sestivo-autumnal fevers of Rome. These fevers differ materi- ally from the regularly intermittent tertian and quartan ague which, prevailing in the milder malarial districts, formed a great majority of all the cases which came under Golgi's eye. The regularly intermittent fevers pursue a character- istic cyclical course, are never pernicious, and yield rapidly to quinine, while the more severe sestivo-autumnal fevers of Rome are much more acyclical in their manifestations, tend frequently to become pernicious, and are more resistant to quinine. * Op. cit. f {a) Arch, per le sc. med., 1890, xiv, f. 1, No. 5, 73 ; also, Fortschr. d. Med., 1890, Nos. 8 and 9; also, Arch. Ital. de Biol., 1890, xiii, 262. {h) Lo Spallanzani, 1890, 172. (c) Arch, per le sc. med., 1890, f. 3, 333. (d) Intorno a recenti lavori sui parassiti della malaria, 8vo, Roma, 1890. 18 LECTURES ON THE MALARIAL FEVERS. Both Canalis and Marchiafava and Celli noted a special variety of tlie organism difiering distinctly from the tertian and quartan parasites, a variety which was apparently defi- nitely associated with these aestivo-autumnal fevers. In many respects their descriptions are quite similar, and un- questionably relate to the same type of organisms which Golgi believed to be associated with fevers with long inter- vals. They both believed that the parasites exist in the blood in groups, just as in tertian and quartan fever. They note that the forms most frequently found in the blood are small hyaline amoeboid bodies which often tend to assume the shape of a ring, and rarely contain more than one or two minute pigment granules. In most instances, indeed, these parasites are quite free fi*om pigment. During the cycle of develop- ment a few small granules appear, which eventually collect into the middle of the parasite as a very small group and finally fuse into a block. The body then undergoes segmen- tation much as does the tertian or quartan organism. The parasite of aestivo-autumnal fever is, however, much smaller, often less than half the size of the red corpuscle. Marchia- fava and Celli in particular note the fact that many of the red corpuscles containing these small parasites become shrunken, crenated, and brassy colored. Now in quartan fever all stages in the life history of the parasite are seen with equal frequency in the peripheral circu- lation, while in the majority of cases of tertian fever the same general rule holds, excepting that at the time of segmentation the bodies tend to accumulate in the internal organs. In in- fections with the aestivo-autumnal parasites, however, only the earlier stages of the cycle of existence of the organism are to be found in the peripheral vessels, while segmenting forms PATHOGEmC AGENT OP MALARIAL FEVERS. 19 are rarely seen excepting in the blood of internal organs, the spleen, liver, bone marrow, brain. Both these observers noted, in this type of fever, the presence of the crescentic and ovoid bodies originally described by Laveran, and recognized the fact that they develop from the small hyaline forms, both asserting that they do not appear until the clinical symptoms have lasted for some days or weeks. The interpretation of the significance of these bodies offered by Canalis and Marchiafava and Celli differs considerably. Thus Canalis distinguishes two distinct cycles in the life history of the parasite : (1) A more rapid cycle similar to that above described, and lasting, he believes, not less than two days on the average, though it may be as short as twenty-four hours. (2) A slower cycle associated with the development of crescentic bodies, in which he believes he has made out seg- menting forms ; an observation which, however, few succeed- ing students have been able to confirm. This cycle lasts a much longer time, varying, he believes, in different cases. The period elapsing from the beginning of the amceboid stage to the appearance of the crescents is not less than three or four days. Marchiafava and Celli, on the other hand, considered that the cycle of existence of the parasite from the youngest forms to the segmenting bodies lasted a varying length of time be- tween twenty-four and thirty-six hours. In some instances, with very rapid development, the parasite undergoes early segmentation before the accumulation of any pigment. They have never observed evidences of segmentation in the cres- centic bodies. A large number of confirmatory observations have been 20 LECTURES ON THE MALARIAL FEVERS. made, the- more important communications coming from Antolisei and Angelini,^ Pate]la,t Terni and Giardina,:}: Bas- tianelli aiid Bignanii,* Sanfelici, || in Italy ; Grassi and Feletti,"'" in Sicily ; Sakharov,^ Korolko,;!; Titov,^ and Gotye,^ in Russia ; Mannaberg,** in Austria ; Plelin f f and Kamen,;}::}: in Germany ; Dock,** Koplik, || j] Hewetson, and myself,^^ in the United States. The main point of difference has been in the interpreta- tion of the crescentic and ovoid bodies. It is generally ac- knowledged that these arise for the most part in the internal organs, particularly in the spleen and bone marrow, and may appear in the blood from the fifth day on, but usually not be- fore the end of the first or the beginning of the second week. It has been noted that while all other forms of the organism disappear rapidly under treatment by quinine, the crescents alone are very resistant, remaining in the circulation in some instances for months. Antolisei and Angelini, Temi,^^ Grassi and Feletti, and Sakharov agree with Canalis in believing these bodies capable of segmentation, the latter two observers classifying them as a special variety of the parasite. The majority, however, assert that the crescents are incapable of proliferation by sporulation, and suspect that they are sterile bodies, some holding that they constitute a more resistant form of the * (a) Arcli. Ital. d. clin. med., 1890, 1. (i) Riforraa medica, 1890, 320, 326, 332. f Op. cit. X Op. cit. * Riforma medica, 1890, 1334, 1340. II Fortschr. d. Med., 1891, ix, 499, 541, 581. '^ Op. cit. l (a) Op. cit. (6) Ann. de I'institute Pasteur, 1891, 445-449. X Op. cit. X Op. cit. % Op. cit. ** Op. cit. ft Virch. Archiv, 1892, cxxis, 285. XX Op. cit. «» Op. cit. II II Op. cit. ^ Op. cit. 00 Gaz. d. osp., Milano, 1896, xvi, 3. PATHOGENIC AGENT OF MALARIAL FEVERS. 21 organism capable, perhaps, of further development outside of the body. Marchiafava and Bignami * have gone further, distinguish- ing two varieties of the sestivo -autumnal parasite, one with a shorter cycle of existence, lasting about twenty-four hours, and another with a longer cycle, lasting about forty-eight hours. The general characteristics of the parasites are very similar ; the main differences consist in the larger size of the tertian parasite, its slightly greater activity, and the fact that the number of segments is more abundant than in the quotid- ian organism. Both organisms develop crescentic forms after a certain length of time. Golgi, in 1893,f studied the sestivo-autumnal parasites in Baccelli's chnic at Eome, and, while recognizing distinctly the association of a third variety of the organism with the more irregular sestivo-autumnal fevers, he believes that there are many points yet to be settled in relation to its life history, and that we are at present by no means justified in distin- guishing two separate varieties. It was early noted by Marchiafava and Celli and Canalis, as well as by subsequent observers, that only the early stages of the cycle of existence of the sestivo-autumnal parasite are found in the peripheral circulation ; the later stages, and par- ticularly the segmenting forms, are observed only in the in- ternal organs. Golgi goes further than this, asserting that in sestivo- autumnal fever the forms found in the peripheral circulation are practically accidental ; that the main seat of the infection * Bull. d. R. aec. med. d. Roma, xviii, f. v, 297: also (English transla- tion, with notes and appendices by the authors), The New Sydenham Society, vol. el, London, 1894. t Arch. Ital. de Biol., 1893, xx, 388. 22 LECTURES ON THE . MALARIAL FEVERS. is in the iiiternal organs. He advances the interesting theory that in the internal organs, more particularly in the spleen and bone marrow, the parasites may develoj) within the bodies of phagocytes. The youngest forms often cause a rapid necrosis of the red blood-corpuscle, which becomes brassy colored and shrunken, and is engulfed by the phagocyte; within this the parasite continues to develop, destroying eventually both its hosts, and escaping again after segmenta- tion. A few of these young forms reach the general cir- culation in much the same manner as nucleated red cor- puscles appear during active blood regeneration. They are an index, almost constant though ^^non necessarie^'' of the infection. Grolgi also hesitates to believe that the parasites of «stivo- autumnal fever are, with any regularity, arranged in groups ; lie maintains that organisms in all stages of development are usually present at one time. Gotye also recognises but one variety of the sestivo- autumnal parasite, an organism possessing a cycle of devel- opment lasting about forty-eight hours. Thus the majority of observers have distinguished sharply three main forms of the parasite : {(I) The parasite of tertian fever. (5) The parasite of quartan fever. (c) The parasite associated with the more irregular eestivo- auturanal fevers. This third variety has been subdivided by numerous ob- servers. Grassi and Feletti distinguish three separate para- sites in this group : (1) The Ilmmamoeba prcBcox, giving rise to quotidian fever with a tendency to anticipation. (2) The Hmnamoeba immaculata, which is similar to this PATHOGENIC AGENT OF MALARIAL FEVERS. 23 except that it runs its course more rapidly without the devel- opment of pigment. (3) The Laverania malaricB. (The crescentic and ovoid forms.) Sakharov distinguishes — (1) The Hmmamceba proBcox (Grassi). (2) The Laverania (Grassi). These he believes to be separate organisms. Marchiafava and Bignami distinguish — (1) The quotidian parasite. (2) The malignant tertian parasite. Mannaberg subdivides this group into — (1) The pigmented quotidian parasite. (2) The unpigmented quotidian parasite. (3) The malignant tertian parasite. Hevs^etson and I have been inclined to regard all the sestivo-autumnal organisms as a single variety of the parasite, an organism whose cycle of development varies between twenty-four hours or less and forty-eight hours or more, ac- cording to various circumstances, depending partly on the organism, partly on the affected individual. In a following lecture I shall enter more minutely into the characteristics of the forms of the parasite observed in this country. While the great majority of observers have recognized the existence of these different types of parasites and their asso- ciation each with special types of fever, it remains yet a wholly unsettled question whether they are varieties of one parasite, types which may be modified, perhaps, by external surroundings, or whether they represent separate and distinct species of closely allied organisms. From our observations I can only say that while there are 24 LECTURES ON THE MALARIAL FEVERS. facts which might suggest that the types of the organism are interchangeable, I have never seen the shghtest actual evi- dence of such change. It should be stated that Laveran is a vigorous opponent of the idea of the existence of more than one actual species of parasite ; still more than this, he hesitates to accept the regu- lar association of certain types of the organism with certain forms of fever, although in a recent paper * he says, " I do not dispute that this or that form of jDarasite is found more often in one clinical type than in another." TJte Finer Structure of the Parasite. — Numerous re- searches concerning the staining reactions and the intimate structure of the malarial parasites have been made, but the results are, unfortunately, as yet rather indefinite. Celli and Guarnieri,f who first studied the subject in speci- mens colored with methylene-blue dissolved in ascitic fluid, dis- tinguished a deeper colored ectoplasm and a pale endoplasm. In the endoplasm they were able to make out a palely stained body, or sometimes one or more sharply staining points which they believed to represent the nucleus. Grassi and Feletti \ described the clear, more palely stain- ing area as a large vesicular nucleus which contains a deeper colored nucleolar mass situated more or less excentiically. Romanovsky* also believes that the small spot which is noted generally toward the periphery of the ovoid or round clear area in the stained parasite, represents the chromatic part of the imcleus. Both he and Grassi and Feletti describe * L'etiologie du paludisrae, Proceedings of the Congress of Hygiene at Buda-Pesth, Revue scientif., October 13, 1894. f Arch, per le sc. med., xiii, 1889, 307; also, Fortschr, d. Med., 1889, vii, No. 14, 521. X Op. cit. « (a) Vrach, 1890, No. 52 (Russian), (i) Op. cit. PATHOGENIC AGENT OP MALARIAL FEVERS. 25 the breaking up and division of this small deeply staining body at the time of segmentation, the former believing that he sees evidences of karyokinesis. Romanovsky's observations were made upon the tertian parasite, while Grassi and Feletti studied the quartan organism. Communications apparently confirming Romanovsky's ob- servations have recently been made by Geppener (Heppener) * (Russian) and Ziemann f and Gotye.;}; Sakharov* also interprets the pale area and the more deeply staining spot in the same manner. Mannaberg |j describes the behavior of the nucleus in the tertian parasite at considerable length. The deeper staining dot in the pale area he believes to be the nucleolus. The nucleolus, he says, grows with the parasite, and, just before segmentation, disappears, passing out apparently into the substance of the organism. With segmentation there begin to appear within the nuclear substance small deeply staining dots which represent nucleoli, about which new spores event- ually appear, Bastianelli and Bignami,^ studying the sestivo-autumnal parasite, conclude that one can not recognize in this variety of organism any body which has the various constituents of a true nucleus. Ths granular bodies of chromatin which form part of the cytoplasm and become dissolved in it when the body is ready for reproduction represent that part of the para- site which performs the function of the nucleus. * Meditzinsk. Pribav., etc., St. Petersburg, 1896. t Gentr. f. Bakt., 1896, Nos. 18, 19. I Op. cit. * («) Op. cit. {h) Amoebae malariae horainis, etc., 8vo, Tiflis, 1892. 1 Cent. f. klin. Med., 1891, No. 27 ; also, op. cit. ^ Bull. d. R. ace. med. di Roma, 1893-'94, xx, 151. 3 26 LECTURES ON THE MALARIAL FEVERS. It may be said, then, in summary that the parasite consists of a more or less deeply staining substance containing pigment granules. At some point within the body, usually near the periphery, there is a round or ovoid pale, non -stain- ing area, containing a small, more deeply colorable body situated usually at one side on the border line between this area and the colored substance of the parasite. The colorless area is generally interpreted as a bladder-like nucleus, the colored body within representing the chromatin substance or nucleolus. Bastianelli and Bignami have been unable to distinguish in the sestivo-autumnal parasite any body which has all the characteristics of a nucleus. Romanovsky, Geppener, and Ziemann assert that they have been able to observe actual karyokinetic figures. Attempts to cultivate the Parasites — Inoculation Experi- ments. — The question of the permanence of these different varieties of parasites has occupied considerable attention. Some observers assume that they represent distinct and sepa- rate organisms, while others believe that they are different varieties of one polymorphous parasite. It is undoubtedly true, as proven by numerous inoculation experiments, that each of these three types of parasites is associated with a defi- nite type of fever. Unfortunately, all attempts to cultivate the parasite out- side of the body have been without result. Numerous attempts to inoculate lower animals with the blood of infected human beings, by Richard,* Guarnieri,f Fischer,:}: Laveran,* * Op. cit. f Arch, per le sc. med., xii, 1887, p. 175. X Verhandl. Internat. Cong. f. Hyg. undDemog , Wien, 1887, H. xxxvi, 99. * Op. cit. PATHOGENIC AGENT OP MALARIAL FEVERS. 27 Celli and Sanfelice,* Bein,t Angelini,:}: and Di Mattei,** have likewise failed. Sakharov | and Rosenbach ^ believe that they have been able to keep the organisms alive for several days in the bodies of leeches. Eosenbach, experimenting with the tertian or- ganism, thought that he could distinguish evidences of de- velopment during forty-eight hours, but his researches have not been confirmed. Sakharov () placed the leeches upon ice, and found amoeboid organisms within red corpuscles as much as seven days after the beginning of the experiment. Inocu- lating himself with blood from one of these leeches on the fourth day, he obtained a positive result, developing fever with similar parasites in his blood on the twelfth day. These experiments have been in part repeated in this clinic by Dr. Blumer and Messrs. Hamburger and Mitchell. Dr. Blumer was able to distinguish the small hyaline bodies of sestivo- autumnal fever for over a week in the blood of a leech kept on ice. There was, however, no evidence of growth, and no amoeboid movement was made out. Mr. Hamburger took the blood from a case of aestivo- autumnal fever with quotidian paroxysms at a time when only small amoeboid and ring-shaped, non-pigmented hyaline bodies were present. During the next several days he was able to distinguish a slight increase in size, with the accumulation in nearly every organism of a few small motile pigment gran- ules. On the eighth day the organisms were distinctly visible, each with a small group of slightly motile granules in * Op. cit. t Charite Annalen, 1891, 181. X Riforma medica, 1891, v. 4, p. 758. * {a) Riforma medica, 1891, 544. (p) L'Ufficiale Sanitario, No. 10, 1894. II Vrach, 1890, 644 ; ref. in Baumgarten's Jahresbericht, 1890, 444. ^ Berliner klin. Woch., 1891, 839. Cent. f. Bakt., 1894, xv, 158. 28 LECTURES ON THE MALARIAL FEVERS. the middle or at some point on the periphery of the parasite. The parasites, as in Dr. Blumer's case, showed no actual amoeboid movement, though some slight change of shape could be at times made out. In both instances the parasite acquired after several days a peculiar refractive, glistening appear- ance. Specimens stained on the eighth day showed characteristic ring-shaped bodies. Mr. Mitchell placed a leech upon an individual suffering with a combined aestivo-autumnal and double tertian infec- tion. The blood showed two groups of active tertian organ- isms and a few crescentic and ovoid forms. In the body of the leech the tertian organisms were to be made out for ten days. The pigment was active for four days, but no amoeboid movement was to be made out in the parasites. The crescentic and ovoid bodies remained un- changed ; no flagellate forms were observed. The experiment of Hamburger, which I was able to follow, furnishes the first demonstration of the actual growtli of the parasite and the accumulation of pigment outside of the human body. Coronado,* of Havana, alone believes that he has cultivated the parasite. His statements are, however, unconvincing, while attempts to repeat his experiments have l)een without result. Gerhardt,t in 1880, first demonstrated that malarial in- fection might be transferred by the inoculation of infected blood into healthy individuals ; at this time the parasite was not generally recognized. * (a) Cronica med.-quir. de la Habana, xviii, Xo. 22. (b) Cron. med.- quir. de la Habana, 1893, 375. • t Zeit. fur klin. Med,, 1884, 375. PATHOGENIC AGENT OP MALARIAL FEVERS. 29 In 1884 Mariotti and Ciarrochi,* and Marchiafava and Cellif showed tliat the fever following such inoculations was associated with the appearance of parasites in the blood of the inoculated patient. These experiments have been followed by a considerable number of observations by Gualdi and Antolisei,:}: Angelini,* Di Mattel, || Calandruccio,'^ Bein,^ Baccelli,!; Sakharov,:!: and Bastianelli and Bignami.| These studies have shown that by intravenous or subcuta- neous introduction of blood from an individual suffering from malarial fever into an healthy human being, the infection may be transferred. Furthermore, the type of fever and of the parasite in the inoculated individual are always the same as in the patient from whom the blood is taken. In every instance, with the exception of the first two cases of Gualdi and Antolisei, the inoculation of one variety of organism has been followed by the development of a similar parasite, and by similar clinical manifestations. In the first two instances reported by Gualdi and Antolisei, where this was apparently not the case, later observation proved that the blood which had been injected was, in all probability, from a patient with a mixed infection. The remarkable regularity with which the tertian and * Lo Sperimentale, 1884, liv, 263. f Arch, per le sc. med., 1885, ix ; also, Portsehr. d. Med., 1885, iii, Nos. 11 and 14. X (a) Bull. d. R. ace. med. d. Roma, xv, 343. (b) Riforma medica, 1889. No. 264, 1580. (c) Riforma medica, 1889, No. 274, 1639. * Riforma medica, 1889, Nos. 226, 227, 1352, 1358. II (a) Riforma medica, 1891, No. 121, 544. (6) Archill Hygiene, 1895,191, ^ Cent, ftlr Bakt., 1891, ix, 403, 429, 461. Op. cit. % Deutseh. med. Woch., 1892, 721. X Cent. f. Bakt., 1894, xv, 158. 1 Bull. d. R. ace. med. d. Roma, 1893-94, anno xv, vol. xx, 151. 30 LECTURES ON THE MALARIAL FEVERS. quartan parasites are to be seen during the early months of the year, and the aestivo-autumnal forms during the later summer and fall, has led many to believe that the organisms are varieties of one parasite, the morphology of which varies, depending upon the time of year and the conditions to which it is subjected. No direct confirmatory evidence has, how- ever, been advanced in favor of this suspicion. I have never been able to trace the change in one individual from one variety of parasite to another. Those cases which come to Baltimore during the spring and winter months from severe malarious districts (Cuba, Jamaica) preserve their original type notwithstanding the fact of its extreme rarity in this climate at that time of year. In one instance quoted in the Johns IIojDkins Hospital Re- ports (vol. V, p. 99) we were able, in a case of mixed infection during the winter season, to follow distinctly the disappear- ance of the tertian parasites under quinine, and the reappear- ance of the more resistant aestivo-autumnal organisms, after two months' freedom from symptoms, at a time of year when cases of this variety are of extreme rarity. Moreover, though such is not the rule, we have seen in- stances in which sestivo-autumnal infection occuring relatively early in the summer and disappeai-ing under quinine, was followed at the height of the malarial season, at the time when aestivo-autumnal fever predominates, by a tertian in- fection. We have believed these cases to represent fresh infections. It is, however, sufficient for all clinical purposes to recog- nize the fact that whether or not these varieties of parasites may change one into another, they are, wdien present, always associated with the characteristic variety of fever. From the clinical chart we may in many instances recognize the variety PATHOGENIC AGENT OF MALARIAL FEVERS. 31 of parasite present ; from the parasite invariably tlie variety of fever. Inoculation experiments definitely proving Marchiafava and Bignami's division of the sestivo-autumnal parasite into a quotidian and tertian variety are as yet wanting. Manner of Reproduction. — All observers agree that the parasite multiplies by segmentation. Laveran,* Danilev8ky,f Mannaberg, :j: Dock,* Coronado, || and Manson,^ however, cling to the idea that flagellation may represent another method of multiplication. The fresh segments from the sporulating form resemble very closely the young individuals. They stain in the same manner, and differ only in that no one has ever observed any amoeboid movement. What the significance of their lack of movement may be is not perfectly clear. There seems to be little doubt that they immediately attack other red corpuscles, and yet the actual process has never been noted. Whether they must undergo some change before they are capable of entering the blood-corpuscles — a change which, perhaps, is prevented from taking place by the abnormal influences to which they are subjected in the preparation of the specimen — or whether they represent already complete new organ- isms (" gymnospores "), is not determined. Plehn ^ believes that they possess small, almost invisible flagella, and in certain instances it must be acknowledged that they have a slight dancing movement, and change their * Du paludisme et de son hematozoaire, Paris, 8°, 189L t Cent. f. Bakt., 1891, ix, 397. X Op. cit. « Med. News, July 19, 1890, 59. II Cron. med.-quir. de la Habana, xviii, 1892, No. 22. ^ Brit. Med. Journal, 1894, vol. ii, 1306. ^ Aetiologische u. klinische Malaria Studien, Berlin, 80, 1890. 32 LECTURES ON THE MALARIAL FEVERS. position in the field in a manner which might almost suggest the existence of organs of locomotion. Classification of the Parasite. — Yarious names have been • suggested for the malarial organism ; the first, that of Oscilkwia i7ialarice, advanced by Laveran in 1881, has since been gen- erally abandoned. Marchiafava and Celli in 1884 proposed the term Plasmo- dium malarice, which, despite its inaptness, has been widely accepted. The term II, 3. Proteosoma Grassii ) XL Gymnosporidia. ■{ 3. Haemamoeba Laverani (man). 4. Dactylosoma splendens (frogs). 5. Cy tamoeba bacterifera (frogs). LECTUEE 11. Methods of examination of the blood. — Description of the haemocytozoa of malaria. METHODS OF EXAMINATION OF THE BLOOD. It is impossihle to indke reliable examinations of the hlood for malarial pwrasites without first ieing familiar with the 07'dinai^y appearances of normal hlood and the 7nore common pathological changes. Large, pigmented, full-grown parasites are easily percep- tible, but the distinction of small unpigmented hyaline forms fi'om vacuoles and other changes in the red corpuscles re- quires an experienced eye. One can not learn to recognize all phases of the malarial parasite in two days or in two weeks. The lack of appreciation of this fact has led good observers in other fields of medicine to commit themselves in print to grievous errors. Thus an excellent foreign clini- cian within a few years published an article on the parasites in the malarial fevers of the city in wliich he lived, asserting that he found segmenting forms in every instance where he had examined the blood. This rather remarkable statement was shown on re-examination of his specimens to be based upon his misinterpretation of clumps of blood platelets which stained readily with methylene blue. It is unfortunate that until recently very little attention has been paid in our institutions for medical instruction to 34 EXAMINATION OF THE BLOOD. 35 tlie examination of the blood. There is no excuse, how- ever, to-day, for any institution which allows a student to graduate without requiring a good passing familiarity with the ordinary appearances of human blood. It is a mistake to attempt to study malarial blood without an oil-immersion lens. An oil-immersion lens is to-day a necessity in the outfit of a physician. Laveran, to be sure, discovered the parasite with a one-sixth dry lens. This achievement, however, while it reflects all the more credit on the observer, should not be used as an argument that good work is easy with such lenses, for this is not the case. The best method of studying the malarial parasite is in the fresh untreated blood at the bedside or in the consulting room. The specimen is easily prepared, though certain pre- cautions must be carried out with absolute accuracy. The cover glasses and slides must be carefully washed in alcohol, or alcohol and ether, in order to remove all fatty substances. They should be washed immediately before use. It is very easy for the physician to carry a small vial of alcohol in his instrument bag or in his pocket. The blood may be taken from any part, Eeinert * having shown that the results are the same no matter whence the specimen be obtained. The most convenient place, however, is the lobe of the ear, inasmuch as it is less sensitive and more readily approached than the finger tip, while a smaller puncture will draw more blood. It is often, also, important that the patient should not be able to observe the proceeding. This is particularly true in dealing with nervous patients and children. The ear should first be thoroughly cleaned; the lobe is * Die Zahlung der Blutkorperchen, 8vo, Leipsie, 1891. 36 LECTURES ON THE MALARIAL FEVERS. then punctured with a small knife or lancet. A needle or a pin may be used ; they cause, however, much more pain, and are not as satisfactory. If one desire to be especially careful, the ear may first be washed with soap and water, and after- wards with alcohol and ether. In many instances, however, it is advisable to make the preparations as short as may be, and unless the ear or finger be extremely dirty one may pro- ceed at once. Pigment or epithelium coming from the skin is readily recognized by the skilled eye. An instrument ^vith a sharp cutting edge, or, better, a very sharp spear-pointed lancet, is taken in the right hand, while the lobe of the ear is held firmly between the fingers of the left in such a way that the skin is held tense. If one pro- ceed in this manner very slight pressure will cause an incision deep enough for all purposes, while the process is almost painless to the patient. I hive in a number of instances obtained blood from a sleeping infant without its awakening. The first several drops of blood should be wiped away, while a fresMy cleaned cover glass held in a pair of forceps is allowed to touch the tip of the minute drop of blood which next appears. This is then placed immediately upon a per- fectly clean slide. It is well if a third person be present to allow the slide to be vigorously rubbed with a clean linen cloth just before the application of the cover glass. This proceeding considerably facilitates the spreading out of the drop of blood. If the slide and cover be perfectly clean the drop of blood will immediately spread between them, so that, unless the amount be too great, the corpuscles may be seen lying side by side quite unaltered in their main characteristics. The drop of blood which is taken should be small unless the patient be very anaemic. It is important that the cover EXAMINATION OF THE BLOOD. 37 should toucli only the tip of the drop of l)lood. If it he applied rudely and pressed, perhaps, against the ear, the blood is so spread out that drying may begin at the edge of the drop before the glass is laid upon the slide. If this be the case the immediate spreading out of the blood between the slide and the cover does not occur. It is an error to exert any pressure whatever upon the top cover ; neither should the cover be pushed or allowed to slide. All of these proceedings damage the specimen. A convenient and satisfactory modification of this pro- cedure is the following : The drop of blood is taken from the ear upon a slide, which is immediately inverted and gently lowered until the tip of the pendant drop just touches a clean cover glass which lies upon the table or bed. It is then lifted, the cover, of course, adhering to it. The blood usually spreads evenly between the two glasses. Such specimens will remain in good condition for a con- siderable length of time — an hour or more — long enough to be thoroughly examined. If it be desirable to preserve the specimen for a greater length of time, vaseline or paraffin may be placed about the edge of the glass. The parasites may thus be examined while yet alive and in active motion. Degenerative and regenerative processes may be followed out, and the most exquisite examples of phagocytosis may be observed. Such a specimen surrounded by paraffin or vaseline may be carried by the physician from the patient's residence to his consulting room, though under such circumstances one generally relies upon dried and stained specimens. Preparation of Stained Specimens. — The preparation of specimens for staining is easy, but, like all other clinical methods, it requires a little experience and practice — practice 38 LECTURES ON THE MALARIAL FEVERS. in observation, also, as well as in preparation. A small drop of blood from the lobe of the ear or the finger tip is collected upon a perfectly clean cover glass, which is imme- diately placed upon another glass. The drop of blood, if the two covers be perfectly clean, spreads out immediately be- tween them. The cover glasses are then drawn apart ; if neither glass be lifted or tilted during the process they will slide apart readily without sticking. If, however, they have remained together so long that they have begun to adhere one to the other, one may be sure that the specimen is no longer of value. The covers should always be held in a forceps. The fingers, of course, may be used, but often the glass will stick to the finger and hinder the smooth performance of the act, while in other instances the slight moisture from the hand may de- form and destroy the corpuscles. The glasses thus prepared are allowed to dry in the air, after which they may be pre- served for an almost indefinite length of time. An interesting accident which occurs not infre(Juently in summer time may be here alluded to. If the specimens be laid upon the table and left for any length of time, one often finds the previously regular layer of blood dotted with a num- ber of clear round spots, while sometimes the blood may have almost disappeared from the slide. One may be at a loss to account for this change until the discovery of the fly in fla- grante delicto reveals the true nature of the process. To prepare the glasses for staining various methods may be used. They may be heated upon a copper bar or in a thermostat at a temperature of from 100° to 120° C. for two hours, according to the method of Ehrlich ; or they may be placed in absolute alcohol and ether, equal quantities (Nikiforov's method), for from an half to eight hours, ac- EXAMINATION OF THE BLOOD. 39 cording to the stain ; while in otlier instances, with cer- tain stains, a good result may be obtained after leaving the specimens for as short a time as ten minutes in absolute alcohol. The malarial parasite is well stained by most of the basic nuclear dyes. Loeffler's methylene blue is an excellent agent. This may be prepared as follows : Concentrated alcoholic solution of methylene blue 30 c.c. Solution of caustic potash 1-10,000 100 " A simple aqueous solution of methylene blue may also give good results. In either instance the specimen, heated or hardened at least one half hour in absolute alcohol and ether, should be stained from thirty seconds to a minute, washed in water, dried between filter paper, and mounted in oil or balsam. The red corpuscles here remain unstained, while the nuclei of the leucocytes and the parasites are of a clear blue color. Good results may be obtained by adding a few drops of a saturated alcoholic solution of methylene blue to two or three cubic centimetres of water, and staining for a similar length of time. Here, however, the red corpuscles take a slight bluish tinge. A good contrast stain may be obtained by the following method : The cover-glass specimen is fixed in absolute alco- hol and ether for from four to twenty -four hours. It is then placed for a few seconds (thirty seconds to five minutes) in a 0'5-per-cent solution of eosin in sixty-per-cent alcohol, washed in water, dried between filter paper, and placed for from thirty seconds to two minutes in a concentrated aqueous solution of methylene blue, or in Loeffler's methylene blue. It is then washed in water, dried between filter paper, and mounted in Canada balsam. The red coi-puscles and eosin- 40 LECTURES OX THE MALARIAL FEVERS. opliilic granules are stained by the eosin, while the nuclei of the leucocytes and the parasites talve on a blue color. Perhaps the most satisfactory stain is that of Romanov- sky.* Two solutions are necessary — a saturated aqueous solu- tion of methylene blue and a one-per-cent watery solution of eosin. The older the m ethyl ene-blue solution the better the results. The staining mixture should be made just before it is used. About two parts of the eosin are added to one part of the jBltered methylene-blue solution. The mixture is care- fully stirred with a glass rod and poured into a watch glass. Do not filter after making the mixture. The cover glasses, fixed according to the methods above described, or by harden- ing in alcohol for from ten minutes upwards,f are allowed to float upon the top of this fluid. The specimens are then covered by another inverted glass, and the whole by an in- verted cylinder, which is moistened on the inside. In from half an hour to three hours — best in two or three hours — good specimens are obtained. This method gives the clearest and best results that we have ever seen. The one objection is its unreliability. An abundant sediment is formed which may obscure the specimen. An excellent method of pro- cedure is the following : Equal quantities of an one-half -per-cent solution of eosin and a saturated soluti(»n of methylene blue diluted one half with distilled water are mixed in a watch glass. Upon this the specimens are floated, and the subsequent procedure is just as above described. The specimens should remain in this mixture twenty-four hours. There is no danger of over- staining. * Op. cit. \ Excellent results may also be obtained with specimens hardened in ab- solute alcohol and ether for half an hour. EXAMINATION OP THE BLOOD. 41 Geppener (Heppener)* has recently proposed a slight modification in the preparation of the specimens. A little filtered methylene-blue solution is poured into a fifty-eubic- centimetre graduate, and to this the one-per-cent eosin solution is added gradually, while the mixture is stirred or shaken, until a well-marked precipitate becomes evident upon the side of the glass. The fluid is then poured into a watch glass and staining carried out as before described. It is well sometimes to test the staining power of such a fluid by observing its im- mediate influence upon the nuclei of leucocytes in test speci- mens. If such a fluid be successful it may be kept and used during several days. Specimens sufiiciently good to justify a diagnosis may ^e obtained in ten or fifteen minutes, though good specimens demand longer exposure. If the preparation has been stained twenty-four hours or more it may be hastily decolorized in absolute alcohol, then washed in water and mounted. The specimens may be prepared for staining by heating, immersion in alcohol and ether, or by immersion in absolute alcohol for ten minutes. Contrast stains with eosin and haematoxylin also give good results. To bring out most clearly the small hyaline bodies of aes- tivo-autumnal fever, which with ordinary stains appear as very pale rings, stronger stains, such as gentian violet, may be used. With gentian violet the small rings with the deeper staining dot at one side are brought out with great distinctness, though the appearance of the specimen as a whole is usually rather unsatisfactory. For quick work in the consulting room a simple stain with methylene blue is satisfactory, and not infrequently the ex- perienced observer may obtain good results sufficient to jus- * Med. Pribav. k. Morsk. Sbornik., 1895, 1, 67. 4 42 LECTURES ON THE MALARIAL FEVERS. tif J a diagnosis by rapid heating of the cover glass over tlie flame and immediate staining. Such results, however, are rather uncertain. DESCRIPTION OF THE HiEMOCYTOZOA OF MALARIA. Our observations have led us to distinguish three types of the malarial parasite : (1) The parasite of tertian fever {Hcemarrmba vivax, Grassi). (2) The parasite of quartan fever {Uoimamceba mala/rm, Grassi). (3) The parasite of sestivo-autumnal fever {Ilcematosoon falciparum, Welch) ; {Hcemamaiba jproBcox, Grassi ; Ha^ma- mmha immaculata, Grassi ; Laverania malarim, Grassi). (1) The Parasite of Tertian Fever {Hcemamaiba vivax, Grassi). — The malarial organism most commonly observed in this country is the parasite of tertian fever. This is a body whose complete cycle of development from the earliest stages to sporulation and the reproduction of a new group of young parasites, lasts approximately forty-eight hours. On examining the blood from a case of tertian infection one notes the interesting characteristic that the organisms pre- sent are all at approximately the same stage of development — that is, the blood contains a group of parasites, which pur- sues a cycle of existence lasting about forty-eight hours, all the members arriving at maturity, undergoing sporulation, and again passing through their cycle of existence in unison. At times there may be two groups of organisms in differ- ent stages of development ; rarely perhaps more. Almost in- variably, however, the fact may be noted that the parasites are present in distinct groups. It is extremely rare in tertian infections to find more than two groups of organisms present. THE H^MOCYTOZOA OP MALARIA. 43 The first stage in the life history of the parasite within tlie red corpuscle is represented by a small, round, colorless, disk- shaped body. This body is usually actively amoeboid, show- ing undulating movements at the periphery, or again chang- ing its shape rapidly from the original disk-like appearance to that of a cross or a star, forming at times most irregular and bizarre figures. (Plate I, Figs. 2, 3, 4.) Sometimes the para- site takes the appearance of a refractive ring with a more shaded, apparently thinner central portion. There may be an apparent fusion of two pseudopodia inclilding a bit of red corpuscle within, thus forming a true ring. (Plate I, Fig. 5.) Some observers believe that such a portion of the corpus- cle included within two pseudopodia is gradually digested by the parasite. Geppener, who has recently studied the growth of the organism in stained preparations, asserts that he can, in many instances, trace the formation of such a ring and the gradual concentric growth of the parasite. That such a pro- cess is, however, a rule in the development of the organism, our observations would lead us to doubt. IS'o evidence of a nucleus is to be made out in the fresh specimen. Sometimes several hyaline bodies may exist within one red corpuscle. As the parasite grows, minute yellowish -brown granules begin to appear ; these are usually distributed toward the ex- tremities of the pseudopodia of the amoeboid organism. The granules are generally in active dancing motion, so marked that it has been ascribed by most observers to undulatory waves of the protoplasm of the parasite, rather than to simple Brownian movements. The parasite at this stage of development is very amoeboid. So delicate is its structure, and so little does its index of refraction differ from that of the including corpuscle, that in this stage it is often ex- 44 LECTURES ON THE MALARIAL FEVERS. treinely diflfieult in fresh specimens to determine the out- lines of the body ; the unskilled observer in many in- stances discovers only the pigment granules which appear to him to lie scattered within the substance of a red corpuscle. (Plate I, Figs. 5, 6, 7.) The parasites appear distinctly to lie within rather than n^on the corpuscles. Of this fact there is good evidence : (1) The outline of the parasite is extremely pale and in- distinct, and the skilled observer readily notes that he is look- ing at the organism through a layer of red corpuscular sub- stance.* (2) On carefully focusing one may readily satisfy himself that the parasite lies below the upper surface of the cor- puscle. (3) Observe as long as one will, the protrusion of a pseudo- pod beyond the outhne of the red corpuscle is never to be seen. (4) An excellent proof of the intra-corpuscular nature of the body is afforded by the observation of the escape of a parasite from its host. While studying one of these parasites under the microscope we may see a sudden explosion, as it were, of the corpuscle. From a small point in the periphery of the red cell the parasite suddenly slijDs out into the field, while at the same time the color of the corpuscle may be seen to flow out at this same point, leaving the disk a pale, almost indistinguishable shadow, very soon to disappear en- tirely from view. (Plate I, Figs. 5 and 21). * On one occasion I demonstrated a specimen of fresh malarial blood to an artist who, though familiar with the mioroscope, knew nothing of the malarial parasite. He immediately turned to me and said that the parasites were not white, as they were represented in a plate which lay before him. " They have a distinctly yellowish tinge. They lie within the corpuscles, and not upon them." THE H^MOCYTOZOA OF MALARIA. 45 The parasite which has escaped may sliow amoeboid move- ments for a short time, though usually it becomes motionless, and often deformed and misshapen. Not infrequently it be- comes fragmented, breaking into several minute round pig- mented bodies, which are often connected by delicate thread- like processes in which pigment granules may lie. The outlines of these extra-cellular forms become very pale and indistinct, so that often they appear simply as collections of scattered pigment granules. As the parasite grows the red corpuscle which contains it becomes somewhat expanded and loses its color. After twen- ty-four hours' growth the body occupies somewhat less than haK of the area of the red corpuscle, which by this time shows a distinct pallor, and is larger than its unaffected neigh- bors. The amoeboid movements of the organism begin to be a trifle less active ; the amount of pigment is increased, while the granules are distinctly coarser and of a darker color. After about forty hours of development the body has reached nearly its full growth. It is then almost as large as a nor- mal red corpuscle, while the element in which it has devel- oped is represented by a pale shell, which is often difficult to distinguish. This decolorized remnant of a red corpuscle may be half again as large as the normal red cell. (Plate I, Fig. 9.) Shortly after this certain changes begin to be apparent within the parasite, which are indicative of the onset of sporulation. (Plate I, Figs. 10-14.) The pigment first shows a tendency to become collected toward some one point, usually near the centre of the body. This proceeds until finally the granules gather into one small clump, or indeed are fused into a single block. This block may lie exactly in the middle, or at times more toward the periphery of 46 LECTURES ON THE MALARIAL FEVERS. the parasite. The surrounding red corpuscle has by this time become ahnost indistinguishable ; it is, however, a ques- tion whether, in the earher stages of segmentation, the shell of the corpuscle ever entirely disappears. If one look very carefully he may almost always distinguish the pale surround- ing rim; in many instances where, in the fresh specimen, it is difficult to make tliis out, well-marked evidences of its existence are brought out by staining. Shortly before and with the collection of the pigment at one point in the parasite certain changes become evident in the protoplasm of the body. This begins to have a slightly opaque appearance, as if it were more dense, while a number of small slightly refractive points appear about the periphery of the organism, and sometimes also within its substance. Soon after this there appear evidences of radial striations, coming in from the periphery, while a slight crenation of the outer margin of the body may be seen, until iinally a figure like that in Fig. 12 of the plate is to be made out ; a central pigment clump surrounded by from twelve to twenty or thirty leaflets. Usually, however, these striations do not extend actually to the pigment mass. Other small refractive points appear within the substance of the body, while gradually lines of separation develop about them until at length each minute refractive point lies within a small separate segment. At last, at a given moment, if we are lucky enough to observe the body at this instant, there is a sudden movement sug- gesting strongly the rupture of a capsule, while the fifteen to twenty little separate segments burst from about the cen- tral pigment which they now surround like a bunch of grapes. The separation of these segments may not occur all at once. At one point on the periphery several of these bodies may THE HJEMOCYTOZOA OF MALARIA. 47 suddenly escape from the group, the others remaining longer about the central pigment mass. These small hyaline bodies may sometimes be followed for some little distance from the original segmenting form. Under these circumstances they may show a slight dancing to-and-fro movement which suggests the possible existence of flagella. Usually they are quite motionless. Sometimes all the pigment may not collect at one point, but separate single granules or collections of granules may be scattered throughout the segmenting organism, while rarely a fresh segment may contain a single granule at the time of its origin. This I have distinctly observed on one oc- casion. These small, clear hyaline segments resemble the young amoeboid intra-corpuscular forms very closely, as well in appearance and size as in staining characteristics ; the latter appear in the red blood-corpuscles simultaneously with or shortly after the appearance of the sporulating bodies. It is generally acknowledged that the segments represent spores or actual young organisms. Whether they are gymnospores (Grassi and Feletti), complete young parasites, or whether the spores must undergo some slight change before they are able to attack the red corpuscles, is a question. Certainly we have never observed the actual invasion of a red corpuscle by a fresh segment, nor have we ever been able to make out distinct amoeboid movements of these bodies. On the other hand, the staining reactions are the same as in the case of the young intra-cellular parasites, while we never have been able to distinguish evidences of a membrane about the spore. The chain of evidence is so strong that there can be little doubt that the fresh segments represent the new group of parasites, which appears almost 48 LECTURES ON THE MALARIAL FEVERS. immsdiately witliiii tlie red corpuscles, starting again upon another cycle of forty-eight hours' development. Not infrequently at a time when the group of organisms has reached nearly complete development bodies may be found which have reached tlie full size of a red corpuscle, while all evidences of their surrounding host has completely dis- appeared. These bodies may, indeed, be considerably larger than the normal red corpuscle. They are usually pale ; their outlines are indistinct, while the pigment granules are in very active motion. (Plate I, Fig. 18.) Studying these large extra-cellular forms we may observe one of several changes : (1) After a certain length of time the organism, the pig- ment of which is usually extremely active, may put forth several bud-like protrusions which finally become cut off, the original parasite breaking into a number of smaller bodies. These become rapidly deformed and indistinct, just as do the half-grown parasites which escape from the red corpuscles. The motions of the pigment granules gradually cease, until finally there &re left a number of small, irregularly shaped, indistinct masses with motionless pigment. (Plate I, Figs. 19, 20.) (2) In other instances there appear a number of small round vacuoles of irregular size, the development of which is usually associated with a deformation of the body, while the movements of the pigment gradually cease. Sometimes an interesting phenomenon may be observed, an appearance which was interpreted originally by Golgi, probably incor- rectly, PS a method of sporulation. A single large vacuole develops, containing one or more hyaline masses, which are not dissimilar in appearance to the segments of the sporulat- ing body. At the same time smaller vacuoles of irregular THE H^MOCYTOZOA OF MALARIA. 49 size appear throughout the rest of the parasite ; eventually the pigment becomes motionless and the body itself deformed and indistinct in outline. There is little doubt that this is a degenerative rather than a regenerative process. (Plate 1, Figs. 23, 24.) (3) The third and, in many ways, the most interesting change which occurs in these large, swollen bodies is the ap- pearance of the flagella first described by Laveran. The pig- ment first becomes extremely active, dancing in a most tumul- tuous manner ; often, in association with this, the periphery of the body is seen to undulate violently, suggesting, as Rich- ard long ago remarked, an attempt on the part of some in- cluded body to escape. Finally, in an instant there appear from one or more points on the periphery of the organism small, thread-like, colorless, actively motile flagella, while at the same moment the pigment tends generally to collect rather toward the centre of the mother body ; it never, how- ever, gathers into a small mass, as in sporulation. (Plate I, Fig. 22.) The flagella have a singularly regular outline, showing often a slightly clubbed extremity, and further, at times, small olive-shaped swellings in their course. Their length is usually not more than two or three times the diameter of the body from which they arise. Their motions are extremely active, the red corpuscles in the neighborhood being stirred about in a violent manner. The pigment is very lively. Occasionally one or more small granules may pass from the interior of the parasite out into one of the flagella. At this period the mother body, which is in active motion, often be- comes extensively fragmented; one usually, however, gains the impression that these fragments have some delicate con- nection one with another. 50 LECTURES ON THE MALARIAL FEVERS. After tlie body has existed for a longer or a shorter time, flagella may break loose from the mother organism, rushing off among the surrounding corpuscles, preserving the same active serpentme movements which they j)ossessed before. Sometimes several free flagella may be seen in a single field. The activity of the flagella may last for a considerable time, certainly up to three-quarters of an hour. Gradually, how- ever, the movements cease, and the filaments, becoming mo- tionless, are quickly lost to the eye. At times there is an appearance as if they were withdrawn again into the body ; often they seem to be folded about it. With the cessation of the movements of the flagella the pigment becomes usually quite motionless, and the central body remains a shrunken, deformed, motionless mass. The significance of these large, extra-cellular forms is not entirely settled. Many observers believe them to be degen- erative stages of the parasite, bodies which are overgro^vn and have failed to enter upon a reproductive stage — involution forms. This would appear to be true in the case of the fragment- ing and vacuolated forms. The true significance, however, of the flagellate bodies is not entirely clear. Certain considerations speak in favor of their representing a degenerative stage of the parasite. The most important of these are perhaps the facts : (1) That they are derived from the same bodies which give rise to fragmenting and vacuolating forms, in association with which they are usually found. (2) That they are rarely found immediately after the for- mation of the specimen, but usually five, or ten, or fifteen minutes after a fresh specimen of blood has been made : that is, after exposure to abnormal and doubtless injurious condi- THE H^MOCYTOZOA OF MALARIA. 51 tions. In bird's blood, where the change from the body temperature to that upon a slide is more marked, the develop- ment of the flagellate forms is rather quicker, and this change may be readily followed out in a number of organisms upon the fresh slide. Within five minutes after the preparation of such a specimen we may observe the rapid change of from five to ten organisms in a field into flagellate forms, which, after existing a certain length of time, become finally motion- less and deformed. (3) That the analogous forms in the sestivo-autumnal para- site, which will be discussed later, are derived from bodies which are incapable of further development, and are con- sidered by some to be degenerate forms. On the other hand, the surprising regularity in the shape of the flagella and their power of individual mo- tion suggest strongly that they are preformed bodies, and permit us to sympathize to a certain extent with those ob- servers who still believe that they represent an important stage in the development of the parasite, the true significance of Avhich we do not yet know. The comparison of the fiagella to the filaments which develop from red blood-corpuscles on exposure to heat, a comparison which has been made by good observers and recently repeated by Bignami,* is, it seems to me, extremely far-fetched. It is difiicult to understand how any one who has observed the two processes can consider them analogous. jS'ow while all these different phases in the cycle of exist- ence of the parasite are to be observed in a fresh specimen of the blood, Bastianelli and Bignami f pointed out some years ago that the different phases are observed with by no means * Lancet, 1895, ii, pp. 1363, 1441. f Op. cit. 52 LECTURES ON THE MALARIAL FEVERS. equal frequency. Thus in a given group of tertian parasites, while a verj considerable number may be seen in the stage of fresh hyaline bodies, and again as half -grown and nearly full- grown forms, the segmenting forms are seen with much less frequency. These excellent observers carried on careful systematic studies not only of the blood from the peripheral vessels, but also of that obtained by aspiration from the spleen. By this means they discovered that as the organism becomes full gro^vn and segmentation begins, the parasites are found with much greater relative frequency in the blood of the spleen. They suggest a very plausible explanation of this fact. The red corpuscles having been almost completely destroyed by the growth of the parasite, become practically foreign bodies, and as such tend to accumulate in the spleen. The reason that in quartan fever the organisms are so much more readily found in the peripheral circulation is simply because the changes produced in the red corpuscles are relatively slight. Thus, in tertian infections with a single group of moderate dimensions it may be rather difficult to find organisms in the peripheral circulation just before or during the early stages of the paroxysm, while not infrequently the discovery of seg- menting bodies may be almost impossible. Tlte Apjjearance of the Organisms in Dried and Stained Specimens. — Our best results have been obtained by staining with eosin and methylene blue according to Eomanovsky's method. In stained specimens the youngest forms of the parasite are represented by delicate blue rings. The central part of the ring is occupied by a colorless area, at one point on the periphery of which there is usually a small, deeper blue spot. THE HiEMOCYTOZOA OF MALARIA. 53 This pale area, it will be remembered, is what has been as- sumed bj many observers to represent the nucleus, the smaller deeply staining spot representing the chromatic substance or nucleolus. As the parasite grows, pigment granules begin to appear in the peripheral blue part of the organism, while the amceboid character of the parasite becomes evident by the excessively bizarre figures which the element assumes. When one studies the stained specimen of a half -grown tertian parasite it is easy to realize how in the fresh blood one might mistake a single organism for several separate bodies. At one point in these pigmented parasites, often at the end of a pseudopod, there is to be made out a clear, pale, non-staining area, inside of which is a round or ovoid body which takes on a blue color, though paler than that of the rest of the parasite. This area is to be distinguished from islands of red corpuscular sub- stance which may be surrounded by confluent pseudopodia of the parasite. The clear, colorless area appears to be quite free from pigment, though at times there may be a single granule which looks as if it might lie accidentally upon rather than vdthin the clear spot. When the parasite has reached full development it is often impossible to make out any further evidences of this non- staining area, though frequently there may be a nonpig- mented area which takes on a clear blue color like the rest of the parasite. With the agglomeration of the pigment gran- ules and the beginning of the sporulation the parasite as- sumes a somewhat granular or mottled appearance, due to the development of small more deeply staining spots throughout the substance. Finally, it is possible to make out that these spots form part of a large number of small separate blue rings, each having exactly the same structure as the fresh 54 LECTURES ON THE MALAEIAL FEVERS. intra-corpuseular bodies excepting that they are a little small- er. In the segmenting body, before separation of the seg- ments, it is difficult to make out the structure of the separate spores, as they are crowded together and often overlap one another. These appearances are readily to be observed ; they cor- respond fairly well, as will be noted, to the observations of Mannaberg. In specimens prepared in the ordinary manner the deep lilac chromatic substance described by Romanovsky, Geppener, and Ziemann has not been apparent. It must be said, however, that our researches have been largely made upon fresh specimens, and we do not feel, as yet, in a posi- tion to dispute their results.* In the large swollen extra-cellular forms there is no evi- dence of the clear area which is called by so many observers the nucleus, while the parasite also takes a very pale stain. Attempts to stain flagellate bodies have always been un- successful, inasmuch as they are practically never to be found upon the freshly prepared slide. Sakharov alone believes that he has succeeded. He makes a fresh specimen of blood, and at the same time puts a number of covers, each ^vith a small drop of blood upon it, into a moist chamber. As soon as flagellate bodies are observed in the fresh specimen under the microscope the covers are removed from the moist chamber and smear preparations made. In these preparations Sakha- rov beheves that he is able to stain the flagellate forms with gentian violet. In later observations f he has stained these bodies with eosin and methylene blue, and convinced himself * Gotye has recently asserted that he has been able to obtain these pic- tures only when using two special varieties of methylene blue, namely, C and BGN from the Badisch. Soda Anilin Fabrik. f Centralbl. f. Bakt., 1895. THE HiEMOCYTOZOA OF MALARIA. 55 that the motile flagella represent the chromatic filaments of the nucleus which have, by a perversion of the process of karyokinesis, broken loose from the cell. Other observers have not confirmed these results. As has been mentioned above, Golgi in 1885 pointed out the remarkable connection which exists between the develop- ment of the parasites and the clinical symptoms. It is easy to confirm his assertions that the paroxysms which in tertian fever occur so regularly at intervals of forty-eight hours, are associated invariably with the segmentation of a grouj) of ma- larial parasites. The first segmenting forms are discovered in the blood several hours before the onset of the paroxysm, while during and toward the end of the paroxysm the appear- ance of a new group of bodies, as shown by the fresh hyaline forms within the red corpuscles, is to be made out. So reg- ular is the association between the cycle of development of the parasites and the clinical manifestations of the case, that one may, within certain limits, prophesy the hour at which a paroxysm will occur. Very commonly the blood shows evidence of an infection with two groups of parasites. These groups are almost in- variably so arranged that they reach maturity on alternate days. As might be expected, in this case the clinical manifes- tations are those of quotidian fever. As has been already stated, the parasite at the time of its sporulation has almost entirely destroyed the red corpuscle. In certain instances, however, sporulating forms may be found within corpuscles which are no larger than the normal red cell, and which are but little decolorized. Bastianelli and Bignami* are inclined to believe that such bodies are more * Op. cit. 56 LECTURES ON THE MALARIAL FEVERS. common in cases of anticipating tertian fever — a fact suggest- ing, tlierefore, a definite connection between the anticipation in the segmentation of the parasite and the cHnical manifes- tations of the case. Our observations have not been sufficient to justify us in forming a definite opinion concerning this point. We have seen not infrequently the presence of occasional small sporu- lating bodies in association with larger forms in cases which showed no very marked anticipation. Yery rarely one finds evidences of infection with multiple groups of the parasites, or perhaps the presence of parasites in all stages of development. This is a discovery which is most unusual with the tertian organism. In over one thousand cases of malaria, the majority of which have been infections with the tertian parasite, we have never observed a case in which two well-marked groups of tertian organisms segmented on the same day, (2) The Parasite of Quartan Fever {Hmmammha malaricB^ Grassi). — The quartan parasite is relatively rare in this coun- try. I have observed it in ten or fifteen instances in over one thousand cases at the Johns Hopkins Hospital. The blood in quartan fever, as in the case of tertian fever, shows the presence of parasites in great groups, all the members of which are at relatively the same stage of development. The cycle of development of the quartan parasite lasts approxi- mately seventy-two hours. Thus in infections with one group of this organism, sporulation occurs every fourth day. The earliest intra-corpuscular forms are similar to those of the tertian parasite ; the small amoeboid bodies, indeed, are practically indistinguishable. Soon, howevei-, after pigment begins to appear within the body certain differences are to be noted. The pigment in the young quartan parasite is dis- THE HiEMOCYTOZOA OP MALARIA. 5Y tinctly coarser than in the tertian organism, while it has also a darker, deeper brown color, possibly owing to the greater size of the granules. The youngest pigmented forms are still quite actively amoeboid, and excepting for the size and color of the pigment, which also tends to collect toward the pe- riphery of the organism, they are difficult to distinguish from the tertian forms. (Plate II, Figs. 3-5.) As the body increases in size, however, and more pigment develops, the distinction between the two varieties is more readily made. The quartan parasite shows a much clearer and sharper outline than the tertian organism ; it has a some- what refractive appearance. The difference in refraction and distinctness of outline between the tertian and quartan parasite may be compared to the difference between a pale hyaline and a waxy cast in the urine. The movements of the quartan parasite are slow and lazy, while the pigment is very much less active. The organisms, as early as the second day, are usually represented by small, round, or ovoid bodies, which show but little amoeboid movement. They are very distinct in outline, and contain relatively coarse, dark-brown pigment granules lying about the periphery, collected usually more at one side. (Plate II, Figs. 6, Y.) The behavior of the red corpuscle which harbors the quartan organism is in marked contrast to that of the element in which a tertian parasite develops. In the latter case the corpuscle becomes expanded and decolorized. In the former there is rather a tendency toward retraction of the corpuscle about the body, while its color becomes, if anything, a little deeper, showing sometimes a somewhat greenish hue, like that of old unpolished brass. As the organism increases in size the amoeboid move- ments practically cease. The pigment becomes coarser and is 5 58 LECTURES ON THE MALARIAL FEVERS. extremely glow and lazy in its movements, while the contrac- tion of the red cell about the body becomes more evident. On the third day the round or ovoid parasite is sur- rounded by but a very small rim of deeply colored corpuscu- lar substance. (Plate II, Fig. 8.) Finally, after about sixty hours, the wholly motionless parasite is surrounded by an al- most imperceptible rim of protoplasm. In fresh specimens the parasites very frequently have a somewhat ellijDtical shape. (Plate II, Figs. 9-11.) Shortly after this the small rim of red corpuscle entirely loses its color, while the first evidences of. the reproductive process set in. Such parasites usually impress one as being free in the blood, though in stained specimens the remains of the surrounding red corpuscle are always to be observed. The first evidences of segmentation are usually made out about ten hours before the paroxysm. The pigment, as in the tertian parasite, tends to collect toward the centre of the body ; but during the process of collection it often assumes a radial arrangement, as though it flowed inward in distinct streams. (Plate II, Figs. 12, 13.) Figures showing this starlike arrangement of the pigment are in my experience quite characteristic of the quartan para- site. I have never observed similar pictures in segmenting tertian organisms, and have more than once been led to recog- nize a quartan infection by coming upon one of these bodies under the microscope. At the same time the body begins to show the opaque, slightly granular, waxy look which was de- scribed in the tertian organism, and small refractive points appear about the periphery. Here, however, the figures are usually much more regular than in the case of the tertian parasite. The radial striations which mark out the future divisions into segments reach THE H^MOCYTOZOA OF MALARIA. 59 completely to the central pigment clump, which eventually is surrounded by from six to twelve exquisitely symmetrical leaflets, the whole meriting well the term Marguerite or ro- sette form so freqently applied to them. This small number of segments, from six to twelve, is characteristic of the quar- tan organism. The process of separation of the segments is exactly similar to that in the tertian parasite. (Plate II, Figs, U, 15.) Often, though somewhat less frequently than in the case of the tertian parasite, large, pale, free, extra-cellular forms of the quartan organism may be observed. These forms show changes quite analogous to those in the similar forms of the tertian parasite. They become expanded and pale, while the pigment granules become most actively motile. They may further undergo deformation, fragmentation, and vacuo- lization, as in the case of the tertian organism, while occa- sionally also flagellate forms may be observed. These flagel- late bodies, as' in the case of the large, free, extra-cellular forms, are distinctly smaller than the corresponding tertian parasites. They are more similar to those observed in the sestivo-autumnal parasite. (Plate II, Figs. 16, 17, 18.) The quartan parasite, then, is to be clearly distinguished, morphologically and biologically, from the tertian organism. (1) It differs in size, being smaller throughout its course. (2) It is more refractive, and has a more distinct outline than the tertian organism. (3) The amoeboid movements of the quartan parasite are relatively much less active. (4) The pigment granules in the younger forms are coarser, darker, and tend much more to seek a peripheral arrangement. (5) The activity of the pigment granules is much less, the 60 LECTURES ON THE MALARIAL FEVERS. movements of the pigment in tlie quartan organism being extremely slight after the first twenty-four hours. (6) The sporulating forms are mnch more regular, and show a smaller number of segments, from six to twelve, instead of upwards of fifteen. Furthermore, they are arranged as definite regular leaflets about the pigment clump. Never, apparently, in the quartan parasite, do we see the irregular breaking up of the organism into segments. (7) The pigment as it collects into a single mass or block before segmentation, tends to flow in toward the centre in radial lines, forming a star-like picture not seen in the tertian bodies. (8) The cycle of development lasts approximately seventy- two instead of forty-eight hours. (9) Its effect upon the surrounding coi*pu8cle differs from that of the tertian parasite in that, instead of becoming ex- panded and decolorized, the red element becomes rather re- tracted and deeper colored. The staining reactions of the organism appear, from a limited number of observations, to be essentially the same as in the tertian organism. ]^ot infrequently we find more than one group of para- sites, and, as in tertian infections, these groups almost invari- ably reach maturity on different days; thus we may have infections with two or three groups of quartan parasites. It may be that infections with more than three groups of quartan organisms occur. Such cases, however, I have never observed. The same rules with regard to the clinical manifestations apply here as in tertian infections. Where one group of organisms is present paroxysms occur every fourth day ; where two groups of organisms are present the paroxysms THE HiEMOCYTOZOA OF MALARIA. gl occur on successive days with a day of intermission between. Where three groups of organisms are present quotidian par- oxysms result. (3) The Parasite of the JEstimo-auturanal Fever {Jlmma- tozoon faloipa/riim, Welch). — While of recent years many observers have given their special attention to the parasites associated with the irregular sestivo- autumnal fevers, we must acknowledge that the subject is yet far from being clearly understood. Infections with the sestivo-autumnal parasites differ in several respects from those with the organisms just described. It will be remembered that one of the most strik- ing characteristics of the tertian and quartan parasites is their tendency to be aggregated in great groups, all the members of which are at approximately the same stage of development, passing through their cycle of existence, reaching maturity, and sporulating practically at the same time. Further- more, the length of the cycle of existence is relatively constant in each variety of the organism, lasting about forty-eight hours in the one instance and seventy-two in the other ; from this rule, variations, while they do occur, are but slight. In the case of the aestivo-autumnal parasite, while we have been able to study all the stages of the existence of the organism morphologically, many questions with regard to its biology remain unsettled. Thus there is reason to doubt that the same constant aggregation in groups is the rule, while the length of the cycle of development of the parasites is by no means as yet clearly determined and is very probably open to extensive variations. Again, in tertian and quartan infections, particularly in the latter, it will be remembered that we are able to observe all the stages in the life history of the parasite in the circulat- (32 LECTURES ON THE MALARIAL FEVERS. ing blood, to follow out the development of the organism, and to prophesy with considerable accuracy, from the stage of development of the parasites present, the time at which the succeeding paroxysm will occur. In infections, however, with the sestivo-autumnal organism, only the earliest stages of its development are ordinarily to be found in the j^eripheral circulation, while occasionally, perhaps, in most severe infec- tions prolonged examinations of the blood from the peripheral vessels reveal little or nothing. In the spleen and bone mar- row, however, one may find all stages in the development of the parasite, while only certain of the youngest forms aj)pear in the peripheral circulation. It is thus easy to see why our knowledge concerning many points in the life history of the organism is much more im- perfect than in the case of the preceding varieties, which may be so readily studied throughout their cycle of existence. By repeated examinations, however, of the peripheral blood, as well as of the blood obtained by punctures of the spleen, we have been able to trace, at least in part, the life history of the parasite. Owing to the fact that we can not follow out all the phases of the growth of the parasite in the peripheral circu- lation, and because often we find organisms present in all stages of development in the spleen, there has been much dif- ficulty in determining the length of the cycle of existence, and many different opinions are held. Thus, it will be re- membered, Canalis believes that under ordinary circumstances the cycle lasts two or three days at least, while others believe the ordinary cycle to be as short as twenty-four hours. Marchiafava and Bignami believe that they can separate two distinct varieties of the parasite, one having a cycle of de- velopment lasting about twenty-four hours, and the other THE H^MOCYTOZOA OP MALARIA. (33 about forty-eight hours — parasites which tliej have termed the quotidian and malignant tertian organisms. Golgi, however, who, it will be remembered, holds the interesting view that the main development of these parasites occurs in the internal organs within the bodies of macro- phages, insists that as yet our knowledge of the duration of the cycle of existence is quite incomplete, and leans toward the view that the cycle may vary greatly in length, in some in- stances being considerably longer than that of any other known form of the organism. Our studies of the organism have not as yet enabled us to settle these much-disputed questions. From a number of simultaneous observations of peripheral and splenic blood we are inclined to believe that in most cases, at the beginning of the infections at least, the organisms are arranged in groups, just as in tertian and quartan fevers. We have not, however, been able to convince ourselves of the existence of the two distinct varieties of the parasite which Marchiafava and Big- nami and Mannaberg describe. The differences between the two varieties of the organism as described by these observers are so slight that we are inclined to believe they result simply from the fact that the organisms grow larger and accumulate more pigment in those instances where the cycle of develop- ment is longer. We further believe that while in some instances groups of parasites of this variety pursue a cycle of development last- ing but twenty-four hours, or possibly even less, in others, probably, the duration of the cycle is longer, lasting, per- haps, forty-eight hours, or even more. To these ideas we have been led especially by the study of cases early in their course, when they show a more or less regularly intermit- tent character, while the parasites appear to be arranged in 64 LECTURES ON THE MALARIAL FEVERS. groups. Later on, in the course of such cases, examination of the splenic blood may show organisms in all stages of develop- ment, and it is practically impossible to determine whether or not actual groups are present ; the clinical symptoms usually suggest either the presence of multiple groups or tlie com- plete absence of such arrangement. "We have been unable to convince ourselves of the existence of two distinct varieties of the parasite. It will be remembered that while the tertian parasite pur- sues a cycle of existence lasting about forty-eight hours, and the quartan parasite a cycle lasting about seventy-two hours, these figures are, however, not absolute, and cases not infre- quently occur in which the length of the cycle varies consid- erably from the mean. This is particularly true of the tertian parasite, where anticipation and retardation of several hours is not at all uncommon. Now our observations suggest to us that the parasites asso- ciated with the sestivo-autumnal fevers, without showing con- stant differences justifying their separation into two groups, yet possess a cycle of development which is subject to vari- ations similar to those occurring in the case of the tertian organism, but so much greater that its duration may in some instances be at least forty-eight hours, in others as short as twenty-four hours. Transitional stages between these parasites with longer and shorter cycles appear to occur. So, then, we must regard the aestivo-autumnal parasite as an organism whose definite arrangement in groups is certainly less constant than in the case of the other varieties ; the length of whose cycle of existence is as yet undetermined, and is probably very variable ; whose life history is to be followed out for the most part in the internal organs ; whose morphol- ogy alone has been fairly well traced. THE H^MOCYTOZOA OF MALARIA. 65 The youngest forms of the sestivo-autumnal parasite are similar to those of the tertian and quartan organisms, and yet certain rather characteristic points of difference may often be made out. In the first place the youngest forms are smaller than similar stages of the parasites of the regularly intermit- tent fevers. They often appear as very small, round, refractive bodies with a central darker point, which at first gives one the impression that he is looking upon a complete ring; on focusing, however, it would appear rather to be indicative of a biconcavity of the parasite. This point is commonly not exactly at the centre of the body, but a little to one side, so that the appearance is not unlike that of a seal ring. Many have believed that these forms represent true rings. That this is not the case the skilled observer may readily convince himself, not only by focusing but also by ob- serving the changes which take place in such a body. If one of these forms be watched for a short time certain striking changes may generally be made out. The small, ring-like, refractive body which may at first have been quite mo- tionless, suddenly loses much of its refractiveness, becomes a trifle expanded, and shows marked undulatory waves about the periphery. With this change the central spot, which looked like the lumen of a ring, suddenly disappears. Such a pale, amcBboid, hyaline disk is not to be distinguished from a ter- tian or quartan organism. Its movements are active and irregular, and every conceivable picture may result. At any moment, however, such a form may suddenly cease to be amoeboid, change into a pale disk, and from that quickly again into a smaller refractive ring-like form. (Plate III, Figs. 1-6.) As the bodies increase slightly in size, at a period differ- 66 LECTURES ON THE MALARIAL FEVERS. ing in different cases, pigment granules begin to appear. The pigment, however, is very scanty. In tlie small ring-like or disk -like body, which may be no larger than a fifth the diam- eter of the red corpuscle, one or two extremely minute dark- brown pigment granules may be observed lying usually upon tlie periphery of the parasite, or sometimes about the border of the central lumen-like depression. The first granules are so minute that only the skilled eye detects them. They are usually motionless, though sometimes they may be seen to dance actively. (Plate III, Figs. 8-12.) One of the most striking features connected with the growth of tlie parasite is the behavior of the red corpuscle which contains it. It will be remembered that during the growth of the tertian organism the red corpuscle becomes pale and expanded, and finally entirely decolorized, while during the growth of the quartan parasite the red corpuscle tends rather to retract about the organism, assuming sometimes a deeper, somewhat brassy color. In infections, however, with the sestivo-autumnal parasite the corpuscles often show more marked degenerative changes. While in tertian and quartan infections the disks con- taining the very youngest forms of the parasite show almost no points of difference from the normal red corjDuscle, in aes- tivo-autumnal fever the changes may come on very early. Not infrequently in the presence of the smallest ring- shaped forms we may notice that the surrounding corpuscle has become wrinkled and crenated or spiculated and of a very distinct greenish brassy color {glohuli rossi ottonati). In other instances the hgemoglobin may retract from the periph- ery of the red disk about the small parasite, leaving the pale rim of the corpuscle still visible upon one side. The col- ored part of the corpuscle in these instances is almost always THE H^MOCYTOZOA OP MALARIA. §7 of a somewhat brassy hue. These changes are probably to be interpreted as necrobiotic. (Plate III, Figs. 7, 13, 16, 22, 23, 29.) According to Golgi, it is to these changes that the great accumulation of parasites in the spleen and certain internal organs is due, the necrotic red corpuscles being readily en- gulfed by macrophages. As the parasite continues to develop the few pigment granules gradually increase, though often at the end of de- velopment they are scanty in number. The parasite itself often reaches its complete development before it has acquired half the diameter of a normal red corpuscle, though in some instances forms may be found which are nearly as large as the red cell. As the full development of the parasite is approached, the pigment begins to gather toward a single point, usually near the centre of the body, at first in a small clump, and later usually as a definite minute block. In some instances the pigment before being fused into a block, may show more or less active movement. Never in this stage of the sestivo-au- tumnal parasite do we see bodies with diflEusely scattered pig- ment. The older the form of the parasite the more frequent- ly does the containing corpuscle show degenerative changes in the forms of crenation, spiculation, or partial decolorization, though not infrequently full-grown forms may be seen in quite unaltered corpuscles. (Plate III, Figs. 13-21.) In the full-grown bodies with central pigment blocks, bodies which may be anywhere from one fifth the diameter to nearly the actual diameter of a red blood-corpuscle, segmen- tation takes place in a manner quite similar to that described in the tertian parasite. The organism takes on the slightly opaque, waxy look ; there is the same appearance of small 68 LECTURES ON THE MALARIAL FEVERS. glistening dots, the same gradual development of radial stria- tion, the same gradual separation into minute segments. The parasite here, as sho-\vn in the plate (Plate III, Figs. 25-28) breaks up, as does the tertian organism, throughout its entire substance, and not always with the perfect symmetry of the organism of quartan fever. It msij be remembered that in tertian and quartan fever, when segmentation actually occurs, the red corpuscle is usu- ally completely decolorized. This rule does not appear to hold in the case of the aestivo-autumnal organisms, as Marchi- afava and Bignami described characteristic segmenting bodies occurring within yet unchanged red-blood corpuscles. Some- times such forms may be seen in shrunken or brassy corpus- cles, or in corpuscles whose coloring matter has retracted about the parasite. Usually, however, according to our obser- vations, the surrounding corpuscle has entirely lost its color at the time of segmentation. The great point of difference, however, between the para- site of aestivo-autumnal fever and those of the regular tertian and quartan fevers consists in the fact that only the youngest forms in the development of the organism are to be observed in the peripheral circulation. Thus while small, hyaline, ring-shaped, and amoeboid forms are common, and also forms with one or two peripherally arranged pigment granules, the forms with central pigment clumps and blocks are unusual. These are most frequently seen during or just before the par- oxysm. If, at the same time, we aspirate the spleen, we find enor- mous numbers of these more developed bodies, and, not infre- quently, segmenting forms. It is a very striking point, how- ever, that the great majority of the more developed forms in the spleen are to be found within shrunken and brassy-col- THE H^MOCYTOZOA OF MALARIA. 69 ored corpuscles, which in turn are not infrequently within the bodies of macrophages — an observation which lends some plausibility to Golgi's idea that an actual development of the parasites may occur within macrophages. Actual segmenting bodies are very rarely observed in tlie peripheral circulation, though most of the Roman observers agree in stating that under rare circumstances an occasional example may be found, while Sakharov asserts that in Tiflis he has found them with greater frequency. At the medical clinic of the Johns Hopkins Hospital we have observed actual segmenting bodies in the peripheral circulation in only two instances. As I have said above, the length of this cycle is uncertain. We believe that it may last from twenty -four to forty-eight hours, and possibly even more. LECTUEE III. Description of the haemoeytozoa of malaria {continued). — General conditions under which the malarial fevers prevail. Crescentic and Ovoid Bodies. — After the fever has lasted for a week or more, other forms of the parasite, which are characteristic of this type of fever, occurring here alone, begin to appear in the peripheral circulation. They may be made out in the internal organs at times as early as the fifth day. These are large ovoid and crescentic bodies, the crescents being sometimes considerably longer than the normal red corpuscles, the ovoid bodies almost as large as the ordinary red cells. The protoplasm of these elements is highly refractive, so much so that they appear often to have a double outline, which many observers have interpreted as a membrane. The periphery, however, often shows a shght yellowish rim ; in stained specimens there is good proof that this represents a coating derived from the red corpuscle in which the parasite has developed. On tlie concave side of the crescentic or at one side of the ovoid body we may observe a slight convex bib-like attachment ; this reaches in some specimens from tip to tip of the crescent, though in most it covers only the depth of the concavity. This bib often shows distinctly a pale yellow- ish color, indicating clearly that it represents the remains of the red corpuscle ; it may have more color and show a cre- nated border, 70 THE n^MOCYTOZOA OP MALARIA. Yl There has been much discussion among different observers as to the origin and significance of these crescentic and ovoid bodies. Grassi and Feletti,* for instance, believe that they are a separate species of the parasite {Lavercmia Tnalarioe). This view is, however, probably incorrect, as their origin from the smaller forms belonging to the ordinary cycle of development may be traced with considerable distinctness. It seems probable that after the infection has lasted for from a week or ten days, certain of the full-grown parasites instead of undergoing segmentation, continue to develop in size and to accumulate pigment, destroying gradually the red corpuscle as they grow. Every stage of transition may be made out between the small bodies and the larger crescentic and ovoid forms. At first the small bodies begin to show coarser, more rod- like pigment granules, while the parasite assumes usually a fusiform shape. The fusiform bodies grow, stretching the red corpuscle as they lengthen. The corpuscle sometimes becomes crenated; usually paler. Generally by the time the body reaches about the length of the normal diameter of the red cell it begins to mould itself along one side of the corpuscle and to assume a crescentic shape. The pigment is scattered throughout the substance of the parasite in the younger forms ; in the older it is collected in a more or less compact clump or ring toward the middle. The granules and rods of pigment become gradually coarser. Sometimes we may trace the progressive decolorization of the body of the j'ed cell, the coloring matter retracting closely about the crescent and forming the glistening contour. The relation of these bodies to the red corpuscle is quite * Loc. cii. 72 LECTURES ON THE MALARIAL FEVERS. clear. Developing ^Yitllin it, and destroying it until nothing is left but a pale shell, the crescent, which has more body than the decolorized corpuscle, becomes enveloped by the shell as Avith a moist veil. The shell of the corpuscle thus clinging to the body, furnishes it with the outer coat which to so many has suggested a membrane, while the remains hang from the concavity as a bib. The crescentic and the ovoid bodies are readily inter- changeable. One may observe upon a single sjDecimen the transition of one form into the other. We have never been able to observe reproductive changes in these crescentic and ovoid forms, and we are convinced that they do not occur. This idea is, however, disputed by certain observers, Canalis,* Antolisei and Angelini,t Grassi and Feletti,:}: and later Terni,* asserting that segmentation does take place. Certain other changes, however, we have repeatedly fol- lowed out. JS^ot infrequently crescents or ovoid bodies may be seen to change into symmetrical round forms somewhat smaller than the normal red corpuscles. To these the remains of the red corpuscles may be attached, though in some in- stances no evidence of the red cell is to be made out, while the sharp, glistening, membrane- like rim is lost. In these round forms the pigment often has a marked tendency to collect in the shape of a ring. Wherever such forms are to be found we may expect to see the development (A flagellate bodies. The process of the development of the flagellate form is much the same here as in the other types of malaria. The central pigment first becomes extremely active ; there are marked undulatory movements of the periphery of the body, * Op. cit. \ Op. cit. X Op. cit. * Op. cit. THE HiEMOCYTOZOA OF MALARIA. 73 and finally delicate flagella, similar to those observed in the tertian and quartan organisms, break out from the periphery. The flagellate forms in sestivo-autumnal fever are not ma- terially different from those observed in tertian and quartan fever, excepting for the fact that they are a trifle smaller than the tertian bodies. They bear a strong resemblance to the quartan flagellate forms. YaGuolization of the crescentic, ovoid, or round bodies is not very uncommon. This is usually associated with a diminution in the refractiveness of the parasite and often with a loss of its regular outline. The vacuoles are small, but may vary considerably in size, sometimes becoming con- fluent and larger. Such a form is shown in No. 3T of Plate II. The process is evidently degenerative. Further, we may observe in certain instances the protru- sion of small, delicate, bud -like bodies which are cut off from the cell ; this probably represents a fragmentative, degenera- tive process (pseudo-gemmation). Under quinine the forms of the ordinary cycle of devel- opment disappear rapidly from the peripheral circulation, just as in the case of the tertian and quartan parasites. The crescentic and ovoid bodies may, however, remain for a much longer time, sometimes even for months. In many instances, however, the presence of these bodies appears to have no influence whatever upon the general condition of the patient who has apparently entirely recovered. What is the significance of these bodies ? This is a ques- tion which has been much disputed. Canalis * and his fol- lowers, Terni f and Giardina,:}: as well as Antolisei and An- gelini* believe that they represent forms having a longer * Op. cit. f Op. cit. X Op. cit. * Op. cit. 6 7i LECTURES ON THE MALARIAL FEVERS. cycle of development, asserting that they have been able to find undoubted reproductive forms. Grassi and Feletti * and Sakliarov f believe that thej are capable of reproduction, although in the opinion of these authors they represent a distinct and separate variety of parasite. Mannaberg :{: holds a view which differs distinctly from other observers, a view which is as yet unconfirmed, and seems, on the whole, improbable. He believes that the crescents result from a pseudo-conjugation of two smaller forms exist- ing in the same corpuscle. He also believes that they are in some way or other capable of reproduction. Sakharov,* who has advanced the remarkable view that the sestivo-autumnal parasites develop in nucleated red cor- puscles, believes that the crescents represent forms which enter the corpuscle at a particularly young stage, before the development in the cell of any large amount of haemoglobin. They obtain their nourishment from the nucleus, about which they grow, thus taking their characteristic shape. Marchiaf ava, II Bignami,^ Celli,^ and Bastianelli believe, on the other hand, that the crescents represent deviate and sterile forms of the organism, which are quite incapable of reproduction. More recently Bignami and Bastianelli have given utterance to the interesting hypothesis that these organ- isms may represent some more resistant form of the parasite, which is sterile as long as it remains within the human being, but which is perhaps capable of further development on transmission to some other medium. Bastianelli and Big- * Op. cit. II Op. cit. f Op. cit. ^ Op cit. X Op. cit. t) Op. cit. * Cent. f. Bakt., 1896, xix, 268. THE II^MOCYTOZOA OP MALARIA. 75 nami * call attention to tlie fact that in certain other allied sporozoa, after the parasite has passed through its ordinary cycle of existence a certain number of times, there appear other forms, usually encysted, which are stationary as long as they remain within their original host, but are destined to preserve the organism for further development outside the body. We have ourselves never been able to observe segmenting forms which we believed to be derived from crescentic, ovoid, or round bodies, nor have we been able in any way to con- firm Mannaberg's ideas. Everything suggests that the cres- cents themselves are incapable of further development within the body of the individual, and there is much which renders the hypothesis of Bignami extremely plausible. Essentially the same ideas with regard to the nature of the crescent have been independently advanced by Manson.f With the object in view of testing some of these hypoth- eses, I have made several incomplete though not uninteresting experiments. In the first instance it was desired to test the capability of the crescentic forms to transfer an infection on inoculation. In all previous instances where inoculations with cres- centic bodies have been made there is good reason to believe that hyaline amoeboid forms were also present, though per- haps in small number. In this instance an hypodermic syr- inge full of blood showing only ovoid and crescentic bodies was injected into the median basilic vein of an healthy man who voluntarily offered himself for the experiment. The pa- tient from whom the blood was taken was convalescent from his first attack. He had had quinine for four days, during * Bull, d, R, ace. med. d. Rom , xx, 1894, 220. f Op. cit. 76 LECTURES ON THE MALARIAL FEVERS. which time no bodies excepting crescentic and ovoid forms were to be found in the peripheral circulation. The inoculated individual was carefully observed for five weeks. There was never any fever, nor did parasites appear in the blood. The inoculation was made in the month of August. This observation would tend to uphold the views of Marchiafava and his students, that the crescents are sterile forms and unable to produce fever. The other experiments were made with a view to deter- mine whether by preserving crescents outside of the body changes might not take place which would enable them or their remains to give rise to an infection on reintroduction into the human org-anism. In these instances the blood was taken from an individual with an acute infection who had not taken any treatment. The blood, containing numerous young amoeboid forms as well as crescentic and ovoid bodies, was taken in sterile Petri dishes, dried in a desiccator, and pulver- ized. In the fine brick-red powder which resulted, masses of pigment were to be made out as well as occasional distinct remains of crescentic bodies. These latter looked somewhat granular, and had lost their refractive appearance and sharp outline ; they were, however, readily recognizable as un- doubted crescents. With this powder two experiments were made upon voluntary subjects. (1) A small quantity of the powder was mixed with ster- ile salt solution and injected into the median basilic vein of a patient with a progressive myopathy. (2) The dry powder was placed in an insufflator and in- haled by a patient with multiple sclerosis. Neither patient had ever been the subject of malarial in- fection. The results were negative in both instances. There was THE H^MOCYTOZOA OF MALARIA. 77 no constitutional disturbance of any sort, nor did parasites appear in the blood. Botli patients are yet under observation nearly a year after the experiment. The Staining Reactions of the yEstivo-autumnal Para- site. — Our studies, as has been before stated, have been largely carried on with fresh specimens, so that for particulars upon this point I must refer you to the excellent work of Bastia- nelli and Bignami,* and that of Gotye. f As far as our studies have gone — and they have been limited mainly to the youngest amoeboid forms and the crescentic and ovoid bodies — they agree entirely with the results of the Italian observers. The youngest forms are represented by extremely delicate blue rings, each of which has a small deeper staining spot at one point on the periphery. In the more advanced bodies with central pigment block (pre-segmenting forms), the proto- plasm, according to Bastianelli and Bignami, stains diffusely blue, the deeper staining spot having entirely disappeared. Later it is noted that the parasite stains more markedly at its periphery, and finally individual deeper colored spots begin to appear, which eventually become the more deeply staining chromatin granules of the fresh rings. The crescents stain more palely than the other parasites. The poles take a pale bluish color, while in the centre of the parasite, in the region where the pigment granules are usually collected, there is a colorless space. There is, however, as a rule, no deeper staining chromatin spot to be made out. The color of the parasite itself in specimens stained with eosin and methylene blue is often not a pure blue, but of a somewhat lilac tint. * Bull. d. R. accad. med. d. Roma, xx, 1893-'94, p. 151. \ Op, cit. '78 LECTURES ON THE MALARIAL FE^^RS. The crescent is always surrounded by a slightly reddish border, which may be clearly distinguished as the remains of the red blood-corpuscle in which it has developed. It is doubtless in part this membrane which gives the crescent its peculiarly refractive double outline. For a more minute description I must refer you again to Bastianelli and Bignami. Concerning the Nature of the Flagellate Bodies. — Many views have been held concerning the nature of the flagellate bodies which are observed in all forms of malarial fever. Laveran,* the discoverer of the parasite, believes that they represent the final and most perfect stage of develop- ment of the organism. He calls attention to the remarkable regularity in the shape of the flagella, to their extraordinary activity, to the power of individual motion which they possess when separated from the central body. He believes that the flagella are preformed elements which have developed within a cyst, represented by the growing parasite. The same view is held by Danilevsky f concerning similar bodies observed in birds. Dock X likewise considers them " resting states of the organism, capable of existing independently, perhaps even of reproducing themselves, but also capable under favorable circumstances of reproducing the typical growth of the para- site." Mannaberg * also believes that the flagella represent " or- gans which permit the parasite to enter into a saprophytic existence." " I suspect," says he, " that the flagellate bodies enter upon the first steps of a cycle of existence outside the * Op. cit. X Op. cit. f Cent. f. Bakt., 1891, ix, 397. * Op. cit. THE H^MOCYTOZOA OF MALARIA, Y9 human body, and that as a result of the unfitting culture medmm the death of the young spores occurs." Golgi * considers the flagellate bodies to be a passing phase in the development of the crescents. He appears to suggest that they are degenerate forms. Antolisei was strongly of the opinion that flagellation is a degenerative process. He noted particularly that in the ter- tian parasite the flagellate bodies develop only from the large, swollen extra-cellular forms of the organism. These forms, he asserts, never segment, but undergo only degenerative changes — fragmentation, vacuolization, and flagellation. He believes the flagella to be sarcodic prolongations of the pro- toplasm. He asserts that he has seen vacuolization of the flagellate body itself. Grassi and Feletti f believe also that they are purely de- generative forms, representing changes exactly similar to those occurring in the red corpuscles when subjected to high temperatures. Marchiafava and Celli ^ and their school are of a like opinion. They call attention to the fact that the flagellate bodies in tertian and quartan fever develop only from the large, full-grown extra-cellular forms. These large forms, they assert, as did Antolisei, never go on to segmentation, but show only degenerative changes — vacuolization, fragmenta- tion. In sestivo-autumnal fever the flagellate organisms develop only from the round bodies, which in turn come from the ovoid and crescentic forms. These bodies also, they say, are never observed to segment, and, with the exception of the flagellation, show only processes of vacuolization and pseudo- * Oj). cit, f Op. cit. X Op. cit. 80 LECTURES ON THE MALARIAL FEVERS. gemmation- (fragmentation), which are degenerative in nature. The analogy, they assert, between these processes is so close that there can be no doubt that flagellation is a purely degen- erative change. Sakharov * has recently advanced a very ingenious hypoth- esis, which, however, needs confirmation. He believes that he has demonstrated that the flagella represent the chromatic filaments of the nucleus of the parasite ; that the process of flagellation represents a perversion of karyokinesis, the chro- matic filaments breaking loose from the body and appearing as the mobile flagella. Manson f has recently reasserted the view that the flagella represent the forms in which the malarial parasite exists out- side of the human body. This supposition he first made in 189-i. He believes that the interesting observations of Eoss form suggestive evidence in favor of this view. Ross placed mosquitoes upon individuals whose blood contained crescentic, ovoid and round bodies, and observed flagellation of these forms in blood taken later from the stomach of the mosquito. This interesting though insufficient evidence has led Manson to assume that the mosquito is a normal intermediate host in the life history of the malarial parasite. Thus, with all the work that has been done, we can not as yet assume that the true nature of the flagellate bodies is en- tirely understood. The arguments of Marchiafava and Big- nami in favor of the degenerative nature of the flagella are certainly strong. It is trua^that regenerative processes are probably never seen in those forms of the parasite from which flagellate bodies develop, the large extra-cellular bodies in tertian and quartan fever, and the crescentic forms in sesti- * Cent. f. Bakt., xviii, 1895. f Lancet, 189G, i, pp. 695, 751, 831. THE HiEMOCYTOZOA OF MALARIA. 81 vo-autumnal fever, while degenerative changes are common. Moreover, it is true that these bodies show no evidence, on staining, of the structure which many believe to be the nucleus. Extremely suggestive that these changes are evidences of degeneration is the fact that the flagellate forms rarely, if ever, appear until after the specimen has been for some little time upon the cover glass. In human beings this is usually from five or ten to fifteen minutes. In certain forms of parasites in the blood of birds it is extremely interesting to observe the formation of flagella. We have never seen these immediately after making a speci- men of blood, but one may often observe the change to the flagellate state, within five minutes, of perhaps four or five parasites in one field. Such a picture certainly suggests that the change is due to deleterious external influences. On the other hand, the regularity of the shape of the flagella, their extraordinary power of individual motion, the suddenness with which they break forth, apparently formed, from the full-grown body, make it really difiicult to believe that they are not preformed elements, whatever the signifi- cance of the process may be. As yet no one has confirmed Sakharov's assertions that they represent the chromatic filaments of the nucleus, while Hanson's idea can scarcely be regarded as more than an inter- esting hypothesis. 82 LECTUEES ON THE MALARIAL FEVERS. GENERAL CONDITIONS rNDER WHICH THE MALARIAL FEVERS PREVAIL. Distribution. — The malarial fevers occur in all parts of the world, but are more frequent in tropical and warmer tem- perate climates. While extensive epidemics and pandemics of malaria have been described, there are certain main foyers of the disease where it has been endemic from all time. These regions, where the most severe forms of malarial fever are seen, are for the most part in the tropics, the disease be- coming less frequent as the temperate and cooler climates are approached. The exact geographical limits within which the malarial fevers exist are very hard to determine, all the more so in that the diagnoses on which the statistics are based are often unreliable. According to Colli,* cases have been ob- served at Ii'kutsk, in Siberia ; Haparanda, on the Gulf of Both- nia (65'5° north latitude) ; Julianshaab, in southern Green- land; ISTew Archangel, in Alaska (ST'S^ north latitude). To the south the disease has been reported as far as the isotherm -fl6°.t The chief endemic seats of malaria lie along the banks and about the deltas of great rivers. In this continent the malarial fevers are frequent in the low regions along the coast south of ]^ew York, while of late the milder forms have not infrequently been observed in southern New England. In the Gulf States, and particularly along the Mississippi and its tributaries in the south and southwest, the most severe forms of the disease are met with. In certain regions about the * Verhandl. d. X. Internat. med. Cong., Bd. v, Abth. xv, 68. f This would pass through the southern part of the Argentine Republic, through Cape Town in .Africa, and about through the most northern point of New Zealand and the southern part of Australia. CONDITIONS UNDER WHICH MALARIA PREVAILS. 83 Great Lakes in tliis country and in Canada, as well as in some of the Middle States, the milder forms are not uncommon. On the Pacific coast malarial fevers occur, though they are less frequent. In Mexico, Cuba, and Central America, as well as in the tropical parts of South America, the most severe forms of the disease are seen. This is particularly true of Guiana and Brazil, while the fatal Chagres fever of Panama is well known. In Europe the disease is common in the lowlands about the coasts of Italy, Sicily, Greece, and on the borders of the Black and Caspian Seas. It is particularly common in the lowlands bordering on many of the great rivers ; about the Tiber, Danube, Yolga, and Po. In Spain, in certain regions about the coast, in several districts in France, Sologne, Les Landes, Le Forez, in Holland and Belgium, the milder forms of the disease are to be seen. About the mouth of the Elbe and on the Baltic coast of Prussia, in Silesia, on the plains of the river Mark, and in Pomerania, occasional mild forms of ma- laria occur. In Austria cases occur along the Danube and on the coast of Dalmatia. In tropical Africa the malarial fevers are everywhere met with in their worst forms. In India, Ceylon, southern China, and the East Indies the disease is frequent. In Japan, on the other hand, malaria is rare, and in some of the South Sea islands, despite the climate and telluric conditions, the disease is infrequent. This is true of Australia and ISTew Caledonia, while in the Sandwich Islands, Samoa, JSTew Zealand, and Yan Diemen's Land the disease is unknown. Effect of Climate^ Seasons^ Time of Day. — From this gen- eral summary of the distribution of the malarial fevers it may be readily seen that warmth is important for the development 84 LECTURES ON THE MALARIAL FEVERS. of the disease. Thus in temperate climates malaria appears only during certain seasons of the year. In the tropics the disease is endemic throughout the year, but passing north- ward there is a diminution in the cases occurring during the winter months, until in temperate climates, as in Baltimore, they are almost entirely absent during the months of January and February, becoming gradually more frequent from this time on, until the maximal number of cases is seen during the months of August, September, and October. In the four years from January 1, 1890, to January 1, 1894, four hundred and ninety cases of malarial fever were observed at the Johns Hopkins Hospital. These cases were distributed through the seasons as follows : January, 9 ; February, 8 ; March, 8 ; April, 17 ; May, 21 ; June, 18 ; July, 38 ; August, 6Q ; September, 122 ; October, 120 ; November, 38 ; December, 25. Total, 490. In like manner, the seasons have an influence on the typo of the fevers which occur. In the more severe malarious dis- tricts all types of the parasites and of the fevers are to be seen throughout the season, but as we approach the temperate climates it is to be noted that the few infections occurring early in the malarial season are of the milder types — tertian and quartan. Moreover, the earlier the season of the year, the less is the likelihood to infection with multiple groups of parasites ; single tertian and quartan infections are the rule. As the season advances double tertian and double and triple quartan infections become more common, and finally toward the height of a malarial season infections with the sestivo- autumnal parasite begin to appear. In Baltimore, sestivo. autumnal fever forms the majority of the cases occurring dur- ing September and October. A few tables from a recent publication by Hewetson and CONDITIONS UNDER WHICH MALARIA PREVAILS. 85 the author will illustrate this point. Out of five hundred and forty-two cases of malarial fever observed at the Johns Hop- kins Hospital, there were in the first half year : rr, ,. . f .. (Single 63 Tertian infection. -^ ^^v , , ( Double 49 — 112 i Single 1 Double Triple — 1 JEstivo-autumnal infection , 5 Combined infections 3 — 8 Total 121 While in the second half year there were : Tertian infection. J t^ , , i Double 139 226 / Single 1 Quartan infection. \ Double (Triple '. 3 — 4 -^stivo-autumnal infection 183 Combined infections 8 — 191 Total 421 These tables show in an interesting manner how the sever- ity of the type of infection increases as the summer and fall approach. Thus in the first half year there are more single than double tertian infections, while in the second haK year, when malarial fever assumes a more severe type, there are nearly twice as many cases of double tertian as of single tertian infection. The increase in severity of the malarial fevers be- comes more evident when we ol serve the course of thesestivo- autumnal cases. While in the first half year only five cases were noted — a little less than one twenty-fourth of the total 86 LECTURES ON THE MALARIAL FEVERS. number of cases observed — in the second half year we see one hundred and eighty-three cases, or nearly half of all the cases which occurred. Thus it may be seen that with the earliest cases of mala- rial fever in the year the mildest types of infection are met with, the single tertian type predominating. As the season advances and the months approach which are richest in mala- ria the single tertian cases become less frequent and the double tertian infections more common ; while at the height of the malarial season a majority of the cases are of the gestivo- autumnal, the most severe type in this climate. It seems to be a well-established fact that the danger of malarial infection is greater by night than by day. The Influence of Moisture. — A very important part in the development of malaria is apparently played by moisture. Almost all the regions where the malarial fevers are regularly endemic are low and marshy or situated about the banks of rivers or lakes. Mixed salt and fresh marshes appear to be particularly dangerous. Rainy seasons are, as a rule, more dangerous than others. Likewise regions where the atmos- pheric moisture is high are generally more malarious than arid districts. Soil. — A damp, marshy region, with an impervious sub- soil, is generally recognized as particularly dangerous. A re- gion rich in organic matter, such, for instance, as is furnished by highly cultivated areas which have been allowed to fall into ruin and are covered with a rank, tropical vegetation, are especially to be feared. On the other hand, fevers may be observed in almost any district and upon sandy or even rocky strata. Marshy regions and districts where the surface of the ground is covered for a part of the time only with water are often rich in malaria. CONDITIONS UNDER WHICH MALARIA PREVAILS, 87 Small islands are, as a rule, healthy. Malarial fevers never arise at sea. Those cases reported owe their infection, doubtless, to exposure before leaving land. Altitude. — The more severely malarious districts are all in lowlands, while the higher regions are usually relatively exempt from the disease. In many malarious districts sana- toria have been established upon hills and mountains in the neighborhood. The exemption of these regions is not, how- evei', an absolute rule. Parkes states that the malarial fevers have been observed in the Himalayas at an elevation of 6,400 feet, while Hertz * asserts that they have been found in the Tuscan Apennines at 1,100 feet, in the Pyrenees at 5,000, in Ceylon at 6,500, and in Peru at a height of from 10,000 to 11,000 feet. In connection with some of these statements one should, however, remember the looseness with which the diag- nosis of malaria is often made. It is still common to see the so-called " mountain fevers " referred to as malarial. These fevers are undoubtedly, in great part at least, typhoid. In a malarious district it has been shown that the dangers of infection are greater to one sleeping upon a lower floor of the house than to one living in an upper story. In regions severely malarious, new-comers, inhabitants of temperate and non-affected regions, are particularly suscepti- ble to the disease. Prolonged residence in malarious districts does not, however, give the white race the relative insuscep- tibility which the colored races generally possess. Prank, out- spoken attacks are said to be somewhat less frequent in old residents, but when they do occur they are usually more severe and intractable. Some observers believe that a sudden change of climate * Zierassen's Cyclopeedia. 88 LECTURES ON THE MALARIAL FEVERS. from a malarious to possibly a non-malarious district predis- poses to a fresh outbreak of the disease. In certain instances outbreaks of the disease may occur in districts quite free from malarial fevers in individuals who have never previously suf- fered from the disease. This has led to the sujDposition that many individuals in malarious districts may actually be the subjects of completely latent infections. That the malarial parasite may exist for long periods of time in the organism without producing symptoms is abundantly proved by the relapses which occasionally occur after very long intervals in cases where a second infection has been practically impossible. Bearing in mind the occurrence of these relapses after very long intervals, one must acknowledge that there is no reason, theoretically, why sometimes a relapse might not simu- late a primary attack. An individual might well be the sub- ject of an infection from which spontaneous recovery might occur before the parasites had reached a number sufficient to produce distinct subjective symptoms. A relapse from such a case as this would of course be considered as the original attack. There are facts which might lead us to suspect that cases of this nature occur. Most of the instances of ma- larial fever developing in individuals who have moved into healthy regions are, however, probably cases where the infec- tion occurred shortly before leaving the affected district — cases where the symptoms would have appeared under any circum- stances. It has also been asserted that in expeditions in tropical Africa, attacks of j)ernicious malarial fever are particularly frequent at the end of long journeys after reaching the coast, while during the expedition, despite the exposure and exertion, the liability to such outbreaks is less. The reason for this fact — if fact it be — is not clear. CONDITIONS UNDER WHICH MALARIA PREVAILS. 89 Winds. — There seems to be some reason to believe that the contagion of malarial fever may be carried by the wind. Thus, it is noticed that of the two banks of a stream in a ma- larious district, that side toward which the prevailing winds blow is often the more affected. It has been brought for- ward as a proof of this, that strips of forest land seem some- times to interrupt the spread of the disease, as if some infec- tious substance were filtered out. Lancisi * believed that it was through the sacred groves, the removal of which was followed by a marked increase in the severity of malaria in the Roman Campagna, that this region had been protected. The winds blowing over the Pontine marshes and carrying the contagion of paludism were purified, he fancied, as by a filter, by passing through these trees. Effects of interfering with the Soil in Malarious Dis- tricts / Cultivation / Drainage. — Most disastrous results have followed the denudation of forest lands in tropical and marshy regions, while, in the main, forest regions, however moist and hot they may be, are relatively salubrious. In the same man- ner, excavations and turning up of the soil may cause out- breaks of malaria in regions where the disease has not existed for 3^ears, or it may aggravate the manifestations in districts where it is permanently endemic. In Paris, in the years 1811 and 1840 during digging the Canal St. Martin and during the construction of the fortifications, outbreaks of intermittent fever occurred where the disease had been for a long time practically unknown. The disastrous effects of the excava- tions for the ill-fated Panama Canal are fresh in the minds of all. On the other hand, cultivation and drainage may do much * Op. cit. 90 LECTURES ON THE MALARIAL FEVERS. toward purifying gravely malarious districts. The drainage, for instance, of the Roman Campagna has greatly improved its condition. The lowlands of Holland were at one time the seat of the most fatal malaria ; to-day only the mildest forms of the disease occur. London used to l)e surrounded by a marshy district where paludism was not infrequent ; now it is unkno^vn. Besides other measures to secure drainage, the planting of trees has often a good effect in rendering an infected region more salubrious. At one time the Eucalyjjtus globulus was thought to possess special virtues from a pi-ophylactic point of view, though its particular efficacy is doubtful. If, however, highly cultivated regions are allowed to fall into decay, the reappearance of malaria in its worst forms is not infrequent. An example of this was the condition into which the Koman Campagna fell after the Augustan era. While the malarial fevers are especially common in trop- ical regions, becoming less frequent as one approaches the temperate climates, and while they occur especially in low, marshy districts about the borders of large rivers or lakes, there are yet remarkable exceptions to this rule. As has been stated, certain south Pacific islands, regions which possess every climatic and telluric characteristic of the most malarious districts, are absolutely free from the disease. This is no proof, however, that the disease, once introduced, might not become widespread and fatal. It is highly probable that, were the infectious agent once brought to these regions, this would be the case, DrinMng Water. — It has long been a widespread view that drinking water is a common source of malarial infection. Many statistics would tend to support this theory. Unfortu- nately, however, many of the so-called malarial infections CONDITIONS UNDER WHICH MALARIA PREVAILS. 91 which become less frequent on purification of the drinking water are probably cases of typhoid fever, while, on the other hand, every experimental attempt to produce malarial fever from drinking water has failed. Celli * allowed six individuals to drink large quantities of water from the Pontine marshes through a considerable time, wholly without effect, while Marino f had similar results from like experiments. Zeri,:j; in Baccelli's clinic, experimented in thirty cases with the administration of water from most malarious sources with- out a single positive result. The water was taken by the pa- tients in large quantities by the mouth, by enema, and as an inhalation. Grassi and Feletti * allowed healthy individuals to drink dew collected from malarious regions without ill effects. They also caused healthy men to drink fresh blood from malarial patients, and fed birds of prey on infected birds, without ob- taining any satisfactory results. This is, of course, no proof that the parasite in some form or other may not live and even multiply in water ; it is, however, strong evidence that infec- tion does not ordinarily take place in this manner. It must be remembered in connection with all inoculation experiments that the individuals upon whom the inoculations are practiced, though in some instances they may be debili- tated, have always been in hospitals or under conditions where they were receiving the best general care and nourishment. And one could not absolutely refute him who might suggest that the infection would have developed had the patient been * Bull. d. Soc. Lane. d. Roma, 1886, vi, f. i, 39. f Riforraa medica, 1890, No. 251, 1503. i Bull. d. R. ace. med. d. Rom., 1889-'90, xvi, 244. * Op. cit. 92 LECTURES ON THE MALARIAL FEVERS. under poorer surroundings, or, perhaps, had previous lesions of the gastro -intestinal tract existed. It is interesting that nearly twelve per cent (11*9) of the cases of anuBbic dysentery treated at the Johns Hopkins Hospital have suffered simul- taneously with malarial infection. Yariatiotis in the Distribution of the Malarial Fevers. Cycles of Severity. — The manner in which the malarial fevers pass from one region to another has long excited interest. Regions which have been malarious for a long period may be- come relatively healthy, while others, after years of almost complete immunity, may be visited by grave epidemics. Many of these changes in the localization of malaria are due to human activity, but others are as yet inexplicable. In like manner, regions where the disease is permanently en- demic show remarkable cycles of years' duration in which the disease is more or less severe — cycles which often are quite inexplicable. Race. — In general, the dark-skinned races who have in- habited southern countries for generations appear to possess a certain insusceptibility to the disease. In this country the negroes are certainly relatively less affected than the whites. FronC'the cases analyzed- by Hewetson and the author, the relative susceptibility of the negro would seem to be by neai-ly two thirds less than that of the white. Age. — The influence which age bears upon the suscepti- bihty to malarial infections depends wholly upon the extent to which it affects the likelihood of the individual to exposure. The very old and the very young are less affected, as they are more likely to remain in the house during the more danger- ous parts of the day and during malarial seasons. Sex. — In like manner, women are less frequently affected than men, because they are less frequently exposed. CONDITIONS UNDER WHICH MALARIA PREVAILS. 93 Occupation. — The influence of occupation on the frequency of malaria depends also wholly on whether or not the individ- ual be compelled to expose himself at dangerous seasons of the year or at dangerous times of the day in malarious districts. Soldiers and tramps who sleep upon the ground out of doors in malarial seasons are particularly liable to the disease. In this country, fishermen and oystermen who live about the bays and inlets on the southern coast are especially open to infec- tion. This is also true of the farm hands in the same regions. Manner of Infection. — Despite all recent studies upon the malarial parasite, we are in complete darkness as to the form in which it exists outside of the human body. In like manner oar views as to the form in which it is introduced are wholly speculatory. Infection has been supposed to take place through : (1) The respiratory tract. (2) The digestive tract. (3) The skin (insect bites, etc.). (1) Clinical observation would lead us strongly to believe that the most frequent method of infection is through the respiratory tract. ]S^o positive proof, however, of this fact has ever been obtained. Most attempts at inoculation which have been carried on in birds which possess a parasite closely similar to that of man have proven unsuccessful. The au- thor has recently made an unsuccessful experiment in this line, which has been above referred to, namely, the inhala- tion of dried and powdered malarial blood. It is, however, in every way probable that the parasites were destroyed in the preparation of the powder, (2) All attempts to introduce malarial infection by the di- gestive tract have been wholly without result. (3) Inoculation experiments have given us positive proof 94: LECTURES ON THE MALARIAL FE^T^RS. that infection may take place by subcutaneous injection of living malarial parasites, while the interesting results of Theobald Smith, who showed that the organism of Texas cattle fever {Pyrosoma Bigeminum) is conveyed from ani- mal to animal by means of the cattle tick, are suggestive evidence of the possibility of some such method of transmis- sion in the case of the similar parasite in man. This question has recently been brought prominently for- ward in Manson's Gulstonian lectures. On the basis of the observation of flagellate bodies in the stomach of a mos- quito which had been placed on an individual whose blood showed ovoid and crescentic forms, Manson suggests that the malarial parasite may pursue a regular extra-corporeal exist- ence, the mosquito, as in the case of the Filaria sanguinis Jhominis, forming the intermediate host. The individual flagella are, according to him, forms intended to live outside of the human body. As an hypothesis, Manson's idea is interestino;, thouo;h it must be acknowledged that it is seri- ously lacking in foundation. Bignami,* in an excellent review of Manson's article, goes over the subject of the manner of infection in malaria in an highly interesting manner. He points out the fact that almost all the conditions which are known to be conducive to malarial infection are at the same time favorable to the presence of certain suctorial insects, more particularly mos- quitoes — the absence of wind, the night, etc. He asserts that many of the precautions that experience has taught the natives in malarious districts to adopt — namely, to avoid going out at night, to avoid sleeping in the open air, to close the windows — are just such as would protect them from in- * Lancet, 1896, ii, 1363, 1441. CONDITIONS UNDER WHICH MALARIA PREVAILS. 95 sect bites. Emin Pasha never failed to take a mosquito net with him on his African journeys, and attributed the fact that he was spared a malarial attack to this precaution. And yet such experiments as have been made have not been successful. Thus, on two occasions Bignami and Dionisi placed mosquitoes collected in malarial districts upon healthy individuals without positive results. Bignami believes that the most important point to study is not, as Manson has sought to do, to attempt to follow the parasite from the human body into the external world — for we do not know that this ever occurs — but to search for the port of entry, which must certainly exist. On the whole, it must be said that we are absolutely ig- norant of the form in which the malarial parasite exists outside of the human body, and equally ignorant of the manner in which it enters. Congenital Malaria. — It has been a disputed point for years as to whether malaria can or can not be transmitted from the mother to the foetus. The possibility of such an occurrence seems not wholly unreasonable, in view of what we know to exist in the case of certain bacterial infections. Many observers assume this to be the case, but positive proof is as yet wanting. Among a number of doubtful cases in literature, the most positive appears to be that of Duchek, reported by Griesinger.* In this instance the child born of a malarious mother died shortly after birth, presenting, on autopsy, an enlarged pigmented spleen, and showing, further, pigment in the portal vein. Since the discovery of the parasite, however, no one has been able to bring positive evidence of the congenital pres- * Traite des maladies infect., 3 edit. (French translation, 1877, p. 20). 96 LECTURES ON THE MALARIAL FEVERS. ence of parasites in tlie blood of the newborn child, or of the development of tiiie malarial fever in the infant where the possibility of post-partum infection was out of the question. On the other hand, a number of instances have been reported where, in abortions occurring during pernicious malarial in- fections, the foetus w^as found quite free from parasites. Bignami reported two cases of abortion during pernicious paroxysms, one at the third and the other at the sixth month. The mothers died, and while the organs of the parent in each instance presented the appearances usual in pernicious fever, in neither case did the foetus show organisms or any sign of a previous infection. Bastianelli also made an autopsy upon a woman dead of pernicious fever who had aborted at the sixth month. The mother's organs contained an abundance of parasites and pig- ment, while the child, upon careful examination, showed neither parasites, pigment, nor evidences of an antecurrent infection. Withm a few days I have had occasion to observe an interesting case of similar nature. A colored woman with triple quartan fever {vide Chart ISTo. IX, page 128) gave birth during a paroxysm to an eight-months' child. The infection in the mother's case had lasted at least five months. While the blood of the parent showed three groups of the quartan parasite, the child's blood, upon repeated examination, was quite free from parasites or pigment. Examination of the placenta showed pigment and parasites upon the maternal side, while the foetal side was quite negative. While some of the cases reported are certainly somewhat suspicious, we must wait for more positive evidence before we can assume the possibility of the transmission of malaria from mother to child. LECTUEE lY. CLINICAL DESCRIPTION OF THE MALARIAL FEVERS. Types of fever. — Period of incubation. — 1. The regularly intermittent fevers : (a) Tertian fever ; (b) quartan fever. — 3. -^stivo-autumnal fevers. Types of Eever. — The malarial fevers may be divided into two main classes : 1. The regularly intermittent fevers : (a) Tertian fever ; (5) quartan fever. 2. The more irregular fevers : ^stivo-autumnal fevers. The regularly intermittent fevers are to be met with in all malarial districts, and form the majority of the cases occur- ring in temperate climates. The more irregular, so-called sestivo-autumnal fevers, on the other hand, are chiefly char- acteristic of intensely malarious distric^ts, particularly those regions in the tropics where the pernicious fevers are com- mon. As one passes toward the temperate climates sestivo- autumnal fever becomes rarer and is met with only at the height of the malarial season, until finally, in the more mildly malarious districts, it is very rarely to be seen. In the warmer temperate countries the first cases of fever, those occurring during the spring and early summer months, are almost entirely of the regularly intermittent types, while in the later summer and early fall the more irreg- ular forms begin to appear ; hence the name " sestivo-autumnal fevers," given to them by the Roman observers. The relation 97 98 LECTURES ON THE MALARIAL FEVERS. of the different types of fever to the times of the year is well shown by the tables upon page 85. Period of Incubation. — By the period of incubation we must understand the time elapsing l)etween the reception into the organism of the infectious material and the lirst subjec- tive symptoms. This represents, in other words, the time required for the malarial parasites to reach by multiplication that number necessary to produce the symptoms of the dis- ease. As we are as yet quite ignorant of the form in which the malarial parasite exists outside of the body as well as of the port of entry and the exact conditions under which infec- tion occurs, it is but natural that our knowledge of the period of incubation of the malarial fevers should be indefinite and uncertain. In the acute contagious exanthemata, where we are equally ignorant as to the nature of the poison and the manner and port of infection, we are yet able in many instances to defi- nitely fix upon the moment of exposure. In the case of the malarial fevers, however, this is in the majority of in- stances impossible. Careful clinical observations have, how- ever, given us data which are of considerable accuracy and value. It has been estimated by most observers that the period of incubation — i. e., the time passing between the supposed ex- posure and the first symptoms of the disease — lasts from six to twenty days. It has, however, been asserted that in some trop- ical regions where pernicious fevers are common the paroxysm may appear \vithin a few hours of exposure. On the other hand, cases are reported where many weeks, and even months, have elapsed after exposure before the outbreak of the disease. Bloxail reports an instance where a man-of-war spent five days in the harbor of Port Louis. As a result, apparently, of CLINICAL DESCRIPTION OF MALARIAL FEVER. 99 this exposure, two of the crew fell ill with quotidian inter- mittent fever at the end of respectively twelve and fourteen days. Two other cases of tertian fever, however, occurred forty-eight and one hundred and sixty-four days after em- barkation. Kecent experimental inoculations have furnished interest- ing information with regard to some of these points. In these instances, where the blood of the patient is introduced hypodermically or intravenously into healthy individuals, the period of incubation ranges from two to eighteen days. Bas- tianelli and Bignami have recently published an admirable note upon the period of incubation of the experimental mala- rial fevers. They conclude that " The period of incubation with one variety of parasites varies inversely to the quantity of material inoculated. . . . " The period of incubation represents the time necessary for the inoculated parasites to reach, by multiplication, the quantity necessary to determine the fever, . . . " The mean and minimum periods of incubation under similar conditions vary in the different groups of fevers ; they are least in the sestival fevers, longer in the tertian, and still longer in the quartan. . . . " The period of incubation in experimental malarial infec- tion is not a constant quantity, but varies in the same group of fevers and in different groups of fever. In the same group of fevers it depends chiefly upon the quantity of the inoculated material. In different groups of fevers it varies with the rapidity of the cycle of development of the organism and with the special capacity for reproduction of the type of the parasite." These authors prepared a table on the basis of their own observations and those of others, showing the variations in 100 LECTURES ON THE MALARIAL FEVERS. the period of incubation of the several types of malarial infection : Quartan fever Tertian fever iEstivo-autumnal fever. Maximum (cbiys). Minimum (daj's). 15 12 5 11 6 2 Mean (days). 13 10 '6 It is interesting to note how closely the period of incuba- tion in these experimental infections agrees with the time which clinical observation has shown to elapse between sup- posed infection and the outbreak of the disease. Particularly interesting is the demonstration that in sestivo-autumnal fever, from the inoculation of two cubic centimetres of blood, cHn- ical symptoms may appear in as short a time as forty-eight hours.* It is but natural to assume that with a given variety of parasites the period of incubation should vary greatly, not only according to the quantity of the infectious material absorbed by the individual, but also according to the time of the year, the conditions under which the infection takes place, the physical condition of the patient himself, and the special virulence of the parasite. Are we justiiied, then, in assuming that in certain instances the period may be as short as several hours, and in others as long as one hundred and eighty-four days ? I^either of these extreme estimates can be said to be proven. In the present state of our knowledge we can not deny the possibility of the * Celli and Santori (Centralblatt f. Bakt., xxi, 1897, 49), in an experiment to determine the incubation period of malarial fever in individuals previ- ously treated with the serum of animals immune against the disease, ob- served the development of fever with parasites in the blood thirty hours after the subcutaneous inoculation of 1'5 centimetres of blood from a case of aestivo-autumnal fever. CLINICAL DESCRIPTION OP MALARIAL FEVER. IQl appearance of symptoms within twenty-four hours after infec- tion. We know parasites whose entire cycle of existence lasts only twenty-four hours, or even less. It is not unreasonable to suppose an infection with so many and so virulent parasites that the very first period of sporulation might be accompanied by well-marked subjective symptoms. Indeed, one is almost tempted to assume this as a probability. The assertion, how- ever, that the disease may appear within a few hours after the first exposure needs confirmation. It is possible that the febrile attacks which occur some- times immediately after exposure at night in damp, marshy, malarious districts may have some other cause than actual malarial infection. Thus, Plehn describes cases where, after exposure at night in very severely malarious districts in West Africa, there was an immediate paroxysm in every way similar to those of malaria, which, however, did not recur until the appearance, ten days later, of a true malarial fever, which doubtless dated its origin to the night of exposure. At the time of the first paroxysm the blood was negative ; the para- sites — sestivo -autumnal — appeared ten days later with the usual symptoms of the disease. How are we to explain those cases where an excessively long period elapses between exposure and the manifestations of the disease ? It is certainly improbable that this long time represents a true period of incubation. One can scarcely imagine that the parasites should exist in the circulation, pass- ing through their regular cycle of existence for periods of months, without ever reaching a sufiScient number to produce any clinical symptoms. It is probable that we must fall back upon another explanation, which, to be sure, is purely hypo- thetical. We must probably assume that in these cases spon- taneous recovery from the infection occurs before the para- 102 LECTURES ON THE MALARIAL FEVERS. sites have reached a sufficient quantity to give rise to symp- toms. The germs, however, of the infection remain within the organism in some form which is as yet unknown to us, possibly, as Bignami suggests, as encapsulated spores within the bodies of phagocytes. In such an individual insults of various sorts — over-exertion, exposure, debility dependent upon any exhausting process — may be the exciting cause of an awakening of these slumbering germs, which, undergoing rapid multiplication, give rise to an outbreak of typical mala- rial fever at a period long after possible exposure. In conclusion, then, we may assume that : (1) The incubation period of malarial fever is very varied, depending (a) upon the type of the potential parasite absorbed at the moment of infection, upon its capacity for rapid multi- plication, and upon the quantity of infectious material ab- sorbed ; (h) upon the conditions under which infection takes place, climate, season of the year, and hygienic surroundings ; (c) upon the physical condition and surroundings (and race ?) of the infected individual. (2) Clinical observation and experimental inoculations would tend to show that the period of incubation of the mala- rial fevers may vary from twenty-four hours, or even a little less, to several weeks. The period is shortest in sestivo- autumnal infection, longer in tertian, and longest in quartan fever. (3) How short the period of incubation may be has not been ascertained. By analogy it is reasonable to suppose that in some instances it may be as short as twenty -four hours, or a little less. (4) In cases where very long periods of time, months or years, expire between exposure and the first manifestations of the disease, we must probably assume that spontaneous recov- CLINICAL DESCRIPTION OF MALARIAL FEVER. 103 ery has occurred with the survival of the parasite in some more resistant form as yet unknown to us — a process similar probably to that which occurs in cases of relapse after long periods of time. 1. THE EEGULARLT INTERMITTENT FEVERS. — («) TERTIAN FEVER. Single Tertian Infections. — Tertian fever is by far the commonest variety of malarial infection in the temperate cli- mates. It is the form of the disease most frequently met with on the eastern coast of the United States. In single tertian infections we have to do with the presence in the blood of one group of the tertian parasite, an organism which passes through its cycle of existence in about forty-eight hours. As has been pointed out in the description of the parasite, tertain infections are characterized by the aggregation of the organisms into groups, all the members of which are at the same stage of development, and pass through their cycle of existence in unison. Thus, the periods at which successive generations of . parasites reach maturity and undergo sporula- tion occur every other day at intervals approximately forty- eight hours apart. As will be remembered from what has been said in the description of the parasite, the sporulation of such a group of organisms is always followed by a par- oxysm of fever, provided only that the number of parasites has reached by multiplication a quantity sufficient to produce clinical symptoms. Thus, if the blood contain but one group of tertian para- sites the clinical manifestations will be tertian intermittent febrile paroxysms. Clinical Sytnptoms. — Prodromata. — For several days before the occurrence of an actual paroxysm the patient may 104 LECTURES ON THE MALARIAL FEVERS. complain of indefinite symptoms of headache, backache, anorexia, pains in the Hmbs — symptoms such as are common in any acute infection. Usually it may be noted that these symptoms occur on alternate days, and often in the morning ; on the day between the patient may feel quite well. In ex- amining the charts of patients in whom malarial fever has developed in an hospital ward, we may almost always trace slight febrile elevations occurring before the first actual par- oxysm — elevations which had passed quite unnoticed. On the other hand, the first paroxysm may come without warning upon an individual in apparently perfect health. The Paroxysm. — The paroxysm may be divided into three characteristic stages : (1) The chill. (2) The fever. (3) The defervescence or sweating stage. The Chill. — Especially characteristic of the malarial paroxysm is its very sudden onset. Often the slight pro- dromata which have been mentioned may be quite absent, and the first symptom which the patient notices of his illness may be the onset of a sharp paroxysm. The actual chill is, however, usually preceded by some indefinite symptoms of mMaise, headache, and slight feelings of general lassitude; often repeated yawning and stretching may be observed. Sometimes there is a little giddiness, and there may be at the very beginning, nausea and vomiting. Frequently at this period a slight rise in the body temperature has already set in. These symptoms are usually followed rapidly by chilly sensations, beginning sometimes in the hands and feet, and running up and down the back. These chilly sensations, at first interrupted by slight flashes of heat, rapidly increase until CLINICAL DESCRIPTION OP MALARIAL FEVER. 105 tlie patient falls into a general rigor. The chill may be most severe ; the patient begs for coverings and hot applications. The actual shaking may be so violent that it is noticeable in other rooms of the house. The face is drawn and pinched ; the extremities are cold and shrunken. The skin is usually cool and cyanotic, some- times pale ; it is often moist, while the hair follicles are erect, giving rise to the characteristic "goose-flesh." The pupils are usually dilated ; the pulse is small and rapid, sometimes irregular, and often of rather high tension. The respiration is short and rapid ; the voice is broken ; nausea and vomiting are frequent ; there may be diarrhoea. The patient usually suffers extremely from headache; there may be vertigo or tinnitus aurium, and sometimes troubles of vision; aching pains in the loins are common. The duration of the chill may vary considerably, being at times as long as an hour, though usually it is shorter, from ten minutes to half an hour. Sometimes no actual shaking may occur, the patient complaining only of more or less severe chilly sensations, while at times, though rarely in this type of fever, the chill may be entirely absent. Out of 332 cases occurring at the Johns Hopkins Hospi- tal, chills or chilly sensations were present in 97*5 per cent. During the chill, despite the intense feeling of cold com- plained of by the patient and the somewhat cool feeling of the moist and cyanotic skin, the body temperature rapidly rises. The maximum point is usually reached within two hours after the onset of the paroxysm, and indeed sometimes in a much shorter time. The climax may occur at the very beginning of the second stage. The Fever. — The intensity of the chill slowly diminishes. The chilly sensations become interrupted by occasional flushes 106 LECTURES ON THE MALARIAL FEVERS. of heat, which, becoming more frequent, finally wholly replace the rigor. Then begins the second or febrile stage of the paroxysm. The patient now complains of intense heat. The skin is flnshed, hot, and dry ; the conjunctivae injected ; the pulse becomes fuller, but remains rapid and is not infrequent- ly dicrotic. The headache, vertigo, and tinnitus aurium often become more intense, the patient complaining bitterly also of general aching pains in the back and extremities. The bed- clothes are thrown aside, while the patient suffers intense thirst ; he is often very restless, tossing from one side of the bed to the other; there may be active delirium. On the other hand, the patient may be dull and drowsy, presenting an appearance not dissimilar to that in typhoid fever, while the only complaint may be of intense headache and general aching pains. Sometimes there may be marked somnolence, and in one instance deep coma has been reported. A slight cough is not infrequent, and vomiting and diarrhcea are common. Bleeding from the nose has occurred in a few of our instances. On physical examination during this period the patient is usually flushed, the conjunctivae are suffused and injected, the tongue dry and coated. There is often a slight sallow, dusky-yellowish color to the skin, a tint which is almost characteristic of malaria, and becomes after a while familiar to the skilled observer. If the fever has lasted for any length of time there is almost always a distinct anaemia, recognizable by the pallor of the lips and mucous membranes. This may be a point of considerable importance in diagnosis. The heart sounds are usually clear, though there may be a soft systolic murmur. On examination of the lungs a few sonorous and sibilant rdles may be heard. The abdomen presents no abnormalities on inspection. On percussion. CLINICAL DESCRIPTION OP MALARIAL FEVER. 107 however, a well-rmarked enlargement of the spleen is demon- strable, while the splenic border is to be felt in the great majority of instances. This has been possible in about seventy-five per cent of our cases. In fresh acute infections the border may be soft and round ; where, however, numer- ous infections have occurred, the edge is usually hard and sharp. After repeated attacks the spleen may attain a very considerable size, extending as far as or even below the umbilicus. There is often, especially in acute cases, a well- marked tenderness on palpation over the region of the spleen. Massuriany* noted the presence of a soft murmur over the splenic area which Bouchard has compared to the uterine bruit. Sometimes well-marked cutaneous manifestations may ap- pear during the paroxysm ; these may begin in the stage of the chill, but are usually more marked during the febrile period. Yarious forms of rash have been observed. The commonest, however, is urticaria, which we have observed in a number of instances. In several of the author's cases this urticarial eruption has had a most interesting morbiliform character. The eruption usually disappears with the parox- ysm. It should, however, be remembered that some of these cutaneous manifestations attributed to the malarial infection may not impossibly be due to the treatment by quinine. Herpes upon the lips and nose is very common in malarial fever, and in certain of the more irregular forms is of value from a point of view of differential diagnosis. The temperature during this period reaches its maximima point. It may be as high as 108° F. The duration of the * St. Pet. raed. Woch., 1884. 108 LECTURES ON THE MALARIAL FEVERS. febrile period is usually four or five hours, though not in- frequently it may be considerably longer. The Sweating Stage. — After the stage of fever has existed for some hours — four or five, perhaps, on the average — the se- verity of the symptoms begins to abate ; the mouth be- comes less dry, the skin begins to become moist, and pro- fuse sweating follows. This is associated with a relief from the distressing sensation of heat from which the patient has been suffering. The sweating is usually excessive ; the bed- clothes are often drenched. The temperature rapidly falls. With the fall of temperature tlie pulse likewise becomes slow and full, and the patient often sinks into a refreshing sleep. Within a relatively short time, rarely more than four hours, often as short as two, the temperature reaches the nor- mal point. It does not, however, remain here, but becomes usually subnormal, and often remains so during the greater part of the intermission between the febrile paroxysms. The length of the entire paroxysm, from the time the temperature passes 99° F. until it again reaches this point, averaged in our cases about eleven hours. The paroxysms are more fre- quent during the day than during the night, and the hour of onset occurs usually perhaps during the morning hours, though paroxysms in the afternoon and at night are not uncommon. The clinical manifestations in children may be very differ- ent from those observed in adults. Frequently l)oth the chill and the sweating stage may be quite absent or only abor- tive ; under these circumstances the first stage is generally represented by a slight restlessness ; the face looks pinched, the eyes sunken, the finger tips and toes become cyanotic and cold, while the child yawns and stretches itself. Nausea and vomiting and diarrhoea are very common. These may CLINICAL DESCRIPTION OF MALARIAL FEVER. 109 l)e the only manifestations of the first stage. Often, how- ever, these symptoms are followed by grave nervous phe- nomena. The chill in malaria, as in other acute diseases, is not infrequently represented in a young child by general convul- sions. These may begin with a slight spasmodic twitching of the eyelids or extremities, the spasm soon becoming general. The febrile stage and the whole paroxysm are often shorter in the child than in the adult, while the sweating stage may be wholly absent. In many instances, besides a slight coldness of the hands and blueness of the finger tips, and a somewhat pinched expression of the face during the first stage, the first and third stages of the paroxysm may be entirely lacking. The InterTThissiooi. — Following the sweating stage, the pa- tient passes through an afebrile period lasting usually fully thirty-seven hours. Often, during the greater part of this time, the temperature is subnormal ; it is almost invariably so during the hours following the paroxysm. After the imme- diate exhausting effects of the paroxysm have passed away, the patient very commonly feels perfectly well, so much so that he may leave his bed and go about his business. Indeed, many patients feel so well between paroxysms that they allow several to pass before seeking treatment, believing, after each paroxysm, that the fever is at an end. Almost exactly forty-eight hours, however, after the onset of the first paroxysm a second similar attack follows, the febrile periods and intermissions continuing thus with great regularity. ( Vide Charts I^o. I and XYII, pp. 110 and 171.) While, as has been said, the cycle of existence of the ter- tian parasite is about forty-eight hours in duration, and the paroxysms are approximately forty-eight hours apart, it must not be forgotten that variations of several hours in the cycle of existence of the parasite are not uncommon. Thus, not ■Nil ■ t 1? - r* •my 01 «- •HVB ^ 00 fe •H»9 - \ L < ■H-Vt s ;2 •IN-VS \ •H 3k ^ _ ^ _ ^ ";> s-s. ■HdOl ~ ~ ~ ~" ' " ' •H'd9 /''^ 3 S •Hd9 •Hd *• V 3 2 •Wd J \ P ■N SI J ,S,2 •HVOl i •H-V9 T 52 •H»9 l,^^ •H-Vt 1 X J ' " ~ •h-va L_ - / -n 31 ^ — ^ ^ — L— — / '" :^g-a ■W'dOl ^ •H-d8 r «! ?i ■H-d9 /^ •Wd* ^ r-l ■3 ri •Wd 5 — ' — •N St ■^ -^ •wvoi •^ ^ •W»9 1 V _ S2i ■WV9 s s 1 •nit > •P - •WV2 I •N Zl ' •WdOl ! ^ •Wd8 J s jj •Hd 9 / ■Wd t s 2 ■WdS 1 ^ S •NSl •( ■i;i:i •bOlHcnns •t in n , ■WVOI _J i ■wvs < ^ ■WV9 _[ ■wvt > S'w ■WVB • •n SI t^ Ls ■WdOl / ■Wd 9 < ■Wd 9 V , ■Wd t ^ > y ■Wd S •^ ri •N Zl .^ f^ 2 ■WVOI ■^ 2^ ■WV8 ■- — -J ■WV9 ^ ■\ •wvt \ ■WV5 / ^ ^ ^, _ _ _ _ ^ _ . A ^ ^ ^f ■WdOl " " " ~ ~ " " ~ ^ '^ ■N^d8 (- S •Wd 9 •Wdt / K * ■Wd S M ■N SV fi ■WVOI 1 •WV9 k s a ■WV9 V •W¥* ^ K s ■WVS r ■W SI ■WdOl / •Wd9 , y g ci ■Wd 9 U" ■ ■Wd t «-• " a£ ■Wd S r — ^1 •N SI ■J Si ■WV 01 "X ■WV9 < , S 2 •WW 9 ■wvt S 2 ■WVS •n SI 9 •WdOl v"" ^?S •Wd8 ; ' H 3 •Wd 9 ( ."•^ rS •Wd t > S - S •WdS •l i S C^ fe-« E ;:::,^rHr-ti-lr-li-lrH _] « 1- Q. "^ 110 CLINICAL DBSCEIPTION OF MALARIAL FEVER. m infrequently, a group of tertian parasites may pass through their cycle in forty -five or perhaps forty-three hours instead of in forty-eight. This results in the anticipation of the paroxysms. In other instances, particularly during sponta- neous recovery or after the taking of small doses of quinine, there may be a marked retardation. The hlood shows the presence of one group of tertian parasites. The cycle of existence of this organism may be usually well followed out in the peripheral circulation. Dur- ing and after the paroxysm small actively amoeboid, hyaline bodies may be made out within certain of the red corpus- cles. Shortly after this, very minute brownish-yellow gran- ules of pigment may be found to have appeared within the amoeboid organisms. The activity of the parasite and the dancing of the pigment is, as will be remembered, much greater than in the case of the quartan parasite, while the sur- rounding corpuscle soon begins to show evidence of expansion and decolorization. On the day between paroxysms the organisms are usually not quite half the size of an ordinary red corpuscle, and ex- tremely amoeboid and irregular in shape ; the pigment is brown, very fine and actively dancing ; the surrounding cor- puscle is expanded and decolorized. On the day of the paroxysm, five or six hours before the onset, parasites may be observed which are nearly the size of a normal red corpuscle. The pigment is somewhat coarser and darker than it was in the beginning, and is usually somewhat less active. The amoe- boid movements of the parasite are almost lost. The sur- rounding corpuscle is scarcely visible. Shortly after this the pigment collects at one point in the centre or nearer the periphery, in a single clump or block, and evidences of incipient segmentation are to be made out. The 112 LECTURES ON THE MALARIAL FEVERS. parasite, as will be remembered, breaks into more segments than the quartan organism, giving rise usually to from fifteen to twenty. At the same time with segmentation there are often to be observed large, swollen, apjDarently extra-cellular forms with actively dancing pigment granules, numerous frag- menting bodies, vacuolated and flagellate forms. All these forms arise apparently from full-grown parasites, which have not segmented. Toward the end of the paroxysm fresh hya- line bodies begin to make their appearance. The discovery of segmenting organisms is much less fre- quent in tertian than in quartan infections for the reason, as has been stated above, that much of the segmentation goes on probably in the internal organs. Thus, just before or dur- ing the early part of a paroxysm in tertian fever, if the in- fection be a mild one, we may at times have to search very carefully before finding any organisms. It is very rare that one is able to follow in the peripheral blood the entire life history of a group of tertian parasites which is not large enough to produce well-marked clinical symptoms. We have never been able to do this. As pointed out by Grolgi, evidences of phagocytosis in the form of pigmented leucocytes may be made out in the regu- larly intermittent fevers at definite cyclical intervals. Thus, during and immediately following a paroxysm the appearance of a considerable number of phagocytes may be observed. These are both polymorphonuclear and mononuclear elements ; the pigment may be in scattered granules, or in blocks similar to those seen in the segmenting forms. Often phagocytosis may be observed in the fresh specimen. It is interesting to note that while a very considerable number of large mononu- clear pigment-containing cells are to be seen, actual phagocy- tosis is never to be observed upon the slide, excepting by poly- CLINICAL DESCRIPTION OF MALARIAL FEVER. 113 morplionuclear neutrophilic leucocytes. Sometimes pigmented leucocytes and phagocytes are to be observed between parox- ysms. At this period only extra-cellular bodies which have escaped from the red corpuscle are attacked. During the paroxysm we may see the engulfing not only of free pig- ment, but also of fragmented extra-cellular organisms, of flagellate bodies, and sometimes also of complete sporulating forms. Beyond the presence of parasites the blood shows usu- ally little that is remarkable. If the infection has lasted for any great length of time, the evidences of an acute anaemia l)ecome apparent — pallor of the corpuscles, marked difference in size of the individual elements, nucleated red corpuscles, and perhaps a little poikilocytosis. The most striking feature is the fact that the number of leucocytes is almost always subnormal^ while the large mono- nuclear forms are relatively increased at the expense of tlie polymorphonuclear varieties. The whole subject will be discussed later in the remarks upon post-malarial anaemia. Double Tertian l7}fections — Quotidian Intermittent Fever. — In this climate we more commonly meet with infections with two groups of the parasite — a double tertian infection. These groups reach maturity on alternate days, and give rise, therefore, to daily paroxysms — quotidian intermittent fever. The paroxysms differ in no way from those observed in single tertian infections, unless they be a trifie shorter, lasting on an average from ten to eleven hours, associated with regular stages of chill, fever, and sweating. The regularity in the recurrence of these paroxysms is not quite so great as in quartan infections. The chills on alternate days often come at hours surpris- ■n-d > r - "" ■" '— ^ '~ '" ^ n r- "1 il ' ■N et j ^ 35 »> nv 01 d ■«y 8 1 '■^ S 3 •«v 9 y S s •H* t L-1 s 2 ■H» 5 _ — _ _ _ ^ _ _ r_ J j . - .- ^ — n-d 01 - - - - - — - 1 ^ ;^ : - ■^ — — •H-d 8 ^ / 1 ■^ 2 •n-d 9 . _ r" § H -Wd * ■11 IHO .^ — "^ ■n-d z "~ r^ ?J S r» •W 21 V, W» 01 !• H :5 •H» 8 , ? 3 ■HI 9 S 3 ■HV t 1 \'S. 2 -WV I ' 'n zi ^ ^ 1 ^_ ^ _ ■-1- _ . ^ ■~l _ ^^ _ s. -Wd 01 - "- ■~ - - - ~ "" r ~ ~ -H d 8 ^ -n-d 9 _ i 1 -Wd t ^ It- -I ;^ _ — — _ _ — ^ - - - ^ ■# - y«» -N 51 -'I ■hI d-- •dJ fl M 10 — — — — — — - -^ r^ - - - 3 1 s -WV 01 i •HV 8 1 ^ •W-V 9 'y S ai •w-v t \ a 2 -wv Z > s 2 ^ ^ _^ — _ _ _ ^ ^ -■» ^ ^ ^ ? «l •H-d 01 ~ ~ "■ ~ ~ ~ ~ ~ ■■ i r ~ ~ ~ ~ ~ -W-d 8 . •W-d 9 ^ 1 — 1 — "^ 3 2 •Wd t 1^ :j _ _ n-d z T IH ol "^ -— ^ ^ S »a -N Zl ^ Ol nv 01 / 3 y nv 8 / •n-v 9 \ •3 s •«-v i \ •nv z _ _ |v. 3 s -n zi ^ — — — — ■ —• ^ ^ ^ ■-•— ^ "- ^ ^ -w-d 01 1 V ■w-d 8 ^ »• 3 -n-d 9 _ _ _ — / o S) •nd t "■ •n-d z T" l^ ■> 1— r^ ^ y s w 'J' •N Zl 1 -nv 01 > -wv 8 » •wv 9 ■nv i .^ -wv z iL ^ •w Zl ™ — — ^ ^ *— ^ ^ ^ L^ — ^ ^ 1^ -w-d 01 '' -w-d 8 •S S •2 •Wd 9 n •Wd t V S 3 -Wd Z es ■N Zl ] g 3 n V 01 )' -wv 8 2 o •wv 9 Ns -wv t > 3 § -wv z ^ -w Zl _ ^ ^ _ _ _ _ .1 ^ i£l_ ^ ^ _ TJ^ Si ■w-d 01 "~ ~ " "■ "" ~ ~ " ~ ■«' -Wd 8 U- j 3 3 •W-d 9 , _ -■ 1 ■W-d t. <: < ^ S -Wd z 1 IH " — — ^ _, ei -N Zl 3 S WV 01 -WV 8 S 2 -WV 9 •WV t g Si •WV Z u 'W Zl — ^ — — ^ ^ ^ '"- ^~ EJ — ^ ^ u_ ^ 'i *¥ ■Wd 01 ^ ^ 1- -w-d 8 < a s -Wd 9 s -Wd t 'v 1 5 s TEMP. 106 105 104 103 102 101 100 99 9S 9" 90 PULSE RES P. STOOLS 114 116 LECTURES ON THE MALARIAL FEVERS. ingly similar {vide Charts Nos. II and III, pp. 11-1 and 116) ; the cause for this is hard to understand. Sometimes, however, the two groups of parasites have distinctly different hours of Bcguientation, the chill on one day comhig in the morning, on the other, perhaps, in the afternoon {vide Chart No. IV, page 117). In such a case the simple ohservation of several paroxysms might lead us immediately to suspect the tiiie nature of the fever — i. e., a double tertian infection. In other instances, where the hours of onset are nearly the same, it may be quite impossible from the fever curve alone to differentiate a double tertian from a triple quartan infec- tion. Often the diagnosis may be made in an interesting way, accidentally or purposely, by the administration of a single dose of quinine just before or during a paroxysm. It is at this stage in the life history of the parasite that quinine is most efficacious, and such treitment may destroy the single group of parasites which is at that moment segmenting with- out materially affecting the other group present, changing thus the chart from a quotidian to a tertian intermittent fever {vide Chart Xo. Y, page 118). Infections with Multiple Groups of Parasites — Irregu- lar or Continued Fever. — Very rarely with tertian infection we may see irregular or continued fever, due probably to the infection with multiple groups of parasites or to the lack of arrangement of the parasites in well-marked large groups. This condition is rare in adults ; it is probably more often seen in children, where the malarial infections pursue a much less regrular course. In a few instances we have observed irregular continued fever where the blood showed only an oc- casional tertian parasite. In two instances the parasites were not found on several examinations of the blood, and it was Tertian and Quotidian Fever — ^Double Thhtian Infection. T)ie Lrlmrt shows tlie ilevt-lopment of quotidiun from nn originally tertian fover. The fever diBnppeared entirely following a single dose of quinine on the 19th. r ■n-at \ ,> SIS ■NZl <' ei H-VOl _ a.^.s ai •WV8 -QT. A-IO IMd sirwa } •WV9 ^^ !£ -,_ ■wvt- ";> •w»z -N.. - -- ----- : X- ~ s s •Wd8 •Wd9 'M' ^. — "C^ •Wd ! \ ss fl •N 31 ^^- __ i to — •WV8 x-10 Hn ns'nif D li si^ ■wvt ■^■« Si ■WV3 y^ 0- o< WdOl X -to HJT ns 'Nir D ^-y — QO 2 "Wd 8 ^ •Wd9 S ' S H •Wd t ^' ^ ■Wd B S § g •NZl (^ ss WVOl •=5 •WV8 ^ -j*^ •WV9 *■■ vj as •w-vt "^ •WV2 -— -- - •Wd 01 JJ- — — S g " ■Wd8 Ji^ ■Wd 9 ^•'- X ti •Wd t ^^- •Wd B S. i^_ Si; C5 1-1 •N 31 ~7 •wvo: < Ka •WV9 t^- ■: = •WV9 ^» ^. K5i ■ •WV3 r -;=t-^ ' -j- SS_ - •WdOl '" -rP Xi S 2 •WdS y _ ■Wd9 ^ =£. - . •Wd t — —■•^ _ •Wd 3 ' — ^-—5^^^ p^ - CO ^ ~~*^^ ^ ■^ S.-J ° 3 '^"^h 3 •WV9 : -<^ ^ iS •wv t - - ^ •WVB ^ — -- » o _ - WdOl j>q__l_. — — S2 - •Wd 8 ^ •Wd 9 ^f SS •Wd t ~^> ■■^ •Wd S ^v. CC « _ •N 21 I\n^ ■wvoi - 4^- - 5 2 •WV8 Ttt •^ WV 9 — cc - . •wv (■ •WW 3 -- — 5M^ - ■Wd 01 ■ J u-c ^ — TT^ - •Wd 8 f- — " ^ •Wd 9 ^a ■Wd t _^7 ■Wd 3 = 3 11 •N 31 ^^^•^^ •wvoi — i. \, = 3 •WV8 -C •! i\x ra vo MOA X l^ -ix •WV9 as •wvi- J •WV 3 ^ __ _ v-H ~~ "■ s? ■Wd 01 !>^ S "5 •Wd8 >!- Npl:?S IM ]V N D '•3i_ = s i-lrHrHi-lr-lr-lrH ^ij o o O" 117 •H-V9 - ~ ~ "" r r ~ ~" ■l sis •H-V9 N :-Wp 1^ •H-V* ^ •H-V! ■N 11 ■H'dOl / ■ z = ■n-de •Wd9 ! •H-dt " ^ ■N-d3 p ■N 2> ? •B'VOl ■H-VB 5S y •WV9 k •wvt -.- ,:n •WV8 ■H Zl / •WdOl •Wd 8 ^ •Wd9 •Hdt g •WdS -N Zl S •♦' ■H'VOl •HV8 'WV9 W, •wvt S •WVB / •W 21 ■H'dOl / -• ■WdB / 8 •H-d9 ^ •Hd t •a-1,-1 (nMO)gL ^ _ fe c!i •WdS (Xiao;) '.S9 ■0 / •N Zl •H dnn< •Nir r ' S ^ ■wvoi ~ — «« •WV9 ■- ii a •WV9 V. •wvt -^ •WV5 y •H 21 •Wd 01 t ■WdS I K s •Wd9 < •Wd t V S s ■N'd Z > j5 ■N 81 r ■" s ■H-VOl \ •WV8 \ s ■WV9 V •HVt y a •wvz •w Zl •WdOl -J •Wd8 t f' ^ s •Wd9 f •Wd t __ .^ ' ig a •WdZ _, •N Zl L_i s a •wvoi ■» •WVB M s •WV9 >, •w-vt s •wvz ) •w Zl •WdOl •WdB »^ 8 ■Wd9 ^ •Wd t , •- ' « •WdZ v^ o •N Zl (A'ao);szE' o' ■^ -~ ■r •wvoi H di Tis •Nir V ■WV8 ■N ■WV9 \ •wvt \ o S •WVZ ^ •W Zl 1^ —J L_ ^ i— p— p— ■ — ■ ^ H^ hi •WdOl X •WdB •» f^oe •Wd9 ^ -^ ^ >^ •Wdt -^p o ?i a; ■WdS •• 1 r.^l giHi-li-li-tr-lr-lT-l'-l -1 EC I— ( ^ c? 118 CLINICAL DESCRIPTION OF MALARIAL FEVER. 119 only after the fall of the temperature and the appearance of regular paroxysms that the organisms were found. These two marked instances suggest that at times the greater part of the cycle of development of the parasites may take place in the internal organs, while the irregularity in the manifesta- tions suggests the presence of multiple groups {vide Chart No. YI, pp. 120 and 121). {b) QUARTAN FEVER. Single Quartan Infection. — Quartan fever, as has been said in the preceding chapter, depends upon infection with the quartan parasite (Golgi), an organism whose cycle of exist- ence lasts about seventy-two hours. This parasite also pos- sesses the remarkable characteristic of appearing in the blood in large groups, all the members of which are at approxi- , mately the same stage of development. The myriads of organisms forming such a group reach maturity and undergo sporulation all together within a period of a few hours. Thus, if the blood of the infected individual contain one group of quartan parasites which has acquired any consider- able size, we may readily see that every fourth day a sporula- tion of this group takes place, and, as might be expected, the clinical manifestations are quartan, intermittent paroxysms. Quartan fever is not common in the United States ; indeed, it appears to be everywhere much less generally disseminated than tertian fever. In Italy there are special foyers where quartan fever is particularly frequent ; such, for instance, are certain parts of Sicily and the neighborhood of Pavia in Italy. In this country we meet only with occasional cases. In Balti- more, out of one thousand six hundred and eighteen eases of malaria observed in the past seven years, there have been but fifteen instances of quartan fever. e .,,^^,1 , . . _ ,•,,,,: , , ,^ " ■ ' ' ' \$ls r- ^ ■ ^ "tx :;* ' a; ?i •n'Jui < •n-ds i^'"' 3 'N'd9 1 1 'N'd> 3! S • •HdJ o •N51 iS S ^ •HYOl •wve S s •WV9 ^ t - •wvt I o =5 ■wys _, - / •H SI s ;:; •WdOl ^ ■wda v\ H LV a <; a S -W'd9 1 11 k; N •WV3 ^ = s ■WV9 < •wvt .1 3 ON 0< s •< ^ ■>1 5 5 ■IN-VZ 1 i IJi> L. ■w Zl s ^ •WdOl i: 3 pN Ot s cr — ~^'s V ■Wd8 -^ T § ■Wd9 ij 3 D^ IS s V ■Wdt ^ fi S ■* ■ndz 1 3 r"" JS «^ ^ i+ •N31 Ot US H JA ji. ~ ^ s o 3^ ■WVOl ■' ' •W V3 . •WV9 ^ •wvt. ^ ^ ■wvs ^ ■W !l o s •WdOl j •WdS I s s •Wd9 ^1 . •Wdt L 9 g •WdZ ''1 = s 120 S t'- e3 irt -+< cc "^l 1— * o -1 en o S •H-V9 a «■» tt / S •H-VJ _ _ _ _ _ _ _ _ _ - - - -r- / A - -- ^ _ - ^iTdTr - - - -^ - - - - - — - - - - — _.. n - Wd 8 X M H'd 9 / •Wd t ' ^ .^ •Wd ; s -1 6 ■N Zl m ■wvoi •W»8 s ■•WV9 ^ S •wv t : £ 3 ■wv a _ _ _ — _ _ _ _ _ — _ _ — - - / — — ^ •Wd 01 - - - - - - - - - - - — — ^ /- - ^ h ■Wd 8 S ^ •Wd 9 / •Wd t. ^ t ■Wd t \ ■M ^^ •N SI 3^ S ^ ■WVOI / ■WV8 SS ^ ■W»9 •WV t ' S ■wvs •H Zl ?i 3 •Wd 01 , ■Wd 3 nd . _ g a •Wd 9 •^ -\ r~ ■Wd i H ' D A ■H D •/> s S ■Wd 3 -^ do 3 Nl Ml ^C "h d in S - L — r •N Zl K — — "^ - oo s ■WVOI n l> <0 >» _ _ ? ■WV 8 ■~ ^ ■WV 9 > •wvt L ^ s g •WV S * ~7 •w Zl s s •WdOl ; ■Wd 8 f ^ •* •Wd 9 !s ■Wd t ■"I \ s S ^x •Wd Z - •N Zl \ 5i ■WVOI \ •WV 8 •WV9 ■wvt \ ■wvz •HI Zl s SJ •Wd 01 ■- ■ •Wd 8 i. _ . S; •Wd 9 , ' — " •Wd t- ' ot f^ "i •Wd Z > - — "■ }S| •N Zl T 11 10 v|J p ^ ^ m •WVOI ' ~ •wve 1 ~». s g •WV 9 ■wvt- ' » o •wvz ■H Zl ^ •Wd OV ' 7 ■Wd 8 i s ■Wd 9 V ■Wd f 1 s ^ - „x ■M-d Z 1 F^ •N Zl > s S ■'iSl ■WVOI S •WV8 r s 5 •WV 9 \ •wvt s s ij 1 ■n-tz N ] 'W SI ^ ^ _ _ _ _j _ _ ^ ^ ^_ ^ _ k_ •Wd 01 ~ ~" ~ ~ "~ ~ "^ ~ ~ ~" ~' ~ ~ " ~ ~ ^' 1" ■Wd 8 -* -- sis ■Wd 9 -< ■Wd (■ »■ r_ S3 ^> •Wd s •- e: c^ S •N SI T Ih ■~ •r 5 " ^ ■WVOI p •< •WV8 L ^ s .?s S •WV9 o 2 121 122 LECTURES ON THE MALARIAL FEVERS. The intgresting fact that in tlie same chmate and with the same general telluric conditions certain regions are the seat of one type of fever, while other regions which may be in the near neighborhood show other forms, was pointed out very clearly some years ago by Trousseau. This keen observer,* when speaking of the different types of malarial fever, states : " The types seem to depend upon the nature of the miasm, and especially upon the locality which it infects, rather than upon conditions relative to the individual who is affected. Tours and Saumur, both situated on the left bank of the Loire, appear to me to present the same chmacteric and telhiric con- ditions ; yet one observes at Tours only tertian fevers, while several cases of quartan fever which I have met with there were in individuals coming either from Saumur or Rochefort, or from other regions where they had contracted it. One of the examples which has most impressed me in connection with the subject is the follomng : Fourteen soldiers imprisoned at Saumur came to Tours to testify before a court-martial ; they had been scarcely ten days in the last town when nine of them were compelled to enter the hospital, affected with quartan fever, the germ of which they had evidently contracted at Saumur, since all the fevers we observed with the inhabitants of Tours and the neighborhood were of the tertian tj^^e." The paroxysms are quite similar to those of tertian fever. Their duration averages about the same length of time, while the defervescence is also followed by a period of subnormal temperature which may last until the onset of the succeding attacks {vide Chart IN^o. YII, page 123). Often for a considerable length of time the paroxysms may recur almost precisely at the same hour every fourth day, the * Clinique medicale, 2d edition, 1865, vol. iii, p. 425. 1 - " ^ =~a=. - *N Zl t: ii ■w»oi ' sU „^- 'M'VIJ s ir. fhi •WV9 :^ - ^X •wv t> . i M. ^ = = = _ = = ;::d = = = . 5--- •WdOl :::::: ;5?:::::::: < ss ■Wd9 - """k- •Wdl' . S ?J3 ^ N'd: jl *N Zl s ^ w] ■wvoi -4^ H -- 2] ■IH-Vf 7 * M •WW 9 ■H I'l' \ s 31 1 M •wvs \ •HSl ^ :~S--mS •Wd 01 P" •WUB « r lat ■Wd9 •n dt IS* s§ T ■WdS z ^^ s «l *N SL •WVOI •W»8 L 31 •WV9 ^\ •WVf . ^s. ii ■WV3 •WdOl ^£ "" •wds 'h ■ X' jj ; N N ^ SSL •Wd9 5 -U- •w dt > i siii •WdZ ^^- s *N il >^ 1 a a ■WVOI ^t ■W V9 i:; "-rrri ■WV9 > i 1 M •wv* -A a ^ ■wvs ^^ •^•dOl ^>- • ■WdU - n 1-0 ' — — r»i- S3 •Wd9 -* ^ ■W d !■ ^"^ ?^ " i ■WdB !i _ „=^ (N 'N ei \ s g= 1 •wvoi -5 ■wve -^ » § •WV9 > ^ •wvt 1 •WV3 - ^^ 5^ ■WdOl ;i , •Wde <' 1 s ■Wd9 •^ •Wdt s S! ; •WdS s Si •N 21 - I s s'' i •WVOI -J •WV8 / & M •WV9 t •wve ?^ s 3 •wvz .;;» ._; ,: 1 — = •Wd8 > ' a ^ " W.'d 9 - 'Z •Wd t - J' » 1 41 Wd 3 4 j4 55 •N 31 w S"^ ^ •WVOI ^^ «* •WV8 --^ s § •WV9 ;s •WVf /^ i •wvs a^ - •WdOl .— ••"' ' - ^ •wd8 - 1 ho •*;:_ W ^ •Wd9 •Wdt> i> ^ s i_ ■n-dz w •N zi •Q 1 1 I -IT d s a v 13 " 1 i° 1 •WVOI •WV9 / » S •WV9 •] ri vpmOA yn •! :•! I^ ■wvt . t: 1 •wvz 7 •WdOl 4 1 i" 1 es •Wd8 < g n - ■ Wd 9 h S >-. ■ Wd t s? •WdZ "***^ 3 51 hb TEMP. 106 105 104 103 101 100 99 98 97 96 PULSE RESP. STOOLS URINE pR 123 1-24: LECTURES ON THE MALARIAL FEVERS. regularity in onset being very remarkable. Not infrequently, however, succeeding paroxysms occur at a period several hours in advance of or behind the hour of the appearance of the earlier attacks. Thus, one speaks of anticipating or re- tarding paroxysms. The anticipation or retardation in some instances of quartan fever may be well marked. This is, however, not very common, the paroxysms appearing, as a rule, at periods nearly seventy-two hours apart. The hlood shows the presence of a single group of the quartan parasites, and the diagnosis may therefore readily be made. This organism may be traced by examination on different days through all stages of its development. Shortly after the paroxysm the small hyaline amoeljoid intra-eellular bodies are to be found withm the red corpuscles; in the course of a few hours a few dark, slightly motile pigment granules begin to appear. On the second day the parasites have grown somewhat larger and have become much less amoeboid ; the pigment is coarser and darker and tends to lie about the periphery of the organism, while the surrounding corpuscle is already usually somewhat smaller than it is nor- mally, and often of a somewhat deeper color. Upon the third day the parasites are a little larger, round or ovoid in shape, almost entirely non-amoeboid. The pig- ment is lazy and slow in its movements ; is coarser and darker, often arranged more particularly at the periphery of the para- site. The red corpuscle is represented by a small rim of deep yellowish-green protoplasm, often markedly darker and more brassy-colored than that of the surrounding corpuscles. On the day of the paroxysm, sometimes as much as eight or ten hours before its onset, some of these large round or ovoid bodies, which now are a little smaller than a normal red corpuscle, may be seen apparently free in the blood current ; CLINICAL DESCRIPTION OF MALARIAL FEVER. 125 on very careful examination, however, they are usually seen to have a slight rim of now, perhaps, wholly decolorized protoplasm. At the same time, or a little later, the collec- tion of pigment toward the centre in the characteristic star- shaped manner described in the section upon the parasite may be observed, while soon bodies with central pigment clumps or blocks and beginning radial striation may be made out. Quartan fever affords an excellent opportunity for study- ing segmenting bodies. These bodies are found throughout the six or eight hours preceding the paroxysm, and are often associated at this time with large swollen forms with dancing pigment, vacuolating and fragmenting bodies, and flagellate forms. The sporulating bodies, as ha& been noted, contain usually from six to twelve segments. During the paroxysm fresh hyaline bodies begin to appear in the red corpuscles. Phagocytosis is to be observed here just as in tertian fever, especially during and just following the paroxysms, while the same elements are attacked. Dovhle Quartan Infection. — Not infrequently the blood contains two groups of quartan parasites, which reach matu- rity on successive days. This naturally results in a tempera- ture curve showing paroxysms on two successive days, fol- lowed by a day of complete intermission — double quartan fever {vide Chart No. YIII, page 126). Sometimes the parox- ysms may occur in this manner when the case comes under observation ; again, however, single quartan fever may, under observation, change into a double quartan. This is probably due to the fact that at the beginning of the infection two groups of parasites are present, one being considerably larger than the other, and reaching a size sufficient to produce paroxysms at a period earlier than in the case of the other O" s 126 CLINICAL DESCRIPTION OP MALARIAL FEVER. 127 group. The paroxysms in these instances are in every way similar to those in single quartan infections. The hlood sliows the presence of two groups of the quar- tan parasite. Triple Quartern Infection — Quotidian Intermittent Fever. — Again, we may have to do with cases showing infection with three sets of the quartan parasites, reaching maturity on successive days. Chnically, quotidian intermittent paroxysms are observed. These paroxysms may occur at almost exactly the same hour on successive days, though not infrequently there is a slight difference in the hours of onset. On study of such a chart we may sometimes make out that the time of onset of any given attack corresponds closely with the hour of onset of the paroxysm occurring upon the fourth day before or after. Thus, on Monday and Thursday the par- oxysm may begin at nine ; on Tuesday and Friday at eleven ; on Wednesday and Saturday at eight. These differences, however, are usually very shght, and, owing to the possible anticipation or retardation of any one group, the definite diagnosis of a triple quartan infection would in most cases be difficult to make without an examination of the blood. The paroxysms are in every way similar to those occurring in single or double quartan infections, and each paroxysm is separated from the following one by a well-marked period of subnormal temperature {ooide Chart No. IX, page 128). The hlood shows the presence of three groups of the quartan parasite. It is not at all infrequent to see cases of double and triple quartan infection where only one set of actual paroxysms occur, so that at first, from the observation of the clinical chart, we might suspect only a single quartan infection. In these instances, however, under further obser- vation of the case, we very often may see the development " .'. ! ' . > ■■■ "• 1 ■.■* J .1 1 ^^ s'l or 'n'd 9' 1 ' ■- I '' 'r. •Hdt 1 t'l 117: •Wd2 ' ^^ s'l \\r. n Bi 1 < \'> 77. — n'voi ~> UK II,'. 'n*vd 1 (^ .-.■ n;. •W»9 ■ V ,-M nr •rev* \ UM M •H-VB / SV 01 ^ ■WdOl / .-,:. \r. •H-dB (I'l (\?. 'H'd9 H^-- • \ n;i IvT •H-dt > ^ , , . "■! ^': 1 -n zi ^p» ro r?:!= WVOl f IIP 17. ,_ HN ,1,-.. n. V, ■wvt / ■■•' "'■ - •WVB i ■sT^ 'W'dOl r-ll m. , 'H'd9 pi ; •iT'^ i; ;.^ RzT — ■Wdt Si c Hdins -Nir 6 V 1 i m r?: ■WdJ "S m «i o •WVOl M ii;t *H'V8 F V) 11?; •«V9 '~ ^ M SI •HVt lZ ; W IK •HV2 n ? 0!) ns -«r- ■WdOl ' -1 . 1 i . ' v/' 9i nK •Wd9 HD 9 Ol'H diris '':i''i'j y^ r.i V7. -n-d9 1 1 V VL V7. •Wdt \~ -> 'it 7.Z - •WdZ 9i \7. •W SI '~ t w tr. r-» WVOl 4 i\L 9?. ■wva w sr. ■n'V9 ^ w II?: ■wvt (IS (K ■WVB m w ■HdOlU rofx ap •Hdins "KTrS"""] '^ ~ •"" ~ IS" TS- ~ ■WdS 1 n« •Wd9 > *-o 61 0)11 ao H( ins •! If ^ w w: •Wdt ', n;: •WdZ 9i (K •w Zl J W (11 f-H WVOl (IK re •n-v8 ' KR w •WV9 y ?.K III'. ■wvt ^ Ofl 9!; •WVB -^"^ ^ 001 V7. r.(lln -Vi- — ■WdOl ^t HI I IX. ■HdB < 9111 Vi ■Wd9 ^^, Mil rx. ■Wdt ■^^^ not r.E - •WdZ ^ » ^ m\ (It: • 'W SI ■ y m K?. o •WVOl f 7X 9?. •n'V8 !l« «?; 'WV9 ^ f (KII •i7. ■wvt f'" (llll (It: •wvz ^-^^ Bfi s;; " -!*■ -9r. •WdOl ^ 8S s?; •Wd8 .'' ID its ■Wd9 c imi 7i: •Wdt ^^ 9?. •WdZ ^s^ 9(i »;; f •W SI •«, 9i re o •WVOl > OS 9?; •WV8 f in 7Z •^•V 9 i ?:i «: 'WVt f SB w: •wvs SK (It: -Kd- r?.!'- •WdOl — T" ~ ~ 9(i ?.S -n-ds / III! »: •Wd9 ^ (W lit: '^'^ >^ (16 SI •Wd S ■• >>. r.(; re » •n SI <* «i (K o ■WVOl "■ » Ki Hit •WV 8 ' ?.?. 'WV 9 KK s;; •wvt ^ SN m •wvs ' 5g 0(> M7. •WdOl J_ " <5, SB sz •Wd9 Aa;An3a|a3i;: ^"^5^ nor ra •Wd9 Aa3An3a 3aoi '= ^ 96 «;: ^ — •w dt 1 1 t 1 1 1 1 ^4l 9B R ■wdsl 1 IT !W 'JS ■s ^3 i 1 3 i *M tH o C: CO I' w • « OOoCiOSCico ^^ 2 = ^ c? o" g 128 CLINICAL DESCRIPTION OF MALARIAL FEVER. 129 on tlie intermediate days of abortive and finally well-marked paroxysms, owing to the multij)lication of the other groups of parasites, which previously have been too small to produce well-marked clinical symptoms. Again, in a double or a triple quartan fever it is not very infrequent to note the disappearance of the paroxysms due to one or two groups of the organism, owing possibly to treat- ment or to a spontaneous partial disappearance of one or more groups of parasites. The microscope will reveal the presence of a double or triple quartan infection. The life history of a group of quartan parasites may be traced for weeks in the blood without its ever reaching a size sufficient to bring about more than a very slight abortive rise in temperature. This is due to the fact of the evenness of the distribution of the quartan parasite throughout the gen- eral circulation — a fact rendering a diagnosis of quartan fever easier than that of any of the other varieties of malarial in- fection. "We may see sometimes a triple quartan infection with single quartan paroxysms, where after treatment one set of organisms diminishes in virulence and another increases. This may result in the disappearance of the paroxysms due to the originally stronger group, and the appearance of manifes- tations due to one of the other groups of parasites which has previously been incapable of producing marked signs. Yery rarely we may see instances in which there are in- fections with multiple groups of the quartan parasite, result- ing in an irregular temperature chart. These cases are, how- ever, extremely unusual. We have never observed such an instance. 130 LECTURES ON THE MALARIAL FEVERS. 2. THE ^STIVO-AUTUMNAL FEVERS. In terapsrate climates, where during the first half of the year the tertian and quartan fevers alone are observed, there begin to appear during the latter part of July, in August, and especially during the months of September and October, other infections which present certain characteristics sharply different from the regularly intermittent fevers wliich have just been described. These fevers are especially notable for the marked irregularity in their chnical manifestations. They depend upon the presence in the blood of the third variety of parasite which has been described above, the so-called sestivo- autumnal organism {Hcematozoon falciparum, Welch). This organism, as will be remembered, has not yet been as satisfactorily studied as the other two forms. Its life history and general biological characteristics are not as well understood. However, from the investigations which have been made, it appears that while at times the parasites may be present in groups undergoing sporulation with consider- able regularity at periods varying from twenty-four to forty- eight hours, there are many instances in which the tendency toward arrangement in definite large groups is apparently lost. Here, probably, the segmentation of smaller groups of parasites occurs at frequent intervals, and, on examination of the splenic and peripheral blood, organisms in all stages of development are found at the same time. At the Ijeginning of an infection the arrangement of the parasites in definite groups is frequently present, but after several cycles of exist- ence this arrangement is often lost. When we consider the relation of the segmentation of masses of parasites to the clinical manifestations of malaria, it is easy to see wliy these fevers present such irregularities in their symptoms. ■w V8 a 33 _VHO "la /> s ?, OS / ■HI vt •H i'- I vao •H dT ns 3N IN nc y '-3 p — 1* / ^ WdOl 1 ■w dS .1 (^ s s •w d9 Oz ON 11 NO 09 a 3N Nl no ? •H dt ;- s ■n-6z -1- ^ s s W\jOl •W|»8 • s ?i •W|»9 •nvi, ^ ,= « f wioi 4 1'' s s •w dB i s o - ■^ ■w d9 \ •w dt w 3 s •w rIS ■" ■> t^ •N !i -^ z wvov •0 •d •.■JV3 a-i'ujl- 11 d 5 .0 nv la \ o cl •W|V9 \ ■«vt J ?, -- -< r^ s ?, C' wio - ■«ld3 — < § g d9 ~-« '^ ■w d. ^ o s •H-(J! V V^ fS ■N|st ^ § s wyo ^ •h t -V as ■H dl T!s|Th IN n 3 ^ ►-~ s g •«ve - ^ >J ■«|v. s ^ - WdOl r— Wd8 i o 3 M d9 r M dt < s c! ■Wd 3 E; •«; ■N SI 7 m S n-yi — A \ •— . S m •«JV9 ""■ ~< ^ ■-r T s o •™|VZ i, ■W PI ^ WdO _ ^•J I— ' •w d8 *- s o ■^ •K d9 w 3 s •Wjdf ^ S s •«d. ^ ^ •* •n]si ' ^ S8 s w?o ■ ■1 ■X — < "^ •.,0 X X IL WC A xn N hi £ s •«|V9 •W|Vt --' t^ g s •WiVZ ^ ^ ■wU c io •w d9 ^ 1! s OS ■w d9 r ■ ■w dt •> g n u lioi'ss m ]V 5 o o © TEMP. 109 108 107 106 105 104 103 103 101 100 99 98 97 96 PULSE RES P. STOOLS 131 132 LECTURES ON THE MALARIAL FEVERS. Clinicallj, sestivo-autumnal fever may be observed in many forms : (a) Quotidian Intevmittent Fever. — In some instances an aestivo-aiitumnal infection may be associated with well-marked quotidian intermittent paroxysms. These may, indeed, pre- sent few differences from the regular paroxysms of tertian or quartan intermittent fever, showing the same suddenness of onset, the same duration, the same rapid defervescence, the whole being separable into the classical stages of the chill, the fever, and the sweating. Generally, however, marked differences may be noted. In the first place the paroxysm in sestivo-autumnal fever is usu- ally materially longer than in tertian or quartan infections ; it averages nearly twenty hours, instead of from ten to twelve hours in the regularly intermittent fevers. Again, while the onset in tertian and quartan fever is ex- tremely sharp, the chill coming on very shortly after the ini- tial rise, in sestivo-autumnal fever the rise is often more or less gradual, the paroxysm beginning with headache and gen- eral pains, while the actual chill, if at all observed, may not occur until some time after the temperature has become al- ready elevated {vide Chart ISTo. X, page 131). "While chills or chilly sensations were present in 97*2 per cent of onr cases of tertian and quartan fever, they were noted in only Yl^ per cent of the cases of sestivo-autumnal fever. The fall in tem- perature is also much more gradual. The regularity in the recurrence of the paroxysms is also much less than in tertian and quartan infections. Anticipa- tion and retardation are common, and when we consider the short period which must of necessity separate quotidian par- oxysms lastmg twenty hours, it is easy to see how a relatively slight anticipation or an unusual lengthening of a paroxysm •Wd 01 - " ~ " ~ — n "" 1 ■Wd B \ Hi 01 •Wd 9 \ \, HH W •Wd S _ _ _ _ _ _ _ _ ^ s . H ■WV 01 p - — - - - L — - ^ ^ — i ' ■WV 8 Kil !■?: •WV 9 ^ ■Wtf t < •W» J 1 - ? ■Wd 01 ;•' •Wd 8 1-8 0! ■Wd 9 'n'd t > W V. ■%- ■n^d z X H NOON ei 1 W i- •W» 01 ^ •W» 8 1 m rH ■W¥ 9 ■Wtf V m K ■WV 3 t ■SK- •Wd 01 J •Wd 8 fS M -■ •Wd 9 •Wd i L. m W , •Wd B «« , ,t NOON 31 \ ^L 8!: k ■S- •WV 8 y 94 W! iH •WV 9 •WV t IW 01 •WV Z •w Zl •Wd 01 ^ •Wd 8 /> OS 02 O •Wd 9 ^ •Wd t ^ ^ JB 9K + •Wd Z wr' •" u NOON Zl 911 8?; O •WV 01 ^~ •WV 8 n ■J !lt> 8!; O •WV 9 V •WV t «h ^ W)I ra -•WV Z _} •W Zl Wd 01 "C •Wd a ^ ON OK CO •Wd 9 ^ ^ •Wd t r Sll 8S ■+- •Wd Z 1 u NOON Zl H B A tJ N N n *) / 9(i 8<'. a ■WV 01 > •WV 8 X r* mi r.K (N •WV 9 2 •WV t 9H •WV Z T Ih ^ ■^ •n Zl •Wd 01 "^ ■Wd 8 Kfi oz r-4 ■Wd 9 •Wd t > Wll Ml •Wo Z } NOON Zl y r.i 8?: ■WV 01 ^ r' •WV 8 r* ' 7S, 8i! rH ■WV 9 X •WV t } . -WV Z I f^ 5 ~ "" L -J - _ _ - - _ -_ - •-^ _ 1 — •H^d 01 - - - -^ - ^ r - - ■'^- — — •Wd 9 WII re iH •Wd 9 •Wd t ' w OK •Wd Z ) r> NOON Zl X xx-w v; mo ft 94 K + 'n'd z Iv •• NOON Zl 9/, 9K •=, WV 01 ^ •WV 8 r^ 86 8K ^ •WV 9 ^ •WV t •^ »< OK •WV z f •n Zl •Wd 01 ■lli ^ ds 1^« S B ■c ll-ac N S Sid^ S Z8 OK 9 •^•d 9 ■f 1 k ■Wd t S -tf •IVd z Noissinav, NO 88 OK ■9 . 0SQ0h;!OlO3;M« :-o -:^ •-^ '"r, < , «■ 0> ■r - r" ?. ■WjdB Z ■w dS i» ■w d* V V, ?; •mid 2 ^ CO ■«!.. )» o P WVOl / ^ o ■w *3 < o P ■w V9 S •w Vt s •w VZ \ w 01 •^ -^ ■w d3 r^' s s •w d9 .>i( •w dt r " o ? 'W d? ^ ' i- ■N 31 r s s N «-yoJ / ■»v» / s o ■«u < •«f. > M o ■wjvs ■H fu (. l-l 0) SB '•0 'a *JIN in si. fl ■K- ?r Iff 01 / _^ •m de (^ ? • HO ei •0 4d nn sa Nl \iir D "~ — S o ■IN d9 " ^ ■n- d t 1 _ , s s •n r" ^ ^ ■f '' 3 o- 50 ^T) V ■W V8 ^ S ■W V9 ^ .o- •w vt ^ (-^ g § ■w ^ *' ^- wJ OL ' ■w d8 s ■H d9 A ■Wd t 's s 3 »C ■WdB — k o- •N 31 •v s % W r° V ^ •w ve > s % ■w V9 •w V* S K S ■HI V3 IP -^ V w 01 > w dS / / o S •w d9 ; f ■HI d + / K s •w d3 ■N Zl > ■£ ?; -* WiO ^ oi ■W|V8 ^ ° 3! ■w V9 __ V ■w V 1" /O- I — S g ■w tz / ■^ w 01 ,r '' ■w d8 > / S s ■w d9 ^ o ■w dt —■ g § CO •w d2 v. g TEMP. 109 108 107 106 105 104 103 103 101 100 99 98 97 96 PULSE RESP. STOOLS URINE DAY OF DISEASE ^ a 135 136 LECTURES OX THE MALARIAL FEVERS. Tlieir onset, tliougli sometimes quite rapid, is often very grad- ual ; the chill is not infrequently wanting, and, when present, conies on sometimes relatively late in the course. During the period of fever there are often very marked oscillations in the curve, the temperature falling sometimes nearly to normal, only to rise again to a point higher, possibly, than it had pre- viously reached. Marchiafava and Bignami have described a typical curve for their sestivo-autumnal tertian fever, consisting of the chill, the febrile period, a pseudo-crisis, a pre-critical elevation in which the temperature reaches often its highest point, and, finally, the crisis. Curves of this nature may often be ob- served, but are by no means the absolute rule {vide Chart ISTo. XIII, page 137). • It would seem that these paroxysms with longer intermis- sions show a much greater tendency toward anticipation and retardation than those with quotidian intervals. It is rare to observe more than two or three such paroxysms without a subsequent confusion and loss of regularity in the manifestations. This may occur in several different ways. 1. Anticipation. This is very common, and often is so marked that one paroxysm almost merges into another, pro- ducing thus a nearly continuous fever, with only occasional very brief intermissions or remissions — malarial remittent fever. Yery frequently this anticij^ation may be actually so great that there results a continuous fever without any actual intermissions — continued malai'ial fever. 2. The same result may be obtained without marked an- ticipation or retardation if the individual paroxysms become greatly prolonged. 3. During a long paroxysm there may be oscillations in •W»F ~ < ^ J li _, WI/9 ■ ■n-it \ 3 ■n'vz __ *. ^ _ _ — — — — — — — — — — \ — <* ■*■ WdOl •Wd8 -J S •WJ 9 ^ -' •Wit •: ^ ^1* ?i ■WdZ ~-l ■NJl \ 3 o O WV 01 % •w ie 'S ?, •w »9 •w srt 1 g s •w is — . > — — — — ^- — — ■" ~" — -?^ — -~ ■J" "T^" Wi 01 ^ •w d8 ■a 1" I [•a 3 Hd nr s N Nl 10 ;^ S S ■w d9 __, -- •w dt \ ^ o •w dZ > •N Zl ,-- .- g ?, o Wl 01 ( <. ■w tf8 —* S K 3 •w V9 > ■H- Vt A / f; 2 •w VZ w 01 f •w dB 1 s S •w 1 w dV ^ s 3 ■w dZ > •N Zl 1 L s 2 ■w »t 3 2 ■w *c W 01 n ■n »8 V s •s* ■w /9 )t ■w / 1 , V « s ■w |(S _ jV Kl do ■*■ -' ■w dS A- - o s •Hd J ^ s a ■n'd 9 *- .. ^ s Wd t ■■ -n s s ■M'd Z r o •N 91 s o n » 01 V, i - •WV9 ^ • s ■HV 9 / U- ' •W¥ » •c ■1 J. f. 10 )9 5£ •0 / g 2? •H ¥ 9 s ■H •W¥ 8 f s " = •W¥ 9 ^ •W¥ t < ■W¥ 9 s »~. •H 91 s 5 •Wd 01 ^ ■Wd a <• ^ •Wd 9 > s •Wd *• s g » •Wd 9 y •N 91 / o ■W» 01 , ^ o 3 J4 •WV 8 ^ g ■ ' =^ •WV 9 ^ V A S •W¥ t r- s 5! •WV 9 \ :i •W 91 ■Wd Oi *» 1 :^ 3 ^ ■Wd 8 "• ■J s IS ■Wd 9 '"■ T ■Wd i 1 s s 3 ■Wd 9 s ^ ■ ■N 91 ^ = % r- •WV 01 1 g •o ■W V > s 5 "^ ■WV 9 ^ •WV t \ s = ■WV 9 ^ I ■n 91 s 2 ■Wd 01 ^ u- ' ■Wd a f ' s s ■Wd 9 J s s ■Wd f 1 f s 2 •Wd 9 1 s <» ■N 91 J* J5 -! •WV 01 r- ■ - » -■ ^ ■WV 8 p» s s; ■WV 9 ^ -^ •WV t s s •WV 9 w. •W 91 s •Wd 01 <. •Wd 8 ^ s s s •Wd 9 s •Wd t S V g s •n-d 9 S « ■N 91 ^ K 5 H n V 01 CJ •W V 8 i != f :i •WV 9 •wvt ^ •J SJ •WV 9 -H •W 91 s g •Wd 01 --■ •Wd a r a :5 6 •Wd 9 o ^ •Wd t < s Si 4 N0IS9 IN av NO 1 s Si 1 138 « bo 140 LECTURES ON THE MALARIAL FEVERS. temperature so marked as to mar the regularit}' of the fever curve and to render the cliart quite incomprehensible. 4. The paroxysms may be markedly retm'ded, so that the intervals between their onset are considerably more than forty-eight hours. This is likely to occur only during a spontaneous recovery or a diminution in the malignancy of an infection. It may, however, be seen even in pernicious cases. The clinical picture, then, in sestivo-autumnal fever may differ materially from that in the more regularly intermittent varieties. The frequent absence of regularity in the fever curve and the modification or absence of the three classical stages of the paroxysm remove two of the most characteristic symptoms of malarial infections. The patient when first observed is often in a distinctly typhoidal condition ; he is dull and drowsy ; the face is flushed ; the conjunctivae in- jected ; the tongue dry and brown ; the pulse often soft and dicrotic. On examination of the thorax little is to be found, ex- cepting, perhaps, evidences of a slight general bronchitis — sonorous and sibilant rales. The heart sounds are usu- ally clear, though a soft, systolic souffle may be heard. The abdomen is negative, though there may be tenderness in the region of the spleen. In the great majority of in- stances the spleen is palpable : soft and round in fresh infections, hard and with a sharp margin in old, continued attacks. The general picture is so similar to that of tyjjhoid fever that confusion is sometimes inevitable without examination of the blood. In malarial fever, however, there is often a well- marked anaemia ; this is the rule if the case has lasted for any length of time ; generally, too, there is a distinct sallow, yel- CLINICAL DESCaiPTION OF MALARIAL FEVER. 141 lowish-gray hue to tlie skin and conjunctivae. Herpes upon the lips and nose are very common. Subjectively, the patient complains bitterly of headache, intense aching pains in the back and extremities, often of gid- diness, roaring in the ears, and vertigo. Delirium is common at the height of the attack ; it may be of the mild, muttering variety, or, in some pernicious cases, violent and maniacal. Drowsiness increasing to actual coma may be observed. !N^au- sea and vomiting are extremely common during the parox- ysm, the patient sometimes being unable to retain any food. Diarrhoea, especially in children, is very frequent. The same cutaneous manifestations may be observed here as in the regularly intermittent fevers. Nosebleed is occasionally ob- served. Certain of these cases may pursue a course quite similar to that of typhoid fever through some days, or even weeks. To these cases Baccelli has given the name of Subcontijiua iyphoidea {vide Charts XY and XYI, pp. 142 and 144). Some cases of this nature have probably been included under the fallacious terra " typho-malarial fever." This term is wholly incorrect and unscientific. Typhoid fever and malarial fever are two diiferent processes. Certain of their manifestations are, however, somewhat similar, and may lead to confusion in diagnosis if proper steps be not taken. Instances of coexistence of the two infec- tions in one individual are rare and should be readily rec- ognized. The regularly intermittent fevers, when left to themselves, pursue usually a favorable course, undergoing spontaneous recovery. This, to be sure, is often followed by relapses, which take in turn the same course. It is rare, however, for a regularly intermittent fever to prove of itself fatal; this f^ HN *l^ v, ,■ — r-t-T — 1 — 1— JTf r.i" •— 1 ~ - ■i^ o\ 1 1 -a V 1 '5 •Kj-d 8 XJC e •^ L. .^ S •Hd 9 1 •rt d t aril < o S ■Wd z TH^. — Q CO }w Zt ) 1 i J •w-v < 4v 8 \ -u -V 1 J s •H|V 9 n|Ax eni •^ "T^-v ■w-v t "j \\ r ' ? s ■J-* Z 1 J} ^«rY ^yy z — i-tAx-eai- ^ *^ ^^ 1 ! 1 ,o. -?- 1 •«(d ^ ~ rT" 1 ^ ^ F 1 1 1 ~ ~ ~ " ~ ~" ~ ~ •Wd 8 lAX ani 1 1 1 s s •i,;-d 9 1 ^ -V •«id t AX a u "N ' 1 ? s ■w-d Z S V, 1 CO N L Zt N, 1 ? s - ■Jv 1 '^ -a-v 1 •inJ'V s IX ar Ji -< 1 1 £ ;; ■vJ-v 9 ' > 1 ■ J-v f A 1 -. s l^|•v z _ i^ani _ 1 >f 1 1 \_\ _ .„. _ _ •w-d - - iTx 1 ani - - "^ ~ -a 'V - M - — - ^ - — — ~ •^•d 8 -a v 1 i g ■^^|■d 9 IX ac ■~- 1 1 ■l^|•d t' ' ■^ 1 ? g •w-d 5 > 1 N (0 h Zl' 1 \ 1 $ g ■ ^■v Oil 1 K 1 — ■^•v 8 I t g ■H|V 9 1 .^•v f 1 vJv Z 1 1 ^w z ' T -r-i1 — — •w-d 01 1 t^l 1 1 1 II 1 ■A-6 8 XI an J- — — ■ ^ s g •l«i-d 9 '^^ •>,j-d t >, 2 •J-d Z ) ^~~ (0 m r Zl ^.2 ■^•v 01 • ^■v 8 5 i 5 ^- •w-v 9 * 1 ■H^'V t y S 1 S •^•v Z ' 1 •IS'd 8 |1I_A ar ^ <, r" 1 1 i. 1 S ■wl-d 9 ' N 1 1 ■Vi d t "S— i-~ _ Z g ■\f ■d Z 1 1 =• in 't 'n Zl 1 1 1 r 1 1 z g _ •W|-V 01 1 1 V 1 1 1 •l^■v 8 1 1 1 Ip -, s z •Ifl -v 9 ii ay 1 1 r+^ ' •l^■v » A aqx t=a3"l " 1 1 1 i s •i\-v Z 1 1 ~-w 1 — -w Z-l •1ft -d 01 A,a^. «r -" 1 •l^ -d 8 ' V i g ■l'^* 9 V ■|A|-d t \ ? s 1 •H 'd Z \ 1 ,— , ■* m tM Zl S S IS < ■i\v 01 ■1^■V 8 ° g lU ■^^■v 9 ^1 an ■L V — — — ■^^ 'V t 'a ? ;; •ift 'V z M Hi, »0 an J. •"id — r 1 — -H z-l 1 -a V- " •Wd oi _M XV i u u n ■Wd 8 w J g _ •l^ 'd 9 > ■H'd t < - s •^^■d Z > fO |W Zl I 2 s 143 — - •K ■d 8 ^ S « •w •H 9 ■|A ■d t > z s ■Vi ■H Z ~ ■ftl Z \ ■i 2 ■V > o •1* ■V 8 < s g ■| ■V 9 \ ■w V * ^ R g ^ ■V 3 \ ■ftl Z-l •w ■d 01 f •IV •d 8 ll S '^ 'W ■H 9 > •K ■d t < s s ■d Z N J ftl Zl k s a CM ■IM ■y 01 ' ft ■V 8 X s g >« v 9 \ ■\H ■V -t" l\ ■St Z ■ftl '1 ■d 01 •» ■d 8 > I g •W ■d 9 ^ '1 •d t s s •w ■d 2 fO ftl Zl 1 s 1 ■V 01 - > — ■l^ ■V 8 ^ s g ■i«Cv 9 «^ IA| V V s g n V Z Vlj 11 ■d 01. <' •l< ■d 8 3 g •w 9 •n ■d t S ■d z CM ■ftl Zu '- •lA ■V 01. / ■w ■V 8 > S g ■in ■V 9 s g •|A ■V Z -ftl z-v ■w ■d 01 ^ ■d 8 K g ■lA ■d 9 > •l\ ■d T « s g ■d z ^ ftl zt s g •w ■V 01 ^ CM •n ■V 8 ■H ■t 6(S 0) ^■a D'^ Hd ns ■h no r ^ s g ■|A ■V 9 ^ ■lAj ■V f j L^ = 3 ■w •V Z fs<,-o-) J r.\ .ao^H, iSA a-, riL 1 L ■ft •d 01 "^ :n ~ ^ ~ ~ ^ ~ ~ •«]-d 8 ■>» s s ■K -d 9 (• Od " ' -N. •W-d t X- us 59 0) 3»: an i: ■N no ■at w ^ o g ■ft 'd z V o ftl Zl > s g CM ■wv 01 ^ • w'V 8 ^ J s ■ft ■v 9 M^epi -H ^V ■ft|-V t f^r i ° s g •ft ■v L-iwJ S XU. ^ =^ -E c:ii - - - - - - - _ - - ■s- - — _ w ^ 143 144 LECTURES ON THE MALARIAL FEVERS. is, unfortunately, not true of aistivo-autumnal fever. Here, while in many instances untreated infections may undergo spontaneous recovery, with or without relapse, yet there is often a steady increase ui the severity of the symptoms until the so-called pernicious manifestations appear. F.f. imo Jnli25 20 27 28 20 ill 31 Aiiit.l 2 3 4 -?nU = :nii = n--hl;;hUin?iitii?:;iOiiiyH^nHiyUh:::ih iiiii ™.__/^ -^^-x ' -^' A'-^ '" ^ i ' ' ' 1 \ \ — \j— -^ 1 ' ' ' ] i^ A — ^' — Lu/-\---L.-iLL _!_!__. („i itr__,._.^^.u-^Ii_aJ_^xL^L_S^^^ t u-M-|-:^^-^±— ^-1- ' v-'vr,^- -^ J •TOOL, i-i --- I-f =1 J "T-- ! + iT 1 "+ 5 + i"T - + -\ BT lhii,,« h ---1 -ESTIVO-ACTUUNAL FeVER — KeUITTENT FeVER — "SuBCONTINtJA TVTHOIDEA." Tlie orguuLsuis liud diwiippeared and the temperatura hiid broken on the^lsL The fever uftor this was duo to on acute parotitiB. LECTUEE Y. CLINICAL DESCRIPTION OF THE MALARIAL FEVERS. — {Continued.) Pernicious fevers. — Fevers with long intervals. — Combined infections — Masked malarial infections. — The urine in malarial fever. "Pernicious" is an adjective which has, through long usage, become definitely attached to the very malignant forms of malarial fever. The term pernicious has come into such general use that it should, I think, be retained, despite the attempt on the part of the English translators of Marchia- fava and Bignami's work to introduce the more fitting ap- pellation " malignant." The pernicious forms of malarial fever are very rarely seen in temperate chmates. They are common, on the other hand, in tropical countries and in the most severely malarious regions. They depend almost invariably upon infection with the sestivo-autumnal parasite, though we can not, I think, assert that this is the absolute rule. French,* of Washing- ton, has recently reported a case of comatose malaria due to infection with ordinary tertian parasites, while the writer has on various occasions seen very grave cerebral symptoms in association with severe tertian infections. In the vast ma- jority of instances, however, the pernicious fevers are due to the Hcenriatozoon falcijparxiTn. * N. Y. Med. Jour., 1896, Ixiii, 674. 145 14,6 LECTUEES ON THE MALARIAL PE\T:RS. Ill a general way pernicious symptoms may be said to be due : 1. To the abundance of the parasites present and to their capacity for rapid multiplication. Thus Golgi long ago pointed out, as a regular rule, that the severity of the symp- toms in malarial fever was to a certain extent in direct relation to the number of parasites present, and clinical ex- perience has tended largely to support this view. 2. To the special involvement of certain vital organs. As has been noted in the description of the parasites, the aBstivo- autumnal organism often undergoes the greater part of its development within certain special organs, and this localiza- tion of the parasite may differ materially in different cases. Thus, while in many cases the parasite may be found with equal frequency in all internal organs, in others certain special parts may be involved. In some instances the spleen, in others parts of the central nervous system, in others the gastro-intestinal tract, may be the main seat of the infection. In these cases, as one might naturally expect, the clinical symptoms often point directly to the seat of localization. 3. To the special malignancy of the parasite. Baccelli, in particular, has asserted that different groups of the malarial parasite may vary greatly in their malignancy ; thus, in some instances a relatively small group of parasites may produce extremely grave, even pernicious, symptoms — symptoms such as under ordinary circumstances would be produced only by infection with enormous numbers of organisms. While from analogy as well as from clinical observation there is every reason to believe that a difference in the malignity of different cultures of the malarial parasite may exist, it is, however, probable that true pernicious symptoms are never seen without the presence of really a very considerable num- CLINICAL DESCRIPTION OF MALARIAL FEVER. 147 ber of organisms in the system as a whole. There may be, it is true, very few in the peripheral circulation, but it may probably be safely said that pernicious symptoms never occur without the actual presence of a very large number of ma- larial parasites. One can scarcely do better than to quote directly from the admirable article of Bastianelli and Bignami. " The conditions through which a malarial infection be- comes pernicious are : " 1. That the infection be produced by one of the varieties of the sestivo-autumnal parasite. On this condition all to-day are agreed, and we shall not insist further.* " 2. The second condition relates to the abundance of the parasites, and it may be stated as follows : In pernicious fevers, if one take into consideration not only the examina- tion of the blood from the finger, but also the condition in the vessels of the various organs (Marchiafava, Celli, and Bignami), it is a striking point that however the distribution of the parasites may vary in individual cases, their total num- ber is always considerable. As regards the distribution, one may make the following distinctions. There exist : " 1. Cases in which the number of parasites is most abundant — yes, enormous — while all the organs are uniformly invaded. These are the commonest forms of pernicious fever, and are usually accompanied by coma. " There are some cases in this category in which the num- ber of parasites in the blood of the finger, of the spleen, of the bone marrow, etc., is enormous, while the number in the brain is scanty. Clinically, the absence of cerebral phenom- ena is noted. * ? W. S. T. 148 LECTURES ON THE MALARIAL FEVERS. " 2. Cases in wliicli the number of organisms is absolutely and relatively scanty in the bone marrow, in the spleen, in the liver, while they may be relatively few in the blood of the finger, and yet other organs are crowded with the para- sites. Among these the following localizations are to be made out : " {a) The brain and the meninges are filled with parasites either in sporulation or in all their stages of development ; in such cases it is difficult to find not only sporulating forms, but even young parasites in the spleen. Clinically, there are cere- bral phenomena. " {b) The stomach and intestines are chiefly invaded. In these organs the mature forms of the parasite are usually found ; these are the cases of pernicious fever which present clinically . . . intestinal phenomena." The pernicious paroxysm, then, may vary greatly in its clinical character, its manner of onset, and the time in the course of the infection at which it appears. In rare instances, usually only in very malarious districts, the first paroxysm which is noted may show pernicious symptoms. This is, however, very unusual. It is most uncommon for the perni- cious manifestations to appear without abundant warning in the shape of previous symptoms. Grenerally the patient has had a number of previous paroxysms, or perhaps a continued fever for some days, in the midst of which the symptoms sud- denly assume a malignant nature. The Comatose Type. — The commonest form of pernicious malarial fever is the comatose paroxysm. Such a paroxysm often begins with a period of excitement, possibly delirium ; there is frequently nausea or vomiting. These symptoms are rapidly followed by drowsiness, somnolence, and finally by coma. The patient under these circumstances is usually en- CLINICAL DESCRIPTION OF MALARIAL FEVER. 149 tirely unconscious. There may be restlessness and jactata- tion, but in other instances the patient may lie quite motion- less. The respiration may be quiet, or loud and stertorous ; it may assume the Cheyne- Stokes character. The pulse may be at first full and slow, but toward the end it becomes rapid and feeble. The skin is often extremely hot and dry ; the pupils may be dilated or contracted, and in some instances irregular. The conjunctivae are usually injected ; the tongue is dry and coated. There is commonly a slight jaundice of the skin and conjunctivae — a very important symptom. There are often evidences of a moderate anaemia. At times there are local spasms, which may, in some instances, point to a special localization in the central nervous system of changes due to the collection in these parts of a more abundant num- ber of the parasites. The examination of the lungs is usually negative, though sonorous rales may be present ; with failure of the heart fine rales appear at the bases. The cardiac sounds are usually clear, though a soft systolic murmur may be present over the body of the heart. The abdomen is, as a rule, negative, excepting for the pal- pable spleen. In a small proportion of the cases the spleen can not be felt. In such instances it may often be difficult to distinguish the case from sunstroke, and, as has been shown by Bastianelli and Bignami, such a confusion probably often occurs in the malarious districts of Italy. In fatal cases the coma continues, the pulse is rapid, feeble, and irregular, becoming quite impalpable before the death of the patient. In more favorable instances the tem- perature, after remaining elevated for a certain length of time, begins to fall more or less rapidly, sometimes in associa- tion with sweating, while the patient gradually returns to con- 150 LECTURES ON THE MALARIAL FEVERS. sciousness. The local spasms which may have been present usually clear up entirely with the disappearance of the cere- bral symptoms. Such an attack may last for hours. Often there may be a temporary improvement in the symptoms, a fall in the temperature, associated with sweating and partial clearing of the sensorium, and improvement in the pulse, only to be followed in the course of a few hours by a fresh attack, which may result fatally. Other Cerebral Manifestations. — Other cerebral manifes- tations are common in the pernicious fevers, sometimes pre- ceding: a comatose attack, sometimes unassociated with it. Thus the most violent maniacal deli 74 am may occur, while active hallucinations and delusions are relatively common. In some instances tetanic convulsions have been observed, while hemiplegia has been reported. All these symptoms may clear up with the paroxysm. A number of cases have been reporte J in which symptoms pointing to the involvement of the medulla oblongata have been observed ; these cases may show symptoms of bulbar paralysis. In one such case the direct proof of the localiza- tion of the parasites in this region was furnished on post-mor- tem examination by Marchiafava.* A special localization of the parasites in the cerebral cor- tex is not to be made out in every fatal case of comatose malaria. In many instances the organisms are to be found almost equally distributed throughout the general circulation, and we must not be too hasty in concluding that the coma in these pernicious cases is always definitely due to the cerebral localization of the parasites. It is readily conceivable that many of the cerebral symptoms miglit be due to a circulating * Lav. del iii cong. della soc. Ital. di med. int., Roma, 1890, 142. CLINICAL DESCRIPTION OF MALARIAL FEVER. 15X toxic substance, tlie presence of which we can not but acknowl- edge as highly probable. The Algid Type. — In regions where the pernicious fevers are very common a train of symptoms not unlike those seen in the algid stage of Asiatic cholera may be observed. Here the patient, when he comes under observation, is often found to be in a condition of profound collapse. The eyes are sunken, the features drawn, the skin cold and blue and often bathed in a profuse sweat. The tongue is dry and tremulous and protruded with difficulty. Great prostration is a marked symptom, the patient being almost unable to raise his hand. The pulse may not be palpable at the wrist, while on auscultation the heart sounds are very rapid and feeble, the second sound being, perhaps, entirely absent. The tem- perature is often little, if at all, elevated. The mind is usu- ally clear almost to the end, though the voice is often ex- tremely weak and husky. During the early stages of an algid paroxysm, owing to the quiet, listless condition of the patient, the severity of the case may fail to be appreciated. Thus, in one of our cases, a man walked into the out-patient department at eleven o'clock in the morning, and took his seat among the others waiting to be seen by the physician. Dr. Smith, noticing that he was some- what blue and looked very ill, examined him and discovered that the pulse was impalpable at the wrist. The blood con- tained numerous sestivo-autumnal parasites. He was sent to the ward, and, despite hypodermic injections of quinine and all stimulation, he died an hour and a half from the time of admission. Laveran * well remarks that in some such instances the * Traite des fievres palustres. 152 LECTURES ON THE MALARIAL FEVERS. attention .may be drawn to tlie case only by the discovery, per- haps accidental, that the patient is practically pnlseless. ChoUrlfonii Malaria. — The occasional manifestation of grave choleriform symptoms in malarial fever has long been recognized. Indeed, the sanitary commissioner for Bombay, in his report for 188-i, makes the surprising statement : " In my opinion, cholera will in time be recognized as an intensified form of the malarial fevers common to the country." More recently the true nature of these choleriform paroxysms has been cleared up by the researches of Marchiafava,* who has shown them, as above mentioned, to depend upon the actual localization of the parasites m the gastro -intestinal mucosa. Usually diarrhoea has accompanied the sevei*al parox- ysms preceding the actual pernicious manifestations. Clin- ically these cases may show a picture closely resemblmg that of Asiatic cholera : sudden profuse watery diarrhoea, associ- ated with intense prostration, the patient sinking into an algid condition similar to that described above. The attack often proves rapidly fatal, though in other instances a gradual re- mission in the symptoms occurs, which under proper treat- ment may be followed by complete recovery. Without treat- ment, however, choleriform malaria proves early and rapidly fatal. The HcBinorrhagic Type. — A type of malaria has been de- scribed which is associated with profuse haemoptysis, epistaxis, and often extensive cutaneous haemorrhages ; there may be haematemesis or melaena. Marchiafava and Laveran have re- ported such cases. It has never fallen to the writer to ob- serve any cases of this nature, though in a number of instances a moderate epistaxis has been noted during a ma- *Pr()c. XI Internat. Med. Cong., 1894; Centr. f. allg. Path. u. path. Anat., 1894, v, 418. CLINICAL DESCRIPTION OP MALARIAL FEVER. 153 larial paroxysm, and in several instances a slight petechial eruption. The Sudoriferous Type. — Some observers have described paroxysms in which the last stage, that of sweating, is so ac- centuated that the patient falls into a condition of profound prostration, from which he recovers only under the most active stimulation. These cases are also unusual. The Bilious Type i^'' Subcontinua biliosa''''). — I have re- peatedly emphasized the frequency in malaria of a slightly yellowish hue of the skin and conjunctiva. This jaundice is not one of pure obstruction but rather of overproduction of bile, with backing up in the ducts and reabsorption. It is associated with dark-colored stools and an increased quantity of urobilin in the urine. There is a class of pernicious fevers where the polycholia and jaundice are among the more conspicuous of the manifes- tations. Here, in association usually with high fever, there is repeated vomiting of bile- stained fluid, while the dejecta contain an excess of bile. The urine is of a deep red color, and may be of a brownish or greenish hue, showing traces of the biliary coloring matters, as well as albumen. There may be obstinate epistaxis or haemorrhages from other mucous membranes, while a grave anaemia rapidly develops. The temperature remains elevated. There is profound prostra- tion. The patient is dull and apathetic, the face sunken and expressionless, the respirations feeble, the pulse almost im- palpable. Delirium or coma may follow, and in the absence of energetic treatment death usually results. Under quinine recovery may occur, the temperature fall- ing usually by lysis and the symptoms gradually clearing up. There may be a more rapid fall in temperature with a critical sweat. The patient is, however, left in a very 11 154 LECTURES ON THE MALARIAL FEVERS. weak, exhausted, ansemie condition, from which recovery is slow. Gastralgic and Cardialgic Type. — Very severe attacks of abdominal pain may be associated with a pernicious paroxysm. There is usually profuse vomiting and not infrequently haematemesis ; intestinal symptoms may be quite absent. Laveran distinguishes a distinct gastralgic or cardialgic type of the pernicious paroxysm, describing well one case of this nature in his Traite des iievres palustres (obs. xxxiii). The Pneumonic Type. — Baccelli has described a type of paroxysm which suggests by its symptoms the existence of a pneumonia. This astute observer early recognized, however, that the condition was quite distinct from a true complicating pneumonia. There is usually a painful cough, great dyspnoea, and severe pain in the chest, while there may be moderate dullness over the afiected lung. On auscultation, coarse, so- norous and sibilant rales, together sometimes with fine, moist sounds, may be heard. The sputum is mixed with dark fluid and clotted blood. In other cases, however, despite the extreme dyspnoea, the physical examination may be negative. The exact pathological basis for these paroxysms is not entirely settled, owing to the insufficient number of autopsy records. It is quite certain, however, that we are not dealing with a true pneumonia. It is more probably an active con- gestion of the pulmonary vessels, a condition not impossibly due to a special localization of the parasites in the capillaries of the lungs. The HcBmoglohinuric Type — Malarial Ecemoglohinuria. — ■ This condition is kno\vn by a number of other terms. The more important are, perhaps, malarial hgematuria, ictero-hsematuric fever, bilious haematuric fever {Fievre hilieuse heinaturique). CLINICAL DESCRIPTION OF MALARIAL FEVER. 155 The association of hsemoglobinuria with malaria has long been recognized. The condition is often referred to as ma- larial hsematuria, which maj indeed exist, though in many instances actual blood-corpuscles are not to be found in the sediment of the urine, or, if they be found, are present in very small numbers ; the condition is then due to the presence of a blood-coloring matter — a true hsemoglobinuria. The coloring matter is always present in the form of methsemoglobin. Malarial hsemoglobinuria is very uncommon in temperate climates, and even in the more malarious tropical regions its distribution is rather remarkable. In some districts where severe malaria prevails and pernicious symptoms are not un- common, as, for example, in Algeria, hsemoglobinuria is rela- tively rare, while in others, as in Sicily, in Greece, and upon the west coast of Africa, it is extremely common. In the United States it is unusual excepting in certain regions in the South, where it has been well described by Joseph Jones.* Malarial hemoglobinuria occurs probably only in sestivo- autumnal infections. Most instances studied by competent observers have shown the Hmmatozoon falciparum,. Unfor- tunately the observations in the regions where this form of paroxysm is commonest have been made for the most part by individuals who were not entirely familiar with the various forms of the malarial organism. In a recent interesting article Plehnf describes figures which suggest strongly the sestivo- autumnal parasite, though he himself seems inclined to be- lieve that it is a special form of the organism. More recently A. Plehn X has recognized their identity. The process rarely. * Medical and Surgical Memoirs, t Deutsch. med. Wooh., 1895, Nos. 25, 26, 27. X Beitrage zur Kenntniss von Vei'laui' und Behandlung der tropischen Malaria in Kamerun, Berlin, Hirschwald, 1896. 156 LECTURES ON THE MALARIAL FEVERS. if ever, occurs in infections with the tertian or quartan para- sites. Hffimogh^binaemia is a constant occurrence in pahidism, owing to the extensive destruction of blood-corpuscles which takes place in every malarial infection. This destruction occurs in various ways : (1) The red hlood-corpuscles are slowdy destroyed by the parasites, the haemoglobin being transformed into the pigment melanin. (2) A number of infected corpuscles, as we have seen, particularly in sestivo-autumnal infections, become early shrunken and brassy colored — a process which is generally believed to represent an early necrosis. (3) We may frequently observe in a fresh specimen of the blood the rupture of a corpuscle which may be but little altered, associated with the escape of the parasite which it contains and the solution of the haemoglobin in the surround- ing serum. This may occur in corpuscles containing very young forms of the parasite. It is not at all impossible that such a process may take place frequently in the circulating blood. Moreovei-, it is probable that the corpuscle containing the full-grown parasite is by no means in every instance wholly free from haemoglobin ; a certain quantity of this sub- stance escapes at the time of segmentation. Thus it is probable that in any malarial paroxysm a con- siderable amount of haemoglobin escapes and becomes diffused in the general circulation. Poufick has estimated that up to one sixth of the total number of red blood-corpuscles may be destroyed within the circulation, and yet the haemoglobin be disposed of in the economy without appearing as met- haemoglobin in the urine. Though in every malarial process there is probably a more or less continuous escape of haemo- CLINICAL DESCRIPTION OF MALARIAL FEVER. 157 globin into the blood plasma, this does not under ordinary circumstances pass through the renal epithelium ; it is in great part taken care of by the liver, by which it is trans- formed into the bile pigments. This results in the poly- cholia which is so characteristic of malaria and other condi- tions where there is extensive blood destruction (pernicious anaemia). In severe cestivo-autumnal infections enormous numbers of red corpuscles, indeed as many as from one to two millions — a third of tbe entire number — may be destroyed in a single paroxysm and yet no hsemoglobinuria occur. It must, to be sure, be remembered that this destruction does not take place at one time, but during twenty-four or thirty-six hours, while many of the corpuscles have lost their haemoglobin gradually through the action of the parasite in developing pigment. That haemoglobinuria should occur there must, however, be an enormous destruction of red blood-corpuscles — a de- struction too great, probably, to be dependent wholly on the disintegration of parasitiferous elements. An infection so extensive that the decolorization of infected corpuscles alone is sufficient to account for an hsemoglobinuria probably never occurs. We are compelled, in seeking an explanation of the occur- rence of this process, to suppose the existence of some condi- tion which renders the uninfected red blood -corpuscles un- usually vulnerable, possibly some change in the blood serum bj which its isotonicity is markedly disturbed. And, further, there must be a direct exciting cause — a cause which appar- ently varies under different circumstances. In addition to the excessive destruction of red blood- corpuscles, it is probable that degenerative changes in certain of the internal organs, the liver and the kidneys in particular, 158 LECTURES ON THE MALARIAL FEVERS. may play an important role in connection with tlie develop- ment of the hsemoglohimiric paroxysm. The fact that haemoglobinnria is rare early in the course of a malarial in- fection is well recognized ; it is particularly common in individuals who have suffered from frequent and long-con- tinued attacks. But when we consider the extensive degen- erative changes wliich occur in the kidneys and in the liver in chronic and frequently repeated infections, it is not incon- ceivable that an increased permeability of the renal epithe- lium due to the grave alterations produced by the infection, together with a relative incapacity of the liver to carry out the extra work demanded of it, may represent important fac- tors among the elements constituting the predisposition to hsemoglobinuria in such conditions.* Let us now consider the conditions under which the haemoglobinuric paroxysm occurs. All observers agree that climate plays an important pre- disposing role. The greater prevalence of the process in certain special regions has been already mentioned. Beyond this there is apparently an individual predisposi- tion the nature of which is by no means clear. There are, however, certain general conditions which appear to be neces- sary for the development of the haemoglobinuric paroxysm. Hsemoglobinuria does not occur early in a malarial infec- tion. It is seen usually in relapses or after oft-repeated attacks where the patient is in a more or less anaemic or re- duced condition. But, as Bastianellif has insisted, it is not in the most * Murri (II Policlinico, 1895, ii, 340), who discusses this subject at length, insists especially upon the importance of grave renal lesions as necessary for the development of haemofjlobinuria. t Ann. di med. nav. ann. II, 1896, xvi. CLINICAL DESCRIPTION OF MALARIAL FEVER. 159 chronic cases of malaria that hgemoglobinuria occurs — tliat is, those cases where already a certain equilibrium has been established between the needs of the organism and the function of the hsemopoietic organs; it is in those cases where the melanosis and the anaemia are yet present — that is, at a period where the organism is actively en- gaged in freeing itself from the residua of the infection and in compensating for the loss of the elements of the blood. If these be important factors in the predisposition above referred to, it is not surprising that it should be variable and transitory. The factors which are necessary for the production of an hsemoglobinuric paroxysm are summed up as follows by Bastianelli : * "1. Pre-existing alterations in the haemopoietic organs due to preceding infections. " 2. Ansemic conditions of the blood. " 3. That one or more febrile attacks have preceded. " 4. An individual predisposition (idiosyncrasy). " The above-mentioned factors create the transitory con- ditions which permit the attack which takes place through the action of " 5. A provocative agent." The latter varies possibly in different cases. Bastianelli has distinguished several different forms of hsemoglobinuria according to their relation to the stage of the infection in comiection with which they occur. 1. Hgemoglobinuria occurring in association with the ma- larial paroxysm. The onset of the attack here coincides with * Op. cit. IGO LECTURES ON THE MALARIAL FEVERS. the sporulation of a group of organisms and with the fresh parasitic invasion. Such attacks may be of relatively short duration. They may be intermittent, being repeated with successive parox- ysms, or, in other cases, continuous or subcontinuous, just as may be the fever in infections with multiple groups of the parasites. 2. In other instances the attack may likewise come on during an ordinary malarial paroxysm in association with the sporulation of a group of parasites ; the parasites, however, which were present at the onset disappear spontaneously during the paroxysm. Such attacks are often severe and of long duration, lasting several days after the disappearance of organisms from the blood. They may be followed by fever of some days' duration. In these forms of hsemoglobinuria the exciting cause is evidently closely connected with the life history of the parasite ; it is present only at the time of sporu- lation of a group of organisms and may very possibly be represented by some toxic substance set free at the time. 3. But there are other forms of malarial haemoglobi- nuria which much resemble these clinically, but occur in patients whose blood and organs are free from parasites. There has, however, always been a recent infection. In other words, we have to do with a post-malarial hcBmoglo- hinuria. These post-malarial attacks may occur : ■ («) Rarely as separate intermittent paroxysms. (b) More commonly as a single, very severe, often fatal attack. The direct exciting cause of such paroxysms is quite un- CLINICAL DESCRIPTION OF MALARIAL FEVER. Ifjl known. Interesting cases of this nature have been reported by Grawitz * and Bastianelli and Bignami.f 4. Lastly, as pointed out originally by Tomaselli, of Sici- ly,:}: and later by Grecian physicians, by Murri,* and espe- cially by Plehn,! hsemoglobinuria may occur in individuals vt^ho are suffering or have recently suffered from malaria, as a direct result of the administration of quinine. From a careful consideration of the reported cases Bastia- nelli shows that : {a) It occurs only in individuals who have suffered from a previous malarial infection, {h) In such cases the hsemoglobinuric attack follows every time that quinine is administered, whether it be during the occurrence of the malarial paroxysm (Tomaselli) or after the infection has run its course (Murri). ((?) Extremely small doses of quinine are capable of bring- ing on the attack. (d) The hsemoglobinuria of quinine has been seen in patients who have already suffered from spontaneous hgemo- globinuria. An important difference between the hsemoglobinuria of quinine and the spontaneous hsemoglobinuria of malaria is that in the former the predisposing conditions, whatever they may be, last usually for a considerable length of time, and while this predisposing condition exists the determining cause, quinine, produces the attack without fail every time that it is administered, be the dose ever so small. Toma- selli believes the predisposing condition to be a personal * Deutsch. med. Woeh., 1892. f Bull. soc. Lane. d. Roma, 1892, xii, 81. i (a) I Cong, di med. int. Roma, 1888 ; (&) Clin. med. Firenze, 1895, 151. « Policlinico, July 15, 1895. || Op. cit. 162 LECTURES ON THE MALARIAL FEVERS. idiosyncrasy; it lias been observed to prevail in certain families. With the spontaneous hsemoglobinurias of malaria the conditions are different. The attack here appears to be merely an episode. In relapses or succeeding malarial parox- ysms, where, so far as we can see, the conditions are exactly the same, there may be no return of the attack. Thus we may see hemoglobinuria due to quinine : 1. Occurring during an acute infection. 2. After the organisms have disappeared (post-malarial). Here, in the words of Bastianelli, "the preceding mala- ria creates the fundamental disposition ; the existing malaria, the accidental disposition ; the quinine, the provocative agent." It may be that in addition to these two forms we must yet recognize a third type where quinine exercises its action only occasionally — "hemoglobinuria accessuale do chinino episodiche " (Bastianelli). The clinical picture of an hfemoglobinuric paroxysm is fairly characteristic. It is never the first symptom of a malarial infection. Usually it appears in the course of a re- lapse, or, at least, the patient has had several paroxysms before the pernicious one appears. As has been above stated, the paroxysm may appear after the acute symptoms of the infection have subsided. It is commonest in individuals who have had repeated attacks and are more or less cachectic. Further predisposing causes may be anything tending to reduce the vitality of the individual. As has been mentioned above, certain individuals and certain families appear to be especially subject to hsemoglobinuric attacks. An individual who has once undergone an hsemoglobinuric paroxysm is not infrequently the subject of further attacks with subsequent infections or relapses. CLINICAL DESCRIPTION OF MALARIAL FEVER. 163 The process usually begins with a severe cliill, which is in marked contrast to the general rule in sestivo-autumnal infec- tions, where the chill is so often abortive or absent. This chill is followed by intense headache and aching pains in the back and extremities, and usually by profuse and obstinate vomiting. The vomitus consists of a deeply bile-stained fluid. The face is flushed, the conjunctivae injected ; the pulse is usually rapid and small. There is a distinct icteric hue to the skin and conjunctivae. The attack is generally associated with great mental anxiety and apprehension. There is commonly profuse diarrhoea. The urine, at first of a reddish hue, becomes deeper in color, and finally an intense brownish-black, with something of a greenish hue. On shaking, there is a greenish -yellow foam. The vomitus, at first yellow, then green, becomes finally almost black. The stools are of a green or brown color, and are usually fluid, though in some instances there may be constipation. The patient often falls into an algid condition. He is quite conscious, but in a state of profound collapse ; often there is great anxiety and mental agitation. There may be severe epigastric pain, which is possibly associated in part with the repeated vomiting. The pains in the back and loins are usually excessive. Kelsch and Kiener* believe that these pains in the loins may be associated with the intense renal congestion. There is usually high fever, the temperature touching in some in- stances 41° C. (106° F.). The jaundice generally increases during the attack. The urine, at the height of the process, is of a deep * Maladies des pays chauds. 164 LECTURES ON THE MALARIAL FEVERS. brownish-black color, and deposits, on standing, an abundance of reddish-brown sediment. The amount varies considerably in different instances. It may be extremely scanty, though at times it may amount to one thousand or fifteen hundred cubic centimetres. The specific gravity varies inversely to the amount of urine passed. It is usually above normal. The reaction varies, being generally feebly acid. Albumen is usually abundant. In some instances there may be a reaction for the bile-coloring matters. Kelsch and Kiener believe this to be the rule at the height of the process, while Plehn, in eight instances, failed to obtain the test. The sediment consists of mucus, bladder epithelium, numerous granules and masses of pigment, renal epithelial cells, and, almost invariably, hyaline and granular casts with epithelial cells adherent. In many instances blood-corpuscles may also be found, actual haemorrhage taking place into the kidney. The severity of the hsemoglobinuric attack varies greatly. In some instances the temperature may remain elevated for nine or ten hours, and then with profuse sweating fall rapidly to normal. The urine clears up, only a slight trace of albu- men with occasional casts persisting for a few days. Com- plete recovery may follow a single such attack. There may be repeated intermittent hsemoglobinuric paroxysms, which may, as Plehn has shown, end in recovery under wholly expectant treatment. Usually, however, the condition is more severe and the fever is prolonged. The vomiting and purging continue and increase in severity, and the jaundice becomes deeper. There may be slight intermissions, but the manifestations are often continuous. During intermissions the urine may show tem- porary changes for the better, but with the exacerbation of CLINICAL DESCRIPTION OP MALARIAL FEVER. 165 the symptoms it returns to its old condition. The amoimt of urine diminishes, the albumen increases, the patient becomes pale, the eyes sunken, the tongue dry, the pulse rapid and feeble, and finally a fatal result ensues. It is surprising, however, from what apparently desperate conditions patients may recover. In other instances the course of malarial haemoglobinuria is extremely rapid and fatal. A very grave symptom in these cases, which begin always with a chill, fever, vomiting, and diarrhoea, is suppression of urine. But a few intensely bloody drops may be passed ; there may be complete anuria. There is great agitation, prostration, and profound collapse; death follows usually within a few days. The hsemoglobinuric attack is always followed by nephri- tis. In the milder cases this may be transient and slight. Sometimes, however, the paroxysm has a definitely nephritic type. The initial suppression of urine never entirely clears up, the quantity remaining steadily below normal. The albu- men and casts persist, and symptoms of uraemia, delirium, coma, and convulsions follow, leading to a fatal result. The hsemoglobinuric attack is in itself one of the most fatal manifestations of pernicious malaria, yet it is very inter- esting to note how frequent are spontaneous recoveries with disappearance of the parasites. These facts suggest strongly the possibility that either the existence of the hsemoglobinae- mia itself, or the presence of some other toxic substance in the blood, may act unfavorably upon the parasite during the time of the paroxysm. In many instances, however, where spontaneous recovery has been noted the process was prob- ably a true post-malarial hsemoglobinuria, like the cases of Bastianelli and Bignami. The hsemoglobinuric paroxysm due to quinine differs little 166 LECTURES ON THE MALARIAL FEVERS. in its clinical manifestations from the spontaneous malarial haemoglobinnria. The Blood in yEstivo-auUimnal Fever. — The blood in aestivo-autnmnal fever shows the presence of the third variety of malarial parasites above described — the so-called testivo- autumnal organism {IIce7nato ^ _. . _ ^ .. _ _ m- ^ -^ H - ■ 5 •Wd Z ^r' OD •N Bl 1 s •WVOI _- r" •WVB L- "■ 5) _r3 ■WV9 T iih i^ -_ _ ■wvt 1 ""' — ^ — < •wvz ^ •n 21 •WdOl •n'ds ' a •Wd 9 ^ '— •Wd f HTIt- ps£ _ ^ ■WdJ 1 ~ ■^— -\ r« •N 31 a •! -ii .x-siio othS laaaj-ax J> ^ •w»oi 1 >-^ •wve ^ — ■ ^ s ••WV9 -' •wvt == 1 £ 5 ■wvz "- — ._ l__ 1 — ^ ^— ^ — — ^ r— ^^ ~5^"!" -??T*J ■w^oi -^ 1 i j ■Wd8 ,^i^ ^i5 •Wd9 , .«■ ^ ■Wd* =g y ■Wd3 ~-. .0 •N 21 »> s a •w«oi < •WV8 > 1 s ■WV9 ^ IS ■wvt c 1 ^ ■WV2 H" IHO r ■W 21 •W dOl ^ "S ■Wd8 •Wd9 J •Wd t __ ' ;J ^ •Wd2 * <■ -" ^ iO •N 21 •^ ,S •WVOI ni IH - -] — -. 1 •wvs r -> Oi 01 •WV9 1 rr •wv* _-^ 5 •WV2 - - — — _ - ^ - ^ — q ■^ -4 — - -^ •Wd 01 - — - — — — — — = -^ ~ — -- -" •WdS S S3 •Wd 9 •Wd t ^ s •Wd2 ^ >* ■N 21 =3 WVOI ^ ■WV8 s SJ •WV9 > •wvt 1 n -" 1 s s ' •WV2 \\___ i ■WdOl ~~ __ 1 ■Wd8 , s s ■Wd9 ^ •Wd* 1 " V g s •Wd2 __t iw 09 •N 21 .-■ — — y •wvci — _ •wva ni IH — — — ^ a s ■WV9 I! ■wv* -4 H ^ ■WV2 / 1 •W 21 _ ^ .^ __ __ s 3 ■Wd 2 ffl •N 51 s 3 ■ WV 01 J ■WV 8 ^ — 1 s s •WV 9 /■ r-' •^■v f ^ 1^ ^ g •WV 3 «= - ■H 3t _ _ Jii — , — ... ._ s; WdOl n^ Ih ^ -^ ~ ~ ~ ~ •Wd 8 I s ■^ ■Wd 9 •Wd i § ^ rH •Wd Z ,s •N 51 ^ , ^ WV 01 r •WV 8 g •WV 9 •WV * a S •WV Z > •|M Zl s 3 WdOl •Wd 8 / ^ i 3 •Wd 9 « ^ 11 •Wd t 1 ■> s S •Wd 3 I f^ •N 51 T^ 1 \ « •g, WVOI 1 \ •WV 8 1 > g; •WV 9 1 < ■WV t \ V, s g •WV 5 1 > ■n z\- K S5 WVOI ^ Wd a S S •Wd 9 •Wd t \ !? s •Wd 5 1 s "N 51 s Si WV 01 1- <■ o ■VV 8 -. s g ■WV 9 ■" ■WV «• o S ■WV 5 3 VCdOl J Wd 8 --•^ 1 m S •Wd 9 •Wd t — ^ 1 ^ 5 •Wd 5 ■< fM •N 51 f S 'n WV 01 t. ■WV 8 > s 5 ■WV 9 1 «. ■WV t > 5 •WV 5 1 / ? ^ VdOl tfd 8 ^ 1 1 %\Z\ 1 .? 275 276 LECTURES ON THE MALARIAL FEVERS. sallow, yellowish-gray color so common in malaria. The mucous membranes are usually of good color, while in malaria there is almost always a slight pallor. The spleen is generally undemonstrable in tuberculosis ; almost invariably palpable in malaria. Herpes is unusual in the former, common in the latter. The examination of the sputa and blood will settle the question. The blood in tuberculosis with intermittent fever shows, generally, a distinct leucocytosis, which is absent in malarial fever. The discovery of the parasites is, however, the deciding point. Chills occurring in the course of gono7'rh-^' ^d^- ■«f 17 IS ,19 2 "^ e .'■^ 1'. -r >«ig[^^ ••"' >■ ' ,">•■ • J '•' . ';'' ' '^ ■'»'-_l.i'^ ■ ?;. ', ■ ""■ ,-•• ''..._ 6 ft? MSrbdel.fcv; l.ifhl.Pane^Co Fy.siih DESCKIPTION OF THE PLATES. The drawings * were made with the assistance of the camera lucida from specimens of fresh blood. A Winkel microscope, ob- jective one fourteenth (oil immersion), ocular four, was used. Figs. 4, 13, 23, and 24 of Plate I, and Fig. 18 of Plate II, were drawn from fresh blood, without the camera lucida. PLATE I. The Parasite of Tertian Fever. 1. Normal red corpuscle. 2, 3, 4. Young hyaline forms. In 4 a corpuscle contains three dis- tinct parasites. 5, 21. Beginning of pigmentation. The parasite was observed to form a true ring by the confluence of two pseudopodia. Dur- ing observation the body burst from the corpuscle, which be- came decolorized and disappeared from view. The parasite became almost immediately deformed and motionless, as shown in Fig. 31. 6, 7, 8. Partly developed pigmented bodies. 9. Full-grown body. 10-14. Segmenting bodies. 15. Form simulating a segmenting body. The significance of these bodies, several of which have been observed, is not clear to the writer, who has never met with similar bodies in stained speci- mens so as to be able to study the structure of the individual segments. They are possibly segmenting bodies which have undergone some changes in the preparation of the specimen. 16, 17. Precocious segmentation. 18, 19, 20. Large swollen and fragmenting extra-cellular bodies. 22. Flagellate body. 23, 24. Vacuolization. * The writer desires here to express his gratitude to Mr. Broedel for his admirable work. 21 313 314 LECTURES ON THE MALARIAL FEVERS. PLATE II. ' TuE Parasite of Quartan Fever. 1. Normal red corpuscle. 2. Young- hyaline form. 3-10. Gradual development of the intra-corpuscular bodies. 11. Full-grown body. The substance of the red corpuscle is no more visible in the fresh specimen. 12-15. Segmenting' bodies. 16. Large swollen extra-cellular form. 17. Flagellate body. 18. Vacuolization. PLATE in. The Parasite of ^stivo-autumnal Fever. I, 2. Small refractive ring-like bodies. 3-6. Larger disk-like and amoeboid bodies. 7. Ring-like body with a few pigment granules in a brassy, shrunken corpuscle. 8, 9, 10. 12. Similar pigmented bodies. II. Amoeboid body with pigment. 13. Body with a central clump of pigment, in a corpuscle showing a retraction of the haemoglobin-containing substance about the parasite. 14-19. Larger bodies with central pigment clumps or blocks. 20-24. Large bodies with central pigment blocks — presegmenting forms. 25-28. Segmenting bodies (from the spleen). Figs. 21-23 represent one body where the entire process of segmentation was observed. The segments, eighteen in number, were accurately counted be- fore separation, as in Fig. 27. The sudden separation of the segments, occurring as though some retaining membrane were ruptured, was observed. 29-37. Crescents and ovoid bodies. Figs. 34 and 35 represent one body which was seen to extrude slowly, and later to withdraw two rounded protrusions. 38, 39. Round bodies. 40. Pseudo-gemmation, fragmentation. 41. Vacuolization of a crescent. 42-44. Flagellation. The figures represent one organism. The blood was taken from the ear at 4.15 P. M. ; at 4.17 the body was as rej)resented in Fig. 42 ; at 4.27 the fiagella appeared ; at 4.33 two of the fiagella had already broken away from the mother body. PLATi: II llll- PaRASHT; Ol- ( MiAUTAN lilVT'.n 10 ^ L:th.l..PR-i PI All- III 'JllE P/VRA.SITI. ()l-AKSTIV(»ArTIJMNAl.lT:Vi:n. ,swis i; 20 29 33 t^'% ':•? J 9 40 4! 42 12 i6 17 18 • Q # 23 24 30 36 3: t ,--5i„.^ .., \[i;;,,-„;pi.(e'' Li!f. LPrangf-'^n. Bostph DESCRIPTION OF THE PLATES. 315 45-49. Phagocytosis. Traced by Dr. Oppenheimer with the camera lucida. Note.— These plates, produced here by permission, are essentially the same as those published in The Malarial Fevers of Baltimore. Thayer and Hewetson, Johns Hopkins Hospital Reports, vol. v, 1895, and in the article of Professor Welch in A System of Practical Medicine by American Au- thors, New York, Lea Brothers & Co., 1897. To the original plates how- ever, four drawings, Nos. 21-24 of Plate III, have been added, while 'other slight changes have been made in Plate I. The figures have been well reproduced by Prang from the original drawings in the shape of three plates, instead of two as previously. INDEX OF AUTHOES. Abbott (and Councilman), 12, 211. Angelini (and Antolisei), 20, 29, 72, 73, 170. Antolisei, 15, 79, 24.6, 247 ; (and Angelini), 20, 29, 72, 73, 170 ; (and Gualdi), 29. Arnstein, 239. BacccUi, 21, 29, 141, 154, 194, 247, 283, 289, 296, 301, 305. Barker, 209, 211, 218, 221, 238, 242. Bassi, 5. Bastianelli, 74, 96, 158, 159, 162, 187, 188, 211, 221, 222, 224, 265, 268, 305; (and Bignami), 15, 20, 25, 29, 77, 78, 99, 147, 161, 165, 168, 196, 198, 209, 284, 291. Bein, 27, 29, Bernasconi (and Eem-Picci), 176. Bourmann, de (and Villejean), 300. Bignami, 74, 75, 94, 96, 102, 170, 171, 184, 195, 211, 219, 222, 225, 229, 236, 238, 242, 243, 270 ; (and Bastianelli), 15, 20, 25, , 29, 77, 78, 99, 147, 161, 165, 168, 196, 198, 209, 284, 291 ; (and Dionisi), 95, 185, 188, 232; (and Marchiafava), 21, 23. 31, 62, 63, 68, 80, 134, 136, 145, 175, 193, 194, 220, 234, 268, 296, 297, 305. Billings, 187. Binz, 7, 294. Blumer, 27, 28. Boinet (and Salebert), 196. Botazzi (and Pensuti), 177, 178, 181, 249. Bouchard, 107. Bouchardat, 6. Boudin, 6, 205. Brousse, 248. Caccini (and Rem-Picci), 176. Calandruccio, 29. Canalis, 15, 17, 18, 21, 62, 72, 73, 169, 170. Celli, 74, 82, 91, 147 ; (and Guarnieri), 24, 308; (and Marchiafava), 10, 11, 15, 16, 17, 18, 19, 21, 29, 32, 79, 197, 200, 2B9, 243 ; (and Sanfelice), 27 ; (and Santori), 100. Childe, 237. Ciarrochi (and Mariotti), 29. Colosanti (and lacoangeli), 181. Coronado, 28, 31. Councilman, 16; (and Abbott), 12, 211. Da Costa, 196. Danilevsky, 31, 73. Del Cinclion, 293. Dionisi, 185, 197 ; (and Bignami), 95, 185, 188, 232. DIauhy, 239. Dock, 12, 15, 20, 81, 78, 211. Dubini, 196. Duchek, 95. Ehrlich, 182, 189, 194, 282; (and Gutt- mann), 308. Emin Pasha, 95. Felctti (and Grassi), 15, 20, 22, 24, 25, 32, 47, 71, 72, 74, 79, 91. Fischer, 26. Flexner, 218, 238 ; (and Welch), 252. French, 145, 289. Frerichs, 193, 234, 235, 239. Geppener (Heppener), 25, 26, 54, 202, 205. Gerhardt, 28. Giardina (and Terni), 15, 20, 73. Golgi, 12, 13, 16, 17, 18, 21, 22, 55, 67, 69, 79, 112, 119, 169, 170, 214, 216, 245, 246, 248, 270, 294, 295, 296, 297, 302. Gotye, 15, 20, 22, 25, 77. 317 318 LECTURES ON THE MALARIAL FEVERS. Grassi, 42 ^ (and Felctti), 15, 20, 22, 24, 25, 32, 47, 71, 72, 74, 79, 91. Grawitz, 161, 198. Gricsinsfer, 95. Gualdi (and Antolisei), 29. Guarnicri, 20, 211, 218, 258; (and Celli), 24, 308. Guttniann, 312; (and Ehrlicli), 308. Hamburger, 27, 28. Heppener. See Geppener. Hertz, 87. Hewetson (and Thayer), 15, 20, 23, 202. Hippocrates, 3. Hischl, 239. lacoangeli (and Colosanti), 181. James, 12. Jancso (and Rosenberger), 15. Jones, 155. Jourdan, 196. Kahler (and Pick), 196. Kalindero, 185. Kamen, 15, 20. Kelsch, 185, 186, 187, 197, 209; (and Kie- ner), 163, 164, 224, 236. Khctagurov, 188. Kiener, 233; (and Kelsch), 163, 164, 224, 236. Kirk bride, 185. Klebs (and Tomassi Crudeli), 7, 10. Koplik, 15, 20. Korolko, 15, 20. Kruse, 33. Labbe, 33. Lancisi, 1, 5, 89. Lanzi (and Terrigi), 7. Laveran, 1, 2, 4, 8, 9, 10, 11, 16, 26, 31, 32, 78, 151, 152, 154, 211, 236, 239, 245, 251, 294, 302. ■ Lemaire, 6. Lemoine (and Eoque), 248, 249. Lepine, 249. Lodigiani, 237. Macallum, 242. Mannaberg, 15, 20, 23, 25, 31, 54, 03, 74, 75, 78, 295, 296, 302. Manson, 31, 75, 80, 94, 95. Marchiafava, 74, 147, 150, 152, 205, 214, 222, 241, 258, 259 ; (and Biguami), 21, 23, 31, 62, 63, 68, 80, 134, 130, 145, 175, 193, 194, 220, 234, 268, 296, 297, 305; (and Celli), 10, 11, 15, 16, 17, 18, 19, 21, 29, 32, 79, 197, 200, 239, 243. Marino, 91. Mariotti (and Ciarrochi), 29. Massuriany, 107. Mattel, di, 27, 29, 173. Meckel, 8, 239. Metschnikoft; 32. Mingazzini, 32. Mitchell, J. F., 27, 28. Mitchell, J. K., 0. Monti, 211, 214, 215, 210, 312. Morton, 1, 5. Muehry, 161. Neumann, 240. Nuiiez y Palomino, 208. (>slcr, 12, 14, 15, 32, 175. Parkes, 87. Patella, 15, 20. Pensuti, 194; (and Botazzi), 177, 178, 181, 249. Pes, 170, 203. Planer, 239, 257. Plehn, A., 155. Plehn, F., 20, 31, 101, 155, 161, 164,251, 306. Pick (and Kahler), 196. Poncet, 197. Ponlick, 156. Qucirolo, 251. Rasori, 5. Reed, 252. Regnauld (and Villejean), 299. Remouchamps, 15. Eem-Picci, 176, 177, 178, 179, 180. Rho, 257, 281. Richard, 10, 12, 26, 246. Ringer, 178. Romanovsky, 15, 24, 25, 26, 52, 54, 295. Roque (and Lemoine), 248, 249. Roscnbach, 27. INDEX OF AUTHORS. 319 Eosenberger (and Jancso), 15. Eoss, 80. Eossoni, 186. Eussell, 207. Sakharov, 15, 20, 23, 25, 27, 29, 54, (J9, 74, 80. Salebert (and Boinet), 196. Salisbury, 6, 7. Sanfelice, 20; (and Celli), 27. Santori (and Celli), 100. Schiavuzzi, 7. Schmidt, 242. Schweinitz, de, 298. Sezary, 312. Smith, F. E., 151. Smith, Theobald, 94. Sternberg, 12. Sydenham, 1. Terni, 72 ; (and Giardina), 15, 20, 73. Terrigi (and Lanzi), 7. Thayer, 188, 308 ; (and Hewetson), 15, 20, 23, 202. Titov, 1.5, 20. TomascUi, 161. Tomasai Crudeli (and Klebs), 7, 10. Torti, A., 196. Torti, F., 1, 2. Trousseau, 122. Uskov, 188. Varro, 5. Vernazza, 306. Villejean (and De Beurmann), 300 ; Cand Eegnauld), 299. Viucenzi, 170, 173. Virchow, 8, 239. Virey, 6. Welch, 42, 61, 130, 166, 236, 243; (and Flexner), 252. Wood, 7. Zeri, 91. Ziemann, 25, 26, 54. GENERAL INDEX. Age, relation of, to malarial infection, 92. Algae as causal elements of malarial fever, 7. Altitude, influence of, on malarial fever, 87. Alum, 309. Amceba coli, 288. Amyloid degeneration, 193, 234. Ansemia, post-malarial, diagnosis of, 287. pathogenesis of, 255. treatment of, 310. types of, 188. Animalcula as pathogenic agents of ma- larial fever, 5, 6. Anticipation of paroxysms in tertian fever. 111. ajstivo-autumnal fever, 136. Arsenic, 309, 310. Ata.\ia, 196. Atrophy of gastro-intestinal mucosa, 194. Auto-intoxications, post-malarial, 197, 198. Bacillus malariEe, 7. Bacteria as causes of malarial infection, 7. Baltimore, deaths from malarial and ty- phoid fever in, 3. Bark, Peruvian, 293. Blood in sstivo-autumnal fever, 166. in amyloid degeneration, 194. changes in, 184. in chronic malarial cachexia, 192. methods of examination of, 34. platelets, confusion of, with segment- ing bodies, 34. in post-malarial ansemia, 188, 189, 190. in quartan (double) infections, 127. (single) infections, 124. (triple) infections, 127. Blood, stained specimens of, preparation of, 37. in tertian (single) infections, 111. Blue, methylene, 308. Loeffler's, 39. Bone marrow in malarial htemoglobin- uria, 222. Brain in acute malarial infections, 212. Brooklyn, deaths from malarial and ty- phoid fever in, 3. Cachexia, chronic malarial, 190. diagnosis of, 287. prognosis in, 290. treatment of, 311. Cerebral phenomena in aestivo-autumnal fever, 147. symptoms, pathogenesis of, 257. Cheyne-Stokes respiration, 149. Chill. See also Paeoxtsms. description of, 104. frequency of, in asstivo-autumnal fever, 132. in tertian infections, 105. Chorea, electric, 196. Cinchona, 293. Cinchonidia, salicylate of, 308. Cinchonidin, 308. Cinehonin, 308. Cinchonism, 307. Cirrhosis and ciiThotic processes in ma- laria, 194, 235. Climate, effect of, on malarial fevers, 83. Cocaine, 309. Coma in pernicious fever, 147, 148. Combined infections, 172. diagnosis of, 278. Complications, 200. diagnosis of, 288. J21 322 LECTURES ON THE MALARIAL FEVERS. Complications, intestinal, 204. prognosis in, 290. pulmonary, 202. treatment of, 311. Convulsions in pernicious fever, 150. Corpuscles, red, areas of degeneration in, 11. changes in, 185. crenated, brassy colored, 18, 66, 67, 68, 267. destruction of, 156. colorless, 186. Crescentic bodies. See Parasites, iEsTIVO-AUTUMNAL. Cultivation, effects of,on malarial fever, 89. Cutaneous manifestations during paro.x- ysm, 107. Delirium in pernicious fever, 150. Diagnosis, 272. Diarrhoea, 288. Diet, 292. Digestive tract as atrium of infection in malarial fever, 93. Distribution of the malarial fevers, varia- tions of, 92. Drainage, effects of, on malarial fever, 89. Dubinins disease, 196, 291. Dysentery, 204, 288. amoebic, relation of, to malarial infec- tion, 92. " malarial," 201. Endocarditis, gonorrhceal, 273. Eucalyptus globulus, 90, 309. Exanthemata, 288. Fever. See Paroxysm. Fever (febrile stage of paroxysm), 105. catheter, 276. Chagres, 83. malarial, sestivo-autumnal, 17, 130. blood in, 166. clinical picture of, 140. diagnosis of, 279. prognosis in, 289. similarity of, with typhoid fever, 140. tertian type of, ] 34. treatment of, 304. with longer intervals, 134. Fever, malarial, anatomical changes fol- lowing repeated or chronic in- fections, 224. occurring in acute malarial infec- tions, 212. clinical description of, 97, complications of, 200. congenital, 95. continued, 136. due to tertian parasites, 116. cycles of severity of, 92. distribution, 82. endemic seats of, 82. general conditions of prevalence, 82. intermittent, pathogenesis of, 245. irregular, due to tertian parasites, 116. pathogenic agent of, 5. pernicious, 145. algid, 151. bilious, 153. cause of, 146. choleriform, 152. comatose, 148. diagnosis of, 284. gastralffic, 154. hremoglobinuric, 154. hfemorrhagic, 152. pneumonic, 154. sudoriferous, 153. treatment of, 304. post-operative, 206. diagnosis of, 286 post-partum, 206. diagnosis of, 286. pulmonary complications of, 202. quartan, 12, 119. diagnosis, 272. distribution of, 119. double infections, 125. parasites of. (See Parasite, Quar- tan.) single infections, 119. triple infections, 127. quotidian, 113, 127, 132. regularly intermittent, 103. prognosis in, 288. treatment of, 303. relations of types of, to seasons, 84, 130. remittent. 136. diagnosis of, 279. aSNERAL INDEX. 323 Fever, malarial, tertian, 14, 103. clinical symptoms of, 103. diagnosis of, 272. double infections, 113. infections, with multiple groups of parasites, 116. parasites of. (See' Parasites, Ter- tian.) single infections, 103. types of, 97. with long intervals, 169. mountain, confusion of, with malarial fever, 87. Eoman, 11. Texas cattle, 94. typhoid, 202, 276, 279, 288. " typho-malarial," 201, 203. typhus, 288. Filaria sanguinis liominis, 94. Forests, influence of, on malarial fever, 89. Furunculosis, 209. Gastro-intestinal symptoms, causes of, 258, tract in acute malarial infections, 219. Gonorrhcea, 276. Htemamoeba immaculata, 22. Hsemamoeba praacox, 22, 23. Hffimamceba vivax, 42. Hffimatomonas malarire, 32. Haematozoon falciparum, 130, 145. description of, 61. Heemocytozoa of malaria, description of, 42. Hffimoglobin, 186. HseraoglobinEemia, 156. Hsemoglobinuria, malarial, 154. anatomical changes in, 221. blood in, 168. clinical picture of, 162. diagnosis of, 285. distribution of, 155. prognosis in, 289. treatment of, 305. types of, 159. post-malarial, 160, 165, 198. predisposition to, 158. quinine, 162. prognosis in, 290. types of, 162. Ilaemosiderin, 240. HajiTiosporidia, 32. Hallucinations in pernicious fever, 150. Helianthus, 309. Hemiplegia in pernicious fever, 150. Hepatitis, malarial, 194. Incubation, period of, 98. long, 101. variation of, 100. Infection, malarial, acute, anatomical changes occurring in, 212. chronic or repeated, anatomical changes occurring in, 224. manner of, 93. mixed, 200, 208. diagnosis of, 288. septic, 209, 272, 283. with multiple groups of parasites, ori- gin of, 259. Influenza, 275. Inoculation experiments, 26. Insolation, 209. Intermission between paroxysms, 109. Intestinal phenomena in pernicious fever, 147. Jaundice, pathogenesis of, 256. Johns Hopkins Hospital, 69. deaths from malarial and typhoid fever in, 4. Kidneys in acute malarial infections, 219, in chronic malarial aff'ections, 233. in malarial hEemoglobinuria, 223. Larvate malaria, 173. Laverania malarise, 23, 71. Leucocytes. See Corpuscles, Colorless, also Phagocytosis. Leucocytosis, absence of, in malaria, 277. in pernicious malaria, 188. Liver, cirrhosis of, 235. in acute malarial infections, 217, 218. in chronic malarial infections, 227. in malarial hcemoglobinuria, 221. " Malaria," misuse of term, 1, 4. Marrow, bone, in acute malarial infec- tions, 220. in chronic malarial infections, 232. 324 LECTURES ON THE MALARIAL FEVERS. Masked molaria, 173. Mental diseases, 197. Moisture, influence of, on malarial fevor, 86. Mosquito as agent in malarial infection, 94. as extra-corporeal host of malarial para- sites, 94. Murmur, splenic, 107. Necroses, focal, 218, 238, 252. Nephritis, malarial, 181, 192. diagnosis of, 287. prognosis in, 290. Neuritis, peripheral, 196. New York, deaths from malarial and typhoid fever in, 3. Nutmeg, 309. Occupation, relation of, to malarial infec- tion, 93. Orchitis, " malarial," 201, 206. Oscillaria malariae, 32. Ovoid bodies. See Parasites, iEsTivo- AUTUMNAL. Pain in bones, pathogenesis of, 256. Palmella as pathogenic agents of malarial fever, 6. Paralyses, malarial, 195. progno.sis in, 291. I'aralysis, bulbar, in malarial fever, 150. Parasite, sestivo-autumnal, IG, 61. accunmlation of, in internal organs, 18, 62, 146-148. aggregation of, in groups, 18, 61, 63. anticipation and retardation of, 64. crescentic and ovoid forms of, 19, 70. cycle of development of, 19, 63. length of, 19, 23, 62. description of, 61. development of, in internal organs, 21. flagellate forms of, 72. flagellation of, in stomach of mos- quito, 80. fragmentation of, 73. inoculation of crescentic forms of, 75. multiple groups of, 64. pseudo-gemmation of, 73. reaction of, to quinine, 73. Parasites, ffistivo-autumnal, resistance of crescentic and ovoid forms of, to quinine, 20, 73. ring-shaped forms of, 18, 65. round bodies of, 72. segmentation of, 18, 67. crescentic forms of, 19. significance of crescentic and ovoid forms of, 20, 73. staining reactions of, 77. of crescentic forms of, 77. vacuolization of, 73. varieties of, 21. of birds, 32. malarial, classification of, 32. confusion of segmenting forms with blood platelets, 34. crescentic forms of, 9. cultivation of, 26. description of, 42. development of, within phagocytes, 270. discovery of, 8. finer structure of, 24. flagellate forms of, 10. flagellate bodies, attempts to stain, 54. nature of, 78. inoculation of, 28. karyokincsis in, 25. marguerite-like forms of, 12. non-pigmented forms of, 11. nucleolus of, 24, 25. nucleus of, 24, 25. nature of spores of, 31. ovoid forms of, 9. portal of entry of, into system, 93. preservation of, in leeches, 27. reproduction of, 31. ring-shaped forms of, 18, 43, 65. round forms of, 10. stability of types of, 30. unity or multiplicity of, 23, 24. variation in distribution of, 146, 212. varieties of, 22. malignant tertian, 23, 63. nature of extra-cellular form of, 50. quartan, 12, 56. description of, 56. distinction of, from tertian parasites, 59, 278. GENERAL INDEX. 325 Parasites, quartan, multiple groups of, 60. segmentation of, 58. quotidian, 21, 23, 63. pigmented, 23. unpigmented, 23. tertian, 14, 42. aggregation of, in groups, 42. deseription of, 42. distribution in the circulation of, 51. escape of, from corpuscle, 44. extra-cellular forms of, 48. flagellation of, 49. multiple groups of, 56. nature of flagellate bodies of, 50. fragmentation of, 48. infection with two groups of, 55. precocious sporulating forms of, 55. spores of, 47. sporulation of, 45. staining reactions of, 52. vacuolization of, 48. Parotitis, 208. Paroxysm, anticipation of, in testivo-au- tumnal fever, 136. in tertian fever, 111. coincidence of, with sporulation of a group of parasites, 13. in children, 108. description of, in tertian and quartan fever, 104. in ffistivo-autumnal fever, 132. duration of, in testivo-autumnal fever, 132, 134. in quai'tan fever, 122. in tertian fever, 108. prolonged, in sestivo-autumnal fever, 136. retardation of, in testivo-autumnal fever, 140. in tertian fever. 111. Pernicious fever. See Fevek, Peenicious. Phagocytosis in ffistivo-autumnal fever, 167, 265. Phagocytosis in quartan fever, 125, 264. in tertian fever, 112, 264. Phenocoll, 309. Phenomena, post-malarial, 197. Pigment, malarial, 8, 239. " Plasmodium malaria," 11, 32. Pleurisy, 202, 288. Pneumonia, 202, 288. Pneumonia, "malarial," 201. Polycholia, 157. cause of, 256. Polyuria, post-malarial, 176. Powder, Jesuit's, 293. Prognosis, 288. Prophylaxis, 312. Psychoses, post-malarial, 197. prognosis in, 291. Pyrosoma bigeminum, 94. Quinidia, 308. Quinine, 293. action of, on the human being, 297. on the malarial parasite, 294. administration of, hypodermically, 300. intravenously, 301. method of, 298. by mouth, 300. by rectum, 302. time for, 302. bimuriate of, 300. bisulphate of, 301. contra-indications to, 307. dihydrochlorate of. 300, 301. efficacy of, as protoplasmic poison, 7. sulphate of, 300, 301. time at which, is most efficacious in tertian fever, 116. and urea, bimuriate of, 301. Quinoidia, 308. Race, relation of, to malarial infection, 92. Raynaud's disease, 197. Relapses, 183. confusion of, with original attack, 88. Remarks, introductory, 1. Respiratory tract as atrium of infection in malarial fever, 93. Rheumatism, acute, 209, 288. Seasons, effect of, on malarial fever, 83. Septicemia — streptococcus infection, 209. Sequelae, 183. " Serafici," 5. Severity, cycles of, in malarial fever, 92. Sex, relation of, to malarial infection, 92. Skin, infection through, in malarial fe- ver, 94. Soil, influence of, on malarial fever, 86. 326 LECTURES ON THE MALARIAL FEVERS. Soil, interference with, effects of, on mala- rial-fever, 89. Spleen in acute malarial infections, 215. in chronic malarial infections, 224. in malarial liaimoglobinuria, 222. Stain, Romnnovsky's, 40. Geppcncr's modilication of, 41. Staining, methods of, 37. Statistics, vital, 3. Strychnine, 309. Subcontinua biliosa, 153. typhoidea, 141. Sulphur, 309. Suprarenal capsules in acute malarial in- fections, 221. Sweat, toxicity of, in malarial fever, 251. Sweating stage of paroxysm, 108. Table, parallel, of characteristic features of continued malarial and ty- phoid fever, 281. parallel, of characteristics of tertian and quartan parasites, 278. of percentage of quinine In different salts, 299. of solubility of different salts of qui- nine, 299. Test, therapeutic, 2, 279, 281. Tick, cattle, 94. Time of day, effect of, on malarial fever, 83. Tonsillitis, 209, 288. Toxines of malaria, nature of, 253. Treatment, 291. Treatment, general, 291. medicinal, 293. Tuberculosis, 205, 283. pulmonary, 274, 288. Types of malarial fever, relations of, to the seasons of tlie year, 84. Typhoid fever. See Fever, Typuoid. Urine, 176. acidity of, 177. albumen In, 18L amount of, 176. bases in, 180. clilorides in, 179. color of, 177. diazo reaction in, 182. injection of, into animals, 248. iron in, 181. nitrogen in, 178. peptone in, 181. phosphates in, 179. potassium In, 180. sodium In, 180. solids of, 178. specific gravity of, 178. sulphates in, 179. toxicity of, m malarial fever, 248. urea in, 178. uric acid in, 179. Urticaria, 107, 298. Water, drinking, relation of, to malarial infection, 90. Winds, influence of, on malarial fever, 89. FINIS. THE PRINCIPLES OF SURGERY AND SURGICAL PATHOLOGY. General Rules governing Operations and the Application of Dressings. By Dr. HERMANN TILLMANNS, Professor at the University of Leipzig. Translated from the third German edition by JOHN ROGERS, M. D., New York, and BENJAMIN TILTON, M. D., New York. Edited by LEWIS A. STIMSON, M. D., Professor of Surgery in the University of the City of New York, Medical Department. 8vo. 800 pages. With 441 Illustrations. Cloth, $5.00 ; sheep, $6.00. " It was a wise combination of subjects in considering the principles of sur- gery and its pathology in the same treatise. It enables the surgeon to refer to both branches of the subject without loss of time, and each serves to accentuate the importance of the other. Not since Billroth's classic treatise on surgical pathology, that appeared some twenty-three years ago, has there been a more satisfactory exposition of surgical pathology than here given by Tillmanns. It is brought down to the immediate present under the light afforded by the most modern researches in bacteriology. A student should be taught pathology before he is instructed in surgical diseases and injuries. These latter he will then understand with a clearness that could not be possible if the method of teaching were reversed. The editor and the translators appreciating this fact have duly emphasized it in bringing out and making available as a text-book one of the best treatises on the principles of surgery and surgical pathology that has yet been written. It is impossible in the space now at our disposal for us to do more than express our opinion of this excelL nt work and to commend it to student and practitioner as a safe and scientific guide, which we do here and now." — Buffalo Mediczl and Surgical fotirnal. "It is strange that this excellent work has been allowed to pass to a third edition in German without a translation in English until this time. The ar- rangement of the book is different from that of the average text-book on the subject. It is divided into thi-ee sections : First, General Principles governing Surgical Operations ; second, Methods of applying Surgical Dressings ; and third, Surgical Pathology and Therapy. The work of translators and editor has been excellently done. The book is printed and bound in the correct and elegant style for which the publishers are noted. The work is strictly modern, and none of the recent advances in surgical pathology have been left uncon- sidered." — Chicago Medical Reco7-der. " It is just the book for surgeons who entered practice before surgical bac- teriology had been developed so as to afford, as it now does, a firm founda- tion for the best clinical work. By its aid one's knowledge of the results of most recent investigations can be, so to speak, brought up to date. No sur- geon, hov^rever experienced, can read it without having his technique con- sciously or unconsciously improved, and his grasp upon the fixed facts of surgical science made more secure. In illustrations, type, paper, and binding, Till- manns's ' Surgical Pathology' is up to the Appleton standard, and that stand- ard, as we all know, is unsurpassed." — Canada Lancet. New York : D. APPLETON & CO., 72 Fifth Avenue. A New, Thoroughly Revised, and Enlarged Edition of QUAIN'S DICTIONARY OF MEDICINE. BY VARIOUS WRITERS. Edited by Sir RICHARD QUAIN, Bart., M. D., LL. D., etc., Physician Extraordinary to Her Majesty the Queen ; Consulting Physician to the Hospital for Diseases of the Chest, Brompton, etc. Assisted by FREDERICK THOMAS ROBERTS, M. D., B. Sc, Fellow of the Royal College of Physicians, etc. ; And J. MITCHELL BRUCE, M.A., M. D., Fellow of the Royal College of Physicians, etc. With an American Appendix by SAMUEL TREAT ARMSTRONG, Ph. D. , M. D., Visiting Physician to the Harlem, Willard Parker, and Riverside Hospitals, New York. IN TWO VOLUMES. Sold only by subscription. This work is primarily a Dictionary of Medicine, in which the several diseases are fully discussed in alphabetical order. The description of each includes an account of its etiology and anatomical characters; its symptoms, course, duration, and termi- nation ; its diagnosis, prognosis, and, lastly, its treatment. General Pathology com- prehends articles on the origin, characters, and nature of disease. General Therapeutics includes articles on the several classes of remedies, their modes of action, and on the methods of their use. The articles devoted to the subject of Hyg^iene treat of the causes and prevention of disease, of the agencies and laws affecting public health, of the means of preserving ths health of the individual, of the construction and management of hospitals, and of the nursing of the sick. Lastly, the diseases peculiar to women and children are discussed under their respective heidings, both in aggregate and in detail. The American Appendix gives more definite information regarding American Mineral Springs, and adds one or two articles on particularly American topics, be- sides introducing some recent medical terms and a few cross-references. The British Medical Journal says of the new edition : "The original purpose which actuated the preparation of the original edition \yas, to quote the words of the preface which the editor has written for the new edi- tion, ' a desire to place in the hands of the practitioner, the teacher, and the student a means of ready reference to the accumulated knowledge which we possessed of scien- tific and practical medicine, rapid as was its progress, and difficult of access as were its scattered records.' The scheme of the work was so comprehensive, the selection of writers so judicious, that this end was attained more completely than the most sanguine expectations of the able editor and his assistants could have anticipated. . . . In preparing a new edition the fact had to be faced that never in the history of medicine had progress been so rapid as in the last twelve years. New facts have been ascertained, and new ways of looking at old facts have come to be recognized as true. . . . The revision which the work has undergone has been of the most thorough and judicious character. . . . The list of new writers numbers fifty, and among them are to be found the names of those who are leading authorities upon the subjects which have been committed to their care." New York: D, APPLETON & CO., Publishers, 72 Fifth Avenue. August, 1897. MEDTCAI ..J HYGIENIC WOEKS PUBLISHED BT D. APPLETON & CO., 72 Fifth Avenue, New York. ADLDE (JOHN). TLe Pocket PLarmacy, with Therapeutic Index. A resume of the Clinical Applicatiocs of Eemedies adapted to tlie Pocket-case, for the Treatment of Emergencies and Acute Diseases. 12mo. Cloth, $2.00. BARKER (FORDYCE). On Sea-Sickness. A Popular Treatise for Travelers and the General Reader. Small J2mo. Cloth, 75 cents. BARKER (FORDYCE). On Puerperal Disease. Clinical Lectures delivered at Bellevue Hospital. A Course of Lectures valuable alike to the Student and the Practitioner. Third edition. 8vo. Cloth, $5.00; sheep, $6.00, BARTHOLOW (ROBERTS). A Treatise on Materia Medica and Therapeutics. Ninth edition. Revised, enlarged, and adapted to " The New Pharmacopoeia." 8vo. Cloth, $5.00; sheep, $6.00. BARTHOLOW (ROBERTS). A Treatise on the Practice of Medicine, for the Use of Students and Practitioners. ScTcnth edition, revised and enlarged. 8vo. Cloth, $5.00; sheep, $6.00. BARTHOLOW (ROBERTS). Ou the Antagonism between Medicines and be-, tween Remedies and Diseases. Being the Cartwright Lectures for the Year 1880. 8vo. Cloth, $1.25. B A STIA N (H. CHARLTON). Paralyses: Cerebral, Bulbar, and Spinal. A Manual of Diagnosis for Students and Practitioners. With 136 Hlustra- tions. Small 8vo, ,671 pages. Cloth, $4.50. BASTIAN (H. CHARLTON). Paralysis from Brain Disease in its Common Forms. With Illustrations. 12ino, 340 pages. Cloth, $1.75. BILLINGS (F. S.). The Relation of Animal Diseases to the Public Health, and their Prevention. 8vo. Cloth, $4.00. BILLROTH (THEODOR). General Surgical Pathology and Therapeutics. A Test-Book for Students and Physicians. Translated from the tenth German edition, by special permission of the author, by Charles E. Hackley, M. D. Fiftli American editioB, revisnl and enlarged. 8vo. Cloth, $5.00; sheep, $6.00. BOYCE (RUBERT). A Text-Book of Morbid Histology. For Students and Practitioners. With 130 Colored Illustrations. Cloth, $7.50. BRAMWELL (BY^ROM). Diseases of tbe Heart and Thoracic Aorta. Illus- trated with 226 Wood-Engravings and 68 Lithograph Plates — showing 91 Figures—in all 317 Illustrations. 8vo. Cloth, $"8,00; sheep, $9.00. BRYANT (JOSEPH D,). A Manual of Operative Surgery. New edition, reyised and enlarged. 793 Illustrations. 8vo. Cloth. $5.00 ; sheep, $6.00. BURT (STEPHEN S.). Exploration of the Chest in Health and Disease. 8vo, 210 pages. With Illustrations. Cloth, $1.50. CAMPBELL (F. R.). The Language of Medicine. A Manual giving the Origin, Etymology, Pronunciation, and Meaning of the Technical Terms found in Medical Literature. 8vo. Cloth, $3.00. OARMICHAEL (JAMES). Disease in Children. A Manual for Students and Practitioners. Illustrated with Thirty-one Cliarts. 12mo, 591 pages. (Students' Seeies.) Cloth, $3.00. CHAUVEAU (A.). The Comparative Anatomy of the Domesticated Animals. Revised and enlarged, with the co-operation of S. Arloing, Director of the Lyons Veterinary School. Second English edition. Translated and edited by George Fleniing, C. B., LL. D., F. R. C. V. S., late Principal Veterinary Surgeon of the British Army; Foreign Corresponding Member of the Soci6t6 Royale de M6decine, and of the Soci6r6 Royale de M6decine Pub- lique, of Belgium, etc. 8vo, 1084 pages,with 585 Illustrations. Cloth, $7.00. CORNING (J. L.). Brain Exhaustion, with some Preliminary Considerations on Cerebral Dynamics. Crown 8vo. Cloth, $2.00. CORNING (J. L.). Local Anaesthesia in General Medicine and Surgery. Being the Practical Application of the Author's Recent Discoveries. With Illus- trations. Small 8vo. Cloth, $1.25. DAVIDSON (ANDREW). Geographical Pathology: An Inquiry into the Geographical Distribution of Infective and Climatic Diseases. 2 vols. 8vo. Cloth, $7.00. DENCH (E. B.). Dil^eases of the Ear. A Text-Book for Practitioners and Students of Medicine. With 8 Colored Plates and 152 Illustrations in the text. 8vo. Cloth, $5.00 ; sheep, $6.00. DEXTER (FRANKLIN). The Anatomy of the Peritonseum! 12mo. With 39 colored Illustrations. Cloth, $1.50. DOTY (ALVAH H.). A Manual of Instruction in the Principles of Prompt Aid to the Injured. Including a Chapter on Hygiene and the Drill Regula- tions for the Hospital Corps, C. S. A. Designed for Military and Civil Use. Second edition, revised aud enlarged. 12mo. 121 Illustrations. Cloth, $1.50. ELLIOT (GEORGE T.). Obstetric Clinic: A Practical Contribution to the Study ol Obstetrics aud the Diseases of Women and Children. 8vo. Cloth, $4.50. EVANS (GEORGE A.). Hand-Book of Historical and Geographical Phthisi- ology. With Special Reference to the Distribution of Consumption in the Lnited States. 8vo. Cloth, $2.00. EWALD (C. A.). Lectures on the Diseases of the Stomach. By Dr. C. A. Ewald, Professor of Pathology and Therapeutics in the University of Berlin, etc. Translated from the German by special permission of the author, by Morris Manges, A.M., M.D. Second edition, revised and rearranged. Cloth, $5.00 ; sheep, $0.00. - FLINT (AUSTIN). Medical Ethics and Etiquette. Commentaries on the National Code of Ethics. 12mo. Cloth, 60 cents. FLINT (AUSTIN). Medicine of the Future. An Address prepared for the Annual Meeting of the British Medical Association in 1886. With Poitrait ot Dr. Flint. 12mo. Cloth, $1.00. FLINT (AUSTIN, Jr.). Text-Book of Human Physiology; designed for the Use of Practitioners and Students of Medicine. Illustrated \\ith three hundred and sixteen Woodcuts and Two Plates. Fourth edition, rcTificd. Imperial 8yo. Cloth, $6.00; sheep, $7.00. FLINT (AUSTIN, Jr.). The Physiological Effects of Severe and Protracted Muscular Exercise; with Special Reference to its Influence upon the Excre- tion of Nitrogen. 12mo. Cloth, $1.00. FLINT (AUSTIN, Jr.)- The Source of Muscular Power. Arguments and Con- clusions drawn from Observation upon the Human Subject under Conditions of Rest and of Muscular Exercise. 12mo. Clotb, $1.00, FLINT (AUSTIN, Jr.), Physiology of Man. Designed to represent the Exist- ing State of Physiological Science as applied to the Functions of tlie Human Body. Complete in 5 vols,, 8vo. Per vol,, cloth, $4.50 ; sbeep, $5.50. *^* Vols. I and II can be had in cloth and sheep binding; Vol, III in sheep only. Vol, IV is at present out of print. FLINT (AUSTIN, Jr.). Manual of Chemical Examinations of the Urine in Disease; with Brief Directions for the Examination of the most Common Varieties of Urinary Calculi, Revised edition. 12mo, Cloth, $1,00, FOSTER (FRANK P.). Illustrated Eneyclopsedic Medical Dictionary: Being a Dictionary of the Technical Terms used by Writers on Medicine and the Collateral Sciences in the Latin, English, French, and Germran Languages. The work consists of Four Volumes, and is sold in Parts; Three Parts to a Volume. {Sold only iy suiscription.) FOSTER (FRANK P.), A Reference-Book of Practical Therapeutics, by various writers. In Two Volumes, Edited by Frank P. Foster, M, D,, Editor of Tlie New York Medical Journal. Vol. I. Cloth, $5.00; sheep, $6.00; half morocco, $6.50, (Sold only hy subscription.) FOURNIER (ALFRED). Syphilis and Marriage. Translated by P. Albert Morrow, M. D. 8vo, Cloth, $2,00; sheep, $3,00. FREY (HEINRICH). The Histology and Histochemistry of Man. A Treatise on the Elements of Composition and Structure of the Human Body. Trans- lated from the fourth German edition by Arthur E, J, Barker, M. D., and revised by the author. With 608 Engravings on Wood, 8vo, Cloth, $5.00; sheep, $6",00. FRIEDLANDER (CARL), The Use of the Microscope in Chnical and Patho- logical Examinations. Second edition, enlarged and impioved, with a Chromolithograph Plate. Translated, with the permission of the author, by Henry C. Coe, M. D. 8vo, Cloth, $1.00. FUCHS (ERNEST), Text-Book of Ophthalmology, By Dr. Ernest Fuchs, Professor of Ophthalmology in the University of Vienna. With 178 Wood- cuts. Authorized translation from the second enlarged and improved Ger- man edition, by A. Duane, M, D. Cloth, $5,00; sheep, $6,00, GARMANY (JASPER J.), Operative Surgery on the Cadaver, With Two Colored Diagratns showing the Collateral Circulation after Ligatures of Arteries of Arm, Abdomen, and Lower Extremity, Small 8vo, Cloth, $2.00. GERSTER (ARPAD G.). The Rules of Aseptic and Antiseptic Surgery. A Practical Treatise for the Use of Students and the General Practitioner. Illustrated with over two hundred i5ne Engravings. 8vo. Cloth, $5.00; sheep, $6.00. GIBSON-RUSSELL, Physical Diagnosis : A Guide to Methods of Clinical In- vestigation. By G, A. Gibson, M, D., and William Russell, M. D, With 101 Illustrations. 12mo. (Stcuent's Series.) Cloth, $2.50, GOULEY (JOHN W, S.). Diseases of the Urinary Apparatus. Part L Pbleg- raasic Affections. Being a Series of Twelve Lectures delivered daring the autumn of 1891. With an Addendum on Retention of Urine from Pros- tatic Obstruction in Elderly Men. Cloth, $1,50. GROSS (SAMUEL W,). A Practical Treatise on Tumors of the Mammai-y Gland. Illustrated. Bvo. Clotb, $2.50. GRUBER (JOSEF). A Text-Book of the Diseases of the Ear. Translated from the second German edition by special permission of the anthor, and edited by Edward Law, M. D., and Coleman Jewell, M. I). "With 165 Illus- trations and 70 Colored Figures on Two Lithographic Plates. 8vo. Cloth. $6.50 sheep, $7.50. GUTMANN (EDWAPvD). The Watering-Places and Mineral Springs of Ger- many, Austria, and Switzerland. Illustrated. 12mo. Cloth, $2.50. HAMMOND (W. A.). A Treatise on Diseases of the Nervous System. With the Collaboration of Graeme M. Hammond, M. D. With One Hundred and Eighteen Illustrations. Ninth edition, with corrections and additions. 8vn. Cloth, $5.00 ; sheep, $0.00. HAMMOND (W. A.). A Treatise on Insanity, in its Medical Relations. 8vo. Cloth, $5.00; sheep, $6.00. HAMMOND (W. A.). Clinical Lectures on Diseases of the Nervous System. Delivered at Bellevue Hospital Medical College. Edited by T. M. R. Cross, M. D. 8vo. Cloth, $3.50. HARVEY (A.). First Lines of Therapeutics. 12mo. Cloth. $1.50. HIRT (LUDWIG). The Diseases of the Nervous System. A Text- Book lor Physicians and Students. Translated, with permission of the Anthor, by August Hoch, M. D., assisted by Frank li. Smith. A.M. (Cantab.), M. D"., Assistant Physicians to the Johns Hopkins Hospital. With an Introduc- tion by William Osier, M. D., F. R. (!. P., Professor of Medicine in the Johns Hopkins University, and Physician-in-Chief to the Johns Hopkins Hospital, Baltimore. Svo, 671 pages. With 178 Illustrations. Cloth, $5.00 ; sheep, $6.00. HOFFMANN-ULTZMANN. Analysis of the Urine, with Special Reference to Diseases of the Urinary Apparatus. By M. B. Hoffmann, Professor in the University of Gratz, and R. Ultzmann, Tutor in the University of Vienna. Tliird edition, revised and enlarj;cd. 8vo. Cloth, $2.00. HOLT (L. EMMETT). The Diseases of Infancy and Childhood. 8vo. Cloth, $6.00; sheep, $7.00; half morocco, $7.50. {Sold only ly subscription.) HOLT (L. EMMETT). The Care and Feeding of Children. A Catechism for the Use of Mothers and Children's Nurses. 16mo. Cloth, 50 cents. HOWE (JOSEPH W.). Emergencies, and how to treat them. Fourth edition, revised. 8vo. Cloth, $2.50. HOWE (JOSEPH W.). The Breath, and the Diseases which give it a Fetid Odor. With Directions for Treatment. Second edition, revised and corrected. 12mo. Cloth, $1.00. aUEPPE (FERDINAND). The Methods of Bacteriological Investigation. Written at the request of Dr. Robert Koch. Translated by Hermann M. Biggs, M.D. Illustrated. Svo. Cloth, $2.50. JACOOUD (S.). The Curability and Treatment of Pulmonary Phthisis. Trans- lated and edited by Montagu Lubbock, M. D. Svo. Cloth, $4.00. KEYES (E. L.). A Practical Treatise on Genito-Urinary Diseases, including Syphilis. Reing a new edition of a work with the same title by Van Buren and Keyes. Almost entirely rewritten. Svo. With Illustrations. Cloth, $5.00; sheep, $6.00. KEYES (E. L.). The Tonic Treatment of Syphilis, including Local Treatment of Lesions. Second edition. Svo. Cloth, $1.00. KINGSLEY (N. W,). A Treatise on Oral Deformities as a Branch of Mechan- ical Surgery. With over 350 Illustrations. 8vo. Oloth, $5.00; sheep, 16.00. LEGG (J. WIOKHAM). On the Bile, Jaundice, and Bilious Diseases. With Illustrations in Chroraolithography. 8vo. Cloth, $6.00; sheep, $7.00. LITTLE (W. J.). Medical and Surp;ical Aspects of In- Knee (Genu-Valpiim): Its Relation to Rickets, its Prevention, and its Treatment, with and without Surgical Operation. Illustrated by upward of Fifty Figures and Diagrams, '•vo. Cloth, $2.00. LORING (EDWARD G.). A Text-Book of Ophthalmoscopy. Part I. The Normal Eye, Determination of Refraction, and Diseases of the Media. With 131 Illustrations, and 4 Ohi'omolithographs. 8vo. Buck- ram, $5.00. Part 11. Diseases of the Retina, Optic Nerve, and Choroid : their Varie- ties and Complications. The manuscript of this volume, which the author finished just prior to his death, has been thoroughly edited and revised by F. B. Loring, M. D., of Washington, D. C, and is now issued in the same style as the first volume. Profusely illustrated. Part II, buckram, $5.00. Two Parts, buckram, $10.00. LUSK (WILLIAM T.). The Science and Art of Midwifery. With 246 Illustra- tions. Fonrtb edition, revised and enlarged. 8vo. Cloth, $5.00 ; sheep, $6.00. MAROY (HE^JRY O.). The Anatomy and Surgical Treatment of Hernia. 4to, with about Sixty full-page Heliotype and Lithographic Reproductions from the Old Masters, and numerous Illustrations in the Text. (Sold only 'by siibscripUon.) MAKKOE (T. M.). A Treatise on Diseases of the Bones. With Illustrations. Svo. Cloth, $4.50. MATHEWS (JOSEPH M.). A Treatise on Diseases of the Rectum, Anus, and Sigmoid Flexure. Svo. With Six Chromolithographs, and Illustra- tions in the text. Second edition. {Sold only hy imhaerwtion.) MILLS (WESLEY). A Text-Book of Animal Physiology, with Introductory Chapters on General Biology and a full Treatment of Reproduction for Students of Human and Comparative Medicine. Svo. With 505 Illustra- tions. Cloth, $5.00; sheep, $6.00. MILLS (WESLEY). A Text-Book of Comparative Physiology. For Students and Practitioners of Veterinary Medicine. Small Svo. Cloth, $3.00. MORROW (PRINCE A.). A System of Genito-IJrinary Diseases, Syphilology, and Dermatologv. By various Authors. In Three Volumes, beautifully illustrated. Vol, I. Genito-urinary Diseases. Vol. II. Syphilography Vol. III. Dermatology. {Sold only T)y subseription.) THE NEW YORK MEDICAL JOURN^AL (Weekly). Edited by Frank P. Foster, M. D. Terms, $5.00 per annum. Binding Cases, cloth, 50 cents each. "Self- Binder" (this is used for temporary binding only), 90 cents. General Index, from April, 1865, to June, 1876 (23 vols.). Svo. Cloth, 75 cts. NIEMEYER (FELIX VON). A Text-Book of Practical Medicine, with particu- lar reference to Physiology and Pathological Anatomy. Containing all the author's Additions and Revisions in the eighth and last German edition. Translated by George H. Humphreys, M. D., and Charles E. Haokley, M. D. 2 vols., Svo. Cloth, $9.00; sheep, $11.00. ITIGHTINGALE'S (FLORENCE) Notes on Nursing. 12mo. Cloth, 75 cents. OSLER (WILLIAM). Lectures on Angina Pectoris and Allied States. Small 8vo. Illustrated. Clotb, $1.50. OSLEK (WILLIAM). Lectures on tlie Diagnosis of Abdominal Tumors. Small 8vo. Illustrated. Cloth, $1.50. OSLER (WILLIAM). The Principles and Practice of Medicine. Designed for tlie Use of Practirioners and Students of Medicine. Second edition, revised and enlarged. Clotli, $5.50 ; sheep, $6.50; half morocco, $7.00. {Sold only hy suliscription.) I^ELLEW (0. E.). A Manual of Practical Medical Chemistry. 12mo. With Illustrations. Cloth, $2.50. PIFFARD (HENRY G.). A Practical Treatise on Diseases of the Skin. By Henry G. Pif!ard, A. M., M. D., assisted by Robert M. Fuller, M. D. With Fifty full-page Original Plates and Thirty-three Illustrations in the Text. 4to. {Sold only hy subscription.) POMEROY (OREN D.). The Diagnosis and Treatment of Diseases of the Ear. With One Hundred Illustrations. Second edition, revised and enlarged. 8vo. Cloth. $3.00. POORE (C. T.). Osteotomy and Osteoclasis, for the Correction of Deformities of the Lower Limbs. 50 Illustrations. 8vo. Cloth, $2.50. QUA IN (RICHARD). A Dictionary of Medicine, including General Pathology, General Therapeutics, Hygiene, and the Diseases peculiar to Women and Children. By Various Writers. Edited by Sir Richard Quain, Bart., M. D., LL. I)., etc. Assisted by Frederick Ihomas Roberts, M. D., B. Sc, and J. Mitchell Bruce, M. A., M. D. With an American Appendix by Samuel Treat Armstrong, Ph.D., M. D. In two volumes. {Sold only by subscription.) RANNEY (AMBROSE L.). Applied Anatomy of the Nervous System, being a Study of this Portion of the Human Body from a Standpoint of its General Interest and Practical Utility, designed for Use as a Text-Book and as a Work of Reference. Second edition, revised and enlarged. Profusely illustrated. 8vo. Cloth, $5.00; sheep, $6.00. ROBINSON (A. R.). A Manual of Dermatology. Revised and corrected. 8vo. Cloth, $5.00, ROSCOE-SCHORLEMMER. Treatise on Chemistry. Vol. 1. Non-Metallic Elements. 8vo. Cloth, $5.00. Vol. 2. Part I. Metals. 8vo. Cloth, $3.00. Vol. 2. Part II. Metals. 8vo. Cloth, $3.00. Vol.3. Part I. The Chemistry of the Hydrocarbons and their Deri v^atives. 8vo. Cloth, $5.00. Vol. 3. Part II. The Chemistry of the Hydrocarbons and their Derivatives. 8vo. Cloth, $5.00. Vol. 3. Part HI. The Chemistry of the Hydrocarbons and their Deriva- tives. 8vo. Cloth, $3.00. Vol. 3. Part IV. The Chemistry of the Hydrocarbons and tdeir Deriva- tives. 8vo. Cloth, $3.00. Vol. 3. Part V. The Chemistry of the Hydrocarbons and their Deriva- tives. 8vo. Cloth, $3.00. ROSENTHAL (I.). General Physiology of Muscles and Nerves. With 75 Wood- outi. 12mo. Cloth, $1.50. 8AYRE (LEWIS A.). Practical Manual of the Treatment of Club-Foot. Fourth edition, enlarged and corrected. 12mo. Cloth, $1.25. SAYRE (LEWIS A.). Lectures on Orthopedic Surgery and Diseases of the Joints, delivered at Bellevue Hospital Medical College. New edition, illus- trated with «24 Engravings on Wood. 8vo. Cloth, |5.00 ; sheep, $6.00. SCHULTZE (B. S.). The Pathology and Treatment of Displacements of the Uterus. Translated from the German by Jameson J. Macan, M. A., etc. ; and edited by Arthur V. Macan, M. B., etc. With one hundred and twenty Illustrations. 8vo. Cloth, $3.50. SHIELD (A. MARMADUKE). Surgical Anatomy for Students. 12rao. (Student's Series.) Cloth, $1.75. SHOEMAKER (JOHN V.). A Text-Book of Diseases of the Skin. Six Chromolithographs and numerous Engravings. Second edition, revised and enlarged. 8vo. Cloth, $5.00 ; sheep, $t).00. SIMPSON (JAMES Y.). Selected Works: Anassthosia, Diseases of Women. 3 vols., 8vo. Per volume. Cloth, $3.00; sheep, $4.00. SIMS (J. MARION). The Story of my Life. Edited by his Son, H. Marion- Sims, M. U. With Portrait. 12mo. Cloth, $1.50. SKENE (ALEXANDER J. C). A Text-Book on the Diseases of Women. Illustrated with two hundred and fifty-four Illustrations, of which one hundred and sixty-five are original, and nine chromolithographs. Second edition. 8vo. {Sold only iy sttiscription.) SKENE (ALEXANDER J. C). Medical Gynecology. A Treatise on the Diseases of Women from the Standpoint of the Physician. 8vo. With Illustrations. Cloth, $5.00. STEINER (JOHANN). Compendium of Children's Diseases: a Hand-Book for Practitioners and Students. Translated from the second German edition, by Law son Tait. 8vo. Cloth, $3.50 ; sheep, $4.50. STEVENS (GEORGE T.) Functional Nervous Diseases: their Causes and their Treatment. Memoir for the Concourse of 1881-1883, Acad6mie Royal de M^decine de Belgique. With a Supplement, on the Anomalies of Re- fraction and Accommodation of the Eye, and of the Ocular Muscles. Small 8vo. With six Photographic Plates and twelve Illustrations. Cloth, $2.50. SrONE (R. FRENCH). Elements of Modern Medicine, includiug Piinciples of Pathology and of Therapeutics, with many Useful Memoranda and Valuable Tables of Reference. Accompanied by Pocket Fever Charts. Designed for the Use of Students and Practitioners of Medicine. In wallet-book form, with pockets on each cover for Memoranda, Temperature Charts, etc. Roan, tuck, $2.50. 8TRE0KER (ADOLPH). Short Text-Book ot Organic Chemistry. By Dr. Johannes Wislicenus. Translated and edited, with Extensive Additions, by W. H. Hodgkinson and A. J. Greenaway. 8vo. Cloth, $5.00. STRtJMPELL (ADOLPH). A Text-Book of Medicine, for Students and Prac titioners. Translated, by permission, from the sixth German edition by Herman F. Vickery, A. B., M. D., Instructor in Clinical Medicine, Har- vard Medical School, etc., and Philip Coombs Knapp, Physician to Out- patients with Diseases of the Nervous System, Boston City Hospital, etc. With Editorial Notes by Frederick C. Shattuck, A. M., M. D., Jackson Pro- lessor of Clinical Medicine, Harvard Medical School, etc. Second American edition. With 111 Illustrations. 8vo. 981 pages. Cloth, $6.00; sheep, $7.oa. 8 THOMAS (T. GAILLARD), Abortion and its Treatment, from tlie Stand- point of Practical P^xpeiience. A Special Course of Lectures delivered be- fore the College of Physicians and Surgeons, New York, Session of 1889-''.*0. From Notes by P. Brynberg Porter, M. D. Revised by the Author. 12ino. Cloth, $1.00. THOMPSON (W. GILMAN). Practical Dietetics, with Special Reference to Diet in Disease. ( vo. Cloth, $5.00. THOMSON (J. AK'IHUR). Outlines of Zoology. With thirty-two full j af.^' niustrations. 12nio. (Stcdekts' Series.) Cloth, $3.00. TILLMANNS (HERMANN). The Principles of Surgery and Surgical Pathology. Translated by John Rogers, M.D., and Benjamin Tilton, M. D., New York. 8vo. With 441 Illusti'ations. Cloth, $5.00 '; sheep, $G.0O. ULTZMANN (ROBERT). Pyuria, or Pus in the Urine, and its Treatment. Translated by permission, by Dr. Walter B. Piatt. 12mo. Cloth, $1.00. VAN BDREN (W. H.). Lectures upon Diseases ot the Rectum, and the Sur- gery of the Lower Bowel, delivered at Bellevue Hospital Medical College. Second edition, revised and enlarged. Bvo. Cloth, $3.00; sheep, $4.00. VAN BUREN (W. H.). Lectures on the Principles and Practice of Surgery. Delivered at Bellevue Hospital Medical College. Edited by Lewis A. Stim- son, M. D. Bvo. Cloth, $4.00 ; sheep, $5.00. VOGEL (A.). A Practical Treatise on the Diseases ot Children. Translated and edited by H. Raphael, M. D. Tlilrd American from tbe eiglith German edi- tion, revised and enlarged. Dlustrated by six Lithographic Plates. Bvo. Cloth, $4.50 ; sheep, $5.50. VON ZEISSL (HERMANN). Outlines ot the Pathology and Treatment of Syphilis and Allied Venereal Diseases. Second edition, revised by Maxinnl- ian von Zeissl. Authorized edition. Translated, with Notes, by H. Ra- phael, M. D. Bvo. Cloth, $4.00; sheep, $5.00. WAGNER (RUDOLF). Hand-Book of Chemical Technology. Translated aud edited from the eighth German edition, with extensive Additions, by William Orookes. With 336 Hlustrations. Bvo. Cloth, $5.00. WALTON (GEORGE E.). Mineral Springs of the United States and Canadas. Containing the latest Analyses, with full Description of LocaHties, Routes, etc. Second edition, revised and enlarged. 12mo. Cloth, $2.00. WEBBER (S. G.). A Treatise on Nervous Diseases: Their Symptoms and Treatment. A Text-Book for Students and Practitioners. Bvo. Cloth, $3.00. WEEKS-SHAW (CLARA S.). A Text-Book of Nursing. For the Use of Training-Schools, Families, and Private Students. Second edition, revised and enlarged. 12mo. With Illustrations, Questions for Review and Ex- amination, and Vocabulary of Medical Terms. 12mo. Cloth, $1.75. WELLS (T. SPENCER). Diseases of the Ovaries. Bvo. Cloth, $4.50. WORCESTER (A.). Monthly Nursing. Second edition, revised. Cloth, $1.25. WYETH (JOHN A.). A Text-Book on Surgery : General, Operative, and Me- chanical. Profusely illustrated. Second edition, revised and enlarged. Bvo. {Sold only ly subaeription.) COLUMBIA UNIVERSITY LIBRARIES This book is due on the date indicated below, or at the expiration of a definite period after the date of borrowing as provided by the rules of the Library or by special ar- rangement with the Librarian in charge. DATE BORROWED DATE DUE DATE BORROWED DATE DUE C2a(1 I 40) Ml 00