MEDICAL BOOKS -69E.59thSt.,N.A CoUwttbia ^ntbmftj) ^Attnmtt SItbrarg Digitized by tine Internet Arcliive in 2010 witli funding from Open Knowledge Commons (for the Medical Heritage Library project) http://www.archive.org/details/endemicdiseasesoOOdead THE ENDEMIC DISEASES OF THE SOUTHERN STATES BY WILLIAM H. DEADERICK, M. D. T of the Hot Springs Medical Society, the Arkansas Medical Society, and th I Medical Association ; JPellow of the American Medical Association and A Society of Tropical Medicine ; Corresponding Member Societe de Path- ologie Exotique (Paris); Member of the Commission for the Study and Prevention, of Malaria; Secretary Mala- ria Section, National Drainage Congress LOYD THOMPSON, M. D. Member of the Hot Springs Medical Society, the Arkansas Medical Society, and the South- ern Medical Association; Fellow of the American Medical Association; Charter Member of the American Association of I mmunologists ; First Lieutenant in the Medical Reserve Corps, United States Army; Formerly Instructor in Clinical Diagnosis and Director of the Clinical Laboratory, University of Arkansas < ( !■ I' W. I: I / 1 l|.|:/.l;V ILLUSTRA TED PHILADELPHIA AND LONDON W. B. SAUNDERS COMPANY 1916 Copyright, igiS, by W. B. Saunders Company J\i4 PRESS OF SAUNDERS COMPANY PHILADELPHIA PREFACE The inception of this book was due to the fact that there is no work in existence deahng solely with the endemic diseases of the Southern States. It must not be inferred that the diseases considered are con- fined to the states of the South. On the other hand most of them are disseminated throughout the United States and some of them are found in most of the states of the Union. It is true, however, that these diseases are more prevalent in the Southern States. It has not been deemed advisable to treat of all the diseases that are especially prone to visit our confines at longer or at shorter intervals as the list of such diseases is long and such a work would necessarily be one on tropical diseases in general to which this work makes no pretension. We have concluded that it would be more practical to consider intensively only the endemic diseases of our Southland rather than to devote brief space to each of a large number of tropical diseases the most important of which will soon be of historic interest only. Filariasis which occurs in an extremely limited area has been omitted. We are grateful to the publishers for courtesies throughout the publication of the book. The Authors; Hot Springs, Arkansas, March, igi6. 13 CONTENTS MALARIA WILLIAM H. DEADERICK, M. D. Page Chapter I. Introduction 17 Chapter II. Etiology 25 Chapter III. Pathologic Anatomy 90 Chapter IV. Clinical History 97 Chapter V. Diagnosis 140 Chapter VI. Prognosis 166 Chapter VII. Prophylaxis 172 Chapter VIII. Treatment 197 BLACKWATER FEVER WILLIAM H. DEADERICK, M. D. Chapter IX. Introduction 219 Chapter X. Etiology 229 Chapter XI. Pathology 247 Chapter XII. Clinical History 250 Chapter XIII. Diagnosis 262 Chapter XIV. Prognosis 265 Chapter XV. Prophylaxis 270 Chapter XVI. Treatment 272 PELLAGRA LOYD THOMPSON, Ph. B., M. D. and WILLIAM H. DEADERICK, M. D. Chapter XVII. Introduction 281 Chapter XVIII. Etiology 287 Chapter XIX. Pathology 313 Chapter XX. Clinical History 324 Chapter XXI. Diagnosis 364 Chapter XXII. Prognosis 379 Chapter XXIII. Prophylaxis 380 Chapter XXIV. Treatment 385 IS i6 CONTENTS AMEBIC DYSENTERY LOYD THOMPSON, Ph. B., M. D. and WILLIAM H. DEADERICK, M. D. Page Chapter XXV. Introduction 395 Chapter XXVI. Etiology 401 Chapter XXVII. Pathology 413 Chapter XXVIII. Clinical History • 419 Chapter XXIX. Diagnosis 427 Chapter XXX. Prognosis 434 Chapter XXXI. Prophylaxis 436 Chapter XXXII. Treatment 438 HOOK-WORM DISEASE WILLIAM H. DEADERICK, M. D. Chapter XXXIII. Introduction 445 Chapter XXXIV. Etiology 451 Chapter XXXV. Pathology 460 Chapter XXXVI. Clinical History 462 Chapter XXXVII. Diagnosis 473 Chapter XXXVIII. Prognosis 478 Chapter XXXIX. Prophylaxis 480 Chapter XL. Treatment 487 OTHER INTESTINAL PARASITES WILLIAM H. DEADERICK, M. D. Chapter XLI. Other Intestinal Parasites 495 References 528 Index 541 ENDEMIC DISEASES OF THE SOUTHERN STATES MALARIA CHAPTER I INTRODUCTION History. — The history of malaria may be traced to the age of fable. The story of Hercules and the Hydra is a familiar one. This monster dwelt in the morasses in the neighborhood of the Lake of Lerna, where Hercules was dispatched to destroy him. As each of the nine heads was struck off two new ones appeared. With the aid of his faithful servant, lolaus, who burned each wound caused by the removed head, the beast was finally conquered. Even before the birth of Christ this myth was construed to typify the reclamation of swamp lands, uninhabitable on account of the presence, of malaria. Anti- pater wrote, "Hercules, the greatest subduer of the foggy atmosphere in times past, was placed among the Gods for hav- ing destroyed the Hydra; in other words for having reclaimed the marshy desert." The slaying by Apollo of the Python which arose from the fertile ground after the recession of the flood is similarly interpreted. More than one thousand years before the birth of Christ malarial disease is mentioned in the Orphic poems, and the tertian and quartan types are alluded to. In the Iliad of Homer, and the Wasps of Aristophanes allusions are made to a fever which was probably malarial. Paludism was probably introduced into Greece from Egypt. According to Groff the word AAT, which is found among the inscriptions of the temple of Denderah, referred to a disease, doubtless malaria, which recurred every year at the same season. 2 17 1 8 ENDEMIC DISEASES OF THE SOUTHERN STATES Hippocrates divided malarial fevers into continuous and in- termittent, which he subdivided into quotidian, tertian, and quartan. He recognized the etiologic influence of season, rains, and stagnant water, and the dangers of malignancy, dropsy, and affections of the spleen. Plato describes splenic enlarge- ment, and other early Greek writers undoubtedly refer to malaria. References by Roman writers to malaria are not numerous, the earliest being that of Plautus, who died 184 B.C. Cato speaks of "black bile and swollen spleen," and Cicero, Varro, Celsus, Livy, and others show unmistakable evidence of a knowledge of the disease. Passing over the development during the middle ages of the knowledge of malaria, the names of Morton, Lancisi, Sydenham, and Torti appear. Morton, 1697, gave accurate clinic descriptions of the perni- cious and intermittent fevers, and attributed them to miasmatic effluvia. He was an ardent advocate of cinchona whose value was at that period being hotly contested. Sydenham, 1723, accurately described the malarial fevers. The intermittent fevers he divided into spring and autumn fevers. He justly concluded that the intermittent and con- tinuous forms of malaria were due to the same cause. Syden- ham ably defended cinchona, and after clinic experiments with its use, formulated useful rules for its administration. Lancisi, 1717, stated the etiologic relationship between marshy regions and malaria, and was the first to seek for a microscopic organism as the cause of the disease. Torti, 1753, wrote an exhaustive treatise upon the various forms of malaria. His classification of the pernicious forms has become classical. Numerous quotations from Torti's" treatise are to be found even in recent works upon malaria. Varro, 118-29 B.C., expressed the opinion that malarial fever was caused by animals so minute that they could not be seen by the naked eye, and which enter the body with the air through the nose and mouth. Similar opinions were held by Columella, Palladius, and Vitruvius. Rasori is quoted as saying, "For many years I have held the opinion that the MALARIA 19 intermittent fevers are produced by parasites which renew the paroxysm by the act of their reproduction which occurs more or less rapidly according to the variety of their species." Le Diberder, 1869, maintained that the fever was due to the presence in the blood of animals which preyed upon the blood, and that the paroxysms depended upon reproductive acts be- tween which apyrexia occurred. Mitchell, 1849, claimed to have found in the sputa of malarial subjects fungus spores in great numbers, which he believed to have been inspired with marsh air and to have caused the disease. Salisbury, 1866, announced the discovery in the urine and sweat of malarial patients of a species of alga, palmella, common on the marshy regions along the Ohio and Mississippi Rivers, which he alleged to be the causative element. Until the true parasite of malaria was discovered, the most widely accepted parasitic theory was that proposed in 1879 by Klebs and Tommasi-Crudeli. These investigators found con- stantly present in the mud of the Roman marshes a short bacillus. They were able to cultivate it upon fish gelatine, and when injected into rabbits produced a fever similar to malaria. They named it the bacillus malaria. The malaria parasites were undoubtedly seen and described before Laveran discovered them. In 1847, Meckel, who first discovered malarial pigment, described bodies containing pigment which correspond to the malarial parasites. Virchow, in 1849, ill 3- description of the pigment, depicted cells now known to be parasites, as did also Frerichs in 1866. The pigment was observed also by Dlauhy, Heschl, and Planer. None of these investigators, however, recognized the significance of these bodies, and their parasitic nature was not suspected until 1880 by Laveran, to whom all the more honor is due. Charles Louis Alphonse Laveran was born at Paris, June 18, 1845. He entered the mihtary service and was assigned to Algeria where his brilliant discovery was made Nov. 6, 1880, and announced to the Paris Academy of Medicine, Nov. 23, 1880. He was using a one-sixth inch dry lens when examining the blood. 20 ENDEMIC DISEASES OF THE SOUTHERN STATES Laveran's discovery was not accepted by the medical world until several years later; now it has been confirmed the world over. Among Americans who first corroborated Laveran's views may be mentioned Sternberg, Councilman and Abbott, Osier, James, Dock, Thayer and Hewetson, Barker, Woldert and Welch. The discoveries of Golgi in 1885 were of great importance with reference to the hfe history of the parasite. He was able to follow tertian and quartan parasites throughout the endogen- ous cycle of development, and showed that a close relationship existed between certain phases of parasitic growth and certain stages of the paroxysm. Other Italian investigators proved the same for the estivo-autumnal parasites. A vague suspicion that malaria and mosquitoes were in some definite way connected has been entertained in certain countries for a long period. A definite mosquito theory, however, was born in America. While reference is sometimes made to a paper on the "Mosquital Origin of Malarial Disease," supposed to have been published by Dr. John Crawford in the Baltimore Observer, in 1807, no such article has been found, and the ref- erence is probably erroneous. In 1848, Dr. Josiah Nott,^^'* of Mobile, published a paper upon yellow fever, in which he maintained the dissemination of that disease by insects, and suggested that malaria was spread by the "mosquito of the lowlands." The most complete theory was proposed by King,*^° in 1883. His views are supported by nineteen arguments, most of which are incontestable at the present day. That mosquitoes are agents in the spread of malaria was advanced by Koch in 1884, by Laveran in 1884, by Flugge in 1891, by Manson in 1894, and by Bignami in 1896. Undertaking the work of Manson's suggestion, and after several years (1895-1898) of toil and discouragement, Ross proved conclusively that certain species of mosquitoes were concerned in the dissemination of malaria. The debt owed him by mankind was acknowledged by the gift of a Nobel prize. MacCallum in 1898 demonstrated that the flagella represent male sexual elements analogous to spermatozoa. Bass' discovery of the method of cultivating the malarial parasites is the most important landmark in the history of malaria since the discovery of Ross. Geographic Distribution. — North America. — In the United States it is chiefly the southeastern portion in which malaria is most prevalent. Along the Atlantic Coast, south of New York and especially the lowlands of Maryland and Virginia, and in the Carolinas, Georgia and Florida the disease occurs frequently. Along the Gulf coast and up the Mississippi River and its tribu- taries, malaria is widely prevalent. The portions of the States lying along the Appalachian Range are almost exempt, but the disease appears as the Mississippi River and the Atlantic Coast upon either side are approached. West of the Mississippi, Arkansas, Louisiana, and Texas present the most numerous foci of malaria. In portions of Pennsylvania and New York au- tochthonous cases are not infrequently observed. In the more southern New England States malaria is still encountered, and in some places is even increasing in frequency. In the neighbor- hood of the Great Lakes malaria is very rare, excepting possibly that of Lake Erie and of Lake Michigan. In the Central States malaria has almost or quite disappeared, except in certain low river valleys. Along the Pacific Coast the disease is not so frequent as along the Atlantic. In Washington it occurs in the Puget Sound Basin and the Columbia River, Chehalis, and the Yakima valleys. In Oregon malaria is found in the Columbia, Williamette, Rogue, and the Umatilla valleys, and in California in the Sacramento, San Joaquin, Tulare, Kern, and Santa Clara valleys. In certain parts of New Mexico malaria is occasion- ally met with. Canada is free from paludism except along the northern shore of Lake Ontario. In Mexico severe forms of malaria occur, particularly in the low coast regions. Malaria abounds in Central America along the Atlantic Coast and to a less extent upon the Pacific side. South America. — The eastern coast of South America is more intensely infested with malaria than is the western coast. Venezuela (in the valleys), Guiana, and the greater portion of 2 2 ENDEMIC DISEASES OF THE SOUTHERN STATES Brazil are highly malarial. Portions of Paraguay and of Bolivia afford a great many cases, while the disease is much less prevalent in Uruguay and almost absent from the Argentine Republic. On the Pacific border the deep valleys of Peru and of Ecuador are malarial centers. The entire island of Cuba is malarial to a greater or less ex- tent, as is also Jamaica. Of the Lesser Antilles, St. Vincent and Antigua are highly malarial, and Barbadoes is exempt. Malaria is said to be almost unknown in the Bermudas. Europe. — Great Britain, once infested, is now free from en- demic malaria. In Germany the disease occurs infrequently in the Rhine and Danube valleys and near the mouths of rivers along the coast. Malaria is met in Holland, chiefly upon the island of Zeeland and in North and South Holland. The valley of the Danube, in Austria, affords a considerable number of cases. There are a few regions in Hungary in which the disease does not occur, but it is especially along the western half of the southern border that it is prevalent. The marshes along the west coast and the south of France give rise to a number of cases of malaria. In Spain and Portugal malaria occurs in the coast regions and in the larger river valleys. The disease is practi- cally unknown in Norway, but is occasionally reported from Sweden, as well as from certain of the islands of Denmark. In Russia it is in the southern portion, particularly along the coasts and along the valleys of the rivers flowing southward, that malaria is encountered. Cases are occasionally observed in the southwest of Switzerland. The portions of Bulgaria most highly malarial are the Danube valley, the coast region, and the southern part. Almost the whole of Italy is sorely afflicted with malaria, as are also Sicily and Sardinia. Greece is the most severely scourged country of Europe. It is said that in the plains of Thessaly, Phthiotis, Acarnania, Boeotia, Elis, Mes- senia, Argos, and Laconia hardly a single inhabitant escapes the disease. Asia. — Asia Minor, Arabia, and Persia present foci of malaria, both in the coast neighborhoods and in the interior lowlands. In the swampy regions of Afghanistan and Beloochistan malaria is common and severe. The foothills of the Himalayas, MALARIA 23 the Duars, and Terai are famous malaria seats. Both the coast regions and the interior highlands of Ceylon are endemic territory. Burmah, Siam, the Malay Peninsula, and French Indo-China are malarial in portions of their extent, and parts of China are intensely infested. Malaria is found in Japan, Formosa, and the PhiHppines, and portions of the East Indies are among the most highly malarial regions of the world. Africa. — On the west coast the territory, between the Senegal and the Congo Rivers, is headquarters for malaria of malignant type. Approaching South Africa the disease diminishes in frequency and in severity. On the east the region from Delagoa Bay to Eritrea is malarial. In the interior of Central Africa, excepting the high elevations, malaria is widespread. Malaria abounds in Madagascar, excepting upon the northeast coast and the mountainous interior. Reunion and Mauritius are also malarial. In Egypt it is chiefly the region overflowed by the Nile in which the disease is most prevalent. Malaria abounds about the coasts and marshes of Algeria. In Australia malaria occurs from Cape York to Brisbane, on the east coast, diminishing toward the south. New Zealand is apparently free from malaria, and the Sandwich Islands and most of the other Pacific islands are markedly exempt. The relative frequency of the forms of malarial infection varies greatly. It may be stated as a general proposition that the quartan is the rarest form, the tertian is the form prevailing in temperate regions, and the estivo-autumnal in warm and hot climates. There are regions, however, in which the quartan predominates, as in certain portions of Italy and of India; in other localities it is the only form of malaria present, as upon the island of Merite, of the Bismarck Archipelago. The following table shows the relative frequency of the types of malaria in various regions : 24 ENDEMIC DISEASES OF THE SOUTHERN STATES Authority Texas Georgia Camp WikofE New Orleans Baltimore Panama St. Lucia Panama Italy Italy Greece Bulgaria Italy British Malaya British Malaya Philippines India Cyprus East Indies Philippines India India Assam Japan Togo German East Africa German East Africa Senegal German East Africa German East Africa German East Africa German East Africa Moore"" Curry"' Ewing'^ Charity Hospital Recs.'"* Thayer and Hewetson'"' Kendall"" Gray and Low*" Gorgas"2 Koch"3 Koch"* Cardimatis and Diamessis"^ MoUow"6 Italian statistics'''" Wright"* Watson"' Craig"' Hope"" Williamson"'- Koch'"2 Chamberlain*'^' Rogers" Buchanan''" Bentley''** Tsuzuki''" Ziemann*' Meixner'' Grothusen" Thiroux and d'Antreville"" Kudicke" Exner'' OUwig'i Schornich'^ 23 34 74 373 338 4,012 32 202 32,392 78 19 98 217 12 S7 55 1.372 56 134 345 I 5 5 7 3 119 3 71 30 16 261 203 188 291 109 10,815 78 191 145 67 23,520 117 28 272 547 4 123 62 1,311 118 74 107 32 102 68 266 118 328 134 130 CHAPTER n ETIOLOGY OF MALARIA Malaria is of very complex etiology, depending as it does for its existence upon the life histories of three species of animals. While within the blood of man the parasite is not subject to great variations of environment, no matter what the season or the latitude, nevertheless exposure to cold, wet or heat, dietary or other excesses, will have the effect of awakening latent malaria. But it is the influence of external factors upon the life history of the mosquito that determines the greatest variations in the prevalence of malaria according to climate, season, temperature, rainfall, altitude, etc. Climate. — It may be said as a general rule, that the frequency and virulence of malaria increase as we approach the equator. The conditions of warmth and moisture are more propitious for the development of the parasites within the bodies of mosquitoes in tropic than in colder climates; this is especially true of the estivo-autumnal form of the malarial parasite. Exposure to the heat of the tropical sun predisposes to the cerebral forms of pernicious malaria, and undue exposure to the sun's rays is ofttimes sufficient to stimulate sporulation of the parasites of latent malaria. With respect to latitude Hirsch^" reached the following conclusions as to the northern boundary of malaria in the northern hemisphere. The line starts from 55°N. on the western side of North America, sinks to 45° on its eastern side, rises to 63° or 64° on the western side of the old world (Sweden and Finland), and runs across Northern Asia in about the latitude of 55°. Long before the discovery of the role of the mosquito in malaria it was known that the disease was not endemic unless the summer temperature maintained a certain average. Hirsch maintained that the summer isobar of S9°-6o.8°F. marks the 25 26 ENDEMIC DISEASES OF THE SOUTHERN STATES limit of the occurrence of malarial fever, and that those regions where the mean summer temperature does not reach that height are exempt from the disease. Curiously enough, it has been recently repeatedly demonstrated that this is the lowest temperature at which the parasite wiU develop in the body of the mosquito. Season. — While relapses may occur at any season, and in certain tropic regions fresh infections may occur during any period of the year, in all temperate and most tropic regions there are seasons during which the disease is especially prevalent. This is commonly known as the malarial season, and varies according to latitude, temperature, rainfall, soil, etc. The season of primary attacks depends entirely upon the Ufe-history of the malaria-bearing mosquitoes. This season usually begins a few weeks after the first brood of anophehnes appears, which is at the height of summer, and continues, in temperate chmates, until after the nights become cool. In each individual locality the beginning of the season is rather definite, the disease recurring at a certain period each year with more or less exactitude. In most of the regions of the Southern States the malarial season begins in the earlier half of July. In the latitude of Baltimore the most notable increase in cases begins during August. The malarial season in Cali- fornia is from August to October. Where both tertian and estivo-autumnal malaria are endemic, the malarial season is usually ushered in by cases of the former, the estivo-autumnal variety appearing at the height of the season. The pernicious forms of malaria occur with greatest frequency at the height of estivo-autumnal prevalence. In Italy quartan malaria begins late in the summer and continues late in the fall. In America this variety is too infrequent to justify any definite conclusions. Mixed and multiple infections occur more frequently late in the season than early. Rainfall. — The influence of rainfall upon the extent of malaria is very decided. Breeding places for mosquitoes are essential in the etiology of malaria, and limited pools, such as result from a fall of rain, are well suited to the taste of the malarial mosquitoes. MALARIA 2 7 Rain has a twofold effect upon the prevalence of malaria. First, exposure to wet is not infrequently followed by a re- crudescence of a former infection. This effect is usually immediate. Second, rainfall produces breeding pools for the disseminators of malaria. The effect of fresh breeding places is not shown immediately. Allowing twenty days for the aquatic stages of the mosquito, ten days for the mosquito cycle of the parasite, and a Hke period for the incubative stage in man, it would be, obviously, several weeks before an increase in malaria could be expected from such a source. This is well exempUfied in the tropics, where so much depends upon rainfall. Here the height of the malaria curve is attained toward the end of the rainy season, or shortly after. A heavy rainfall in the spring and early summer has long had the reputation of being favorable to the spread of malaria. While rainfall is essential to the development of malaria, if excessive it may have the opposite effect by scouring breeding pools and destroying the contained ova and young of the mosquito. Moderate rains at short intervals are more pro- ductive of breeding pools than heavy downpours at long intervals. Hence, the number of rainy days, as well as the actual rainfall in inches, is a factor in the etiology of malaria. In very low countries rainy years may be healthy years. This is said to be the case in the Netherlands. Dew and a high atmospheric moisture were formerly ac- credited with being factors in the cause of malaria. This was doubtless on account of the well-recognized danger of contract- ing malaria between sunset and sunrise. Other than as an index of ground-moisture it is doubtful whether atmospheric moisture bears any relation to primary infections with malaria. Soil. — The chemical composition of the soil has an effect upon the reign of malaria only so far as the relation of the soil to the retention of water is concerned. More depends upon the physical conformation than upon the geologic characteristics of the soil. As a rule, clay soils retain moisture better than the sandy, though there are exceptions. Rocky regions are less apt to harbor breeding pools because of good drainage, but pools upon a rock bed are very persistent. The soil must be of such a 28 ENDEMIC DISEASES OF THE SOUTHERN STATES character as to retain surface water sufi&ciently long for the aquatic stages of mosquito life to be completed. More depends upon the nature of the subsoil than upon that of the surface soil. Even where the surface soil is very porous, an impervious subsoil favors the accumulation of surface water by preventing further percolation. Thus the height of the ground-water during the malarial season bears a close relation to the volume of the malarial endemic. Proximity to collec- tions of water, by raising the height of the ground-water, favors the development of malaria. Topography. — In countries designated malarial, regions entirely free from the disease are not uncommon. In a region within a short distance of a severely scourged locality malaria may be entirely absent. The difference in the prevalence of malaria within limited areas is dependent, in great measure, upon the physical characteristics of the surface of the land. It has been known for centuries that malaria is partial to low marshy places, swamps, lakesides, low coast levels, and river valleys, and especially the deltas of large rivers. The cleaner the banks and the swifter the current of the streams at all stages the less apt they are to be malarious. Streams with sluggish or no currents, and with weedy banks which foster eddies, are breeding places for mosquitoes. It is generally believed that salt marshes are never malarious, and that anopheles larvae cannot develop in sea- water. This is, however, not strictly true. DeVogeP^^ has recently shown that anopheles larvae may develop in sea-water evaporated to half its initial volume, and a number of other observers have found larvae in salt water. But marshes of pure sea-water are not nearly so noxious as those of brackish water, a mixture of salt and fresh water, which are famous anopheles breeders. It appears that in some instances, where salt water is inimical to the development of the aquatic stages of mosquitoes, they may gradually become accustomed to the environment. Altitude. — Malaria is essentially a disease of the lowlands, high altitudes being relatively exempt. This is partially ac- counted for by the better drainage of elevated altitudes and fewer pools in which malarial mosquitoes may breed. The MALARIA 29 lower temperature of high altitudes is also a factor in maintain- ing a low malarial morbidity in these regions. It is known that anophehne mosquitoes do not fly to great heights. Hence sleeping in an upper story or in a building situated high above the ground gives a measure of protection from malaria. Laborers employed in highly malarial sections, and who sleep in the surrounding hills, even of moderate alti- tude, often remain entirely free from infection. A few hundred feet in altitude may show a more marked difference in the prevalence of malaria than as many miles in latitude. The general rule that malaria is a disease of low countries has some exceptions. This is especially true in the tropics, where the disease may be encountered at very high altitudes. It may be said that the altitude at which malaria may occur varies in inverse ratio to latitude. Malaria has been found on Lake Nyssa at an altitude of 1,560 meters; at Colico, 2,500 meters; in the Himalaya Moun- tains, at 2,000 meters; in the Andes, at 2,500 meters; at Blan- tyre, at 3,000 feet; German East Africa, at 1,550 meters; at points in Central Africa, at heights of over 5,000 feet; and in some of the high-lying valleys of Syria, at altitudes of 1,200 meters. Some of the cases in high altitudes reported as malaria may be mistakes in diagnosis; other cases may be malaria contracted in the lowlands. Thus Tosari, at an elevation of 1,177 meters, has been cited as a place where malaria prevailed without the presence of mosquitoes, and this was used as an argument against the "mosquito theory." Koch,'-^ investigating the place in 1899, examined the blood of eighty- two children; in none was the parasite of malaria detected. The only case of malaria found was in a man who, twelve days before the beginning of his illness, had spent the night in a highly malarial place upon the coast. However, malaria is endemic in certain places of high altitude. Such are Eritrea, in altitudes of 1,750 meters; Upper Tonkin, at 1,000 meters; parts of Madagascar, at 1,100 meters; parts of Reunion Island, 1,200 meters; in Java, at 1,000 meters; and in 30 ENDEMIC DISEASES OF THE SOUTHERN STATES the Philippines it is said that, while certain valleys are almost free from malaria, the hills in the vicinity are notoriously in- fected. Wright,'*''^ in British Malaya, found anopheles larvae in pools at an elevation of 2,300 feet. Earthquakes and volcanic eruptions have been followed by a great development of malaria. Examples are cited of Rome in 1703, in Reggio in 1783, and Palermo in 1828. Remarkable instances have occurred in Peru also. The most recent illustration is that of Amboina, in the East Indies, which had until 183 s been remarkably free from malaria. In that year a severe earthquake occurred, and since then the malaria has increased both in extent and intensity. Such results can be explained only by an increase of stagnant water following these violent disturbances, probably through the interruption of the flow of ground-water. Invmdations. — Since very early times overflows have been recognized as a prolific cause of epidemics of malaria. Tacitus, Suetonious, Livy, Dionysius, Cassio, and Strabo, mention such results from inundations of the Tiber. This stream experienced an overflow in 1695, which was described by Lancisi. The water covered a broad area of country, filling ditches, sewers and canals. The following June, July and August were extremely hot. An epidemic of malignant malarial fever ensued and, spreading far and wide, occasioned a great mortality. Epidemics of malaria following overflows of the Nile, Ganges, Indus, Euphrates, Niger, Senegal, Volga, Danube, Saone, Rhone, Loire, Mississippi, and other rivers have been described. The immediate effect of an inundation is to check the devel- opment of malaria. This is a result of a destructive effect of the flood upon the breeding pools of mosquitoes. It is only after the waters have subsided and pools and marshes are left that the epidemic develops. Trees and Vegetation. — It was formerly beheved that, while decaying vegetation was the cause of malaria, living plant life greatly retarded its development. Whole volumes have been devoted to this subject. It was supposed that vegetation filtered the miasm from the air. It was argued that if air vitiated by respiration be confined in a bottle containing a living plant MALARIA 3 1 and exposed to the rays of the sun, the carbonic-acid gas will be absorbed and the air restored to its original condition, plant life consuming carbon dioxide and exhaling oxygen. So firm was this belief that in the days of ancient Rome trees were protected by law. It is needless to say that the protective power of living plants was as much overestimated as the faculty of decaying vegetation to cause malaria. Their power of absorbing moisture from the soil is more than outweighed by the shade they afford the ground. While the clearing of land of trees and vegetation may be followed by an outbreak of malaria, this may be due to the over- turning of the soil, which usually goes hand in hand with open- ing land, and to the hardships attending such labor. The ulti- mate effect of clearing trees from the land is to diminish malaria by permitting the sun to dry the soil. If trees have any protective virtues whatever, it is probably through affording shelter and food for mosquitoes. The culture of eucalyptus trees is now known to have no prophylac- tic effect upon malaria. Weeds and other vegetation growing in the water favor the development of mosquito larvffi by protecting the surface of the water from agitation by the wind. Vegetable decomposition bears no relation to the etiology of malaria other than as an index to heat and moisture. Wind. — The wind was formerly held responsible for trans- mitting malaria long distances. It was believed that the malaria of Edinburgh was imported by the winds from Holland, and that Italy became malarious through the agency of the African sirocco. The land breezes, especially if they blew over marshy areas, were regarded as more highly noxious than the sea breezes. As a matter of fact, the wind has little or no power to transmit malaria for distances of any consequence. While it is theoret- ically possible for infected mosquitoes to be borne by the wind, in reality these insects, especially the anopheles, being weak fliers, seek shelter while a breeze is blowing. The immunity from mosquito bites afforded by the Indian punkah, or a common fan, is evidence of this. 32 ENDEMIC DISEASES OF THE SOUTHERN STATES Furthermore, the disturbing effect of the wind upon the sur- face of the water interferes with oviposition of the adults and with respiration of larvae and pupae. Exposure to cold winds may have the effect of arousing latent malaria. The occurrence of malaria upon shipboard has been cited as an argument that malaria is an air-born disease. Bilge water in the holds of vessels has also been accredited with pro- ducing malaria at sea. Malaria occurring upon ships may be accounted for in several ways. These cases may be manifestations of malaria contracted upon shore. Even cases occurring long after embarking may be explosions of latent malaria. If vessels anchor too close in shore in malarial regions infected mosquitoes may easily gain access to the crew — a half mile from shore is probably a safe distance. It has been proven that mosquitoes may be carried for considerable periods in the holds and sleeping apartments of ships. There are many places where, notwithstanding apparently favorable topographic and meteorologic conditions, malaria is entirely absent. This is due to the absence of either malaria- bearing mosquitoes, or malarial parasites, or of both. Among a number of such places may be mentioned the city of Rome and other portions of Italy, Madeira, portions of Cameroon, Chole Islands, portions of India and of Borneo, the French Islands, Ponape, Saipan, Samoa, New Caledonia, Tahiti, Barbadoes, and portions of Brazil and of the Argentine Republic. The majority of such localities are islands and in the southern hemisphere. Race; Immunity. — Certain protozoan diseases among lower animals confer immunity. In the Texas fever of cattle an attack, if recovered from, is followed by immunity. There are said to be breeds of cattle naturally immune to the disease. In the large game animals of Africa one infection with try- panosoma brucei confers immunity. Koch found that birds that had been infected with proteosoma grassii could not be reinfected. From analogy it might therefore be expected that immunity MALARIA 33 to malaria might exist with some individuals or races. This is true, however, in only a limited sense. While the various races of mankind vary somewhat in sus- ceptibility to malaria, none can be said to possess absolute immunity. Caucasians residing in non-malarial countries are, when exposed, most liable to contract malaria. Negroes bred in highly malarial regions are, as long as they remain upon the native soil, least susceptible to paludal infection. Immunity within the race increases generally as we go toward the equator. Thus the negroes of the Southern States display less immunity than the negroes of the West Indies or of tropic Africa. Likewise it may be said that immunity is much more marked in countries with a high than in those with a low endemic index. The immunity of the negro race has been variously estimated, some observers maintaining that they are absolutely proof against malarial invasion, while others hold that they are as susceptible as the whites. The truth lies between these two extremes. Adult negroes reared in malarial regions are much less liable to paludism, as long as they remain indigenous, than are the whites. The negro race does not, however, enjoy an absolute but only a relative immunity from malaria. According to Sternberg,^^^ there were in the department of Texas of the United States Army during the year ending June 30, 1883, among the white soldiers 21.36 per cent., colored, 6.27 per cent, of periodic fevers to all kinds of fevers. Sternberg*"^ gives the ratio per thousand of mortality from malarial diseases in the United States Army thus: 1868 1869 1S70 White 94.20 74.62 140.67 15.62 72.99 38.46 Colored During the Civil War both the morbidity and the mortality from malaria in the negro race were greater than in the white race. However, the negro soldiers are said to have been more 3 34 ENDEMIC DISEASES OF THE SOUTHERN STATES exposed to malaria than the whites, having been aggregated in malarial locahties. With the better hygienic surroundings and more limited exposure of the whites the negroes would probably be attacked less often than they are. Whether the color, thickness, or other qualities of the skin of this race have anything to do with relative immunity is not known. At Stephansort, Koch*^^ found various races infected in the following proportions: Number infected with Europeans. . Chinese Malays Melanesians Total 240 209 264 12 S7-I 63 26.3 53 25 -3 29 10. 9 Immunity from malaria is probably an acquired immunity in the great majority of instances, though the contrary opinion is held by some competent authorities upon the subject. The reasons for believing that this immunity is acquired by re- peated infection, especially in childhood, and by prolonged residence in a malarial region, a sort of acclimatization, are, that immunity is much more prevalent in adults than in children; that immunity is often diminished by a change of resi- dence or may be entirely lost by a temporary residence in a nonmalarial climate; and that immunity in an individ- ual may exist toward one form of malaria and not toward others. That immunity is much more manifest in adults than in children is evident from the consideration of the endemic index of malarial regions, particularly of countries where the latter is high. During the first years of life many individuals ex- amined show evidence of malarial infection, older children in a less proportion, and adults evince a relative immunity. This would hardly be the case if the immunity were racial and congenital. MALARIA 35 The effect of a change of residence upon malarial immunity is a well-known fact. Plehn^ says that the Soudan negroes, relatively immune at home, are often afiflicted with malaria when going as soldiers to other parts of the continent. Smith''*'' states that, while the native negroes of Sierra Leone are in- frequently attacked, and only with mild degrees of malaria, in the West Indies regiment of negroes stationed in Sierra Leone the fever is of a severe and often fatal character. Individuals once immune to malaria may become susceptible on returning home from a temporary residence in a malaria- free country. Plehn^ mentions three Cameroon negroes who, shortly after returning from a several years' sojourn in Europe, were attacked with severe remittent fever. Repeated infection and consequent immunity to one form of malaria does not usually protect the individual from the other forms. In the South there is Httle difference between the races as regards susceptibility to the various forms of malarial infection — tertian, quartan, and estivo-autumnal. Clinically, however, pernicious cases, cachexia and hemoglobinuric fever, are rarer in the negro. Instances of cachexia followed by immunity have been ob- served, especially by the Itahan school. In these cases, after recession of the spleen and liver, and restoration of the blood elements, a stable immunity resulted. Subjects of existing cachexia, even though free from clinic evidences of acute malaria for years, can hardly be regarded as immune. Rarely are persons encountered in highly malarial localities who have never been attacked with malaria. Such persons are supposed to possess congenital immunity. Celli''"* obtained precise histories of four persons living in the Pontine Marshes who were absolutely immune, having never had malaria, though they took no prophylactic precautions; their color was good, and their spleens and livers normal. In persons claiming never to have had malaria allowances must be made for the possibility of unrecognized attacks, especially in early childhood, which might give rise to an acquired immunity. 36 ENDEMIC DISEASES OF THE SOUTHERN STATES In conclusion, the resistance of the black race to malaria is due to repeated attacks in early childhood, and not to any great extent to heredity. While in a sense natural selection is a factor, it is largely an individual struggle, the selection of the fittest occurring in infancy, and but little being derived from progenitors. Sex. — As a general rule, females are less often attacked with malaria than males, though in childhood the proportion is about even. That women are less frequently infected is not due to a higher degree of resistance, but to the fact that they are less often exposed and are more temperate in their habits. It is probable that if they were equally exposed with males they would be even more often infected than the latter, on account of the greater delicacy of the skin and the manner of dress. In certain localities women are not less frequently attacked than men. In Panama there is said to be very little, if any, difference between the sexes in this respect. In the Dutch East Indies European women are more susceptible than men. Davidson*""^ says that from 1871-75 the death rate of soldiers' wives in India was 4.20 per thousand, as compared with 2.81 for the men; and that in Bombay, 1885-86, the female death rate was 10.14; that of males, 7.56. In an institution in Alabama, Sims and Warwick*^" found among deaf mutes 1.05 per cent, of the males and 6 per cent, of the females infected; among blind, 6 per cent, of the males and 3 per cent, of the females. Pregnant women are probably less often infected because, on account of their condition, they are less often exposed ; when exposed they are very susceptible. The puerperium predis- poses to malaria. Age. — Children are more frequently and more severely afflicted with malaria than adults. This is probably due to their more dehcate skin, their manner of dress, sounder and more pro- longed sleep, and inability to defend themselves against mos- quito bites. The fact that cases of malaria in children more often escape correct diagnosis may account somewhat for the greater frequency, especially of relapses. MALARIA 37 The subjoined figures show the distribution of malaria accord- ing to age: Age O-IO 10-20 20-30 30-40 40-so So-60 60-70 70-80 80-90 Thayer and Hewetson"' Rogers-^ x8 2 729 146 13 499 146 204 10 398 83 69s 130 3 230 61 424 65 36 II 3 I 144 63 100 55 Conti-"" Total 994 804 272 136 66 18 4 Endemic Index. — The percentage of children infected in a given locality is the index to the prevalence of malaria in that region. As Ross**- expresses it, "There is probably only one really accurate method by which we can determine the degree of malaria in a given locality, and that is by ascertaining the average time in which a newcomer becomes infected. The shorter this period the greater, evidently, the malaria potential of the locality. Native children constitute the class of new- comers most accessible for making the estimate." The most accurate method of determining the index endem- icus of an area is to make a large number of blood examinations of native children at various ages. This requires a great deal of time. It has been repeatedly shown that in regions where malaria prevails extensively a large per cent, of young children harbor the parasites without manifesting any symptoms of the disease, the index decreasing as the age increases. For this reason young natives with latent malaria are the source of the greatest danger to the community. Endemic indices for the United States have been determined in very few instances. Sims and Warwick^^" examined the blood of 610 apparently healthy children and adults in Alabama and found that between 8 and 9 per cent, were infected with malaria. Surgeon von Ezdorf of the United States Public Health Service examined the blood of a number of persons in several Southern States with the following results: ENDEMIC DISEASES OF THE SOUTHERN STATES Number examined Per cent, infected 664 802 3613 6S 3-7 6.6 North Carolina 8.5 12.3 In calculating the endemic index a sufficiently large number of persons should be examined in order to eliminate error. It has been estimated that if fifty persons be examined and the blood of twenty-five found to contain parasites, the margin of error being 20 per cent., the index would not be 50 per cent, but between 30 and 70 per cent. Furthermore, while a high index indicates widespread malaria, an index of zero must not be construed to indicate an entire absence of the disease, since experience has shown that it may exist where the index, esti- mated in this manner, is zero. In comparing the indices of two localities the figures should be taken at corresponding seasons, since the index of a given locality varies according to season. The prevalence of splenic enlargement has been employed to calculate the extent of paludism, this method requiring much less time than the examination of the blood. The spleen rate and the endemic index, estimated by a microscopic examination of the blood, do not usually correspond even approximately. Stephens and Christophers"^' have pre- pared the following table to illustrate the relation between the spleen rate and the parasite rate: Endemic index Calcutta Jalpaiguri Bustee children School children. Babu children. . Mainaguri Rungamutty Sam Sing Kurseong I Kurseong II MALARIA 39 These investigators draw the following conclusions: i. A high endemic index may exist without any appreciable spleen rate (Africa). 2. A high spleen rate may exist in adults without a cor- responding parasite infection. 3. In India (Bengal) among children a high spleen rate is a fair indication of the parasite infection. 4. The spleen rate, unlike the parasite rate, increases up to a certain age limit and may be considerable when the parasite rate is nil. I do not beheve that the spleen rate would disclose the true endemic index of regions in the Southern States. Length of Residence. — In highly malarial regions, especially in the tropics, newcomers are usually infected during the first year. In the Southern States the period before infection varies greatly according to circumstances. Newcomers who Kve in hygienic surroundings, and who observe ordinary precautions, may go for years without developing the disease. On the other hand, persons coming South who take no precaution, and who expose themselves carelessly, are liable to be attacked early. Thus it is said that when the Beaumont oil fields were opened up people flocked there from nearly every section of the country, and nearly every newcomer was struck down within a few weeks with malarial fever of some form. Residence, even prolonged, in a malarial locahty does not con- fer absolute immunity to malaria. Change of Residence. — The effect of a change of residence upon the immunity in the negro race has been referred to. It is a common observation that moving to another locahty "brings the malaria out of the system." This malaria is usually latent — always so, of course, if the new residence is in a non- malarial region. It is not uncommon for persons who have never had recognizable paroxysms to suffer an outbreak upon leaving the endemic region. Occupation. — This is a factor in the etiology of malaria in two respects : first, by reason of certain occupations exposing the person to the bites of mosquitoes; second, by reason of the 40 ENDEMIC DISEASES OF THE SOUTHERN STATES exposure and exertion attending certain occupations awakening latent malaria. Rural avocations more commonly expose to malaria than urban. Occupations which necessitate residence at highly malarious spots are especially dangerous, as well as those that require being out of doors at night. Overturning the soil, as in gardening, farming, ditching, rail- road, levee, and canal construction, predisposes to malarial infection. Fishermen, soldiers, night-watchmen, engineers, and timber workers are often exposed. Rice culture, requiring as it does the retention of water from the surface of the ground, is not an unalloyed boon as an in- novation into many of our Southern States. The dangers to the community from the growth of rice were recognized many decades ago near Savannah and Charleston. Social Condition. Civilization. — Formerly malaria attacked all classes. Many noted persons were frequently infected, and James I and Cromwell died of the disease. Moats and lakes near castles and country estates were doubtless to blame. Now malaria is chiefly a disease of the poor and ignorant classes. The man in the well-constructed and properly screened residence is much less hable to become infected than the one in the loosely built and unprotected hut. The occupa- tions and food of the poorer classes are also factors in the greater prevalence among them. Persons living in cities and towns are much less apt to be exposed to infection than those living in villages and in the country. Many towns and cities in the heart of malarial areas are relatively free from the disease. Suburbs are more highly malarious than the more densely populated sections, for the reason that the mosquito has more opportunity to breed in the former. Other Factors. — There are certain factors of the utmost importance in the etiology of malaria, and before the truth was known were looked upon as causing the disease. These are over-work, fatigue, exposure to sun, rain, and cold, excesses in Bacchus and Venus, psychic emotions, loss of sleep, traumatism, surgical intervention, over-eating, hunger, thirst, digestive MALARIA 41 disorders, menstruation, parturition, intercurrent affections, and the administration of certain medicaments. Watermelons, muscadines, cucumbers, and other articles have yet the reputation in parts of the South of causing chills. The administration of tuberculin and of potassium iodide is said to be followed not infrequently by outbursts of malaria. It is obvious that the influence of these factors is upon la- tent malaria, or the parthenogenetic cycle of the parasite's life history. Insufficient and improper food both lower the resistance to new infections and kindle latent malaria into activity. While the major portion of many older works on malaria was devoted to the role of drinking water in the contagion of malaria, it is now known that it is of minor importance. In regard to the immunity to malaria enjoyed by opium- eaters, Russell'"''' states that the observations of several sur- geons of extensive experience in opium-eating regions confirm th'e popular belief that the opium-eater in the early stages of the habit, while as yet not constitutionally broken by its long continuance, does, as a matter of fact, enjoy considerable im- munity from malarial aft'ections. This writer concludes that this power of opium is partially responsible for its prevalence in some of the eastern countries. Moore*^^ testifies also that opium-smokers are more resistant to malaria. Epidemics. — Malaria, known as an endemic disease, occa- sionally prevails so intensely as to acquire the dignity of an epidemic. Becoming more frequent and fatal in its native haunts, it may spread to regions ordinarily immune, and may even assume the extent of a pandemic. The first pandemic of which we have any knowledge occurred in 1557 to 1558, and is said to have overspread all of Europe. The next appeared from 1678 to 1682, and was nearly as exten- sive as the former. Similar epidemics arose during 1718-1722, 1748-1750, 1770-1772, and 1779-1783. During the past century an epidemic occurred from 1806 to 181 2, and one from 1823 to 1827 is said by Hirsch to have been one of the most extensive, severe, and persistent of pandemics, of which reports were received from almost all parts of the world. Between 42 ENDEMIC DISEASES OF THE SOUTHERN STATES 1845 ^^'^ 1849, 3-iid 1855 and i860 malaria assumed epidemic form, and the great pandemic of 1866 to 1872 marked the inva- sion of Mauritius and Reunion, where malaria was previously unknown. What may be called house epidemics or domestic epidemics are common in the experience of many observers. It is well known that the residents of certain houses suffer much from malaria, and that certain houses are seldom free from the disease during the malarial season. For this local condi- tions are responsible. I have more than once seen as many as half a dozen cases in one family at the same time, and in many famihes every mem- ber is successively attacked during the season. Modes of Infection. — The only known modes of transmission of malaria necessary to consider are: (i) congenital; (2) arti- ficial inoculation; and (3) inoculation through the bites of cer- tain species of mosquitoes. Congenital Malaria. — It was formerly beheved that ma- laria was not infrequently transferred from mother to fetus. Ducheck^- pubUshed a case in 1858 of a child whose mother suffered from malarial paroxysms during pregnancy. The child djang three hours after birth, at autopsy the Hver and spleen were found to be enlarged, and the spleen and blood of the portal vein contained considerable pigment. Two cases are reported by Felkin.*^" In the first case the diagnosis was based upon intrauterine quivering of the fetus, enlarged spleen at birth, and fever later, the date of which is not recorded. In the second case the mother had never had malaria, having never been outside Edinburgh, but the infection is attributed to the father, who had contracted malaria in Africa several years previously and, as Felkin beHeves, had trans- mitted the disease to no less than three infants. Watson''^^ cites the case of a woman who was suffering with tertian ague. On alternate days when she missed the paroxysms she could feel the child shiver with chills. Bark was prescribed and the paroxysms of the fetus were first interrupted, then those of the mother. However, of numerous cases recorded by a score or more of MALARIA 43 early writers, all are open to two objections: First, the diagno- sis was not certainly estabKshed; secondly, postnatal infection was not excluded. Marchiafava and Bignami^^ mention four cases in which the blood of the fetuses of malarial mothers was entirely negative. Thayer"*^^ records a case of a negress who had had malaria at least five months and whose blood contained three groups of the quartan parasites when she gave birth, during a paroxysm, to a child whose blood, upon repeated examination, was found free from parasites and pigments. While both parasites and pigment were found upon the maternal side of the placenta, none were found upon the fetal side. Sereni,-' who examined the blood of four infants born of malarial mothers, was unable to find evidences of malaria in any case. Ziemann,^^ likewise, in four cases of new-born children of malarial infected mothers, had uniformly negative results. I have upon several occasions obtained blood from infants, immediately after birth, whose mothers harbored malarial parasites, and in no case have parasites been detected. Similar results have been obtained by Bastianelli,'^ Caccini,^^ Borne, ''^ Schoo," F. Plehn,-' Terburgh,^^ A. Plehn,^^ Wellman,!!^ and others. Pezopoulos and Cardamatis,''^* based the following conclu- sions upon six cases, five full-termed labors and one abortion, which they studied. 1. In the blood of the six mothers there were parasites, more or less abundant. 2. In the blood of the new-born and of the aborted fetus, examined a few hours after expulsion, there were no parasites. 3- In the blood of the liver and spleen, as well as in sections of these organs of the two fetuses which were examined post- mortem, no parasites were found. 4. In the blood taken from the maternal surface of the placentce of the five new-born children there were parasites in abundance, while in the blood taken from the fetal surface there were no parasites, or at most a very few. 44 ENDEMIC DISEASES OF THE SOUTHERN STATES 5. In blood taken from the umbilical cord no parasites were found. 6. In the blood of the placenta of the aborted fetus no para- sites could be detected. Bein and Kohlstock-^ are said to have found malarial para- sites in the blood of a four-months-old child born some time after the arrival of the mother in a region free from malaria. Winslow*** records a case which he believes to be congenital, though the parasites were not detected until the child was eleven weeks old. A case of malarial fever in infancy thought to be maternal in origin is reported by Peters.*^" The examination of the blood on the second and third days after birth was negative, though parasites were found on the fifty-first day. Moffatf*^^ observed a case supposed to be congenital malaria, though the parasites were not detected before the seventh week. Bouzian,"'^ in Algeria, detected parasites in the blood of an infant only twelve days old. Hitte^'^ collected from the literature twenty-one cases of malaria considered congenital. In thirteen of these the blood was not examined ; in one parasites were detected four months after birth, and in five parasites were found from several weeks to two months after birth. The remaining two cases were ob- served by Hitte personally, who claims to have found parasites in the blood obtained from the umbilical cords. The mothers of both children were suffering with malaria. Parasites were found by Simms and Warwick*^" in the blood of three babies between three and seven days old; the mothers had previously had malarial paroxysms. Holt^^"* mentions a case in which he states there seems little doubt that the disease was contracted in iitero. The mother had been suffering with tertian intermittent. Eighteen hours after birth the child showed evidences of a malarial paroxysm. The next day malaria organisms were found in the blood. Ecocomous*^^ reports six cases with almost conclusive evi- dence of congenital origin. In each of these cases the blood, examined from eight to forty-eight hours after birth, contained MALARIA 45 malarial parasites. The mothers had, previous to delivery, suffered with malaria. BeP''® mentions a female patient who died of pernicious malaria. The parasite was found in the blood, pericardium, meninges, and spleen, as well as in a seventh-month fetus. As may be inferred, properly proven cases of congenital malaria are rare. This reluctance of the parasites to pass through the placenta is in keeping with their aversion to leave the blood-vessels. It has been pointed out that no parasites are found in the hemorrhages and perivascular exudates in cases of pernicious malaria, though they may exist in hordes within the vessels. Congenital malaria is probably to be explained in the majority of cases through placental lesions permitting direct mingling of maternal and fetal blood during parturition. Inoculation. — Even before the parasite of malaria was dis- covered Gerhardf^^ succeeded, employing the blood of malarial subjects, in inoculating healthy persons with malaria. Since then many similar experiments have been performed. Tertian malaria has been transmitted by inoculation by Bein, Bacelli, and Celli and Santori; estivo-autumnal by Gualdi and Antolisei, Di Mattei, Celli and Santori, Bastianelli and Bignami, and Elting. The injection of blood containing only crescents gave nega- tive results in the experiments of Thayer, Bastianelli, Bignami, and Elting. Di Mattei and Calandruccio, however, observed an irregular form of fever to follow such an injection. This can be explained only by parthenogenesis. The injection of blood containing certain species of parasites is followed by fever characteristic of that species, and these parasites are to be found in the blood of the person inoculated. There are those who cannot be successfully inoculated with one species of parasite but can with another. It has been shown also that one species of parasite often disappears from the blood upon inoculation with a different species. The degree of development of the parasites apparently has no effect upon the result, since the disease develops as readily after the injection of blood containing adult organisms as after that containing young parasites. It is immaterial also whether the 46 ENDEMIC DISEASES OF THE SOUTHERN STATES blood be injected intravenously or subcutaneously. A very small amount of blood, even less than one drop, is often suffi- cient for inoculation. The injection of defibrinated blood, of centrifugalized cor- puscles, and of blood diluted with an equal quantity of distilled water and inoculated immediately have given positive results. The injection of dissolved dried blood, and blood diluted with an equal quantity of distilled water and allowed to stand an hour, have proven negative. Jeffries"'^'' reports the case of a New York surgeon who had never had malaria, supposed to have contracted the disease by pricking his finger several times during an operation upon a woman infected with malaria. .Sixteen days after the operation the surgeon had the first chill and had several subsequently. The blood contained many estivo-autumnal parasites. Efforts to inoculate the lower animals with human malaria have been fruitless. Such attempts have been made upon horses, mules, dogs, monkeys, rabbits, mice, guinea-pigs, hedgehogs, bats, wolves, cats, pigeons, doves, magpies, screech- owls, turtles, frogs, and lizards. DISSEMINATION OF MALARIA. BY MOSQUITOES The discovery by Ross of the role of the mosquito in the dissemination of malaria is the most startling achievement of modern medical science. Mosquitoes do not cause malaria; they carry it from infected to healthy persons. The parasites, sucked with blood from a malarial individual, undergo a cycle of development within the body of the mosquito, and are then inoculated into healthy persons. Man is merely the intermediate host of the parasite, the mosquito is the definitive host, and it has been said that man gives malaria to the mosquito, and not the mosquito to man. Not all species of mosquitoes can serve as hosts for the ma- laria parasite. It is only certain members of the subfamily Ano- phelinas that have been found to act in this capacity. Of this subfamily the following have been determined, with more or less certainty, to be malaria carriers: 47 Anopheles annulipes. Anopheles bifurcatus. Anopheles cohaesa. Anopheles crucians. Anopheles farauti. Anopheles formosaensis . Anopheles maculipennis. Anopheles martini. Anopheles pscudopunclipennis. Anopheles pursali. A nopheles quadrimaculalus. Anopheles larsimaculala. Anopheles vincenli. Cellia albimaniis. Cellia argyrotarsus. Cellia pharoensis. Cycloleppleron grabhamii. Myzomyia Christopher si. Myzomia culicifacies. Myzomyia ftmesta. Myzomyia Hispaniola. Myzomyia Ludlowii. Myzomyia Lutzii. Myzomyia picla. Myzomyia Rosii. Myzomyia Turhhudi. Myzorhynckus harbiroslris. Myzorhynchiis Coustani. Myzorhynchus fuliginosus. Myzorhynchiis paliidis. Myzorhynchus sinensis. Myzorhynchus iimbrosus. Myzorhynchiis Ziemanni. Nyssorhynchus annulipes. Nyssorhynchus Jamesii. Nyssorhynchus maculalus. Nyssorhynchus maculipalpis. Nyssorhynchus Stephensii. Nyssorhynchus Theobaldi. Nyssorhynchus Willmori. Pyretophorus Chaudoyei. Pyretophorus costalis. Pyretophorus jeyporensis. Pyretophorus superpiclus. Not all of these mosquitoes serve equally well as hosts of the malaria parasites. Myzomyia Rosii is a very poor carrier of malaria, while the Christophersi is a very efficient carrier. As yet very little is known of the relation between the species of mosquitoes and species of malarial parasites. Pyre- tophorus costalis is known to transmit tertian, quartan, and estivo-autumnal malaria, while Myzorhynchus sinesis carries tertian and quartan, but not estivo-autumnal malaria. It is possible that some mosquitoes acquire a sort of immunity to malaria which may account for their incompetence as malaria disseminators. There are certain regions where, in spite of members of a malaria-bearing species of mosquito and the immi- gration of infected persons, malaria does not spread, though temperature and other conditions are apparently favorable. The food of mosquitoes has much to do with their suscepti- bility to infection. Experiments have shown that Anopheles maculipennis fed upon fruits and sweets are not readily infected from feeding upon malarial blood, but if allowed only water for several days before and after feeding on malarial blood they are almost always infected. 40 ENDEMIC DISEASES OF THE SOUTHERN STATES One feeding upon blood containing parasites does not always sufSce to infect the mosquito. Daniels,^^* investigating this subject, examined 57 mosquitoes which had fed once or oftener at intervals of two days. Per cent. Nineteen fed only once, and five had zygotes 26.0 Thirteen fed twice, and six had z3'gotes 46 . o Sixteen fed three times, and ten had zygotes 62.0 Nine fed four times, and six had zygotes 66 . 6 Of these 57 anopheles 27, or 47.5 per cent., were infected. The effect of fertilization upon the power of mosquitoes to transmit malaria is not definitely settled, but it is thought by some that fertilized females are the most desirable, if not indeed the sole, hosts of the parasite. In order that anopheline mosquitoes may be infected from malarial blood it is necessary that the sexual forms of the para- site be present in sufhcient numbers, of proper maturity, and suitable proportion of sexes. How is the existence of the malaria parasite perpetuated? Why does not the disease become extinct over winter when there are apparently no mosquitoes to further the life history of the organism ? The subject of latent or chronic malaria furnishes the solu- tion. The parasites here lie dormant or undergo parthenogene- sis at longer or shorter intervals, and are ready the following season for the sexual cycle in the body of the definitive host, the mosquito. It is possible that in a few instances the parasites persist in the bodies of hibernating mosquitoes. While some investi- gations have led to a different conclusion, Martirano has found in the neighborhood of Rome as late as the middle of March that from i to 5 per cent, of anophehnes were infected, and Stephens and Christophers observed at Freetown, during the dry season, that from 5 to 20 per cent, were infected.*^ From analogy with the transference of Texas fever hematozoa by the tick to its progeny, it has been sought to establish such an inheritance of malaria parasites by mosquitoes, but it must be considered as yet unproven that infected mosquitoes can communicate the infection to their offspring. MALARIA 49 The relation of the mosquito to malaria explains the preva- lence of the latter with reference to season, temperature, and rainfall. It explains malaria as a disease chiefly of low altitudes and marshy regions; a disease of the country rather than of the city. House epidemics of malaria are thus rendered clear and the relation of ship malaria and proximity to the shore become obvious. The bearing of age, sex, and occupation upon the endemic is in thorough harmony with the theory. That malaria is more easily contracted at night is understood from the feed- ing habits of the malarial mosquitoes. That all measures di- rected toward the prevention of mosquito bites are followed by a commensurate reduction of the prevalence of malaria is one of the strongest arguments. The analogy with filiariasis, Texas fever, hematozoan infection of birds, and similar diseases strengthens the theory. Numerous and accurate experiments have absolutely proven the dissemination of malaria by certain mosquitoes. The sexual cycle of the parasite within the mosquito has been followed many times. An objection that has been frequently urged against the "mosquito theory" is that there are numerous locahties in which mosquitoes abound and from which malaria is entirely absent; indeed, mosquitoes are said to be well nigh intolerable in portions of the arctic regions. It must be remembered, however, that only a certain subfamily of mosquitoes can serve as hosts for the parasite. Furthermore, the surrounding temperature must be suitable for the sexual development of the parasite within the definitive host. It was formerly maintained that there were highly malarial regions in which there were no mosquitoes, and a number of such places have been reported. But in each case where investi- gated by a competent observer anopheline mosquitoes are such that they may be easily overlooked except by an expert. Re- tiring to dark recesses during the day, biting only at night, and not singing a great deal, their presence may not be felt, espe- cially by persons in whom the bites do not cause much irritation. It may therefore be stated confidently that there is no endemic malaria without mosquitoes. 4 50 ENDEMIC DISEASES OF THE SOUTHERN STATES The misproportion between the number of infected anophe- lines and the number of cases of malaria has been cited to over- throw the mosquito doctrine. In Algiers Sergenf"^ found 4 per cent, of the anopheles and 100 per cent, of the children infected. A. Plehn*^ found in one of the most malarial localities, Cam- eroon, among 860 anopheles, only 2.2 per cent, infected. Stephens and Christophers*'^ believe that about 5 per cent, of all the anopheles of tropic Africa are infected. At Aro they found the sporozoit rate in anopheles caught in native huts to be 50 per cent. It should be borne in mind that one infected anopheline mosquito is capable of infecting a number of persons. Also the sporozoit rate varies according to season and according to the kind of mosquito, since it has been shown that some species are better malaria carriers than others. Finally, it has been maintained that persons who have never had malaria have contracted it in uninhabited wildernesses, where, obviously, only uninfected anophehnes would be found, since man is the only intermediate host of the parasite. To this may be answered that no such instance has been so accurately reported as to prove conclusively that infection has ever occurred under these circumstances. THE MALARIA-BEARING MOSQUITOES The genus Anopheles was estabHshed in 1818 by Johann Meigen. The bestowal of the name appears prescient, since anopheles signifies troublesome or hurtful. Of the fifty or more species and subspecies of anophelines now known eight occur in the United States: A. maculipennis, A . punctipennis, A . crucians, A . franciscanus, A . pseudopuncti- pennis, A . barberi, C. argyrotarsus, and C. albipes. Breeding Places. — The different species of anophelines vary a great deal in the choice of a breeding place. Furthermore, with each species there may be said to be places of choice and places of necessity. Contrary to the usual custom of culex, the anopheles usually selects water more or less pure in which to deposit her ova. MALARIA 51 Ground-water appearing at the surface is especially suitable. Pools of at least some degree of permanence are preferred to those which might dry before the aquatic stage of the insect is completed. Natural accumulations of water more often con- tain anopheles larvae than do artificial collections. Pools, ponds, swamps, inlets of lakes, and of small, slowly flowing streams, ditches along roadsides, canals, borrow pits along railroads and levees, and rice fields are common breeding places. Water contained in the tracks of animals may harbor larvce. When water is scarce, as during the dry season, anopheline larvae may be found in tubs, barrels, buckets, bottles, cisterns, mollusc and cocoanut shells, in water retained by the leaves and stalks of tropic plants, or even within vases in dwellings, though these locations are to be regarded as places of necessity and not of choice. In regard to salt water as a medium for anopheline larvae many opinions are held. It seems that the species indigenous to the United States do not breed in salt water, and this was the experience of Celli and other Italian investigators. However, Centanni and Orta^*" found anopheles larvae in water containing 8.77 per 1,000 of sodium chloride. Ficalbi and others'*^" found them in water containing 40 to 50 grams of sodium chloride per liter. In Algiers and the Dutch Indies anophelines are found breeding in concentrated sea-water, and Banks"^ found M. Ludlowii breeding in sea-water in the Philippines. Bancroft in Queensland found a species of anopheles breeding in sea-water, and at Accra, on the west coast of Africa, Stephens and Chris- tophers''^^ obtained numerous anopheline larvae from water containing 6 per cent, of salt. De VogeP^^ at Semarang found certain kinds of anopheles breeding not only in sea-water, but in that which had been condensed to half its volume. Ova of Anophelines. — These mosquitoes do not deposit their eggs in a raft-hke mass, as do the culex. They are laid in irregu- lar piles, but soon become scattered, he horizontally, and may form attractive patterns upon the surface of the water. In captivity the eggs may be laid upon some floating object. The ova are from 0.7 to i.omm. in length by about 0.16 mm. in breadth. They are fusiform in shape and somewhat broader 52 ENDEMIC DISEASES OF THE SOUTHERN STATES at one end than at the other. The lower surface is convex, the upper nearly flat. From the middle third of each side protrudes a transversely corrugated membrane which acts as a float, some- -A raft of culex ova. what after the manner of the air chambers of a lifeboat. Around the margin of the upper surface of the ovum is a frill, usually transversely corrugated. When first laid the eggs are whitish, Fig. 2. — Patterns assumed by anooheles ova. Fig. 3. — Anopheles ova. but soon become almost black. The head of the larva lies in the broad end of the egg and escapes by loosening a circular cap from this end. It is said that if an ovum is partially removed from the water the broad end always hangs downward in order Fig. 4. — A young anopheles larva. Magnified. that the larvae may be born into the water instead of into the air. , The duration of the egg stage varies with the temperature, but is generally from two to four days. Stephens and Christophers^-" did not succeed in hatching the 56 Fig. 5. — Half-giown anopheles larva, ilagnified. Fig. 6. — Full-grown anopheles laiva. Fig. 7. — Anopheles pupa. Magnified. 54 ENDEMIC DISEASES OF THE SOUTHERN STATES ova after desiccation for two or three days, but Grassi''*" is said to have hatched them after keeping them dry for twelve days. The Larva. — The head of the anopheles larva is more or less globular; the eyes are situated laterally at the broadest part of the head. The antennas are rod-shaped and unjointed; at the end are two leaflets, between which arises a branched hair. The mouth parts consist of the feeding brushes or whorl-organs, -■^^^ate; Fig. 8. — Head of anopheles. Magnified. the maxillary palps, the mandibles, the under lip, and the clypeus. The neck is very narrow in the full-grown larva. In the young larva the thorax is little, if any, wider than the head, but in older specimens it is much wider. There are nine post- thoracic segments. The first three seg- ments bear branched lateral hairs. The third to the seventh segments have upon the dorsum a pair of fan-shaped structures, known as the palmate hairs. The eighth segment contains the two openings of the respira- tory system, which ends abruptly at the dorsum of this segment MALARIA 55 without the prolonged breathing tube of the other subfamihes. The ninth or caudal segment bears four flaps containing re- spiratory branchiae. This segment is armed with two large tufts of hair Fig. g. — Tail of anopheles larva. Magnified. The color of the larva varies greatly, according to food and environment, and may be grayish, green, almost black, reddish, or mottled with black or white. The full-grown larva is about 8 mm. in length. Anophehne larvae are omnivorous. Their diet consists of the spores of alga, diatoms, animalcules, bacilli, other larvae, moulted skins, mosquitoes, and other small insects. In captivity they eat dry rice greedily. The customary location of these larvae is at the surface of the water near the edge of the pool where they may remain almost mo- tionless for long periods. The characteristic position is par- allel with the surface of the water and so close to it that a portion of the dorsum appears to rise above the surface, which. Fig. lo. — A pal- mate hair. 56 ENDEMIC DISEASES OF THE SOUTHERN STATES however, is not the case. When feeding, the constant motion of the mouth parts creates a flow of water toward the mouth, bringing in small particles of food. The head is often rotated suddenly, so that it turns through an arc of i8o degrees the lower II. — Adult culex larva. surface looking uppermost. On taking hold of something too large to swallow the larva will often shake the head vigorously and may bend the body to steady the particles against the last segments of the body. In captivity they often rest with the tail against the sides of the container and the head toward the center, when numerous forming a fringe around the circumference. Locomotion is very jerky and irregular. When disturbed they Fig. 12. — Resting positions of laivae: c, Culex; b, anopheles. not infrequently feign death. From the behavior of the ano- pheline larvae it does not appear that the sense of sight is very acute. Culex larvae have been thawed out of ice in which they were imbedded and have proceeded to develop into insects, but MALARIA 57 SO far as I am aware this has not been done with anopheles. The latter have, however, been found in water under a frozen Fig. 13. — Male ano|ihfles. Fig. 14. — Female anopheles. surface. They may exist for a few hours to a few days upon moist mud. The duration of the larval stage varies according to tem- 50 ENDEMIC DISEASES OF THE SOUTHERN STATES perature, food, and possibly other conditions. The limits may be placed at from ten to twenty-six days. In warm climates when suitable food is abundant the duration is ordinarily twelve or fourteen days. In cooler climates and seasons the duration is longer. Anopheles and culex larvae may be differentiated by the fol- lowing gross characteristics: Anopheles Culex Habitually at the surface of the water. At the surface to breathe only. Position parallel with the surface. Jiangs at an angle of 50 to 60 degrees to the surface. No respiratory tube. Large respiratory tube. In full-grown larvfe the head is smaller Relatively larger head, than the thorax. The Pupa. — While the larva bears some resemblance to the imago, the pupa resembles neither. It has been compared in shape to a hypertrophied comma. The anopheles resembles culex more closely in this stage than in any other. The head and thorax are enclosed together in a semitransparent shell, through which portions of the mouth parts, wings, and legs may be detected. Respiration is no longer transacted through the eighth abdominal segment, as in the larva, but through the trumpet-shaped spiracles or syphons of the thorax. This ne- cessitates a change in position, the abdomen hanging or rather curved around the cephalo-thoracic segment. The eighth abdominal segment bears a pair of broad paddles for locomotion. The young pupa is rather light in color, but rapidly becomes darker. The pupce are more easily alarmed than the larvae, and when disturbed dart wildly ■j^ downward with rapid jerks. Being of p; J Breathing lower specific gravity than the water, they syphons of (a) anoph- rise quickly without effort. They do not ales and (6) culex pupae. eat. Italian investigators'*^" observed that the nymphae of some mosquitoes resisted freezing and desiccation to a remarkable degree. Enclosed for several hours in ice they were yet able to develop, and kept in dry soil for two or three days they de- veloped when placed in water. MALARIA 59 The duration of the pupal stage is ordinarily from two to five days. The following points may serve to distinguish anopheles and culex pupse: Anopheles Culex Position in water more horizontal. Position more vertical. Syphons short, square truncated ends, Syphons long and narrow, slit-like attached to middle of thorax. opening, attached to posterior part of thorax. Longer anteroposteriorly, narrower Shorter and broader, laterally. a- lb Fig. i6. — Heads of {a) cule.x and {h) anopheles females. When approaching the emergence of the imago the pupa ■ becomes motionless at the surface of the water; the abdomen is extended parallel with the surface; minute air bubbles are seen under the membrane, which then splits along the dorsal line of the thorax. The imago emerges head first, then the thorax and wings, then the legs. At this stage the insect is very liable to be drowned by a breeze or by a ripple in the water. The Imago. — Anopheles is distinguished from the culex especially by the palpi, which in the former are in both sexes almost as long as the proboscis, in the latter the palpi of the female being very short. Anopheles is more slender, the head is smaller, and the legs more delicate. The palpi of the female, being thickly scaled and lying close to the proboscis, give the impression of a thick beak, which contrasts strongly with the short palpi and slender proboscis of the culex. The wings of the anopheles are speckled, which is not the case with any of the common species of culex. The sitting of anopheles is characteristic. The body of 6o ENDEMIC DISEASES OF THE SOUTHERN STATES the insect is at an angle with the surface upon which it rests, the proboscis pointing toward the surface, sometimes even touching it. This angle varies in different anopheline species, in some being almost a right angle, when the insect appears almost Kke standing upon its head. The proboscis, head, thorax and abdomen are in the same Kne. The mosquito at rest has been compared to a brad-awl stuck into the wall. It often rests upon the first two pairs of legs, waving the last pair in the air. Culex at rest is angular and humpbacked. Stegomyia may be recognized by its smooth, velvety coat of jet black and a- \f Fig. 17. — Resting positions of (a) anopheles and (J) cule.x. silvery white, the banded legs and abdomen, and the lyre- shaped ornamentation of the thorax. The principal malaria carriers of the United States are thus described by Giles:''*"' Anopheles Macixlipemiis (Meigen). — "Wings with four tufted spots on the wing-field, the costa being uniformly dark except at the apex, where its color fades to form a fairly distinct spot; tarsi unhanded, but with an apical yellowish spot I0 the first joints. Thorax with four broad ferruginous stripes formed of golden hairs, between which the darker ground color is left bare, with a tuft of large golden scales on the anterior border. Abdominal segments brown with yellowish basal markings; anterior femora not thickened at the base. "Female. — Head with two patches of creamy scales divided by a central Kne, the rest of the head with black scales, a small tuft of white hairs in front; borders of the eyes white; eyes deep purplish black; antennee dark brown with pale bands and with ferruginous basal joint, pale pubescence, and brown hairs; proboscis brown; palpi yellowish brown with dense, dark scales at the base, which is swollen, shorter than the proboscis. Legs MALARIA 6 1 with pale coxae; femora and tibiae yellowish brown below, cov- ered with dark brown scales above; knee spot yellow, apex of the tibise paler; tarsi slightly darker than the rest of the leg. "Male. — Antennas banded, plume hairs brown, last joint darker; proboscis black to dark brown; palpi dark brown; the last two joints, which are clubbed, have a number of short golden hairs internally and are yellow in color, clothed with thick black scales, through which the yellow underground shows; the last joint is truncated. Length 4 to 7.5 mm., male, to 8 or 10 mm., female. This species varies greatly in size, the wings shown me in Italy by Professor Grassi being quite small, while some Canadian specimens in the British Museum are huge gnats, and to illustrate this I have superposed on the plate the drawing of one of Grassi's specimens on the outline of a Canadian specimen." Anopheles Crucians (Wied). — " Wings with white spots here and there on the brown veins, uniform along the costa; tarsi unhanded, dusky brown; abdomen uniformly brown with gray hairs. Thorax red brown with linear markings." Description from Wied, A. Z. I., page 12: "Tawney; the thorax with three deeper- tinted lines ; the abdomen covered with gray hairs; the wings with dusky spots and costa. Length sj^^ lines (German)." "Coquillett, in his recent synoptic table of North American Culicidae, states that 'the scales of the last veins are white, marked with three black spots; palpi with white at the bases of the last four joints,' and without any spot on the costa, as seen in A. punctipennis. "Professor Nuttall sent Mr. Theobald two females from America in spirit, which, although much damaged, show the two features mentioned by Coquillett very clearly, readily distinguishing the species from the C. punctipennis of Say." The hatching of the first brood of anophehnes bears an intimate relation to the seasonal occurrences of malaria. The seasonal variations of different species are probably dependent upon the presence or absence of breeding pools suitable to par- ticular species. Temperature also exerts an influence, the hibernating females of some species leaving winter quarters 62 ENDEMIC DISEASES OF THE SOUTHERN STATES earlier than others, and hibernating larvae mature at different temperatures. While the anophelines are mosquitoes of low altitudes, they may be found at considerable elevations. Thus in the Alps they are found at an altitude of 1,145 meters; in the Apennines at 1,283 nieters; in Java at 1,000 meters; at Harrar at 2,000 meters; in Africa at 1,900 meters, and in the high plateaus of Mexico at 2,000 meters. ^^^ It is the rule among mosquitoes that only the females are blood suckers, hence it is this sex alone that is concerned in the Fig. 18. — .\ female mosquito in tlie act of biting. propagation of malaria. The female insect sucks not only the blood of man, but of other mammals, birds, occasionally of cold- blooded animals, and even other insects. There are a few exceptions to the rule that males do not bite. While males do not infrequently Hght upon the skin and probe around with the proboscis, they usually fly away without par- taking of any blood. The habitual diet of male mosquitoes is vegetarian. They are very fond of fruits, as bananas, dates, pears, apples, melons, and of the nectar of flowers, wine and beer. Anopheline mosquitoes rarely suck blood except during the night. After feeding they usually retire to remote and dark corners or to breeding places to oviposit. During the day their reserved habits make them difficult of detection. A point of great practical interest is the length of ilight of the mosquito and the extent to which it may be borne by the wind. It is a general rule that mosquitoes do not migrate far from their native pools or from dwellings where nourishment may be obtained. It is very unusual for anophelines to fly farther than a few MALARIA 63 hundred yards, and half a mile may be regarded as the maximum limit of flight. They are poorer flyers than most other species. For this reason they are less often borne by the wind, since they seek shelter when a breeze arises. While the wind is not so generally a vehicle for the dissemination of mosquitoes as com- monly beheved, certain species, especially of salt-water breeders, are borne by the wind for several miles. The preference of anophelines for certain colors has been Fig. ig. — Midgut and Malpighian tubules of anopheles. demonstrated by GalH-Valerio and De Jongh^*" who counted 119 anopheHnes resting upon dark colors and ^^ upon bright colors, and 349 culex upon dark colors and 120 upon bright. Mosquitoes are fond of the odor of leather and are usually plentiful upon harness hanging in stables. They are said to prefer the odor of the negro to that of the white man. Anophelines, hke other malefactors, prefer darkness rather than light, and seek the sequestered nooks during the day. A meal of blood is a prerequisite to fertilization. Females confined with males, then isolated and fed, do not deposit fer- tile eggs, but must be fed first. A single fertilization is sufficient for several batches of eggs. These are usually deposited be- tween dusk and dawn. Still water is necessary, since the female may be drowned if the surface is agitated. The female sits upon 64 ENDEMIC DISEASES OF THE SOUTHERN STATES the water or upon the edge of floating leaves or debris. The ova of anopheHnes are deposited upon the water in clumps, but soon separate and He horizontally. A batch of ova usually numbers from 100 to 150. Pressat**^ has calculated, on a basis of 150 ova for each female, hatching 50 per cent, females, that a single female in one season produces about 5,000,000,000 mosquitoes. It is impossible to determine the length of life of mosquitoes in nature, though even in captivity they have been kept for weeks. AnopheHnes have been kept alive five days without food or water, and for about two months fed upon bananas. The males are not so long lived as the females. Stephens and Christophers^-" say there is evidence that the ova can survive for some months in moist earth and exposed to frost. Eysell*^'' and GalH-VaJerio and De Jongh"**" state that the ova of most species of mosquitoes of the northern temperate and frigid zones may hibernate. Mosquitoes hibernate in the larval stage also. STnith^*" found, in New Jersey, larvae of culex pungens in ice contained in pitcher plants, and beHeves that larval hibernation must be extremely common. MitchelP^^ found anopheles larvae in tanks and barrels in the Botanical Gardens of Washington, D. C, during winter, and Woldert"'^^ found these larvae in December at Tyler, Texas. Mitchell^^^ beHeves it probable that mosquitoes do not hiber- nate in the pupal stage, though GalH-Valerio and De Jongh'**" maintain the opposite opinion. It is chiefly in the winged stage that mosquitoes hibernate. In the late fall the males die, the fecundated females seeking shelter in dwellings, cellars, stables, barns, cisterns, hollow trees, or under bridges. THE PARASITES OF MALARU Zoological Relations. — The parasites of malaria belong to the animal kingdom, to the division of protozoa, to the class of sporozoa, and to the order of hemosporidia. The hemocytozoa are not peculiar to man, but are found in other classes of verte- brates, and are distributed by Manson-^ into three genera, as follows: MALARIA 65 HEMOCYTOZOA I. Genus IL-EMAMCEBA Names Hosts H. subtertiana. The malaria parasites of man, the H. quartan. sexual phase being evolved in mosqui- H. tertian. toes of the genus Anopheles. H. relicta (Proteosoma). Birds: sexual phase in mosquitoes of the genus Culex. H. Danielewski (Halteridium). Birds. H. Kochi. Several species of monkeys. H. melaniphera. Bat (Miniopterus Shredeibersii). H. Metchnikovi. Trionyx indicus. 2. Genus Piroplasma P. bigeminum. Bovines: transmitted by the cattle tick (Boophilus bovis). P. canis. Dogs. P. ovis. Sheep. P. equi. Horse. P. hominis. Man. 3. Genus PLemogregarina H. ranarum (Drepanidium). Frog (Rana esculenta). H. splendens. Frog (Rana esculenta). H. Magna. Frog (Rana esculenta). H. lacertarum. Lizard (Lacerta muralis). About twenty additional but less readily procured species. There are three sharply defined species of parasites of malaria, the parasite of tertian malaria, the parasite of quartan malaria, and the parasite of estivo-autumnal malaria. The latter is divided by most observers into three, or at least two, varieties, the tertian and the quotidian, of which latter variety a pig- mented form and an unpigmented form are described. My opinion is that there are two varieties of the estivo-autumnal parasite, the tertian and the quotidian, and that the pigmented and the unpigmented quotidians are merely forms of one variety. Stephens"**^ described a form of the parasite which he behaved was a new species and named it Plasmodium tenue. It was char- acterized by extreme ameboid movement, irregularity of form, abundance and irregularity of chromatin and an absence of pigment. I have recently obtained similar specimens from a case of s 66 ENDEMIC DISEASES OF THE SOUTHERN STATES comatose malaria and believe that this organism is an atypical form of estivo-autumnal parasite. \ ill' \ 11 \ M /^ ^ #^- V Fig. 20. — Diagram illustrating the cycles of the parasite. — . — . — . — . Schizogonic cycle. Sporogonic cycle. Paithenogenetic cycle. Biology. — The life history of the parasites of malaria is some- what complicated, inasmuch as man, the mosquito, and the parasite are involved, and as there are three species of parasites and each species has three biologic cycles. These three cycles are: MALARIA 67 I. The schizogonic, or human cycle, also called the asexual cycle, monogonic cycle, endogenous cycle, cycle of Golgi, or trophic cycle. Fig. 21. — The entrance of the sporozoit into the red cell. 2. The sporogonic or mosquito cycle, also called the sexual cycle, amphigonic cycle, exogenous cycle, or cycle of Ross. 3. The parthenogenetic cycle, or reproduction by unfertil- ized macrogametes ; the cycle of chronic malaria, of latency and relapses, an immaculate conception yielding saviors to the species necessary for its salvation at a time of crisis, a vicarious atonement of macrogametes that the human cycle may be saved. The first cycle is that of active malaria; the last two are des- tined for the perpetuation of the species, and without them the interruption of the schizogonic cycle would result in the ex- termination of the species. The Schizogonic Cycle. — In the act of biting, the mosquito injects into the blood sporozoits, elongated or needle-shaped organisms. The sporozoits have the power of bending, con- traction, and of locomotion, and each immediately penetrates into a red blood-cell. Here it loses its slender form and appears as a mere dot of protoplasm, whose index of refraction varies but little from that of the red blood-cell. The size of the young parasite varies in different species, but is about i or 2 microns in diameter. Ameboid motion is more or less active, pseudo- podia being protruded and retracted, the parasite even changing its position within the cell, and has no constant form. There is usually only one parasite in each infected cell, but there may be several. As the parasite grows it acquires pigment, a few grains at first, gradually increasing in amount with the growth of the parasite. This pigment is from the hemoglobin of the 68 ENDEMIC DISEASES OF THE SOUTHERN STATES infected cell, and occurs in the form of grains, rods, or clumps. The adult parasite occupies a relatively large portion of the cell, and ameboid motion is less active, though the pigment may be in violent motion. The organism is composed of cell proto- plasm, nucleus, and nucleolus, but appears structureless in fresh, unstained blood. Prior to sporulation the pigment becomes concentrated and fused, and fission occurs, dividing the para- site more or less symmetrically into spores, constituting the Fig. 22. — Diagram representing the development of the malarial parasite: a, Young form; b, half-grown parasite; c, sporulating body; d, free spores; e, macrogamete;/, microgametocyte. so-called rosette or marguerite forms, each spore containing a fragment of nucleus. The cell ruptures and the spores, or merozoites, escape into the blood current, where they rapidly enter the blood-cells to repeat the cycle. The corpuscular remnants and the pigment are rapidly taken up by the phag- ocytes. Rowley-Lawson'*^*' has attempted to prove that the malaria parasite is extracellular throughout its life cycle, migrating from cell to cell, destroying each before it is abandoned, and that in the brief intervals between, the parasite is free in the blood serum. These observations have not been confirmed; on the other hand the experiments of Bass and Johns^^" seems to over- throw them. Instead of proceeding to sporulation some of the parasites develop into sexual forms, or gametes, large parasites of round, ovoid, spindle, or crescentic shape. It is these bodies which are taken up by the mosquito, undergo a sexual cycle in its midgut, develop into sporozoits, which are injected into man, MALARIA 69 where they pass through the schizogonic cycle above outlined. The Tertian Parasite {Hcemamceba vivax, H. tertiance, Plasmodium vivax). — The duration of the asexual cycle of the simple tertian parasite is forty-eight hours. The young para- sites are about one-fifth the size of the red blood corpuscles and unpigmented. They are difficult to distinguish from the young parasites of the other species. They are actively ameboid, protruding and retracting short pseudopodia with rapidity; Y-shapes, T-shapes, and crosses are common forms. The index of refraction of the parasites is low, so that their contours are not easily distinguished from the substance of the red blood-cells. As the parasite increases in size pigment gradually appears. The pigment of the tertian parasite is fine, rod-shaped, rather light in color, and in active motion. This motion of the pig- ment has been compared to the bubbling of boiling water and to the swarming of insects. The infected red cell becomes enlarged, swollen and pale. The half-grown parasite fills about half or two-thirds of the red blood corpuscle. At this stage the para- site assumes fantastic and bizarre shapes. The adult parasite is more or less spherical, as large as or larger than a normal red cell, and occupies three-fourths or four-fifths of the swollen infected cell, the margin of which may be difficult to see on account of its pale color. The pigment tends to become more abundant about the periphery. When sporulation is immi- nent the parasite and its pigment become less active or motion- less, the pigment gathers in clumps at the center, and radial striations appear from the periphery toward the center. Usu- ally the sporulating tertian parasite is not so symmetrical as the corresponding stage of the quartan, resembling, rather, a bunch of grapes or a mulberry. Less often there are two concentric rows of spores. The spores are small and vary in number from twelve or fourteen to twenty-six, oftenest sixteen, and more often an even than an uneven number. Sporulation takes place, especially in the circulation of certain viscera, but sporu- lating tertian parasites are much more frequently encountered in the peripheral circulation than in the case of estivo-autumnal infections. The parasites develop with remarkable uniformity, nearly all yo ENDEMIC DISEASES OF THE SOUTHERN STATES appearing to be of the same age. Even in infections with two groups of tertian parasites, which is very common, it is unusual to find a parasite which does not belong to one brood. The early development of the gametes is not well understood. Half-grown gametes are hard to differentiate from schizonts, but small parasites, without ameboid motion, with much pig- ment, and with large nucleus may be twice as large as a red blood corpuscle. Ameboid movement is very slight. The pig- ment is profuse, fine, reddish, or blackish, and actively motile. The vesicular appearing nucleus is commonly situated near the periphery, and is visible in fresh preparations. An interesting phenomenon which occurs in the case of the microgametocytes, or male sexual forms, is exflagellation. This takes place from ten to thirty minutes after the blood has been withdrawn, and is favored by exposing the blood for a few minutes to the air, by the addition of a minute quantity of water, and exposure to moisture, as breathing upon the slide before applying the cover-glass. Before exflagellation the pigment is observed to undergo violent and tumultuous motion, then to collect toward the center. Undulations at the periphery are then noticed, as if something within were trying to escape. Suddenly the flagella break forth from different points of the margin. These are from four to eight in number and in length are two and a half to three times the diameter of the red blood corpuscle. They may show ovoid swellings at the end or in their continuity. Lashing madly to and fro, the red cells are displaced and a fiagellum may be seen to break off from the microgametocyte and dart in a serpentine manner among the cells. The flagella are known as microgametes, and have been shown by McCallum to be spermatozoa. Their function is to fertilize the macrogametes, or female forms, in the midgut of the mosquito. Tertian gametes may be distinguished from adult schizonts by the former being of larger size, less ameboid motion, their pigment appearing earlier, being more abundant and in more active motion. The following may serve to differentiate tertian male and female gametes: DESCRIPTION OF PLATES I AND 11 Various forms of malarial parasites: Figs, i to lo inclusive, tertian parasites; Figs. II to 19 inclusive, quartan parasites; Figs. 20 to 26 inclusive, estivo- autumnal parasites. I. — Normal red blood cell. 2. — Young tertian ring. 3. — Large tertian ring. 4. — Half-grown tertian parasite. 5. — Infected cell showing Schiiffner's dots. 6. — Adult tertian parasite. 7. — Beginning sporulation. 8. — Sporulation com- pleted. 9. — Tertian microgametocyte. 10. — Tertian macrogamete. 11. — Young quartan ring. 12. — Older quartan ring. 13. — Quartan band. 14. — Older quartan band. 15. — Full-grown quartan parasite. 16. — Mature parasite with divided chromatin. 17. — Sporulation completed. 18. — Quartan microgameto- C3'te. 19. — Quartan macrocyte. 20. — Young estivo-autumnal ring. 21. — Large estivo-autumnal ring. 22. — Mature parasite. 23. — Sporulation completed. 24. — Estivo-autumnal microgametocyte. 25. — Estivo-autumnal macrogamete. 26. — Estivo-autumnal ovoid. ■ ., '"#4 PLATE I O mi .AiCdb^^ o Q 16 PLATE 11 »«i^ 13 14 o o 23 21 ■ *3S2 354 12 7 23 14 18 S 8S 3S 286 66 BLACKWATER FEVER 267 Treated without Quinine, 1183 Cases, 123 Deaths, 10.4 Per Cent. Number of Tomaselli"" Navarre' Henric"' Kohlstocki" Koch" Hopkins"^ Bertrand"" OUwig=" Wittrock'^ Ziemann'' A. Plehn^ Kleine'* Krauss'"* McElroy84 Goltman and Krauss''^ Malone'" Costei" Hearsey^" Seal>3» Ruge"2 Dryepondt and Vancampenhouf Howard" Ketchen"! Masterman'* . . Herrick*' Curry'"" Cardamatis'-^ Ensor'*" Brodeni" Pancot"" Theophanidis"* Oeconomou"" McDanieli" F. Plehn^ Cardamatis"^' Woldert^s Alexandropoulos'^' 456 II 25 7 9 31 93 25 IIS Number of deaths 268 ENDEMIC DISEASES OF THE SOUTHERN STATES Treatment Mixed or not Recorded, 3815 Cases, 779 Deaths, 20.4 Per Cent. Number of cases nber of deaths Kanellis"'' Poole' Rothschuh' GuioP Gouzien^'^ Meixner^' Hofft=3 Wendland^' Daniels'' Wellman'n Ipscher""! Kruger" Simon'" Kerr Cross^" Osborn^*' O'Neill^' Burns" Shropshire'^' DempwolS'^'^ Lipari'" Gouducheau'^' • . Cochran'** Kelsch and Kiener'* Bolton" Grail™ Forde"* Grenet'" Rousseau"^ Carmouze"' Mericourt"* Koryllos'" Pampoukis"* Cardamatis"* Parathyris"^ Prout'"' Jacobs'" DeCruz'** DeBlasi'«« Orme'»« Thompstone'" Canal Zone Reports'*' Hearsey '*' Baker'" Langley'*'' Will'** Fagan'** Deaderick'* Skeleton'*" German Protectorate Reports'*' S6 i8s S3 17 27 10 5° 16 177 17 19 IS 642 109 17s 113 158 35 22 6 30 9 22 3 28 5 156 35 30 6 23 3 24 8 147 16 13 6 3 27 S 423 73 14 3 7 2 27 4 lOI 15 538 BLACKWATER FEVER 269 that he treated over loo cases in the Congo State without a death. Pampoukis^^ gives the mortality of blackwater fever as 6.6 per cent.; Crosse^ 20 per cent.; Kanellis* 22.4 per cent.; Berenger-Feraud*- 23.1 per cent.; Barthelemy-Benoit^- 25 per cent.; Bertrand^"" 25 per cent.; Carre^ 27 per cent.; Man- son^^ 25 per cent.; Cassan^' 32.1 per cent.; MicheP^^ ^;i to 50 per cent.; Schellong^ 42 per cent.; Reynolds^ 50 per cent.; Scott^ 60 per cent. The following Hst of 7105 cases, with 1440 deaths, shows a mortality of 20.2 per cent. It is compiled from various sources. The first column of figures shows the number of cases, the second the number of deaths. F. Plehn^ asserts that mortality is highest in first attacks, but the following table of Daniels-^ does not bear him out: Of 136 first attacks 31 or 22. 7 per cent, were fatal. Of 33 second attacks 8 or 24.0 per cent, were fatal. Of IS third or fourth attacks . 2 or 13.3 per cent, were fatal. CHAPTER XV PROPHYLAXIS OF BLACKWATER FEVER A. Plehn has shown that hemoglobinuric fever is preventable to a greater degree even than malaria. In 1897-99 among the officers of Cameroon who used no prophylaxis there oc- curred in 578 months of residence 287 cases of malaria and 31 of blackwater fever, or i malaria case for every 2 months and I of blackwater for each 18.5 months. Ten per cent, of the blackwater cases terminated fatally. During the same period among those who used prophylaxis there were in 446 months of residence 90 cases of malaria and 6 of hemo- globinuric fever, or i case of malaria for each 5 months of residence and i of hemoglobinuric fever for each 74 months, none of which were fatal. Thus, while malaria was reduced by half, the morbidity of blackwater fever was lowered to one-fourth. The lowered mortality of these cases is even still more remarkable; similar results were observed by Moffatt.^'* Even Koch^^ beheves that through appropriate quinine prophylaxis not only malaria but blackwater fever, in an overwhelming majority of instances, can be exterminated. The prophylaxis of hemoglobinuric fever consists of the prophylaxis and proper treatment of malaria. There are two chief methods in vogue for the use of quinine as a pre- ventive of hemoglobinuric fever: Plehn's method, Y2 gram every fifth evening, and Koch's, i gram on two successive days of each week. The results of A. Plehn, recorded above, were obtained with i^-gram prophylaxis, but Ruge*^ maintains that better consequences follow Koch's method, and gives the following figures: According to the 1903 statistics of Cameroon, there were among those who used quinine regularly 12 cases of blackwater fever, of which 8 employed the Plehn method; 3 first Plehn's, then Koch's; and only i Koch's method 270 BLACKWATER FEVER 271 regularly. Of 35 cases among irregular users, 17 employed the i2-gram method and only 3 the i-gram method. From these figures it is evident that Koch's method is preferable even when not systematically employed. It is necessary to persist in prophylaxis not only while in the blackwater fever district, but for several months thereafter. As a majority of the first cases occur from the second to the fourth year of residence, it is evident that greater care should be exerted during this period. CHAPTER XVI TREATMENT OF BLACKWATER FEVER The discussion of the treatment of hemoglobinuric fever has probably been productive of more harsh and prejudiced con- troversies than has any other question in therapeutics. The bone of contention is quinine. It is unnecessary to review the discussions or to rehearse the arguments for or against the etiologic relation of quinine to blackwater fever. No vaHd conclusion can be reached except through results of a large series of cases treated with and without quinine. The collection recorded under Prog- nosis shows a mortality of 25.5 per cent, in cases treated with quinine, and 10.4 per cent, in cases in which no quinine was used. This number of cases probably eliminates all errors and should be convincing. \Vhile the results of the series prove that the mortality is higher under the routine treatment with quinine, they should not be taken to exclude absolutely the use of quinine in some cases of hemoglobinuric fever, for under certain circumstances quinine may be of value. It is difi&cult — in fact, sometimes impossible — to say whether quinine is indicated or contra-indicated in a certain case. Mannaberg*- gives the following general rules to aid in a decision: 1. When, without quinine preceding, hemoglobinuria occurs and the blood examination shows the presence of malarial infection, quinine is undoubtedly to be exhibited. 2. When the hemoglobinuria occurs after one dose of quinine, while the anamnesis shows that the patient previously took quinine without bad effect, and the parasites are present in the blood, quinine is also to be exhibited. If a paroxysm of hemoglobinuria should follow within a few hours, the repeti- tion of the drug should be made dependent upon whether or not the parasites have in great part disappeared. In the for- BLACKWATER FEVER 273 mer case the quinine may be stopped, at least for a time. But if the blood examinations show that the parasites have increased in number the quinine is to be continued. 3. When anamnesis shows that the patient suffered previ- ously from hemoglobinuria following quinine and the blood examination is negative, quinine is to be absolutely avoided. 4. When the case manifests a severe malarial infection (numerous parasites on examination) and at the same time an assured intolerance to quinine in the shape of hemoglobinuria, the decision is very difficult. Marchiafava and Bignami^^ believe that the only guide in- dicating to the physician whether to give or to withhold quinine ought to be the result of a blood examination. Bastianelli's'^^ canon is as follows: 1. If a hemoglobinuria occurs during a malarial paroxysm and the parasites are found in the blood, quinine should be given. 2. If parasites are not found in the blood, quinine should not be given. 3. If quinine has already been given before the hemoglo- binuria has appeared and no parasites are found, its use should be suspended; but if parasites persist it should be continued. Thayer'-^'' states his rules, modified from BastianelH, thus: 1. If the attack occurs spontaneously with a malarial paroxysm, the blood showing the presence of parasites, quinine should be freely administered hypodermically or intravenously. 2. If the parasites have disappeared, either as a result of the paroxysm itself or of doses of quinine already given, it may be as well to abstain, at least for a time, from the adminis- tration of the drug. It cannot ameliorate the further course of the paroxysm, and the possibility, if it has been already given, that the symptoms may be in part due to quinine may be thought of. 3. If an attack arise in the middle of an ordinary malarial infection, after taking quinine, it is best to abstain, for a time, at any rate, from the further use of the drug. That which has been given may have been enough to control the affection. 4. If, however, in an attack coming on after quinine, the 274 ENDEMIC DISEASES OF THE SOUTHERN STATES parasites continue to develop, quinine should be again adminis- tered, despite the slight possibility of its injurious action. The dangers from the further development of the parasites are probably the greater. 5. In post-malarial hemoglobinuria quinine is, of course, useless. The following rules of Vedy^^ are practical: 1. If Uving parasites (not merely evidence of their former existence, pigment) are detected twenty-four hours after the beginning of the attack 80 centigrams of a salt of quinine may be injected subcutaneously. 2. If the parasites are not visible do not administer quinine. 3. If in doubt, that is to say if the microscopic examination of the blood cannot be made, do not give quinine. It may be seen that the authorities quoted lay great stress on the presence of the parasites as a guide to the administration of quinine. I, however, cannot agree with those who hold that quinine should be exhibited in every case where the microscopic examination shows the presence of parasites. It has been shown conclusively that parasites are present in a very large proportion of cases examined early. It has also been shown that in an equally large number of cases the parasites disappear spontaneously. In these cases quinine is, to say the least, superfluous. In my opinion, the only conditions in which quinine is indicated are: first, where the parasites show no tendency to disappear after forty-eight hours from onset; second, in the infrequent cases of intermittent hemoglobinuria where the outbreak corresponds with parasitic sporulation. If it is decided to give quinine, it should be injected, in dilute solution, into the muscles as directed for the treatment of pernicious malaria. Given by the mouth it upsets the stom- ach and may not be absorbed. Even in cases of mildest onset the patient should be con- fined to bed from the start, and should be kept quiet, either by persuasion or by sedatives. Sudden death on slight exer- tion sometimes occurs. The patient should not be trans- ported from one place to another; the Plehn brothers observed BLACKWATER FEVER 275 anuria as a frequent consequence of moving patients from place to place. Chilling of the body, especially when the tem- perature is low, should be carefully avoided. When vomiting is not a prominent feature, liquid nourishment may be given freely; buttermilk and albumen water are the most suitable. Sweet milk is often ejected as a thick curd, molded ropy by the esophagus in the act of vomiting. Animal broths, barley and oatmeal water, lemonade, and orange juice are allowable. Rectal alimentation is unsatisfactory. There is ao specific. Methylene-Uue has proved disappoint- ing. Besides being a renal irritant, it masks the color of the urine, a most serious objection. Salicylic acid probably has no effect further than to upset the stomach and increase the discomfort. With the false idea that a hemorrhage has to be checked, gallic and tannic acids, ergot, and similar drugs are frequently given; these cannot possibly be of any benefit. Carbolic acid and other renal irritants should not be used. The bowels should move early and often, and calomel pos- sesses advantages over other purgatives; it is more easily retained, is a bland diuretic, and is the best of intestinal anti- septics. Two large doses are usually advised; 3 to 5 grains are, as a rule, sufficient, repeated pro re nata. Quennec's^^^ chloroform treatment has been successful in some hands. The originator claims for the method three points of value: 1. Controls vomiting. 2. Increases output of urine. 3. Diminishes albuminuria. He treated more than fifty cases with no mortality. The following is his formula: Chloroform, 6 grams; gum arabic, 8 grams; sweetened water, 250 grams. This amount is used daily, a sip taken every ten minutes. In addition, Quennec used quinine i gram daily subcutaneously, and sulphate of soda and senna by rectum. The excessive administration of chloroform might be harmful, as it is a cardiac depressant, renal irritant, and lowers the blood pressure. Cardamatis^- gives ether in every case of hemoglobinuric fever. In ordinary cases he prescribes a teaspoonful in sweet- 276 ENDEMIC DISEASES OF THE SOUTHERN STATES ened water every three hours, and increases the dose if the urine diminishes in quantity. In cases of suppression he gives as much as a teaspoonful every hour, at the same time injecting hypodermically i c.c. every two or three hours. He maintains that by this means the pulse is strengthened, pre- cordial anxiety, dyspnea, and vomiting are relieved, and a profuse diuresis is provoked. I have had no experience with ether in the treatment of blackwater fever, but would consider it too irritating to the kidneys for general use. Hearsey^^" used with good results a modification of Stern- berg's yellow fever treatment. The original Sternberg formula is: sodium bicarbonate, 150 grains; mercury perchloride J^ grain; water, 2 pints. Sig.: i^^ ounces every hour. Hearsey gives sodium bicarbonate, 10 grains; liquor hydrargyri per- chloride, 30 minims, every two or three hours. A method of treatment recently introduced and extrav- agantly extolled by its originator is that of Vincent.^'* This writer maintains that calcium chloride is not only a pre- ventive, but has extraordinary curative powers. During the attack from 4 to 6 grams are given daily by the mouth, or from I to 2 grams dissolved in normal salt solution hypodermically. He asserts that it acts as an antihemolysin, and that in persons in whom an attack of blackwater fever may be provoked at will, by a dose of quinine, the previous administration of calcium chloride will forestall the outbreak. It is worthy of mention that this drug has been used successfully in parox- ysmal hemoglobinuria by Saundby, and in hemophilia by Wright and others. I have employed calcium in six cases, of which three ended fatally. The series is too small to permit of very definite conclusions as to results of treatment, but it would appear that the results claimed by Vincent were not obtained. The three fatal cases were in persons whose health was probably not more undermined from previous attacks of malaria or other causes than the average patient who is attacked with hemo- globinuric fever. It is worthy of note that the cause of death in these three cases was not syncope nor suppression, but BLACKWATER FEVER 277 exhaustion due directly to hemolysis, the very process which calcium chloride was used to combat. No treatment other than supportive was used which might modify the antihemo- lytic effects of the calcium chloride. Hyposulphite of soda, introduced into the treatment of ma- laria by Polli'^^ in 1867, has been used extensively in the treatment of hemoglobinuria. Its use is probably not attended with any signal results. O'Sullivan-Beare^'^ used with good re- sults a decoction of the root of cassia beareana, a native plant. Gouzien employed an infusion of the leaves of cassia occidentalis. Teas made from the leaves of folia combreti alti and of aphloia theaeformis are also highly recommended.-' The fever does not usually run sufficiently high to call for treatment. The coal-tar preparations should be assiduously avoided. Cold baths may be productive of harm by increasing the blood destruction, but the hyperpyrexial cases sponging with tepid water may be resorted to. Vomiting, if not intense, is often benefited by a mustard plaster on the epigastrium. The fly-blister formerly used should be abandoned. Draughts of hot water or carbonated water sometimes assist in relieving this troublesome symptom. Cracked ice may be tried. Morphine hypodermically should be given unhesitatingly when other measures fail. Any evil effects are more than outweighed by its enabling the stomach to retain liquids. An important measure toward the prevention and relief of nausea and vomiting is to maintain the recumbent position. Medicine, water, and nourishment should be taken through a drinking tube or the ordinary invalid's cup, and the bed pan or urinal should be used when evacuating the bowels or bladder. It is imperative to allay the restlessness often present in these cases. For this purpose chloral and bromide of soda by rectum, morphine hypodermically, or sulphonal or small doses of chloroform by mouth are useful. Probably the most important indication in the treatment is the prevention of suppression. Medicinal diuretics usually do harm. One, turpentine, widely used in some sections, should be. condemned in the strongest terms. It is one of the most 278 ENDEMIC DISEASES OF THE SOUTHERN STATES violent renal irritants, and in some persons small doses may cause suppression or hematuria. Water is the best diuretic, and as much should be given by mouth as can be retained. Lewis, *^ of North Carolina, was the first to recommend the use of normal salt solution by hypodermoclysis and by the rectum in the treatment of hemoglobinuric fever, though Laveran^' attributes the priority to Gouzien. The latter recommends the daily injection of 100 to 300 grams of a ?xo per cent, solution, in conjunction with the rectal injection of 200 grams four to six times in twenty-four hours. The use of salt solution is the very best means of combating and treating anuria. It is probably better to use a hypertonic solution. In mild cases where the urine is free the rectal use is usually sufficient, but in cases where suppression threatens or is im- minent the solution should be given subcutaneously or in- travenously and in larger quantities and oftener than advised by Gouzien. Mild counter-irritation over the region of the kidneys may be tried. Werner^" in 1902, suggested nephrotomy for anuria. Such an operation has been recorded in only three instances. Zie- mann^^ mentions a case in a young female patient in whom suppression had existed two days. The capsule of the right kidney was split and peeled off to the hilum and nephrotomy performed through the convexity of the organ. The operation was well borne, and subsequently 200 c.c. of cloudy, albuminous urine was voided from the bladder. During the following days complete suppression recurred, and the patient died. In Kruger's^^^ case decortication of one kidney was done five days after the onset of anuria, and, although the secretion of urine was profusely reestablished, the patient died of progressive weakness. Kulz^^' reports a case in a man during his second attack. Three and a half days after the onset of anuria nephrotomy upon one kidney was performed through Simon's incision. Vomiting, which was formerly uncontrollable, ceased im- mediately. Three hours after the operation 30 c.c. of blood were voided from the bladder. In eight hours the dressing was saturated with bloody icteric urine, which necessitated changing BLACKWATER FEVER 279 the dressing every three hours. Twenty-four hours after the operation the patient died. Though a microscopic examination of the kidney could not be made, upon gross inspection the nephrotomized kidney appeared much more nearly normal than the other. Supportive measures are essential. Alcohol in all its forms is inadmissible. Strychnine is useful, and should be given hypo- dermically when circumstances permit. Digitalis has proved serviceable in my hands. Doering^^ had good effects from stro- phanthus. The aromatic spirits of ammonia and hypodermic injections of ether have been recommended. Transfusion of blood has been used, it is said, with excellent results. The elder Plehn^" says that he had four attacks, in which Kohlstock treated him with inhalations of oxygen, and that nothing else did him so much good. Unfortunately this method of treat- ment is not often possible in private practice. The after-treatment should have a care for the diet, which should be non-nitrogenous and consist largely of liquids at first. A tonic of organic iron is indicated, and digestive dis- orders when present should receive appropriate treatment. A question of practical importance is, how soon after the attack to begin the administration of quinine. A dose given too early might possibly, in some persons, precipitate hemolysis. On the other hand, delay may permit an outbreak of malaria accompanied by hemoglobinuria. Upon the ground that most of the sensitive cells have succumbed during the attack and that the newly formed cells are probably more susceptible than those that have withstood the attack, I am of the opinion that quinine should be begun, carefully at first, a short time after the attack has subsided and before blood regeneration is fairly established. One grain of quinine three times daily, increased gradually every other day, is a safe procedure. If the temperature rises or the urine becomes distinctly darker no further attempt to increase the dose should be made. In the present state of our knowledge it is probably Utopian to discuss the treatment of hemoglobinuric fever by anti- hemolytic sera, but such has been successfully accomplished by Widal and Rostaine in paroxysmal hemoglobinuria. PELLAGRA CHAPTER XVn INTRODUCTION Pellagra is an endemic disease, the cause of which is at the present time unknown, is usually of slow progress, and charac- terized by more or less seasonal periodicity, and by lesions of the skin, alimentary tract and nervous system, terminating in recovery, cachexia, insanity or death. The list of names by which the disease is known is a long one, the chief of which are Alpine scurvy, dermotagra, Asturian leprosy, Asturian rose, disease of the Landes, Italian leprosy, maidismus, corn bread disease, sun disease, elephantiasis italica, psychoneurosis maidica, mal de rosa, mal del sole, mal de misere, etc. History. — Our history of pellagra begins in Spain. It was first observed in the province of Oviedo by Caspar Casal who in 1735 wrote a treatise in which he described it, which, however, was not printed until 1762. He called the disease mal de rosa. In 1787 Townsend in his description of his travels through Spain refers to his observation of the disease in Oviedo and definitely states that the subjects ate little meat and largely of corn and other vegetable foods. Corn is said to have been introduced into Spain between 1680 and 1700. Oviedo remains to this day a hot bed of the disease. Pellagra was, according to Terzagli, known in Italy even earlier than 1730, isolated cases having been observed in the neighborhood of Sesto Calende. The disease appears to have spread rapidly appearing simultaneously in the districts of Milan, Brescia, Bergono, and Lodi and soon after in the vicinity of Como, Cremona, Mantna and Paira, toward the end of the century extending almost entirely throughout Lombardy. The name Pellagra was given the malady by Prapolli in 1771, and 282 ENDEMIC DISEASES OF THE SOUTHERN STATES probably means "rough skin." As the disease invaded new areas in Italy the number of cases in the earlier foci increased rapidly. In 1 784 a pellagra hospital was established in Legnano under the supervision of the elder Strambio. Marzari in 1810 is said to have been the first to infer an etiologic relationship deitqnxnV. \CCJiCetacartKnaan Fig. 66. — Casal's illustration of the cutaneous lesions in pellagra. between the consumption of maize and pellagra. On account of the early invasion of Italy, of the extensive prevalence of the disease in that country and of the attention paid to the scourge by scientists and by the government, Italy may well be regarded as the home of the disease. PELLAGRA 283 Our first knowledge of pellagra in France originates with Hameau who, in 1829, published his observations of cases since 1818 in the vicinity of Teste-de-Buche and in the plain of Arcachon and in the coast region of the Giroude. For the last quarter of a century there has been little if any pellagra in France. Pellagra was first described in Roumania by Caillat in 1854, who states that the disease was unknown there prior to 1846. In Corpi isolated cases were observed in 1839, but only since 1856 has the malady assumed an endemic character. Nicholas and Hambon reported cases in Austria near Vienna in 1794 and in 1846 an epidemic occurred in Roumania. It is stated that pellagra was observed in Great Britain in i860. In Africa pellagra was first described by Prumer in Egypt in 1847. The disease was practically ignored until 1893 when Sandwith found it to be prevalent in patients he was treating for anchylostomiasis. In the United States the definite history of pellagra goes back to 1864 when a case was reported by Dr. John Gray of Utica, New York, and another by Dr. Tyler of Somersville, Massachusetts. Both patients were insane. Shewell of Brook- lyn reported a case of pellagra in 1883 in an Italian sailor. Bemis of New Orleans, in 1889, left a written diagnosis of a case in a white female in the Charity Hospital. Babcock-^" has adduced very strong evidence in favor of the existence of pellagra in the South Carolina State Hospital from its opening in 1828. A case history which he reproduces in full from the records of the institution is certainly very con- vincing. This case was admitted in 1834. It is believed that the terrific mortality among the prisoners in the Confederate prison at Andersonville, Georgia, was due in part to pellagra. The medical records of the Civil War, however, do not conclusively support this theory. Harris,-*' Atlanta, in 1902, reported a case of ankylostomiasis in an individual presenting all the typical symptoms of pellagra. The patient was a native of Georgia and had always resided there. It is worth noting that both Sandwith and Harris discovered the disease in the investigation of uncinariasis. 284 ENDEMIC DISEASES OF THE SOUTHERN STATES The report of Harris does not seem to have excited any terest and it was not until 1907 that the disease was next ported, this time by Searcy^*- as an epidemic at the asylum in Mt. Vernon, Alabama. Reports of cases then followed PELLAGRA 285 rapidly. MerrilP^' reported a case in Texas in i907;Babcock and Watson^^^ in South Carolina in 1908; Bellamy-^'' in North Carolina in 1908; Card-*^ in Mississippi in 1908; Williamson-" in Arkansas in 1909; Hewit-^^ in Virginia in 1909; Pollock-*^ in Illinois in 1909 and King^^° in Tennessee in 1909. Thayer-^^ is said to have observed cases in Maryland in 1905 and 1909. Geographic Distribution. — The distribution of pellagra is peculiar. In Europe it is found in Italy, Roumania, Austria, Hungary, France, Northern Portugal, Northern Spain, Bessa- rabia, Poland, Kherson, the Island of Corfu, Bosnia, Herze- govina, Servia, Bulgaria, Turkey, Greece, England, Scotland, Ireland, Wales and the Shetlands. In Asia it has been found in Asia Minor, Persia, Straits Settlements and in North Behar, India. In Africa it is encountered in Lower Egypt, less in Upper Egypt, in the coastal regions of the Red Sea, in Algeria, Tunis, Nyassa and Rhodesia, South Africa and Robben Island. Pellagra has been found in New Caledonia, Hawaii, Cuba, Porto Rico, Barbadoes and Jamaica. In South America it has been reported from Brazil, Argentina and the Columbian Republic. Numerous cases are recorded in the Canal Zone and the disease is found in Mexico. In the United States there is no other disease known to be so widely disseminated so soon after its recognition, pellagra being found in thirty-nine states including the District of Co- lumbia. The most intense foci of infection are in Virginia, North Carolina, South Carolina, Georgia, Florida, Kentucky, Tennessee, Alabama, Mississippi, Arkansas, Louisiana, and Texas. The disease is frequent in part of Illinois; pellagra is found sporadically in Maine, Vermont, Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Penn- sylvania, Maryland, District of Columbia, West Virginia, Kansas, Wisconsin, Oklahoma, Ohio, Indiana, Iowa, Missouri, Michigan, Minnesota, Colorado, New Mexico, Arizona, Wash- ington, Oregon and California. Prevalence. — As pellagra is not a reportable disease except in a small portion of the country in which it is endemic, accu- 286 ENDEMIC DISEASES OF THE SOUTHERN STATES rate statistics of its prevalence are not available. In 19 12 ]vj;jgg305 estimated that there were between 6,000 and 10,000 cases in the United States. Roberts'"" believed that there had been at least 30,000 cases in the United States between the years 1907 and 191 2. Basing our opinion from personal observation on the increas- ing prevalence of the disease in Arkansas and upon the pub- lished reports from other localities we believe that there are at least 25,000 cases of pellagra in the United States at this time (August i, 1915). CHAPTER XVIII ETIOLOGY OF PELLAGRA Season. — Pellagra is subject to decided seasonal variations. In the United States the months of most frequent occurrence are from March to July, particularly April, May and June. The following table is compiled from cases reported in the United States and shows the occurrence of the disease by months. January. , . February. . March. . . . April May June July August . . . . September October. . . November December. 57 3° 13 18 Most of the cases seen by one of us in eastern Arkansas came for consultation for the first time in May and June, while of ninety-one cases seen by one of us in the Arkansas State Hos- pital for Nervous Diseases, the admissions for pellagra by months were as follows: January 12 February 3 March 2 April 4 May II June 6 July 7 August 8 September 9 October 10 November 12 December 7 By an analysis of 115 cases the Thompson-McFadden Pellagra Commission^^^ have shown that there is no particularly marked 287 288 ENDEMIC DISEASES OF THE SOUTHERN STATES tendency for the seasonal recurrences to reappear during the same month year after year. Relapses may occur during the fall months of the same year in which the onset appears. The onset appears earlier in countries lying farther south. In Florida, more cases originate in the early spring months than in states farther north. In Italy the majority of first cases are said to occur from the middle of March to the middle of May and the disease appears somewhat earlier in the central prov- inces than in the northern ones. Sandwith^"" states that in examining 300 patients in Egypt two-thirds of them stated that their skin lesions were first seen during the months of January and February. Rainfall. — The Thomson-McFadden Commission^^^ observed that if during the spring precipitation is high, the temperature low, and the number of rainy days excessive the appearance of acute symptoms, more particularly those involving the brain, is delayed. Altitude and Topography. — In the United States pellagra is found in mountainous regions, as in southeastern Kentucky and northwestern Georgia, in rolling upland regions and in lowland and swampy regions. In the eastern hemisphere also pellagra occurs from the Tyrolean Alps to the delta of the Nile. In Europe the disease is especially prevalent about the lower slopes and foothills of mountainous regions. Sambon-'^ has emphasized the frequency with which pellagra cases are found on the narrower valleys of hilly and wooded country trenched by swift-running streams. His observations were conducted in northern and central Italy. In Kentucky, Georgia and South Carolina, Grimm^^^ classified 323 cases with reference to the distance from water courses with the following results: to s° ya-rds 31 50 to 100 yards 35 100 to 200 yards 49 200 to 500 yards 118 500 to I mile 51 1 to 3 miles 10 Exact distance not determined 29 PELLAGRA The Tennessee Pellagra Commission^'' record their observa- tions with reference to proximity to creeks as follows: Yes 78 Not observed 141 No g 7 Wood's-'^ experience in North Carolina was similar to that of Sambon in Italy. On the other hand, the Thomson-McFadden Commission^'^ investigated conditions on a large island off the coast of South Carolina, the distinguishing feature of which was the absence of streams. Pellagra was found to be endemic here. In- vestigations were also undertaken in the Panhandle of Texas where the rainfall is very slight and running streams remarkably scarce. Pellagra cases were found originating here. The most that can be said regarding the relation of altitude and topography to pellagra is that it seems to be restricted to certain areas which vary widely in these characteristics. Race.— Generally speaking pellagra is commoner in the white race than in the negro as shown in the table below: j White Colored 9,881 a6 298 680 46 1,223 74 4,048 6 Roberts""" 24 18 Albright-"". Randolph and Green^'" 6 Siler, Garrison and McNeaP™ Tucker^"-* 9 203 17 Ark. State Hospital Total 12,266 4,431 Siler, Garrison and McNeaP'* believe that this ratio is not necessarily indicative of a relative racial resistance to pellagra in negroes but rather as the end-results of the influence of several factors, prominent among which are the poor hygienic conditions under which the people live in villages as compared with the relative isolation of the bulk of the colored population on farms. 19 290 ENDEMIC DISEASES OF THE SOUTHERN STATES There are undoubtedly areas in which the disease is far com- moner in negroes than in whites. This was the experience of one of us in the lowlands of eastern Arkansas where many cases were seen in negroes and only few in whites. It is true that relatively few white persons live in the rural districts of that particular locality. As recently shown by Wolff^"^ pellagra is an exceedingly rare disease among Jews. Sex. — Foreign observers have failed to note any significant influence of sex on the prevalence of pellagra. In the United States, however, and particularly in the South, the disease is known to occur with a notable preponderance among females. Sixty-five per cent, of Niles^°° cases and 81 per cent, of Low- gj.y'g306 -^ere in females. At least two-thirds of the eastern Arkansas cases seen by one of us and 73 per cent, of the cases in the Arkansas State Hospital were in females. A compilation of cases from numerous sources shows that females are affected about two and a half times more frequently than males: Clark=i>2 Harrington-'' MizelP" Siler and Nichols^*^ Thomson-McFadden Commission BealP"^ Tucker^M Grimm-'- , Lavender Thomson-McFadden Commission Albright"' Roberts^" Thompson Canal Zone Rhode Island Maryland Illinois South Carolina Texas Virginia Kentucky, South Carolina United States South Carolina Tennessee United States Arkansas The sex distribution of the cases investigated by the Thomson- McFadden Commission is interesting, i. The rate of preva- lence among children under 10 years of age and among adults PELLAGRA 29I aged 45 years and older is practically equal in the two sexes. 2. The rate of prevalence drops among males between the ages of 19 and 45 years, whereas for females there is a remarkable excess of prevalence between these ages. 3. In both males and females there is a striking fall in prevalence between the ages of 10 and 20 years. Age. — No period of life is free from the attack of this disease. It has been found in infants at the breast and in the centenarian. The youngest pellagrin of which we can find a report is one mentioned by Haase.'"^ which was but 4 weeks old. He also speaks of two others respectively 6 and 8 weeks of age. The age of the oldest pellagrin on record is 102 years, that being the age of a pellagrous woman reported by Roberts.""" These extremes of age, however, are rare. The youngest pellagrin we have seen was a child of 2, while the oldest was 69. The following table shows the ages of the 91 cases seen by one of us in the Arkansas State Hospital for Nervous Diseases: Between 11 and 20 years 2 cases. Between 21 and 30 years 19 cases. Between 31 and 40 years 28 cases. Between 51 and 60 years 11 cases. Above 60 years 7 cases. Lavinder^"^ found 532 cases in children under 5 years of age, 2,192 cases between the ages of 5 and 20 years, 9,404 between 20 and 40, and 5,309 cases in individuals over 40 years old. Merck's'^"" table of ages shows that the greatest number of cases occur between the ages of 40 and 50 years, and the smallest number of cases under 5 years. From o to 5 years 46 cases or 0.9 per cent. From 5 to 15 years 406 cases or 8.3 per cent. From 15 to 30 years 715 cases or 14. 7 per cent. From 30 to 40 years 919 cases or 19.0 per cent. From 40 to 50 years i)Or7 cases or 21.0 per cent. From 50 to 60 years 868 cases or 18. 7 per cent. From 60 to 70 years 638 cases or 13 . i per cent. Over 70 years 228 cases or 4.6 per cent. 4,836 100.3 per cent. 292 ENDEMIC DISEASES OF THE SOUTHERN STATES Heredity. — The role of heredity in pellagra has been a moot question for many years, and is one that in all probability will not be settled until the etiologic factor of the disease is dis- covered. Some investigators contend that pellagra is truly hereditary, that it may be transmitted from parent to child, but there is little or no evidence to prove that such is the case. No instance of pellagra has been reported in the new-born and as stated above the youngest case on record was in a child of four weeks of age. On the other hand, the majority of investigators contend that pellagra is not hereditary in the sense that syphilis is, but that pellagra in the parents predisposes the children to the disease. Civil Condition. — While it would seem from our present knowledge of pellagra that the civil condition of an individual could have little or nothing to do with him contracting the disease, it will be seen from the accompanying table that pellagra is much more prevalent among the married than those of any other civil condition. Grim=== Tucker=»< Roberts^" Albright^"' Thomson and McFadden Arkansas state Hospital Total Married 208 37 42 204 150 S3 698 Single 83 14 12 92 25 20 246 Widowed.... 32 4 5 20 9 18 88 Divorced. . . . I I 323 55 60 316 184 91 1,033 Occupation. — It has long been considered in Italy that pellagra is found almost exclusively among farmers or field laborers, and that "peasant life, poverty and polenta" are the three p's responsible for this disease. While it is undoubtedly true that the majority of the pellagrins of Italy are of the farmer class, this does not seem to be the case in America. According to the Thompson-McFadden Pellagra Commission, ^^^ the most significant fact concerning occupation brought out by their investigation is the prevalence of the disease among housewives. They state, however, that this means httle more than that PELLAGRA 293 pellagra is most prevalent among women of the age at which they are usually employed in the house. Social Condition. — As stated above, poverty has long been considered as one of the prime causes .of pellagra, and the studies of numerous investigators show that while pellagra may attack those of affluent circumstances it is much more preva- lent among the poor. Thus the Thompson-McFadden Pellagra Commission^'^ re- port as follows: Cases living in squalor 2 Cases living in poverty 28 Cases living where only the necessities of life were obtained 200 Cases living in comfort 41 Cases living in affluence 6 277 Lavinder,'"'* in a study of 16,960 cases of pellagra, found 8,491 were poor, 6,970 were of moderate means, and only 1,499 were well-to-do. Hygiene. — That the hygienic surroundings of an individual may play an important role in the etiology of pellagra seems at least possible. Grimm-^- found that of 296 cases 11 lived under good sanitary conditions in the home, 36 under fair conditions, while 249 cases came from homes where the sanitary conditions were bad. Marie^"* states, however, that lack of cleanliness in the home is not a cause, as many peasants keep their houses neat. Siler, Garrison and McNeal-"^ consider inefficient methods of the disposal of human excreta a material factor of the epidemiology of pellagra in those sections where the disease is endemic. In Spartanburg County, S. C., they found pellagra endemic in all of the mill villages, and in all they found un- screened surface or pail privies. In two mill villages of other counties where every house contained a water-carriage flush closet they failed to find a single case of pellagra which had certainly originated in these villages. In the city of Spartan- burg these investigators observed that the active foci of the disease were found in the portions of the city where unscreened pail and surface privies were used. They found that 230 cases 294 ENDEMIC DISEASES OF THE SOUTHERN STATES of the 241 observed in the city came from homes where the above-named privies were used, and several of the remaining eleven cases, while using the water-carriage system themselves, lived in communities where unscreened surface privies were common, and some of them used by pellagrins. Rural and Urban Dwellers.- — Aside from the tilling of the soil it has been alleged that the mere fact of dwelling in rural dis- tricts predisposes to pellagra. Practically all writers on Italian pellagra are agreed upon this point, and Roberts^"" writing of conditions in general, including America, states that this is a disease of rural districts, that "pellagra stops at the city gates." This statement is not in accord with the findings of most observers in the United States. The Thompson-McFadden Pellagra Commission-^" found the disease much more prevalent in the congested districts of the mill villages than in either the urban or rural districts. This coincides with the findings of Grimm,-'' who observed more pellagra among dwellers of towns than among city or country residents. Of the 17,763 cases reported by Lavinder^"* 5,212 were city dwellers, 784 lived in towns, while 11,767 were inhabitants of rural districts. In Arkansas, however, the inhabitants of even the largest cities have easy access to the country and most of such make visits of more or less extent to rural districts. This statement is true also of a great deal of the pellagrous area of this country, and we have never seen a city pellagrin who has not made visits to the country. Other Predisposing Causes. — Among the other factors which seem to be predisposing causes of pellagra the incidence or previous occurrence of other diseases is important. However, the occurrence of disease in childhood does not seem to predis- pose the adult to pellagra. Alcoholism appears to play an important role in predisposing the individual to this chsease, while many pellagrins are found to have indulged in venereal excesses. Pregnancy and fre- quent child bearing may account for the development of the disease in some cases. One case in this connection which has PELLAGRA 295 been under treatment by one of us for some time is of more than ordinary interest as it followed pregnancy and puerperal convulsions. Malaria and hook-worm are frequent concomitant diseases with pellagra, the former having been seen by us in several cases. It seems to us that the factor to be considered in this connec- tion is not that the previous or concomitant disease per se predisposes the individual to pellagra, but that by lowering his vitality and power of resistance it renders him more prone to contract it. Theories of Etiology. — There are two theories as to the etiology of pellagra: (i) that it is due to some dietetic error; and (2) that it is an infectious disease, caused by some as yet unknown parasite. It might be well to mention here, not because it has any scientific bearing upon the subject of the etiology of pellagra, but for historic interest, that there are certain French pella- grographers who contend that pellagra is not a disease entity, but that it is a symptom-complex which may develop in any cachectic state. Outside of a small group of writers this theory has received scant attention. Dietetic Dyscrasia. — From the earliest description of pellagra by Casal down to the present time Indian corn or maize has been incriminated in connection with the etiology of the dis- ease. However, Casal and his contemporaries, some of whom in all probability independently thought of corn as the cause of pellagra, did not formulate their views on the subject and only in a vague indefinite sort of way laid the malady at the door of maize. Pellagra was a new disease — at least it had only newly been observed — and Indian corn was a new product, so it was rather natural that the physician of the times should connect the two. It was not until 1810, however, that any definite theory as to the manner in which corn caused pellagra was formulated. At this time Marzari propounded his theory that the disease was due to a lack of certain nutritive elements in the corn, and almost immediately there sprang up two schools of thought: 296 ENDEMIC DISEASES OF THE SOUTHERN STATES the zeists (from Za Mays), who supported the corn theory, and the anti-zeists, who discredited it. However, it was not long before the zeists became divided among themselves and many new theories were formulated as to the exact manner in which corn caused this disease. The following list comprises the principal theories as to the manner in which corn acts as an etiologic factor in the production of pellagra: 1. Lack of nutritive elements. 2. Toxicity of normal corn itself. 3. Toxicity of corn due to germination process. 4. Toxicity of corn due to products elaborated by the action of certain microorganisms. 5. Toxicity of corn due to products produced in the ali- mentary tract after ingestion. 6. Toxicity of corn due to poisonous substances in the grain which act only after being sensitized by the rays of the sun. 7. Action of certain parasites of corn ingested with that grain. The first and second of these theories have been thoroughly disproven by the many careful analyses of corn which show that this grain is rich in nutritive value, containing a large percentage of fat and nitrogenous substances, and is readily assimilated by the body. Further, it has been shown that pellagra is often found in well-nourished persons, thus proving that it is not a disease due to lack of nutritive elements; and finally, there are many districts in which corn has been very extensively used as an article of diet for long periods of time in which pellagra has never been found. The third theory, that pellagra is due to a toxin elaborated during the process of the germination of the corn, has also been shown to be untenable by the above-mentioned facts, and even the most ardent zeists have abandoned these theories. The fourth theory, the so-called toxico-chemical theory, that pellagra is due to toxins produced in corn by the action of certain microorganisms, has probably had the widest vogue of any theory as to the etiology of this disease. It was to the PELLAGRA 297 elaboration and promulgation of this theory that the great Lombroso gave the last twenty-five years of his life. A great many microorganisms, moulds and bacteria have been described by investigators in this field, but even Lom- broso, himself, was unable to incriminate any one of them. The most frequent parasite of spoiled corn is the Penicillium glaucum or common blue mould. This organism penetrates into the interior of the corn and has been thought by many to produce the specific toxin of pellagra. Other microorganisms, which have been described and defined as the cause of the toxin of pellagra, are Sporisorium maidis, Eurotium Herbariorum, Aspergillus glauciis, Oidium lactis maidis, misentericus vulgaris, bacterium thermo, etc. Numerous chemical studies of spoiled corn have been made and several substances have been isolated, the chief of which, according to Marie, ^"^ are the so-called red oil, pellagrosine, and a resinous substance. With these substances and with the spoiled corn itself Lom- broso conducted many experiments in animals, especially in dogs and chickens, and considered that he had produced a true pellagra in them. So firmly convinced were the Italian people that Lombroso was correct in his contentions that they instituted the most elaborate measures calculated to prevent the use of spoiled corn as food and thus act as a prophylaxis to the disease. De Giaxa^"^ considered that pellagra was due to a toxic substance elaborated in the intestinal tract by the action of the colon bacillus on ingested corn. He considered that the properties . of the organisms were changed by growth with the corn, and alleged to have produced a toxic substance from the growth of this bacillus on a corn culture media. Another auto-intoxication theory, advanced by Neusser,"" was that a toxin was produced in the alimentary tract from a so-called "receptive mother substance" which was the product of the action of the Bacillus Maydis on corn. The so-called photodynamic theory of the etiology of pellagra was advanced by Ravbitschek^" and others. They maintained that all corn contains a certain toxic substance which, after 298 ENDEMIC DISEASES OF THE SOUTHERN STATES ingestion of the corn, is taken up by the blood stream where it remains inactive until it becomes sensitized by the action of the sun's rays on the exposed portion of the body. Next to the toxico-chemical theory so strongly defended by Lombroso and his followers the idea that pellagra is due to a specific microorganism, either mould or bacteria ingested with corn, has probably been the most popular. The organisms which have been described and incriminated in this respect are legion and only a few of them will be men- tioned. The ordinary blue mould, Penicillium glaucum, has probably been accused in this respect by more investigators than any of the other parasites of corn. Cini'^- contended that pellagra was an aspergillosis due to two moulds, Aspergillus fumigatus and Aspergillus fiaverscens. Tizzoni"^ described a specific bacterium which he termed Streptohacillus pellagrce, which he isolated from spoiled corn and from the blood, spinal fluid, and tissues of pellagrins. This organism usually appears as a short bacillus, grows both in short and long chains, stains readily with the ordinary aniline dyes and often shows polar staining. It is non-spore forming, and obtains its optimum growth on human or rabbit blood agar at 37°C. The main arguments advanced by the zeists for their beliefs as to the etiology of pellagra are based upon the following assumptions : 1. Pellagra first developed in Europe almost immediately subsequent to the introduction of Indian corn from America. 2. Pellagra appeared everywhere that corn was cultivated, and the number of cases increased as the new grain became more popular as an article of diet. 3. Pellagra is found only in localities where corn is cultivated or imported and only in individuals who consume it as food. 4. And finally, since the institution of the prophylactic measures of the Italian government which have reduced the consumption of spoiled corn, the number of cases of pellagra has diminished. The anti-zeists offer the following arguments against the maize theory: PELLAGRA 299 1. That pellagra first appeared in Europe soon after the introduction of corn from America is without foundation in fact. 2. That many districts exist, where corn has been cultivated and used as an article of diet for generations, in which pellagra is unknown. 3. That pellagra is often found in individuals who have seldom or never partaken of corn as food. 4. That the peculiar topographic distribution of pellagra even in the worst endemic centers is untenable with the corn theory. 5. That the erythema and other characteristics of the disease may recur each spring for several years in patients removed from the endemic centers and who have been on a corn-free diet. 6. That all prophylactic measures based on the corn theory have failed to prevent the disease. Other dietetic factors than corn have from time to time been proposed as the cause of pellagra. Thus Strombio, as far back as 1784, considered bad food as an important cause. Others thought the lack of salts in the diet was responsible, while by some the abstinence from wine by those who were used to it was considered the cause of the disease. In 191 1 Mizell"* proposed the theory that pellagra was due to the use of cotton-seed oil; this theory is untenable be- cause of the fact that cotton-seed oil is not used as an article of diet by the vast majority of European pellagrins, if at all, and that it is used very extensively in this country in locaKties where pellagra is unknown. We are very much in accord with Lavinder,"'' who states that the publication of such speculations founded upon personal opinion, especially when they add to the fears of the laity, are strongly to be deprecated. Goldberger^" in 1914 asserted that pellagra is a disease essentially of dietary origin and that it is caused in some way by the absence from the diet of essential vitomines or perhaps, as is suggested by the work of Meyer and Voegtlin, by the presence in the vegetable food of such poison as soluble aluminum salts in excessive amounts. 300 ENDEMIC DISEASES OF THE SOUTHERN STATES Goldberger cites as evidence of the correctness of his theory the fact that of 996 patients admitted to the Georgia State Sanatorium during the year 1910, excluding those who died, were discharged or had pellagra upon admission, there were remaining in the institution after one year 418 patients and of this number 32 or 7.65 per cent, developed the disease. He continues that none of the 293 employees of the Sanatorium who came into contact with the pellagrins developed pellagra, while if the disease had developed in the employees at the same rate as in the patients 22 of them should have been afflicted. Further studies at the Jackson orphanage showed that 68 or 32 per cent, of the 211 inmates had pellagra. To Goldberger the remarkable fact to be observed is that practically all of the cases developed in children between the ages of 6 and 1 2 years, that only 2 cases developed in the group of 25 children under 6 years of age and only i case in the group of 66 children over 12 years of age. Goldberger found that in both the institutions cited the groups which were exempt from pellagra subsisted on a better diet than those who developed the disease, that the diet of the pellagrin was noticeable for the marked lack of meat or other animal protein and that of the vegetable food, such as corn and sirup, were in excess and legumes relatively inconspicuous. He therefore concluded that this one-sided diet is the cause of pellagra. That the disease develops in certain groups of individuals outside of institutions is due mainly to economic conditions such that the more expensive foods, meat, milk, eggs, legumes, etc., are not procurable among the poorer classes. That it develops in certain well-to-do individuals is accounted for by Goldberger by more or less well-recognizable eccentri- cities of taste, which causes them to partake of a one-sided diet. He further states that such eccentricities of taste are found in the insane, some of whom will not eat at all. This, Gold- berger thinks, accounts for the development of pellagra among residents of insane asylums where the diet is otherwise satisfactory. PELLAGEA 3OI Goldberger (547) has recently conducted a feeding experiment upon eleven convicts on the Mississippi State Penitentiary farm. These men were fed a proteid-free diet from April 19, 191 5 to October 31, 1915. Of the eleven subjects not less than six are claimed to have developed symptoms, including a typical dermatitis, justifying a diagnosis of pellagra. The nervous and gastro-intestinal symptoms are said to have been mild but distinct. The skin lesions were first recognized on the scrotum. Later there appeared lesions on the backs of the hands in two cases and on the back of the neck in one case. This experiment while suggestive would have proved more convincing had it been conducted in a pellagra-free territory. The theory that water may be responsible for pellagra is an old one, and many attempts have been made to connect the etiology of pellagra with the source of the water supply of the individual. Numerous investigators have collected statistics of this nature, and many theories as to the manner in which water could cause the disease have been advanced. Quite novel among these theories, however, is the contention that pellagra is due to the presence of certain chemical sub- stances in drinking water. Alessandrini and Scala^^^ propounded the idea that the etio- logical factor of pellagra is to be found in the silica in the colloidal state contained in certain potable waters. In support of their view they cite a large amount of experimental data, the work being conducted on guinea-pigs, dogs, rabbits and monkeys. They injected the animals with and caused them to drink artificial colloidal solutions and gelatinous suspensions of silica and natural potable waters of various pellagrous dis- tricts. From the results of their experiinents they conclude that they hav£ produced in animals a chronic intoxication which very closely simulates, even in the details, pellagra as seen in human beings. They claim to have produced typical clinical symptoms as well as typical pathologic findings. Infectivity. — The second great etiologic theory of pellagra, that it is an infectious disease, has, especially of recent years, received the enthusiastic support of many investigators. There are four well-known theories concerning the infectivity of 302 ENDEMIC DISEASES OF THE SOUTHERN STATES pellagra: first, that it is a bacterial disease; second, that it is a parasitic disease transmitted by a blood-sucking insect; third, that it is a form of amebiasis; fourth, that it is a parasitic disease due to a water-borne nematode worm. Contagion. — One of the first questions asked when the in- fectious theory is considered is concerning the contagiousness of pellagra. Can non-pellagrins associate with pellagrins without fear of contracting the disease? This is one of the most important questions which confronts us and one which cannot be answered with certainty. Most of the early observers considered pellagra as non-contagious, although by some it was considered to be spread by direct contact. Marie,^"^ who holds so rehgiously to the corn theory, natu- rally does not believe in its infectivity. Sambon^^* says pellagra is not contagious and tells of having an Italian pellagra girl as nurse for his children, and this inti- mate contact failed to convey the disease from one person to another. Other facts, which seem to refute the idea of contagion are: first, pellagra is usually confined within certain narrow centers while there is free intercourse between the inhabitants of these centers and those of neighboring communities; second, pellagra is very rarely, if ever, found in physicians, nurses or attendants who come into almost daily contact with pellagrins; third, pellagra is never transmitted from a pellagrous wet nurse to a child, or from a pellagrous child to a healthy mother. Krauss'^^ mentions two cases which bear out the latter con- tention : one, a pellagrous infant of twelve months of age which had contracted the disease at the age of six months and had had no nourishment except the milk of a healthy mother; the other, a mother with a virulent pellagra, had nursed an infant for four weeks, the child remaining in perfect health. The case mentioned above under other predisposing causes which followed pregnancy and puerperal convulsions is of interest also in this connection. Five months after conception the mother who has active symptoms of pellagra is nursing the child which is perfectly normal. Family Tendency. — The opinion of most observers has been PELLAGRA 3O3 that family tendency is of little or no consequence in the etiology of pellagra, and that by far the vast majority of pellagrins are members of families of which they are the only member af- fected. Thus, according to Roberts,^"" Alessandri found only five families with more than one pellagrin. Lavinder^'^ found in nearly 16,000 cases more than one case to the family 933 times and more than two cases 235 times. Grimm^^^ gives the follow- ing table covering this point : (a) Families having one case 264 (b) Families having two cases 23 (c) Families having three cases 6 (d) Families having four cases i The findings of the Thompson-McFadden Pellagra Com- mission,^'* however, are sHghtly at variance with those quoted above. Of 316 cases of pellagra they found 160 or 50.6 per cent, occurred only one case in a family, 84 or 26.6 per cent, two cases in a family, 42 or 13.3 per cent, three cases in a family, 20 or 6 per cent, four cases in a family, and 10 or 3.2 per cent, five cases in a family. One case which we have seen was the only surviving member of a family of four, the father, mother and sister having died from three months to seven years previously of pellagra. Immunity. — When the various facts concerning the contagion and family incidence of pellagra are considered, the question of immunity naturally arises. Sambon-'^ is inclined to the opinion that a certain kind of immunity is acquired by residents of pellagrous districts. This he thinks is especially apparent in children, as pellagra is more prevalent in very young children than in older ones. Roberts'"" contends that there is probably no immunity either natural or acquired to pellagra, but that there is a variation in susceptibility. Bacterial Disease. — The theory that pellagra is a disease caused by bacteria other than those of corn has had many enthusiastic supporters, and many attempts to isolate the in- fecting organism both microscopically and culturally have been made. Bravetta^" after exhaustive cultural studies with the blood 304 ENDEMIC DISEASES OF THE SOUTHERN STATES and spinal fluids of pellagrins reached the conclusion that these are sterile. MacNeal and Hamilton-^' isolated approximately 100 strains of bacteria from the intestines of pellagrins and subjected them to agglutination tests with the blood serum of pellagrins. All but two of these strains reacted negatively. These two strains, however, showed a very definite agglutination with the sera of pellagrins in the acute state and less agglu- tination with the sera of pellagrins taken during the interval between attacks. The possible significance of these facts was much lessened, according to the authors, by the fact that agglutination occurred, sometimes as definite as ^vith pellagrins, with the sera of insane non-pellagrous patients and normal individuals. Early in 191 5 Page^-° announced the isolation of a bacillus from the feces of pellagrins which he insists "must be the cause of the disease." According to this author the organism is from 4 to 10 microns long with the ends more sharpened than those of the colon group. It is a spore bearer and is found in many forms. Just before the formation of a spore an area of cloudiness or bright refraction appears and the bacillus gener- ally elongates. The spore grown, the membrane of the bac- terium bursts and the young organism emerges through the opening. At first the young bacillus is very active and as- sumes a spiral or cork-screw shape. It gradually grows in length and the motility decreases. The organism is aerobic and Gram negative. Sterile feces, according to Page, is the best culture medium, and the bacilli grow well at a temperature of 80° to 90°. Page states that a cat fed on food inoculated with pure cultures developed mild diarrhea and nervousness, and that a man accidentally infected with the organism developed pellagra. Page says that he has found the organism many times in sixty-four cases of pellagra and that he has been unable to find it in normal individuals and in those suffering from other diseases. Sanders'" describes a similar organism which he isolated PELLAGRA 305 from the spleen of a pellagrin at necropsy and grew on a special culture media containing corn meal. He considers it the same organism as that described by Page. Intermediate Host. — The theory that pellagra is an insect- borne disease had its origin with Sambon,^^^ who in 1905 stated before the British Medical Association that such was his belief. He later incriminated the Simulium reptans as the offending insect and backed his theory by extensive epidemiologic studies. Sambon gives as his reason for this belief the following: 1. Pellagra is a parasitic disease because: (a) The characteristic eruption and other symptoms of the disease may recur each spring for a number of years, notwith- standing the removal of the patient from the endemic districts and the strict eHmination of maize from his diet. This peculiar periodicity of symptoms can be explained only by the agency of a parasitic organism presenting definite alternating periods of latency and activity. Analogous periodicities are met with in other parasitic diseases — as, for example, in tertian fever, in which the periods of activity of the parasite {Plasmodium vivax) recur each summer in correlation with the activity period of its anophelic definitive host. No toxic substance could account for it. {b) It presents the peculiarities of distribution and seasonal incidence found in all parasitic diseases. (c) Its symptoms, course, duration, and morbid lesio-ns are analogous to those of other parasitic diseases. 2. It is an insect-borne disease because: (a) It is not directly contagious. (6) Neither food nor drinking water accounts for its pecuhar epidemiology. (c) It is hmited to certain rural districts only, towns and villages almost invariably escaping. (d) It presents a definite and peculiar seasonal incidence — viz., spring and autumn. (e) It is practically restricted to only one class of people — viz., the field laborer, owing to greater exposure to infection. 3. It is conveyed by a Simulium, because: 3o6 ENDEMIC DISEASES OF THE SOUTHERN STATES (a) Simulium, so far as we know, appears to effect the same topographic conditions as pellagra. (b) In its imago stage it seems to present the same seasonal incidence. (c) It is found in rural districts and, as a rule, does not enter towns, villages, or houses. (d) It explains most admirably the peculiar limitation of the disease to agricultural laborers, a limitation which nothing else can explain in a satisfactory manner. (e) It has a wide geographic distribution which seems to cover that of pellagra, although certainly exceeding it, in the same way that the distribution area of the Anopheline ex- ceeds that of malaria, and the range of Stegomyia calopus that of yellow fever. (y) It is known to cause severe epizootics in Europe and America. {g) Other similarly minute blood-sucking diptera, such as Phlebotomns papatassi and Dilophus feverilis, are strongly suspected of being propagators of human diseases. While Sambon does not state definitely the nature of the hypothetical infecting organism transmitted by the sand-fly, he is inclined to regard it protozoal in nature. Since the formulation of Sambon's theory many investigators have written pro and con concerning it and much valuable information has been obtained. Babes, -^^ who holds to the corn theory, considers that the fact of being unable to find any relation between the Simulium and corn is sufficient reason for discarding Sambon's theory. Roberts'" discards the theory of Sambon, that the etiologic factor of pellagra is borne by the sand-fly, and incriminates the mosquito. He bases his opinion on alleged analogies of pellagra and the mosquito. He does not accuse any one species of this insect, but states that it will probably prove to be a rural- breeding, house-living, day-biting mosquito. Jennings and King^'° after a most exhaustive study of the insects of Spartan- burg, S. C, including ticks, lice, bedbugs, cockroaches, horse- flies, fleas, mosquitoes, buffalo gnats (Simulium), house-flies, and stable flies (Stomoxys), reach the following conclusion: PELLAGRA 307 Horseflies have nothing and cockroaches little to support them as the intermediate host. On account of their scarcity and the nature of their biting habits ticks and fleas may be excluded. It is even doubtful if the existence of an animal reservoir of infection would cause these insects to become prominent. The sex and age incidence and the rural nature of the disease cannot be accounted for by lice and bedbugs. Further, lice are rather scarce. Mosquitoes are eliminated on account of their comparative rarity, the night-biting habit of the local species, which would not account for the sex incidence, and the lack of coincidence between their distribution and that of pellagra. House-flies {Miisca domestica) are considered from the point of view that pellagra may be an intestinal infection, the organisms being passed with the feces and infecting others through contaminated food. Buffalo gnat {Simidium) could hardly have been considered had it not been for Sambon's theory. In Spartanburg County they seldom attack man, and when they do it is only locally and their attacks are largely confined to field workers. Further, they are present in this locality only in comparatively moderate abundance. In the stable fly (Stomoxys calcitrans) is found certain promi- nent peculiarities which, according to Jennings and King, lead them to consider it a possible intermediate host of pellagra. The range of the stable fly covers and exceeds that of pellagra. While the season of the greatest numbers of the stable fly is somewhat later than the season of greatest prevalence of pel- lagra, it however appears earher in the spring than do most recurrences and new cases of the disease, and when these do occur the stable fly is found in great numbers. This insect is exceedingly plentiful and is found most in rural districts, thus corresponding to the rural distribution of pellagra. On account of the great number of stable flies it seems an efficient transmitter of disease. The stable fly is intimately associated with man whom it bites often and persistently. It is a day-biting insect, which explains the sex and age incidence. The life of the stable fly '308 ENDEMIC DISEASES OF THE SOUTHERN STATES seems long enough for the development of a possible infecting organism. This insect is easily and often transported over long distances, which may account for the development of sporadic cases of pellagra. Amebiasis. — In 1909 Siler and Nichols-^^ called attention to the large number of pellagrins in whom amebse were found. Jelks'-^ reported having found amceba histolytica in the mucopurulent material taken from the rectum of a pellagrin. Long^-^ proposed the hypothesis that pellagra is a disease due to the injury of the intestinal mucosa caused by amebas, and in support of this theory reported finding the ameba in the stools of fifty out of fifty- two pellagrins, and that the ulceration and damage to the intestine was shown by the presence of blood, mucus and pus in the feces. Nematode Worm. — To Alessandrini^-^ is due the theory that pellagra is due to a water-borne nematode worm which he found constantly in shallow wells and slowly flowing streams of pel- lagrous regions. These were found only rarely or were entirely absent from the potable waters of non-pellagrous districts. Later Alessandrini was forced to abandon this theory and while he continued to incriminate potable waters, he adopted the colloidal silica theory mentioned above. Inoculation Experiments. — As far back as 1780 Gherardini attempted the inoculation of healthy individuals with pellagrous material, such as ichorous matter from the skin lesions, the blood and saliva, but with negative results. Since that time numerous attempts have been made to reproduce pellagra in the lower animals. In 1910 Anderson and Goldberger^-^ attempted to infect the Rhesus monkey with the blood and spinal fluid of pellagrins. Similar experiments were conducted by Lavinder^^' and by Singer, MacNeal and Rooks,^^* all with negative results. In the summer of 1913, however, came the announcement of Harris^-^ of New Orleans that the experimental production of pellagra in the monkey had been accomplished. The tissues from different parts of the body, central nervous system, portions of skin lesions and alimentary tract, were removed at PELLAGRA 309 necropsy soon after death from a typical case of pellagra. After mixing with an equal amount of normal saline solution and ground in a mortar they were allowed to stand in the ice chest over night. They were then coarse filtered and the juice passed through a Berkefeld filter, Letter N. The filtrate was injected subcutaneously, intravenously and intracranially in Fig. 68. — Monkey 2, shomng lesions of face. (Courtesy of Dr. W. H. Harris.) large quantities into monkeys (Macacus rhesus). The first of these animals remained apparently normal for many months when he developed irregular dark patches on the hands, fore- arms, face, back and sides of the body. He gradually became emaciated and weak and finally died "with all the signs of pellagra." The second monkey after a period of about three months developed similar lesions to monkey i, and at the time of pub- lication was still living, though growing progressively weaker and thinner. Stimulated by this work of Harris, Lavinder, Francis, Grimm and Lorenz^^^ attacked the problem anew and by 103 experi- ments with 77 rhesus monkeys, 2 Java monkeys and 3 female baboons administered pellagrous material from every conceiv- 3IO ENDEMIC DISEASES OF THE SOUTHERN STATES able source and in every conceivable manner. The pellagrous material consisted of tissue extracts, pericardial and spinal fluids from necropsies, and blood, urine, feces and spinal fluid collected during life. f Fig. 6g. — Monke>' sho\Mn_; liMon, o( hands and face. Dr W . H Harris.) (Courtesy of The inoculations were made intravenously, intraperitoneally, intraspinally and material was fed by stomach tube. Eight of the animals died after varying periods following inoculation. Four of them showed plainly death was not due to pellagra. The cause of death was not determined in the other four. The remaining monkeys with one exception had up to the time PELLAGRA 3II of the publication of the report shown no indications suggesting pellagra. The following is the history of the exception: M. Rhesus, 98, was injected intraspinally with 6 c.c. of spinal fluid, April 14, 1914, and again inoculated, May 2, intraspinally with 4 c.c. of spinal fluid drawn from another pellagrin. The first change in this monkey was noted May 4, 1914, at which time the right forearm appeared slightly swollen and looked as though some of the hair was falling out. The following day the left forearm showed a similar condition. Later both forearms became entirely denuded of hair, the skin became roughened and scaly with red cracks in which appeared a slight serous exudate. Over both wrists the superficial skin seemed to be denuded and the condition gave the appearance of superficial ulceration. On the posterior surface of each hand a similar condition was noticed; the knuckles of the fingers were swollen and reddish and presented cracks and broken skin. May 9 the skin was dry and more scaly. The bowel movements were occasionally loose. Later thick crusts on the skin came away, leaving a pale and slightly scaly surface. The monkey is now again in his usual condition. These investigators admit that the interpretation of the above manifestations is not clear and state that they may be accidental or that they may indicate pellagra. If they do indicate pellagra they were brought about either by a living organism or by an unorganized toxic element. Pathogenesis. — The subject of the pathogenesis of pellagra as with every other disease is, of course, intimately associated with the etiologic factor, and until this is determined any statements concerning this feature of the disease must perforce be little more than conjectures. The sun has long been accused of exerting some influence over pellagra and has even been considered the sole etiological factor. Sandwith^^^ says the sun is certainly responsible for some of the skin eruption. As stated above those who hold to the photodynamic theory consider that the sun's rays acting on the exposed surfaces of the body sensitize a hypothetical toxin of ingested corn. 312 ENDEMIC DISEASES OF THE SOUTHERN STATES It has been suggested that the actinic rays of the sun are responsible for the erythema and others consider the direct heat of the sun the cause. It is a fact that those pellagrins who are more exposed to the sun's rays usually develop the skin eruption before the onset of the other manifestations and those who are well protected from the sun usually develop the gastro-intestinal and other symptoms before the erythema. Nevertheless it is not the sun which causes the erythema but the pellagra. Allessandrini and Scala'^' who proposed the theory of silica in drinking water contend that there is more or less afhnity for mineral salts exhibited by colloidal silica and they conclude from their experiments on dogs that "without doubt silica in the animal organism acts by accumulating mineral substances and produces in consequence a destruction of tissues." They trace the chemical changes and relations which the silica under- goes and further conclude. "Therefore it seems to us without doubt that the silica fixes the mineral salts on the proteins of the tissues with a continuous incessant action quite similar to the action of an enzyme or diastase." They finally arrive at the following conclusion, that ' ' pellagra is a malady caused by the forced retention of mineral salts which in turn produces a liberation of acids in excess of the needs of the particular organism ; or in other words, pellagra is nothing more than a mineral acidosis with all of its consequences." Gosio and Anatonini-^^ contend that pellagra is a form of anaphylaxis, that the organism becomes sensitized by the toxins produced by the parasitic moulds of Indian corn, and that repeated ingestion of these toxins brings on the phenomena. Long^-* who proposed the ameba-intoxication theory of the disease assumed that the skin lesions are caused by pressure on the nerves at their exit from the spinal canal due to a deposit in the foramina, and to degeneration of the nerves themselves as a result of toxemia. Jelks'^" thinks that pellagra is not a morbid entity but a series of symptoms-complex, due to the absorption of certain toxins or toxin-developing bacteria carried into the blood stream or to the central nervous system by ameba which he claims are almost constantly found in these cases. CHAPTER XIX PATHOLOGY OF PELLAGRA The pathology of pellagra presents no characteristic features which are absolutely constant, but certain morbid changes usually take place which serve as distinguishing factors. For example, there is usually anemia and more or less emacia- tion, but we have seen pellagra in well-nourished individuals. Again the eruption is a very constant manifestation but "pellagra sine pellagra" is not unknown. The pathologic findings described are usually those of the skin, gastro-intestinal tract and the central nervous system, although other organs and tissues are frequently involved. Skin. — The skin lesions are more or less characteristic. Among foreign writers, and to some extent among those of America also, it is customary to divide the skin manifestations into three stages, viz. : first, the stage of congestion or erythema; second, the stage of thickening, pigmentation and added scaliness; and third, the stage of atrophy. To us this seems an artificial classification and that the skin manifestations of pellagra do not present stages, so much as degrees of the lesions. The lesions of the skin in pellagra usually start as mild ery- thema scarcely distinguishable from the erythema of sunburn. They may, however, as Merk has shown, start as discreet maculae which last for a few days to a few weeks. The pellagra erythema is of a vivid red color and perhaps slightly darker in shade than erythema of sunburn. After a variable period of time a hyperkeratosis may take place and the lesions are covered with scales and shed-off epithelium. As a result of this process the tissues are swollen due to the increase of blood and serum to the derma, causing the skin to have a wrinkled appearance. In some instances there is a pigmentation following the desqua- mation while in others the skin is of lighter hue than before. 313 314 ENDEMIC DISEASES OE THE SOUTHERN STATES Frequently, instead of a hyperkeratosis, there may be super- imposed upon the erythema vesicular or bullous lesions. These may be quite large in size and are always monolocular. In a few days they gradually dry, leaving a thickened crusted condition of the skin. This class of lesions is not infrequently the seat of secondary pyogenic infection. Often the edema is sufficient to produce marked fissures. It not infrequently occurs that the bulla is broken by mechanical action and the surface of the lesion appears raw and bleeding. After this class of lesion has cleared, the skin is somewhat thinner than formerly and there is no pigmentation. The microscopic picture of the skin in pellagra is one very similar to erythema multiforme. It is evidently due to dis- turbances of the nervous system and the peripheral circulatory apparatus; in other words, it is an angioneurosis. The greatest pathologic change is seen in the superficial part of the corium, the most marked infiltration being found in the stratum papillare. With low power magnification the stratum corneum is seen to be more or less thickened while the stratum granulosum and the rete Malpighii are usually not involved. The upper portion of the corium usually shows a considerable inflammatory proc- ess while the subcutaneous tissue is more or less edematous. With the higher magnifications the hypertrophy of the corneum is seen to be quite marked. Usually more or less parakeratosis is demonstrable by the finding of nucleated cells in the upper layer of the corneum, and pigment granules are seen scattered through it. The only pathologic finding in the rete Malpighii is a shght infiltration of cells. The most marked cellular in- filtration is seen in the pars papullaris, especially around the blood-vessels. Collagen, showing edematous change and elastin are seen. The other layers of the corium show little or no pathologic change. Gastro-intestinal Tract. — Here again, as with the skin lesions, the pathologic findings, while usually quite marked, have no absolutely characteristic features. The tongue is usually swollen and more or less denuded and nearly always presents a bright red appearance. Along the PELLAGRA 31S edges and on the undersurface ulcerated areas may be seen and sometimes yellowish sloughs which bleed easily are found. The lips and cheeks also, in the worst cases show similar ulcera- tion and sloughing. The stomach often shows a chronic gastritis. The mucosa is frequently found pale, while there is more or less atrophy of the muscular coat. The intestines usually show a similar condition. There may be either anemia or hyperemia. Ulcers may be found along the entire tract but are more frequently seen in the ileum and jejunum. There is usually a thickening of Peyer's patches and the mesenteric lymph glands are often markedly enlarged. The histopathology of the gastro-intestinal tract in pellagra presents nothing absolutely characteristic. Sections of the tongue show a similar picture to sections of the skin. There is a desquamation of the epithelium and some infiltration of the tunica propria. Sections of the stomach wall show more or less superficial necrosis with destruction and exfoliation of the glandular epi- thelium. The gland tubules may show cystic dilatation with infiltration of connective tissue between them. The blood- vessels of the submucosa are usually dilated, while the muscular coats are more or less atrophied. As a rule the condition is less marked in the cardiac end than in the pyloric end. The microscopic picture of the intestines shows chronic in- flammation with atrophy and disappearance of some of the columnar cells. There is sometimes entire destruction of the epithehum, only a narrow line of necrotic tissue marking its location. Central Nervous System. — The most exhaustive study of the pathologic anatomy of the central nervous system which has been made in this country is that of Singer and Pollock.''^ These investigators found that the dura mater is usually thickened, streaked with increased formation of connective tissue and sometimes adherent to the pia mater. The pia- arachnoid is found to be cloudy, opaque, edematous and. thickened. This is most marked over the convexity of the brain, and at times the membranes are separated from the 3l6 ENDEMIC DISEASES OF THE SOUTHERN STATES brain by the collection of fluid. Occasionally instead of being separated from the brain by fluid the pia-arachnoid is adherent to the cortex. In the meninges of the spinal cord are seen similar pathologic findings to those found in the cerebrum. Small bony plaques are sometimes noted. No abnormalities are found in the basal ganglia, cerebellum, pons and medulla as a rule. 1. Pia Mater. — Microscopically the pia always shows rather marked change consisting of a thickening of the connective tissue with a proliferation of the fibroblasts. Occasionally the gha of the cortex invades the pia, especially in the neigh- borhood of the sulci. The most marked changes are found in the blood-vessels. An exudate, consisting of cells which are swollen and undergoing fatty degeneration, and fibrinoid pig- ment granules and lymphocytes, is often seen. This exudate is scanty compared with that found in cerebral syphilis, paresis, etc. These changes in the pia are most pronounced over the convexity of the brain and very rarely are severe. Similar findings are observed in the pia mater of the spinal cord. 2. Blood-vessels. — Singer and Pollock describe the pathologic changes which are found in the blood-vessels under two head- ings, acute and chronic, and state that the former may be re- lated to pellagra, while the latter certainly are not. The larger arterioles show the most evidence of chronic change. All the coats of the vessel are thickened while there is some proliferation of the cells, which are swollen and fre- quently are found to contain pigment granules. Some en- dothelial cells of the intima also are swollen and often contain granules due to degeneration. The vessels are usually sur- rounded by numerous fatty and fibrinoid granules, and some- times basophilic granules are seen. Granule cells {Ahraum- zellen) containing fatty and fibrinoid material are very often noted. In the smallest vessels also is seen to some extent the chronic thickening and occasionally splitting of the intima. Neither hyaline change of the vessel wall nor occlusion of the lumen is noted. The smallest vessels present the more acute changes. The intima is thickened by proliferation of the endothelial cells PELLAGRA 317 which are found either swollen or shrunken. Fatty degenera- tion is frequently seen and often the intima is spht, although few, if any, cells are found in the spaces thus formed. Pro- liferation, with swelling and distortion, of the muscle cells is seen. These are elongated, poor in chromatin and contain pigment of various kinds. Thickening of the adventitia with proliferating and degenerating cells is noted. Singer and Pollock state that in some cases these changes are very slight. These authors tell of a whole set of specimens from one case in which were found in the adventitial cells a number of meta- chromatic basophile bodies presenting various shapes; "rosettes curved and elongated masses with small projecting buds or lobules, etc." They further state that these bodies resemble very closely the bodies described by Borrel in carcinoma, and, slightly. Councilman's variola bodies. They stained a purp- lish red with thionin, similar in color to the nucleus of the speci- mens but as these authors were unable to demonstrate them again with an apparently identical technic they conclude that if they were not degenerative products, they were cell nuclei. Singer and Pollock state that in all cases there is more or less perivascular infiltration. This consists of vessel cells, pig- mented and degenerating lymphocytes, fatty and fibrinoid pigment granules, glia cells and granule cells. No basophile cells are noted, and no example of etat crible or blood cyst was seen. These authors state that there is nothing in the picture to indicate a local invasion of the nerve tissue with micro- organisms. 3. Neuroglia. — (a) Fibers. Increase of the glia fibers is noted in the outermost layer of the cortex, especially prominent in and about the sulci and around the blood-vessels. Numer- ous amyloid bodies are observed among these fibers. The glia fibers sometimes are found in the pia mater and cause it to adhere to the cortex. This proliferation of the glia fibers is also noted in the spinal cord, especially marked around the periphery and the central canal. Singer and Pollock state that while this increase of the glia fibers is sometimes quite ex- tensive it is never found as great as usually found in senile dementia. 3l8 ENDEMIC DISEASES OF THE SOUTHERN STATES {b) Cells. In regard to the cells it is stated that while several types of glia nuclei and cell bodies with thionin staining are found no definite conclusions can be drawn from them, since the normal limits of these cells are not well known. A large number of pyknotic distorted cells with long fibers, "star-shaped lanceolate, biscuit-shaped, and semilunar" nuclei are seen in the superficial layers of the cortex. The proto- plasm of the cells takes stains poorly, while many bluish-red or pink-staining granules are observed. The deeper layers of the cortex present glia cells containing a small dark nucleus rich in chromatin, and a small amount of poorly staining protoplasm. Here also are found cells with a pale nucleus often swollen and distorted and filling almost the entire cell, con- taining a few fine chromatin granules and sometimes one or two pink-staining nucleolus-like bodies. Occasionally a cell with a similar nucleus but with deeply staining protoplasm is seen. Two types of cells are seen in the white matter, one con- taining a small dark nucleus, while the other contains a large pale one. In the bodies of the glia cells of the cortex is noted marked fatty degeneration and pigment material staining blue, green and reddish with thionin. SatelHtosis is said by Singer and Pollock to be constantly present in a varying degree depending on the amount of chronic change in the ganglion cells. The satellites are sometimes found directly around a ganglion cell, even forming a fence around it leaving a space between them and the cell. Satel- Htosis is most marked about the cells undergoing degeneration and also the shadow cells. It is not present about the cells showing axonal reaction. The astrocytes are said always to be increased in number, but especially so in the deeper layers of the cortex and the white matter. This condition, however, is not so marked as in paresis or senile dementia. When stained by Alzheimer's Methods IV and V the cell processes are usually thickened and show darkly staining streaks of wavy outHne, although they may be small and thin and are frequently broken. The cell bodies vary in size. The large ones are more homogeneous. The protoplasm often contains PELLAGRA 319 granules corresponding to the Alzheimer methyl-blue granules which probably is a degenerative condition. Variously shaped nuclei containing granules are seen. Some of the astrocytes are observed near but parallel to the blood-vessels; others encircle them, but seem to bear no relation to them. In some cases cystic degeneration, not fatty, is seen. The significance of this condition is in doubt, but, according to Singer and Pollock, it suggests a degenerative condition. Rarely giant astrocytes are found. These investigators state that while the increase in the astrocytes is less than found in senile dementia they take issue with Kozowski in his assertion that this increase is the exception rather than the rule. They further state that the significance of the increase in astro- cytes is undetermined. According to Alzheimer, Wever and Schroeder it would seem to indicate the presence of an active process, while Orlow and others consider them more numerous in chronic conditions. Alzheimer considers of great importance the finding of the ameboid transformation of astrocytes and small glia cells, which are found by him mainly in recent and active diseases of the brain, such as infection deliria, alcoholic delirium, dementia prsecox in the acute stages, paresis, cerebral syphilis, etc., and never in old standing softening, old hemorrhages, old dementia prascox, etc. Singer and Pollock state that these ameboid glia cells are found in pellagra, often clinging to a vessel by means of the insertion process, but they draw no conclusions from such findings. 4. Nerve Cells. — The most marked changes in the cells of the cortex are found in the large pyramidal cells, which consist of a decrease in the number of cells, changes in their relative positions, and an increase in the glia elements. The changes in the ganglion cells are most marked and are considered by Singer and Pollock of great importance. These changes they divide into two classes: (i) the indirect or axonal types of reaction, and (2) the direct types. I. In the indirect or axonal reactions two grades of intensity 320 ENDEMIC DISEASES OF THE SOUTHERN STATES are seen, the first or typical reaction in which the cell is swollen and rounded, the nucleus displaced to the periphery, distorted, staining more or less uniformly with a pale color and containing a well-preserved nucleolus rich in chromatin; and the second or central chromatolysis, in which the cells are not swollen, the nucleus is well reserved with a darkly staining nucleolus, and showing a marked disappearance of the Nissl granules from the central portion of the cell. These changes are most marked in recent cases, that is, in those dying during or soon after an acute attack. Singer and Pollock state that the cells showing axonal reac- tion are, except in very severe degrees, capable of recovery and that the findings are probably due to the condition which causes the acute pellagrous attack. The widespread axonal chromatolysis involving especially the Betz cells and those of the column of Clark has been ob- served by all workers in pellagra with modern methods of staining. Singer and Pollock state, however, that this picture is identical to the one described by Meyer as central neuritis, and to one seen by them in a case of alcoholism in which there was nothing to suggest a history of pellagra. They therefore conclude that pellagra is not recognizable post-mortem, except by finding typical skin lesions, although this is contrary to the opinion of Kozowski. Singer and Pollock further state that these changes can be interpreted in only one way, namely, that they are reactions to "some harmful agent circulating in the blood, acting on the axis-cylinder processes of the neurons at some point in their course." Further, it seems clear to these investigators that various ultimate causes may account for the reaction while it is "conceivable that the actual excitant of the reaction is the same in all and a product of body metabolism under morbid conditions." 2. Direct cell reaction is due to direct injury to the cell and according to Singer and Pollock six types are observed as follows: Type I. — Cell body shrunken and distorted with crenated edges but in some cases normal in size, more or less uniformly staining, pale in color. Nucleus rich in chromatin. PELLAGRA 32 1 Type 2. — Similar cell bodies with pale nucleus which may be of the same color or lighter than that of the cell body which may be reticulated. Within the nucleus or nucleolus are granules staining a bluish green with thionin. In some of these the nucleus is lost, with or without the nucleolus. Type 3. — Shrunken, uniformly dark-staining cell body and dark nucleus sometimes filling almost the whole cell. Type 4. — Simple chromatolysis. Body normal or a little larger. Nissl granules are scattered diffusely throughout, rare- fied and pale or present only as a fine dust. Nucleus approx- imately normal in staining and position. Nucleolus dark. Type 5. — Shadow cells, a more extreme degree of the same type as the last. Nucleus absent. The outline of the cell indistinct. Type 6. — Vacuolated cells. Nucleus present. No Nissl bodies. The cell body contains vacuoles. The first four of these types of reaction are found constantly in all regions of the cortex, while Types 5 and 6 .are found in the majority of cases. These changes, especially Type 3, are found in the cells of the gray matter of the cord, principally in the posterior horns. That these reactions are due to intoxication of the cells is shown by the satellitosis which is here present. The following changes in the neurofibrils were found by Singer and Pollock: (a) Agglutination. (b) Fragmentation. (c) Loss of febrils (in small cells only with one exception). (d) A peculiar encircling of the nucleus and pigment masses with agglutinated fibrils. Pigment is found in all types of cell change as well as in normal staining cells in all cases, and is especially marked in the Betz, large pyramidal and other axonal reacting cells. The pigment is of various kinds, black staining with osmic acid, red with scharlach, and blue with nilblue sulphate. 5. Nerve Fibers. — Scattered degeneration of radial fibers of the cortex is shown by the Marchi method of staining. This is not seen in the superadiary or tangential fibers. 322 ENDEMIC DISEASES OF THE SOUTHERN STATES Degenerated fibers are seen in all regions of the spinal cord, the posterior columns being most involved. In the crossed pyramidal tracts the reaction is not more marked than in the other portions of the cord, in fact is sometimes practically absent here. Some degenerated fibers are seen in the anterior and posterior roots, and occasionally the number is quite large. 6. Amyloid Bodies and Pigment Granules. — All eases of pellagra show an excess of amyloid bodies, beneath the epin- dyma, along the blood-vessels, in the thickened glia of the most superficial layers of the cortex, the periphery of the spinal cord and around the central canal. The origin of these bodies is not certain, but they are found in chronic degenerative conditions such as the senium. The occurrence of pigment granules of fatty and fibrinoid nature in the tissues and perivascular lymph spaces is seen in all cases. By their most exhaustive study of the pathology of the central nervous system Singer and Pollock reach the following con- clusions: 1. The acute pellagra attack is accompanied by evidence of both acute and more chronic intoxication. 2. In common with other intoxicative conditions, the acute pellagra attack gives rise to a "central neuritis" reaction. 3. None of the changes are characteristic of this particular form of intoxication. 4. There is no evidence of a local infection of the nervous system with microorganisms. 5. From our cases it is impossible to determine whether the more chronic changes found in the absence of a recent pellagrous exacerbation belong to the pellagra picture. 6. There is no evidence to show that chronic vascular changes are essential to the picture of pellagra. Lungs. — No definite lesions of the lungs due to pellagra per se are found. This disease may be found complicated with many pathologic conditions of the lungs, such as pleurisy, pneumonia, edema, hyperemia and emphysema. It has been stated that pellagra is rarely comphcated by phthisis. PELLAGRA 323 Heart. — While this organ frequently shows changes from the normal such as hypertrophy, atrophy, hydropericardium and myocardial softening, none of these lesions can be ascribed to the pellagra itself. Microscopically brown atrophy and fatty degeneration are often seen. Spleen. — The spleen of most pellagrins is atrophied, although it may be found enlarged in some instances. Pancreas. — The pancreas is usually normal, but may be atrophied. Kidneys. — These organs may appear normal, but usually show some pathology, being nearly always diminished in size. Chronic interstitial nephritis is often seen, while fatty degenera- tion of the epithelium of the tubules is not uncommon. Adrenals. — The adrenals are said always to be normal. Liver. — Atrophy of the liver is very frequent, it often being decreased in size to half the normal. Hypertrophy may occur, while fatty infiltration is sometimes seen. Bones. — The most marked changes in the bones are seen in the ribs which are very frequently found to be fragile. Other bones are at times also fragile. The bones of the calvarium may be thickened although some- times they are thinner than normal. Muscles. — The muscular system is usually atrophied al- though it may be normal and even well developed. Fatty degeneration has been noted. CHAPTER XX CLINICAL HISTORY OF PELLAGRA As may readily be inferred a disease showing so varied and marked pathology as pellagra will have a symptomatology as varied and marked. This fact led to Lomborso's famous epigram, "there is no disease; only the diseased." Neverthe- less pellagra is a definite morbid entity and may be differentiated from other diseases. The clinical history of pellagra may be divided into those symptoms referable to the skin, those of the gastro-intestinal tract and those referable to the central nervous system. To these may be added certain general signs and symptoms. Most pellagrographers divide the clinical history of pellagra into stages, as follows: The prodromal stage, during which there is little deviation from the normal but a general malaise and vague undescribable symptoms; the first stage, during which the gastro-intestinal and skin symptoms are manifest; the second stage, which is marked by the nervous and mental manifesta- tions; and the third or terminal stage, in which cachexia is seen. While this artificial and arbitrary classification of symptoms is in some respects convenient for ease of description, pellagra does not by any means always follow such a regular course, nor can the stages definitely be separated by a sharp Kne of demarcation. Further, no definite period of time can be named as covering the course of the disease. Pellagra is essentially a chronic disease and as stated above is marked by more or less seasonal periodicity, exacerbations alternating with periods of remission. The average pellagrin will give a history of having "felt bad" for a varying time previous to the active outbreak of the disease. The first actual symptoms noted are usually those of the gastro-intestinal tract, red and coated tongue, dyspepsia with flatulence and distention, occasionally abdominal pain, and diarrhea. The 324 PELLAGRA 325 latter symptom may be replaced by constipation. Vertigo and headache are frequent and the deep tendon reflexes may be exaggerated. The skin manifestations usually occur early and as a rule select the exposed surfaces of the body. They may be the first symptoms noted. Sometimes at a very early date there are psychic disturbances, usually of a mild character, although as a rule they occur later in the course of the disease. The first outbreak may be mild in - ^^^'' P^ig. 70. — Showing wrinkled condition of skin following eruption. nature and pass almost unnoticed, to recur at a variable time, usually the following spring in an exaggerated form or the first outbreak may be severe in type. The skin eruption will be more marked and the gastro-in- testinal symptoms more severe, while the nervous and mental manifestations will take on a more serious aspect. The disturbances of motility are usually marked, such as muscular weakness, and even paralysis. The psychic nianifestations are most variable, ranging from the deepest depression to great excitability. There may again be periods of remission followed by exacer- bations, each one usually becoming more severe until finally 326 ENDEMIC DISEASES OF THE SOUTHERN STATES there is a most distressing picture of cachexia, dementia and paralysis and the chapter is closed with death. Incubation Period. — It seems paradoxical to attempt to as- sign an incubation period to a disease about the etiology of which so little is known, and it is a fact that the majority of writers who have so assigned an incubation period have done so on the assumption that the cause of the disease is known. Fig. 71. — Slight dermatitis of feet and ankles of negress. Thus Sandwith,^"' who so religiously holds to the spoiled- corn theory of the etiology of pellagra, considers the incuba- tion period to be from nine to twelve months in length. He bases his opinion on the fact that corn is harvested in Egypt in November and December, while in the majority of patients the disease begins in January. From these facts he assumes that the corn could not have become sufficiently spoiled in this time to cause the disease, and he therefore incriminates the crop of the previous season. Merk,'^- who also believes in the corn theory, states that the incubation period is from seven to nine months. PELLAGRA 327 Sambon,'-- the author of theSimuhum theory, is of the opinion that the incubation period is short, and of course bases his opinion upon the assumption that the bite of the insect is necessary to the development of the disease. He states that he has seen pellagra in infants of five months of age who have not been taken to the fields until two or three weeks previous to the appearance of the eruption; he therefore fixes the period of incubation at about two weeks. While the above-mentioned pellagragraphers are undoubtedly Typic eruption on backs of hands of gir! of sixteen. convinced of the correctness of their views, it seems to us that all discussion as to the incubation period of pellagra is irrelevant until the etiologic factor of the disease has been scientifically demonstrated. Skin S3Tnptoins. — While as stated above the symptoms of the gastro-intestinal tract are usually the first to be observed, it often occurs that the skin eruption develops first. The most frequent time of the first occurrence of the skin lesions is in the spring, but they may develop first in the fall. Recurrences in the fall following a spring eruption may occur. These manifestations are usually spoken of as an erythema. 328 ENDEMIC DISEASES OF THE SOUTHERN STATES but, as Fox^-- has pointed out, the erythema with which the lesions usually begin is of minor importance owing to the Fig. 74. — Extensive and severe eruption on arms. . comparatively short time it lasts, and dermatitis would be a more appropriate term. PELLAGRA 329 Fig. 75. — Rather unusual eruption affecting but small portion of backs of hands. Fig. 76. — Typic eruption on backs of hands and arms. 33° ENDEMIC DISEASES OF THE SOUTHERN STATES The most frequent location of the skin lesions of pellagra is the backs of the hands. The palms are rarely affected and the last two phalanges of the fingers sometimes are not involved, while the nails are never attacked. The eruption may extend to the wrist and for some distance up the extensor surface of the forearm. Occasionally the lesion may completely encircle r Fig. 77. — Extensive eruption of face and backs of hands, parallel to border of dermatitis. Note white band the forearm. The line of demarcation between the normal and diseased piortion of the skin is usually quite pronounced and the so-called "pellagrous glove" is not infrequently seen. A condition which we have observed in one case and have not seen described elsewhere, is a distinct narrow white Hne in the dermatitis about a half inch from the line of demarcation between the diseased and sound skin. This condition is shown in Fig. 77. Probably the most characteristic feature of the skin mani- PELLAGRA 331 festations of pellagra is the symmetry. This condition is most constant and may be considered almost pathognomonic, although the lesions on both sides of the body need not develop simultaneously. The lesions seem to prefer the exposed surfaces of the body Fig. 78. — " Butterfly " eruption on face of child two years old. and are found very frequently on the face, back of the neck, chest and dorsal surfaces of the feet. The attacking of the exposed surfaces is by no means constant, as the lesions are frequently found on the covered portions of the body. The upper arms, elbows, knees and thighs are often the seat of the dermatitis. Sometimes the external genitalia, the vulva 332 ENDEMIC DISEASES OF THE SOUTHERN STATES in women and the scrotum in men, are involved and the eruption has been noted on the buttocks extending from one cheek to the other, while complete involvement of the in- tegument of the body is occasionally observed. It is rare to see lesions on other parts of the body when the hands are not involved. The lesions on the backs of the hands may cover the entire surface or they may occur in spots 4 or 5 cm. in diameter with <-f- Fig. 79. — Desquamation of skin of backs of hands. areas of normal skin between. The spots may become confluent or they may remain separate. On the face the lesions may also occur in spots, the most frequent location being the alse of the nose, after which in the order of frequency the lesions occur on the forehead, cheeks and chin. The lips usually escape as do the ears and eyehds. The face may be the seat of a diffuse eruption known as the pellagrous mask. The lesions of the neck are very variable in character. The back of the neck alone may be involved or there may be a complete circle of the eruption corresponding to the exposed portion, such as in women accustomed to low-necked clothing or in men who leave the shirt unfastened at the neck. The PELLAGRA 333 so-called "Casal collar" is described by Mark as beginning on the back of the neck a little below the margin of the hair and Fig. 80. — Extensive dermatitis of arms and feet. (Dr. T. E. Sanders.) extending around the neck parallel to the lower jaw and several finger-breadths from it. The two lines meet on a level with the larynx above. The lower border is said to begin a little be- 334 ENDEMIC DISEASES OF THE SOUTHERN STATES low the vertebra prominens, pass around the root of the neck on either side and unite over the upper part of the manubrium. The pellagrous eruption of the feet is of rather frequent oc- Fig. 8i. — Back of same patient as shown in Fig. 80. currence. The dorsal surfaces alone are usually involved, al- though rarely the soles of the feet are affected. The line of demarcation is usually in the region of the malleolus, although the lesion may pass on up the ankle. While the toes are PELLAGRA 335 generally not involved there are exceptions, the great toe being most frequently the seat of the eruption. While the pellagrous dermatitis of the feet is most frequent in those who do not wear shoes and stockings, it is often noted in those who do and even in those who are bedridden. There is nothing especially characteristic about the skin lesions of the Fig. 82. — Casal's collar in negress. upper arms, elbows, knees and thighs except the symmetry. It is of importance not to confuse the simple roughening of the skin over the knees and elbows with the pellagrous eruption. Lesions of the external genitalia are not of rare occurrence and should not be overlooked. Dermatitis in the anal region, especially in patients with diarrhea, is sometimes observed. It is customary to divide the skin eruptions into "wet" and "dry" lesions depending on whether or not bullse are formed. As stated above, the usual beginning of the skin manifesta- 336 ENDEMIC DISEASES OF THE SOUTHERN STATES tions very markedly resembles a severe sunburn and often is indistinguishable from it. It is usually, however, darker in color without the usual pinkish hue of the erythema of sunburn. In dark-skinned individuals, especially the negro, the color of the eruption may take a grayish hue, while the normal pigment of the part deepens Fig. 83. — Extensive dermatitis on back. in color. The skin of the affected area is generally slightly puffed and a slight burning sensation is complained of, while there is some pruritis. At first the color disappears on pressure but returns when the pressure is removed. Later this phe- nomenon is not observed. The color of the eruption gradually deepens and when at its height is a reddish brown or chocolate shade, this depending upon the color scheme of the individual. The first eruptive PELLAGRA 337 symptoms may disappear in two or three weeks with exfoha- tion of the epidermis usually in light scales, although exfolia- tion may occur in large flakes. The area is left pigmented according to the severity of the lesion. As stated above, the pellagrous eruption may begin not as an erythema but with discrete maculae which may persist for two to three weeks and then disappear. ■Typic eruption on elbows. The so-called "wet" pellagrous eruption, as distinguished from the "dry" form just described, begins with the typical erythema, upon which in a short time are superimposed vesicu- lar or bullous lesions of greater or less extent. These lesions are always monolocular, and the' contents which in the be- ginning is sterile fills the space without, leaving the covering epidermis in a flaccid condition. 338 ENDEMIC DISEASES OF THE SOUTHERN STATES The bullae are not found in all regions where the dry derma- titis is found, but are located chiefly on the backs of the hands, the neck and occasionally on the feet and legs. Secondary infection with pyogenic organisms is not an in- frequent occurrence, the bleb being converted into an abscess. Following this there is edema of the underlying skin and that adjacent, with more or less inflammatory reaction. Fig. 85. — Typic dry eruption on liands and forearms. The bullae may be ruptured by some mechanical means and the lesions become granulating wounds, or they may gradually dry up, the covering being converted into a fine crust of a yellowish-green color beneath which the epidermis gradually becomes regenerated. Skin lesions developing from the original erythema in which fissures are developed have been noted. These at first are PELLAGRA 339 confined to the corium, but later invade the deeper layers. This type of lesion may heal, leaving little or no trace if infection does not occur. In the event of the latter a granulating wound develops, which is followed by cicatrization. Not infrequently, when thi,s class of lesion develops, blebs also are seen. Desquamation without erythema is sometimes seen, but this is certainly rare. Pustular lesions have been reported, especially on the face. The pustules vary from the size of a millet seed to that of a pea and are said to occur either without the erythema or com- plicating it. We have never seen a case of pustular pellagra except one in which the bullous lesions had become infected. Pellagra hemorrhagica is another rare form of the skin lesions. It occurs as small hemorrhagic areas beneath the skin and is seen on the backs of the hands, arms, face and neck. Pellagra sine pellagra, the disease without the skin manifes- tations, has been described. This condition will be discussed more fvilly later. The eruption of pellagra begins rather suddenly, reaches its maximum intensity in a variable time from several days to a few weeks, and retrogresses gradually, requiring from a few weeks to several months to disappear. After the first attack the skin remains pigmented for some time. Following attacks leave the skin much thickened, roughened, hard and pigmented. The color is a peculiar bronze or yellowish green. After several attacks the skin may become atrophied and lose its elasticity almost entirely. White spots are also often seen. Gastro-intestinal Symptoms. — The symptoms referable to the gastro-intestinal tract are usually, as stated above, the first to appear and undoubtedly they are the most important. Not only are there many symptoms present due to the actual demonstrable organic changes, but usually there are also many functional symptoms observed. Stomatitis of varying degree with glossitis is one of the most constant symptoms of pellagra. Often this condition is so mild as to pass unrecognized by the patient, and is detected only after a careful and painstaking examination by the physician. 340 ENDEMIC DISEASES OF THE SOUTHERN STATES The tongue is usually- denuded of epithelium and is always red, especially along the edges. It may be thick and beefy or it may present a pointed appearance. Along the edges there may be ulcers. The outer borders of the Ups are dry, and in severe cases present a more or less cyanotic appearance. The inner borders of the lips in severe cases are tender, raw and swollen. Black spots may be noted. The stomatitis and glossitis may be so severe that the tongue cannot be protruded and eating and swallowing may be ac- complished only with the greatest difficulty, while taking into the mouth of even weak acids is accompanied with considerable burning. Most pellagrins complain of a "bad taste" in the mouth. The breath is usually very foul and saliva may flow so freely that the patient cannot speak. The teeth are not always affected, but pyorrhea is not uncommon. There is sometimes a bilateral, non-suppurating, painless parotitis. The other salivary glands are usually normal in size. There is a sensation of heat in the mouth, throat and stomach; in fact, these symptoms may precede any noticeable pathologic change. This sensation of heat is undoubtedly due, in part at least, to the pathologic changes, but may also be caused by a neurosis. The appetite is usually diminished, although some patients are loud in their clamor for food. Some suffer from thirst, while others will only drink when forced to. The principle gastric symptoms are those of gastritis, dis- tention, belching, gastralgia, nausea and rarely vomiting except in advanced cases. It not infrequently occurs that a patient consults a physician for more or less vague indefinite gastric symptoms and is treated for the same for some time, when the typical stomatitis or skin eruption develops and the true nature of the condition is revealed. The distention and belching are often most severe causing the patient great discomfort. Gastralgia varies from the vague indefinite "hunger pains'' to most severe epigastric pains and bear no relation to the in- PELLAGRA 34I take of food. These are often mistaken for the gastric crises of tabes dorsalis, especially in the later course of the disease when the nervous system is involved. There is usually more or less epigastric tenderness. The gastralgia is usually intermittent even during the acute attack, but often persists after the dermatitis and other symptoms have disappeared, in fact, it may last in a more or less severe form until another acute attack occurs. The nausea of pellagra is generally not marked. It may occur early in the disease, but more frequently as a later manifesta- tion. Sandwith^"' states that vomiting does not occur. Niles'"^ says that in 200 cases vomiting was seen less than twenty times. Other observers find it a rather frequent ac- companiment to the final stages of the disease. We have recently had a case in which vomiting was an early and ob- stinate symptom. Roberts^"" is of the opinion that the burning pains are re- ferred, having a common origin with the burning sensations of the hands and feet, that they do not arise from a gastric con- dition, "but are rather due to cord involvements and impulses reflected through the sympathetic ganglia." With these views we cannot agree. In the first place these symptoms occur in the vast majority of cases long before any demonstrable nervous symptoms exist; and in the second place, the pathologic anatomy of the stomach in pellagra is usually sufficient to account for the gastric symptoms. One of the most frequent symptoms, and also one of the most difficult to control is diarrhea. However, instead of diarrhea there may be constipation, and not infrequently the two symp- toms alternate one with the other. Various investigators report that from 85 to 100 per cent, of their cases show diarrhea at one time or another. The time of the appearance of the diarrhea is somewhat variable. Very often it is the first symptom to be noted; however, it is not at all unusual for the three symptoms, diarrhea, stomatitis, and dermatitis to appear at nearly the same time. The development of the diarrhea is nearly always gradual, and its disappearance with the recession of the disease is also gradual. 342 ENDEMIC DISEASES OF THE SOUTHERN STATES In the beginning the diarrhea is usually of a spasmodic character and is accompanied with more or less pain and griping. The stool is dysenteric and muco-sanguinolent in character. It is hard for the patient to control the sphincter and often his clothing may become soiled. In the mild cases the diarrhea as described gradually improves with the other symptoms. In the severe cases it becomes worse. The stools assume a more watery appearance, and are of more frequent occurrence. Neither rest nor food influence the condition, there being as many bowel movements at night as during the day. There may be distention and paralysis of the intestines. Opium even in large doses has little or no effect, and the condition persists until a remission occurs or death ensues. In the severe cases the stool may be almost watery in consistence, of a hght gray color, often tinged with blood, and is usually very irritating to the parts. The odor of the pellagrous stool is most characteristic, some writers even going so far as to state that a diagnosis may be made upon this feature alone. Diarrhea is frequently the only symptom to appear in the fall after an acute pellagrous attack the previous spring, and this symptom is a rather good index to the severity of the disease; the less severe the diarrhea the more mild the case and vice versa. Often the cases which show constipation run a mild course. Should the patient become convalescent for a long time his appetite is variable, indigestion is usually brought on by slight indiscretions in diet, the flatulence and eructions are rather frequent. Nervous Symptoms. — The nervous symptoms of pellagra as usually described are most varied, and by most pellagra- graphers great importance is attached to them. Thus Sandwith^-' states that in the acute stage there is usually pain in the back, which may be so severe as to compel the patient to walk with body arched. The pain is elicited on both sides of the vertebral column by pressure over the spinal nerves. These symptoms generally disappear if the patient remains in the hospital for a month. PELLAGRA 343 The lower tendon reflexes are found disturbed in the majority of cases. According to Sandwith 46 per cent, show marked exaggeration, 29 per cent, slightly increased, 9 per cent, dimin- ished, 14 per cent, absent and 2 per cent, normal. While these reflexes are usually on both sides they may be asymmetrical. Ankle clonus is occasionally noted. Tremor of the fingers and of the tongue are often observed rather early in the disease, while in the later stage tremors are usually most marked. There is no typical "gait" in pellagra; nevertheless there may be a spastic gait. A positive Romberg is often noted. Vertigo is a frequent symptom, and usually occurs when the patient is standing, but may develop when the patient is in bed. Singer^^^ has pointed out that there are none of these symp- toms but may be observed in other severe intoxicative condi- tions such as tuberculosis. He further states that "faulty nervous organization seems for some reason to be associated with a predisposition to pellagra." Singer gives in detail the history of the only case which came under his observation in which there were evidences of chronic structural change in the nervous system. In this case there were noted occasional brief attacks of loss of power in the lower extremities following an attack of pellagra. These attacks lasted from fifteen to twenty minutes followed by apparently complete recovery. Following a second attack of pellagra there was atrophy of the small muscles of the hands and spastic paraplegia of gradual development. In spite of these manifestations Singer is of the opinion that the pellagra merely acted as a precipitating force and was not the cause per se of the nervous symptoms. Mental Symptoms. — For a long time it has been recognized that pellagra is very frequently accompanied by mental dis- orders, and of later years some investigators have even gone so far as to consider the involvement of the central nervous system (both nervous and mental symptoms) as the principle evidence of this disease. Others ascribe to it the cause of mental derangement and describe a pellagrous insanity. 344 ENDEMIC DISEASES OF THE SOUTHERN STATES This insanity according to most writers takes various forms; thus Marie^"* states that the most frequent form of psychosis in pellagra is mental confusion, with depressive states and with dehrium, while Sorbets, according to Babcock,-^^ says, "For ahenists, hallucinations are the chief characteristics, the pathog- nomonic phenomenon of pellagrous insanity." Green as quoted by Roberts^"" states that at the present time it is impossible to recognize a pellagrous insanity as an entity, and temporarily it is best to classify the mental condition as the "psychosis accompanying pellagra" and to subdivide the groups into types according to the symptoms. He therefore describes the following types: infective exhaustive, manic depressive, dementia praecox, general paralysis, senile, involutional melan- cholia and unclassified. Gregor^^'' has distinguished between the abnormal mental pictures directly attributable to pellagra, that is, caused by change in the brain due to the presence of the pellagra toxin and those which are secondary. Singer^'''' has proposed the following classification of the types of mental disorder associated with pellagra. Group I. Disorders directly due to the pellagra toxin (or toxins) . 1. Symptomatic depressions. 2. Delirious pictures. Group II. Disorders based on peculiarities in the personal make-up, the attack of insanity being precipitated by pellagra. 1. Manic depressive disorders. 2. Hysteria. 3- Psychasthenia. 4. Dementia prsecox. 5. Paranoic developments. Group III. Disorders due to definite brain changes with pellagra merely as a complication. 1. Arteriosclerosis dementia. 2. Senile dementia. 3. Presenile psychoses. 4. General paralysis of the insane. Singer considers the relation of pellagra to mental disturb- PELLAGRA 345 ance the same as that of other general diseases, and that while similar pictures as observed in pellagra are encountered in t3T)hoid fever, yet a separate grouping is not made. There may be cases in which the mental condition, such as delirium, is due to the action of toxins of the disease on the brain, or there may be a picture of dementia praecox or manic- depressive insanity which runs a similar course to those cases in which there is no infection. If pellagra develops in a de- mentia prsecox predisposed individual it will be the "lalt straw" to bring on the symptoms of the mental disease. Another view of the matter is taken by Singer, which is that the relation of the functional psychoses (including dementia precox) and pellagra is the reverse of the usually accepted theory. That instead of the pellagra being the cause of the psychosis, it may be that the psychosis or "the poor adaptability and peculiarity of make-up," predisposes the individual to pellagra. It is certainly a fact that pellagra very frequently develops among the chronic insane. Singer admits that "the relation of pellagra to the psychoses due to more definite brain disease or degeneration such as the presenile, senile and arteriosclerotic dementias, is a somewhat different question. He states that there is no doubt of the occurrence of pellagra with these conditions, and that they may predispose the body to pellagra or that the pellagra might favor the early development of involution change or even provoke arterial degeneration. While admitting the occurrence of pellagra with paresis. Singer cannot agree that there is a type of mental disturbance in pellagra comparable with the general paralysis of the in- sane. The picture which is generally so described is that of general intoxication with central and possibly peripheral neur- itis, and much more resembles the severe toxic forms of the infective fevers, such as typhoid, than it resembles paresis. In describing the symptomatic depressions which occur in pellagra, Singer states that they are by far the most frequent if cases outside hospitals for the insane are included. There is a marked depression, although there need be no objective signs of fatigue. The most striking characteristic of this class of 346 ENDEMIC DISEASES OF THE SOUTHERN STATES cases is that the mental symptoms are severe or mild as the other symptoms progress or recede. There is more or less hopeless sadness, thinking is difficult and general lowering of tone exists while apprehension without definite fear is often observed. This may be expressed by the patient by words or by restlessness. The delirium sometimes found in pellagra, Singer says, in the vast majority of cases, is the result of intoxication of the brain causing' changes in the functional activity involving the high- est cerebral levels. All degrees are met with in the mild cases; there are short periods of clouding of consciousness, while in the intervals the mind may be practically clear, yet with depression manifest. There is nothing to distinguish these conditions from those found in other intoxications, such as in typhoid. In pellagra, as with other conditions, these manifestations probably depend upon two factors, viz., the virulence of the toxin, and the ability of the individual to resist the poison. The relative frequency of delirium in pellagra may be due to the extreme virulence of the pellagra toxin or that the indi- viduals who contract pellagra are of poor nervous organization. The mental pictures of pellagra which are due to the person- ality of the individual, manic-depressive, dementia praecox, etc., are in no way distinguishable from those conditions in which pellagra is not present. There may be some delirium due to the intoxication which will make the diagnosis of the type more difficult, but this delirium will run a course parallel to the other symptoms of the pellagra. The frequency of mental disorders in pellagra is the subject of some differences in opinion. Wood-''' states that the "probable outcome of the ordinary types of pellagra will be insanity." Grimm-'- found 7.5 per cent, of 1,436 cases were insane. Roberts'"" states that it has been estimated that 10 per cent, of the pellagrins in Italy are insane, and considers that figure much too high for this country; in fact that 5 per cent, would be nearer. In regard to the various "t3rpes" of mental change found in pellagrins. Green's'"" table is as follows: PELLAGRA 347 Infective exhaustive 30 Manic-depressive 9 Dementia prsecox 9 General paralysis 2 Senile 3 Involution melancholia 2 Unclassified 5 Total. 60 Of the cases reported by Singer^ ^^ the following table shows the number and percentage of types: Types or Mental Disorders IN A Series oe Pellagrins Thirty-four unselected the author One hundred and thirty unselected cases seen by Total unselected cases Eighteen hospital cases selected for severity No. of Per cent. No. of Per cent. No. of Per cent. No. of Per cent. Group I: Symptomatic depression. . . Delirious pictures Group II: Manic-depressive disorders Hysterical disorders Dementia praecox disorders Group III: Arteriosclerotic dementia . . Presenile psychoses Senile dementia 9 2 I I 26.5 5-9 0.0 0.0 0.0 3-0 0.0 41 10 I 31-5 7-7 0.0 0.0 0.8 0.0 0.0 0.0 5° 12 I I I 30-5 7-3 0.0 0.6 0.6 0.0 0.6 0.0 10 2 I l(?) I I S5-S II . I 5-5 0.0 5S S-5 0.0 S-5 The following table shows the mental condition of the ninety- one cases seen by one of us at the Arkansas State Hospital for Nervous Diseases: Intoxication psychosis 55 Dementia praecox 20 Inbecility 5 Epilepsy 3 Senility 3 Manic-depressive 2 Paranoia i Arteriosclerosis i Paretic i Total 91 348 ENDEMIC DISEASES OF THE SOUTHERN STATES Special Senses. — ^Eye. — While the eyes of pellagrins are rarely normal there are, with possibly one exception, no pathog- nomonic findings in the eyes in this condition. This exception is one reported by Whaley,-*^ who states that as his number of cases is small (thirty-five) he wound not like to be too san- guine about its being pathognomonic. He further states that Lombroso found it. The symptom as described by Whaley "appears as if the retina; were thickened and gives the fundus reflex a peculiar indistinct yellowish color, and is not so pro- nounced as the senile reflex." The pellagrous eruption may appear on the eyelids and ptosis is not rare. Ectropion has been observed and conjunctivitis is a rather frequent occurrence. The ocular muscles and visual powers fatigue rapidly so that pellagrins are rarely able to per- form work which requires close inspection for any length of time. Cataracts are not infrequently observed. Diplopia, hemianopia, and photophobia, especially the latter, are very common. Marie^"* states that he has seen patients who remained for years with eyes closed owing to the fear of light. Bilateral and monolateral mydriasis is seen. If the condition is confined to one eye the right is the one usually affected. The pupillary reflexes, both to light and accommodation, are frequently sluggish. In very advanced cases are seen ulcers of the cornea, retinitis, choroiditis, retinochroiditis and inflammation of the optic nerve. Sclerosis of the retinal vessels and dilatation of the retinal veins are frequently noted. All these symptoms, as would be expected, appear more exagerated in the severe cases and less so in the mild ones. Marie^"^ gives the following table of the ocular findings of Ottolenghi, Manfredi and Flarer: Number examined 36 Depth of eye normal 12 Changes in the retina 15 Atrophy of arteries 12 Anomalies in fundus of left eye i Anomalies in fundus of right eye 6 Atrophy of optic nerve 3 Increase of pigment 3 Dilatation of the veins i PELLAGRA 349 The other special senses show Uttle or no derangements, and certainly nothing which may be regarded as pathognomonic. General Symptoms. — Cachexia, varying from slight loss of weight to great emaciation, is observed. The cachexia varies with the severity of the disease and especially with the severity of the diarrhea. In the first attack, which may be mild, there may be little or no loss of weight, while in subsequent attacks the cachexia often advances very rapidly. The temperature in uncomplicated pellagra is usually normal. Marie^*^ quotes the observations of Alpato-Novello on loo pellagrins. He states that 22,274 observations were made, the maximum temperature being 4i.5°C. and the minimum 35°C.; 2,059 were above normal and 5,251 below normal. Marie further states, that when fever does occur it is very ir- regular, rarely continuous and often remittent, almost always with an evening rise. The pulse rate in pellagra is usually increased, and its rate depends upon the severity of the disease. During the acute attacks it may run as high as 100 or more, gradually dropping to normal as a remission occurs. In the final stages it often runs as high as 130 or more, which is considered a grave sign. In spite of its rapidity the pulse is usually regular. It is, however, soft and compressible and as the disease progresses, decreases in volume. The blood pressure, as would be expected, is usually low, except in pellagrins with arteriosclerosis. Those cases which are seen in the terminal stages with marked cachexia show a very low blood pressure; one case in particular observed by one of us had a blood pressure of only 85 mm. As stated in the chapter on pathology, the heart frequently shows hypertrophy, atrophy, hydropericardium and myocar- ditis. Endocarditis with incompetent valves is rare, although it may be noted as a complication. The lungs show no characteristic symptoms, though as stated above pellagra may be complicated by various pathologic conditions in the lungs, which will display typical symptoms. Blood. — Most investigators have found that there is usually a deficiency in the blood stream in pellagra. Not only is the 35° ENDEMIC DISEASES OF THE SOUTHERN STATES total volume of the blood diminished, but the red blood cor- puscles and hemoglobin are below normal. The anemia is usually said to be secondary in type, that is, the decrease in the hemoglobin is greater than the decrease in the erythrocytes. Most investigators find either a normal or slightly increased leucocyte count. Lavinder-*'' in a review of the literature of the hematology of pellagra gives the findings of the following investigators: Carletti reviews the work of Lombroso, Capezzuli, Sepilli, Agostini and D'Ancona, and Randi, and noted that all found similar results, viz., reduction in both the red blood-cells and the hemoglobin which is fairly constant. Sepilli was the only one who reported the leucocyte count, which he found to be normal. In his own work Carletti found a constant slight reduction in the erythrocytes, a variable number of whites (never a leucocytosis), constant reduction in the hemoglobin (65-75 P^^ cent.) with a low color index. He found rather a large number of small red cells and the varieties of leucocytes in about the normal proportions with a possible increase in the large mononuclears ; eosinophiles were rarely found. Galesesco and Slatineano, according to Lavinder, found in thirty-one cases a constant diminution in the number of red cells (three to four million) without qualitative changes; hemoglobin (von Fleischl) from 70 to 90 per cent. ; slight leu- cocytosis (nine to ten thousand) of which the polynuclears con- stituted 55 to 78 per cent. ; lymphocytes 17 to 33 per cent. ; large mononuclears 10 to 22 per cent.; eosinophiles 2 to 4 per cent. These investigators conclude that there is a large mononuclear increase from which no deduction can be drawn as to etiology. In a study of thirty-four cases, Frateni using the Thoma-Zeiss counting apparatus and the von Fleischl hemoglobinometer, found a rather constant reduction in the number of red cells (three to four and one-half million) and in the hemoglobin (55 to 92 per cent.) leucocyte counts from 7,412 to 11,418. Differential counts showed polynuclears 55 to 76 per cent., large lymphocytes 2 to 5 per cent., small lymphocytes 18 to 39 per cent., eosinophiles 2 to 9 per cent. PELLAGRA 351 There was also a rather constant finding of macrocytes, microcytes and poikilocytes. This investigator states also that he found nothing resembling a protozoal parasite. Lavinder continues, that Manson states that Sambon and Terni in Italy, and Grigoresou and Galasesco in Roumania, have noticed a relative increase in the large mononuclear leucocytes. Fiorini and Gavini in non-alienated pellagrins found no leucocytosis, but a typical mononuclear increase and a decided eosinophilia. Masini, Lavinder states, "in a study of the eosinophile cell in the blood of pellagrins concludes that, contrary to what is found in many acute infectious diseases, there is produced in the pellagrous intoxication a conspicuous and decided eosino- philia, which occurs in cycles corresponding with the increase or diminution of the pellagrogenous toxines; that is, the more toxemia the greater the eosinophilia. He suggests that this constant eosinophilia may prove at times a valuable aid in the early differential diagnosis." Peserico found the following percentages of the varieties of leucocytes: polynuclears, 53.7 to 64.4; lymphocytes, 26.1 to 37.4; large mononuclears and transitionals, 1.2 to 7.7. These results, Lavinder says, in many ways seem decidedly discordant, but continues, that it may be concluded that a usually mild secondary anemia is very frequent; such qualitative changes in the red cells as are found are only such as would be expected. The only factor concerning the differential leucocyte count upon which there is an agreement, is that there seems to be a majority opinion of a definite relative large mononuclear increase. Lavinder's own work consisted of twenty-four ex- aminations. He used a Thoma-Zeiss counting chamber with Turck's ruling; in counting the red cells the four corner unit squares (twenty-five small squares each) were counted in two preparations, and if the results were discordant, a third prepa- ration was counted; in counting the leucocytes the whole ruled space was counted in two preparations, and again if results were discordant, a third preparation was counted. A new Dare hemoglobinometer which gave very uniform results in normal individuals was used for estimating the hemoglobin. 352 ENDEMIC DISEASES OF THE SOUTHERN STATES Lavinder states that most of the cases were of an advanced t3^e showing nervous and mental symptoms, and nearly all in negro women. The same time of day (morning) was chosen for making nearly all the counts. Many had been taking arsenic in some form with full dosage either at the time of the examination or a very short while previously. Lavinder's results were given in a table which shows that the red cell count ranged from 2,826,640 to 5,520,000, with an average of 4,474,000; the lowest hemoglobin reading was 38 per cent, (two cases), the highest 95 per cent, and the average 68 per cent., while the leucocytes varied in number from 4,000 to 17,000, with an average of 9,040. The average color index was .77. Lavinder does not tabulate his differential counts which were not made in all cases, but states that there was an increase in the large mononuclears and no eosinophilia except in cases complicated with round worms or hook-worms. Hillman^'^ in thirty-two examinations of twelve pellagrins found the average number of erythrocytes to be 4,758,000, the average hemoglobin 83 per cent., with the following percentages for the different varieties: Polynuclears 59- 13 per cent. Small lymphocytes 29 . 36 per cent. Large lymphocytes 4 ■ 63 per cent. Large mononuclears 2 . 59 per cent. Transitionals 1.3° P^r cent. Eosinophiles 2 . 73 per cent. Mast cells 0.34 per cent. Hillman in connection with Schule^^" later published the results of further investigations, which corroborated the find- ings described above. Of the ninety-one cases seen by one of us at the Arkansas State Hospital for Nervous Diseases complete blood counts were made on forty-eight. The table on page 353 shows the results. The average number of erythrocytes was 3,800,000, the average hemoglobin being 79 per cent. This gives a rather high average color index. The average number of leucocytes was 8,500 with an average PELLAGRA 353 SS 6,S78 6,222 7.090 S.S2I 7. 119 6,968 6,432 6,977 5.906 6.797 4.893 7.292 7.301 7.319 7.148 S.6S3 S.967 7,164 6,418 6.701 6.992 6.691 6,7SS 6,380 6.720 7.036 6.334 7,323 S,004 6,390 3.220 3,460, 3.950, 4.390, 2,000, 4.180, 3,920 4,020 4,640 3,360, 4.870, 3.320, 2,880, 5,590, 4.500, 4.240, 3,710 S,OSO 3.650 4.400, 4.430, 2.880, 3,680, 3.SIO, 3,410 3.880, 4.400, 4.130, 4.040, 3.960 4.350 3.670, 4.740, .3.180, 4.830, 4.370, 4.760 3.SSO, 4.230, 3.940, 4.670, 3.660, 3.580, .000 64 ,000 90 ,000 85 ,000 82 ,000 88 ,000 68 ,000 70 6,400 6,200 6,400 S,S6o 4.700 9.500 18,400 lO.SOO 15.400 4.400 8,000 5.500 11,600 7,700 12,200 6,200 6,200 7,600 6,600 9.600 11,000 9,200 6,400 4,600 7.400 10,200 8,200 7,600 6,200 18,200 79 5,600 5t 5,480 70 9,000 79 9,000 67 7,000 76 10,800 9,600 12,200 354 ENDEMIC DISEASES OF THE SOUTHERN STATES of 72 per cent, polymorphonuclears and 24.5 per cent. lympho- cytes. Eosinophiles were found in only twenty cases, the high- est percentage being 2 and that in only one case. Numerous investigators have made blood cultures from pel- lagrins, using every conceivable medium and under both aerobic and anaerobic conditions, but with uniformly negative results. While no definite data are to be found concerning the coagu- lability of the blood of pellagrins, in a rather extensive experience with such blood in making various tests and examinations we have never noticed any abnormalities in the time of coagulation. Wassermann Test. — Several investigators have applied the Wassermann complement fixation test to the blood of pellagrins. Bass,''' using an alcoholic lecithin antigen, reported six posi- tive reactions in pellagra. Later'*" he reported on ten more cases. Four of the sixteen cases were ruled out on account of malaria, syphilis or autopsy blood. Of the remaining cases eight were positive, seven of them being mild or chronic cases and one a severe case, while four were negative cases. Fox,-** using the Noguchi modification of the Wassermann, secured eight weakly or moderately positive and twenty-two negative reactions with thirty cases. Carletti, using the origi- nal Wassermann technic, tested the sera of twenty pellagrins, securing all negative results. With Bass' lecithin antigen he secured one positive, the others all being negative. One of us using the technic described by him"^ performed the Wasser- mann reaction on thirty-five pellagrins with uniformly negative results. In attempting to develop a complement fixation test for pellagra one of us prepared an antigen by macerating portions of the brain, spinal cord, skin (the area affected with the der- matitis) and intestinal mucosa washed thoroughly, and ex- tracting with alcohol. The technic employed was that described by one of us,'" while the amount of antigen used was an amount a little less than would slightly inhibit hemolysis with the pooled sera of several known normal individuals. The sera of ten pellagrins with active lesions were examined with absolutely negative results. PELLAGRA 355 Nitzesco^'* claimed to have been able to diagnose pellagra with a dialization test, using Abderhalden's ninhydrin technic with a maize albumin or zein. The reaction was particularly pronounced with eight cases with predominating gastro-in- testinal symptoms, and negative with fifty-six non-pellagrins and two pellagrins who had been in the hospital for over two years and had eaten no maize during this time and had had no symptoms except slight mental confusion at times. Another case with merely nervous manifestations was shown by the serologic test to be suffering from an otherwise latent pellagra and later developed other characteristic symptoms. Nitzesco's work has not been confirmed and in the light of the present evidence against the corn theory of the etiology of pellagra must be taken with the greatest reserve. Urine. — The urine of pellagrins shows nothing characteristic, although certain abnormalities very frequently occur. Marie'"^ states that in loo pellagra patients the 24-hour quantity showed an average of 900 c.c. with a minimum of 500 c.c. and a maximum of 1,900 c.c. He also found marked variation in the reaction as follows: 76 times slightly acid; 14 times neutral; and 10 times alkaline. The specific gravity ranged from 1,005 to 1,025. Albumin was found but twice in no urines. Most investigators find indican a very frequent constituent of pellagrous urine. Thus Watson'"^ found indican present 175 times in 180 urines. Meyers and Fine^^^ found indican in large quantities in all of the 14 cases, while the Illinois Pellagra Commission^"^ found a very marked reaction in all cases. Of the ninety-one cases seen by one of us at the Arkansas State Hospital for Nervous Diseases, urinalyses were made for thirty-nine. The table on page 356 shows the results. It will be seen that the specific gravity varied from 1,003 to 1,030 with an average of i,or8. The reaction was acid in all but two cases, it being neutral in them. Alkaline urine was not observed. Indican was found eleven times usually only in traces, although some cases showed a fairly strong reaction. Albumin was found five times, hyaline and granular casts 3S6 ENDEMIC DISEASES OF THE SOUTHERN STATES twice — once in a urine containing albumin and once in one free from that protein. Sugar was not found in any of the cases. Case No. Sp. gr. Reaction Indican Albumin Sugar Casts I 1,016 Acid Trace Negative Negative Negative 2 1,016 Acid Trace Negative Negative Negative 3 1,026 Acid Negative Positive Negative Negative 4 1,003 Acid Negative Negative Negative Negative 5 1,022 Acid Trace Positive Negative Negative 6 1,022 Acid Positive Negative Negative Negative 7 1,024 Acid Negative Positive Negative Negative 8 1,014 Acid Negative Negative Negative Negative 9 1,028 Acid Negative Negative Negative Negative lO 1,020 Acid Trace Negative Negative Negative II 1,022 Acid Negative Negative Negative Negative 12 1,018 Acid Negative Positive ■ Negative Negative 13 1,024 Acid Negative Negative Negative HandG 14 1,010 Neutral Negative Negative Negative Negative IS 1,010 Acid Negative Negative Negative Negative i6 1,030 Acid Positive Negative Negative HandG 17 1,020 Acid Negative Negative Negative Negative 18 1,016 Acid Negative Negative Negative Negative 19 1,020 Acid Negative Negative Negative Negative 20 1,026 Neutral Negative Negative Negative Negative 21 1,012 Acid Negative Negative Negative Negative 22 1,026 Acid Negative Negative Negative Negative -3 1,020 Acid Negative Negative Negative Negative 24 1,022 Acid Trace Negative Negative Negative 25 1,022 Acid Negative Negative Negative Negative 26 1,018 Acid Negative Negative Negative Negative 27 i,oiS Acid Negative Negative Negative Negative 28 1,020 Acid Positive Negative Negative Negative 29 1,004 Acid Negative Negative Negative Negative 30 1,020 Acid Positive Negative Negative Negative 31 1,020 Acid Negative Positive Negative Negative 32 1,028 Acid Negative Negative Negative Negative 33 1,026 Acid Trace Negative Negative Negative 34 1,016 Acid Negative Negative Negative Negative 35 1,010 Acid Positive Negative Negative Negative 36 1,010 Acid Negative Negative Negative Negative 37 1,028 Acid Negative Negative Negative Negative 38 1,008 Acid Negative Negative Negative Negative 39 1,018 Acid Negative Negative Negative Negative Gastric Contents. — The gastric contents following a test meal have been analyzed by numerous investigators. Lom- PELLAGRA 357 broso, Filippi and Roncoroni, according to Marie, ^"^ made four tests each of the gastric contents of two pellagrins. The test meal consisted of a porringer of soup, 85 grams of meat, 200 grams of bread and 100 grams of wine. The length of time the meal was allowed to remain in the stomach is not stated. The following table shows the results in detail: Analyses Case I Case 2 Reaction of gastric juice. Once neutral; three times slightly acid. Acid. Hydrochloric acid (Guns- Always negative. Always negative. berg reaction). Lactic acid (Uffelmann Present three times out of Always appreciable. reaction). four. Percentage of acidity. . . . Average 60 per cent. Average 50 per cent. Peptone (Biuret reac- Present. Present. tion). Digestion of starclies. . . . Twice complete; once Three times complete; arrested in the second once arrested in the stage. first stage. The following table is part of one quoted by Roberts'"'' from the work of J. Clarence Johnson: No. Test meal Case No. Test meal I HCl - R - II HCl - R -i- 2 HCl - R -f 12 • HCl - R -1- 3 HCl - R - 13 HCl - R - 4 • HCl - R + 14 G -1- F 30 T 38 S HCl - R + IS G -f F 24 T 42 6 G -1- F 36 T 66 16 G - F 18 - T 38 7 G -f F 38 T 74 17 HCl - R -H 8 HCl - R - 18 HCl - R - 9 HCl - R -h 19 HCl - R - G -h F32T50 20 HCl - R - HCl = hydrochloric acid; R = renin; F = free (presum- ably free HCl, L. T.); T = total acid; G = Gunzburg's test. It is not stated what test meal was used by this investigator nor the length of time it remained in the stomach. Nisbet-^^ made fifteen analyses on ten cases but he also failed to give data concerning the test meal and the period of diges- tion. The following table is compiled from his findings: 3S8 ENDEMIC DISEASES OF THE SOUTHERN STATES Case No. T. A. Free HCl Ferments Mucus 30 28 80 40 28 33 24 18 56 76 42 22 40 5° 4 35 10 4 8 4 24 39 20 8 19 20 XXX Diminution Normal XXX XXX Diminution XXX Normal Normal XXX XXX XXX Normal XXX XXX 3. Second analysis 3. Third analysis Normal Normal 4. Second analysis Excess 6 7 7. Second analysis Excess Normal Normal 8 9 Normal Excess It will be seen from the above that the most constant find- ings in the gastric contents in pellagrins is a diminution in the total acidity and the free hydrochloric acid. This is no more than would be expected from the pathologic findings and cannot be considered at all pathognomonic. Feces. — The feces of pellagrins vary greatly in consistency and volume. The consistency varies with the degree of diarrhea or constipation, from watery stools to hard stools, and according to Myers and Fine^^^ the daily elimination varies from 60 to 700 grams of moist feces, yielding 20-40 grams of dry excrement, the moisture varying between 75 and 95 per cent. There is usually an increase in the undigested food particles, especially muscle libers, starch granules and fats. The fact that the feces of pellagrins very frequently contain amebas, which are considered by some of etiologic significance, has been mentioned in the chapter on etiology. Other animal intestinal parasites such as uncinaria, strongyloides, trichiuris, ascaris, etc., have been found but are without doubt merely incidental and bear no relation to the etiology of the disease. The fecal flora of pellagrins has been the subject of study by numerous investigators who have hoped to discover the etiological factor. McNeaP^" found that there were present unusual quan- PELLAGRA 359 titles of certain types of bacteria which are normally found in the intestinal tract, such as B. bifidus, B. welchii and micro- cocci, as well as a large number of organisms not found in normal feces. McNeal states that none of these changes appear constant. During the acute attack when diarrhea is present the Gram-positive cocci are nearly always abnormally numerous and Gram-negative bacilli less numerous than normal. McNeal continues that these changes are also ob- served in the subacute cases and might persist to a slight degree after recovery from the skin lesions. They are nearly constant, but are such as might be expected as a natural result of digestive derangement. This investigator further states that there was no indication that a substitution of normal bacteria by abnormal ones occurred. Spinal Fluid. — The spinal fluid of pellagrins has been the subject of investigation by several workers. Marie^"^ states that the spinal fluid is found to be negative. Boveri,^'*- on the other hand, found an increase in albumin and a slight pleocytosis in the spinal fluid of pellagrins. This is somewhat in accord with the findings of Hindmann-^^ who in 191 2 reported the results of the examination of the spinal fluids of over ninety insane pellagrins. He found an average cell count of 16.69 cells per cubic millimeter, with 64 as the maximum where no complication existed. Seventy-four, or over 87 per cent., of eighty-five specimens showed increase in globulin by Noguchi's butyric acid test. Later Hindmann'^'*^ revised his conclusions to a certain ex- tent, stating that some of the cases in which a pleocytosis and increase in globulin exist show positive evidence of syphilis, although "many cases have shown a decided increase in globulin and slight increase in cells, and invariably gave negative Wassermann reactions." The Illinois Pellagra Commission^** found the spinal fluid of pellagrins without increase in the cellular elements and globulin and sterile. Lorenz,"^ who has made the most detailed study of the spinal fluid in pellagrins yet reported, after examining 153 fluids from 106 cases of pellagra reached the following conclusions: 360 ENDEMIC DISEASES OF THE SOUTHERN STATES 1. A lymphocytosis of the cerebrospinal fluid does not occur in uncomplicated pellagra. 2. Globulin excess is only occasionally observed. 3. Lange's colloidal gold chloride test is uniformly negative in pellagra. 4. The Wassermann is negative with a few exceptions. In this investigation the exceptions were moribund cases which gave weakly positive reactions with blood serum. 5. The spinal-fluid findings would seem inconsistent with a conception that pellagra is an infectious disease of the central nervous system. In a limited number of cases the findings of one of us have been in accord with those of Lorenz. In six cases upon whom lumbar puncture was performed at the Arkansas State Hospital for Nervous Diseases the spinal fluid showed no pleocytosis nor increase in globulin and the Wassermann was negative. Types of Pellagra. — While pellagra is without doubt a morbid entity showing many characteristic symptoms and lesions, it very frequently assumes different forms, certain symptoms predominating, so that various types of the disease have been described. One of the most interesting conditions seen in pellagra is that described as typhoid, the so-called typhus pellagrosus. This is a most unfortunate term, for, while pellagra is occasionally complicated by typhoid, there is nothing in the condition usually termed typhoid pellagra to warrant this name. This condition is, however, characterized by great prostra- tion. It may begin either as an acute outbreak developing suddenly, or as an incidence to the chronic course of pellagra, or finally it may mark the fatal ending of the disease. Fever is usually present to a more or less marked degree, the temperature ranging from 99° to io5°F. The fever is con- tinuous, without morning or evening variation. The pulse is rapid, rarely falling below no, and may run as high as 130-140. This height is out of proportion to the temperature, which is the reverse of the condition in typhoid fever. The pulse is small and often irregular. The gastro-intestinal symptoms are accentuated, the sto- PELLAGRA 361 matitis and gastroenteritis being present to a marked degree. Diarrhea of a persistent type is seen, the stools being as a rule of watery consistency. The mental symptoms are nearly always aggravated. There may be delirium or there may be stupor. The nervous phenomena are most marked. Tremors of the hands, tetanic contractions, convulsions, and opisthotonos are seen. There may be incontinence of the urine and feces. The course of the attack is usually short — from one to two weeks — and nearly always ends fatally, often with a terminal bronchitis. Recovery from the attack may, however, occur, but there is always a recurrence. Pellagra sine pellagra, mention of which has been made above, is a condition in which, as the term implies, other symptoms of pellagra than the skin lesions alone are present. Whether or not pellagra can exist without the skin manifestations being present at some time during the course of the disease is a moot point. Lombroso as well as Strambio recognized this condition, the former considering that it appeared only in an hereditary form. It seems to us that if pellagra sine pellagra does exist it is an extremely rare condition, and that in any given case the skin eruption has either already occurred without recognition and has faded or it will occur. Most cases exhibiting other symptoms of pellagra will, upon a careful anamnesis, give the history of some sort of skin manifestation attributable to pellagra, perhaps a severe sunburn or a roughening of the skin of the elbow. Other types of pellagra have been described, such as cerebral, spinal, tabetic, spastic, gastric, atrophic, cutaneous, enteric, etc., depending upon the symptoms which are predominant. Duration. — The duration of pellagra is most variable. The severe acute attacks that sometimes occur may end fatally in from one to two weeks or the disease, which is, as has been reiterated, a chronic one, may last with recurrences and periods of remission for five, ten, fifteen years or longer. Sambon^-- states he has seen pellagrins who declared they had had the disease for twenty, thirty or more years. He tells of cases 362 ENDEMIC DISEASES OF THE SOUTHERN STATES eighty years of age who claimed to have been pellagrous since childhood. Albright'*^ gives the following concerning the duration of the disease: Number of cases To I year 160 To 2 years 67 To 3 years 34 To 4 years 13 To s years 6 To 6 years 2 To 7 years 3 To 8 years 7 To 10 years i To II years 3 To 15 years i Unknown 19 Of course the duration of pellagra will depend upon the severity of the symptoms. As stated, the acute attacks sometimes terminate in death in as short a time as one week, or they may last as long as three months, a remission following and the disease recurring again the following year. The number of recurrences will, as can readily be seen, de- pend upon their severity, the first, second, third or later attack proving fatal, or the attacks may be mild, extend over a period of years, and the patient succumb to some intercurrent disease. Complications. — As may readily be imagined, a disease so chronic in its nature as pellagra will very frequently be com- plicated by other diseases. This is certainly true, and there is scarcely an ill to which human flesh is heir which may not be found in conjunction with pellagra. As has been mentioned above, pellagra has been found very frequently complicated by ankylostomiasis and amebse by various investigators, and according to Sambon^"*^ the infection with hook-worm disease accounts in a large measure for the anemia found in pellagrins. Other intestinal parasites found more or less frequently complicating pellagra are Ascaris lumbricoides, Trichiuris irickiura, oxyuris vermicularis , Cerco- monas hominis and Hymenolepis nana. PELLAGRA 363 Sandwith^^^ says that in Italy pellagra is often complicated by alcoholism, syphilis and malaria, but that in Egypt alcohol plays a small part. He finds it, however, frequently associated with ankylostomiasis, bilharziosis, and favus of the scalp. Alcoholism is certainly a frequent complication in this country, and Marie'"^ considers that it may be difficult to determine which of the symptoms are due to pellagra and which to alcohol. Tuberculosis is a rather frequent complication of pellagra and may be found affecting either the lungs or other portions of the body, especially the intestines. Sambon'^^ states that in Italy pellagra is frequently found in conjunction with scurvy. That pellagrins are also not infrequently syphilitics is un- doubted. This is borne out by the statements of many ob- servers — Marie, '"^ Sandwith^" and others. It has been pointed out above that pellagra not infrequently develops in the insane, even in individuals who have been patients in insane hospitals for many years. It may therefore be said to complicate any of the psychoses. (See page 359.) Many pellagrous women are sufferers from gynecologic com- plications, dysmenorrhea, amenorrhea, menorrhagia, leucorrhea, etc., and in male pellagrins a urethritis is not uncommon. According to Lavinder^"*^ certain investigators, especially in Italy, consider that chronic alcoholism may produce in its victims a condition much resembling pellagra, even including skin manifestations similar to those of this disease. This con- dition comes under the classification of pseudopellagra according to the Italians, but Lavinder considers it a true pellagra. Roberts'"" gives the following table showing the complica- tions seen by him: Number of patients 31 Pulmonary tuberculosis 10 Syphilis S Valvular heart disease 10 Arteriosclerosis 6 Chronic nephritis i Enlarged thyroid 2 Bronchitis, chronic i Drug habit i 364 ENDEMIC DISEASES OF THE SOUTHERN STATES Albright''" in an analysis of 298 cases gives the following table of complications: Hook-worm. 10 Tuberculosis 18 Mental 4 Age 8 Invalid 4 None 168 Syphilis 6 Typhoid disease 25 Indigestion 4 Epilepsy 3 Alcoholism 2 Other diseases 46 Pregnancy and Pellagra. — Mention of a possible relation of pregnancy in pellagra as a predisposing cause of the malady has been made above. Saunders-^^ states that 17 per cent, of pregnant pellagrous women are liable to abort, to give birth to still-born infants, and at delivery to post-partum hemorrhage. This author further states that gestation and lactation, especially when frequent, predispose to pellagra, and that parturition is often an exciting cause for the outbreak of the dermatitis. Recurrences. — In what has gone before we have made use of the term recurrences in describing the repeated outbreaks of the pellagrous symptoms, but it is not an absolutely proven fact that these repeated outbreaks are recurrences and it is recognized that they may be reinfections. It seems to us, however, that the well-known fact of certain individuals suffering from repeated attacks of pellagrous symptoms year after year and the comparative rarity of those suffering from one attack and remaining well is almost proof of the theory of recurrent attacks. However, we admit that this question cannot be settled with finality until the etiologic factor is known, or at least until some means of determining when a pellagrin is cured other than the absence of pellagrous symptoms is developed. Pseudopellagra. — This term was first applied by Roussel to a certain symptom-complex which, while resembling pellagra to a certain extent, was to his mind not related PELLAGRA 365 to that disease. Pseudopellagra has received scant atten- tion in this country, and such attention as it has received is more or less in the nature of ridicule of the idea. How can there be a pseudopellagra when the essential nature of the disease is unknown? Of course most of those who employ this term believe in the corn theory of the etiology of pellagra and there- fore make the disease conform to the supposed etiology. That is, if a symptom-complex resembling pellagra develops in an individual who does not use, nor has not used, maize, it is termed pseudopellagra. Of course inasmuch as the etiologic factor of pellagra is unknown, we admit it is possible that there are other conditions which resemble this malady but are distinct from it. Thus, if the disease is due to a parasite, there may be similar parasites which cause similar clinical pictures but when the cause is known will be readily differentiated. A similar condition is found in typhoid and paratyphoid infections, which show great similarity — and which are caused by very similar bacteria but which may be differentiated by cultural procedures. The following case observed by one of us at the Arkansas State Hospital for Nervous Diseases is illustrative: Case No. I. — J. S. U., white man, aged twenty-two years, single, college student. Family History. — His father is said to have shown signs of mental derangement for the past ten years, being of a sad disposition and continually wanting to "trade." He was brought to the Arkansas State Hospital for Nervous Diseases in October, 191 1, where he remained for six months when he was discharged. Eight months later he again developed acute mental symptoms and when upon his way to the above hospital escaped and has not been heard of since. The patient's grandmother also was said to have been insane. Previous History. — No history of previous illness was ob- tained, the patient stating that he had been healthy all his life. Present Illness. — The patient states that an eruption on the backs of the hands has appeared each spring for the past six years, seeming to grow a little worse each time. Attacks were accompanied by diarrhea and sore mouth. He says that 366 NDEMIC DISEASES OF THE SOUTHERN STATES the duration of the present attack has been longer than any other. Examination July 25, 191 3. — The patient is not emaciated, the muscles being well formed and firm. The general nutri- tion is good. The chest is full and well formed, expansion is thoracic-abdominal in character. The lungs are negative to auscultation, palpation and percussion. The heart is normally situated and there are no murmurs audible. His pulse is of good volume, medium tension and regular. The rate is 96 per minute, reclining posture. The systolic blood pressure is no taken in the right arm, patient in reclining posture. The abdomen is negative and the spleen and liver are not palpable. The tongue is moist and only slightly coated and the teeth are in fair condition. The skin is dark over the entire body and is free from eruption, except beginning at the elbow on each arm and extending down over the backs of the hands and forearms there is a dry con- dition and the superficial layer of the epidermis is exfoliating in places. Blood Examination. — Erythrocytes 2,870,000, hemoglobin 58 per cent., leucocytes 17,000. A diagnosis of pellagra was made, but on account of lack of sufficient evidence no diagnosis of a psychosis was made and the patient was paroled August 2, 1913. For a few weeks his condition was favorable, but he soon developed symptoms of restlessness and insomnia and attempted suicide, and was therefore readmitted to the hospital November 27, 1913. At this time his cutaneous manifestations were most marked, and he soon developed diarrhea and fever. A Widal test was negative as was a Wassermann upon his blood. The spinal fluid showed a negative Wassermann, three lymphocytes per cubic millimeter and no increase in globulin. He was placed upon sodium cacodylate i grain three times a day, but steadily grew worse. On December 12, 1913, he received 0.3 gram neosalvarsan intravenously. On December 15 this treatment was repeated. December 16 his temperature became subnormal and he gradually passed into coma, dying Dec. 17, 1913. PELLAGRA 367 Case No. II. — H. M., white man, aged thirty-nine years, no occupation. Family History. — Four members of the immediate family have been addicted to the use of morphine. No cases of pellagra have occurred in the family. Previous Illness. — He has had very little sickness, none of a serious nature. About twenty years ago he began the use of mor- phine and is now taking 25 to 30 grains daily. He has abused alcohol for a number of years and has been drinking regularly for the past three months. He smokes about a sack of tobacco daily as cigarettes. The regular weight is about 200, now weighs 160. Present Illness. — About four weeks ago the legs began to ache, then got weak and numb and began to tingle. They pain considerably now. He feels very weak from the knees down but is strong elsewhere. The eruption began on the backs of the hands three weeks ago. Four or five weeks ago the mouth became sore and is still inflamed. He has no appe- tite and is drinking a pint of whiskey daily. The bowels are fairly regular. Examination May 6, 1914. — The temperature is 99:^5, the pulse no, and the blood pressure 195. The radials are not palpable. The apex beat is normally located and there are no adventitious sounds, excepting an accentuation of the aortic sound. The lungs are negative. The tongue is coated in the center and red and sore looking along the sides; the gums are sore and there are ulcer patches on the cheeks. The liver is palpable half way between the costal margin and the umbilicus, the upper border being normally located. The knee jerk is absent, the pupils normal, and the Romberg sign is present. The eruption on the backs of the hands is symmetrical, extending from the wrists to the knuckles, being more intense toward the radial sides. There is a suppurating area on the right hand near the base of the index-finger. The urine has a specific gravity of 1,020, acid reaction, contains no sugar but an abundance of albumin and some bile; microscopically are seen numerous cylindroids and a few hyaline casts; the hemo- globin is 90 per cent, and a stained blood film is negative. 368 ENDEMIC DISEASES OF THE SOUTHERN STATES The patient was started on small daily injections of iron cacodylate, but on account of its effect on the urine this had to be discontinued after a few injections, the Hot Springs baths being continued daily. On May 25 a diarrhea began which lasted about a week. By June 2 the hands were nearly healed, Beck's bismuth paste having been used. The mental condi- tion was normal except when the whiskey was diminished a mild delirium supervened. The patient continued to drink and use morphine until in December, 1914, he was committed to an institution for the cure of those habits. After his release in March, 1915, he remained free from the morphine habit but resumed the abuse of whiskey. The only symptom which reappeared in the spring of 191 5 was the symmetrical lesion on the backs of the hands, and at the present writing the patient is free from any symptoms of pellagra. CHAPTER XXI DIAGNOSIS OF PELLAGRA Owing to the fact that the etiology of pellagra is unknown there is no laboratory procedure, such as the exaraination of the blood for a parasite, as in malaria, or the feces for ova, as in hook-worm infection, which will aid in the diagnosis. So it is upon the symptomatology past and present that the phy- sician must rely. The diagnosis of this disease when the classical symptoms — dermatitis, stomatitis, diarrhea and nervous disturbances — are found presents little or no difficulty, but it is in those cases in which some of the above-mentioned symptoms are absent or which are complicated by other diseases that try the acumen of the most experienced physician. One of the most important factors in arriving at a diagnosis in pellagra is the anamnesis, which should be most thorough. If no eruption or evidence of past eruption is present, most diligent inquiry should be made concerning a severe sunburn or burning sensations of the hands, feet and face. A thorough investigation should be made into a history of sore mouth, coated tongue, indigestion and diarrhea if these symptoms are not present, and finally a thorough interrogation concern- ing abnormal nervous and mental states, especially depression and excitability, should be made. Skin Lesions. — As stated above the most frequent location of the skin lesions of pellagra is the backs of the hands, and their most typical feature is their bilateral occurrence, and finally, that the line of demarcation is most clear cut between the diseased and sound skin; and while the erythema does occur on any part of the body surface, the diagnosis of pellagra would be unjustified in the absence of the symmetrical lesions on the exposed surfaces of the body, unless other symptoms are most marked. 24 . 369 370 ENDEMIC DISEASES OF THE SOUTHERN STATES Menage'^^ considers the shriveling and furfuraceous ex- foHation of the horny layers of the epidermis described above as absolutely characteristic of pellagra, whether accompanied or not by the whole symptom-complex. The most common condition which must be differentiated from the pellagrous eruption is the erythema of sunburn. The two conditions are strikingly similar, the pellagrous lesion, however, usually being darker in shade than the sunburn. This is especially noticeable in blonde individuals. The sun- burn may be bilateral, on the backs of the hands, and the line of demarcation most distinct. If such is the case, in the absence of other symptoms of pellagra a diagnosis cannot be made at once, and the future course of the erythema must be noted. A sunburn, if not severe, will usually fade in the course of a few days leaving nothing more than a slight pigmentation, while the color of a pellagrous eruption will deepen to a reddish- brown or chocolate shade, and either disappear in two or three weeks with exfoliation of the epidermis or go on to the bullous state. A severe sunburn may result in a dermatitis with ves- icle formation, and present an impossible problem for differen- tial diagnosis from pellagra in the absence of other symptoms. Eczema, especially of the vesicular tjqoe, might be mistaken for pellagra, but is differentiated by the persistence of the vesicles and by the distinct line of demarcation in the latter disease. Erythema multiforme often presents an appearance similar to the pellagrous eruption and is sometimes most difi&cult of differentiation. Here again the symmetry, the line of demarca- tion and the symptoms of pellagra not referable to the skin will serve as distinguishing features. Pellagra may be differentiated from pityriasis rubra pilaris by the absence of itching (usually), the configuration and the associated symptoms. Not infrequently pellagra may be mistaken for vitiligo, es- pecially if seen during exfoliation. The history of the condition will usually clear up the diagnosis, as vitiligo is as a rule of insidious growth and does not begin with an erythema. The common roughening of the skin of the backs of the hands frequently seen in men and occasionally in women who are PELLAGRA 371 continually exposed to the weather has been mistaken for the pellagrous eruption. This error is especially likely to occur if the patient is suffering from stomatitis or diarrhea. The absence of a marked line of demarcation in these cases should serve as a distinguishing feature. Acrodynia is mentioned by most pellagrographers as a disease which may be mistaken for pellagra. This disease, which is of obscure origin, begins with anorexia, nausea, vomiting and diarrhea, followed by swelling of the face, hands and feet, and injection of the conjunctivae. Soon symptoms of the nervous system develop, such as prickling and burning sensations. In the beginning there is marked hyperesthesia of the extremities which is followed by anesthesia. Severe pains in the extremities are characteristic. The skin manifestations make their ap- pearance early in the form of erythematous spots, first on the hands and feet, especially on the palms and soles, and later spread to the arms and legs and even to the trunk. The portions of the skin affected desquamate, are thickened and brownish and may even take on a black pigmentation. It usually runs a favorable course of one or two month 3, but may be fatal in debilitated individuals or in those of advanced years. Acrodynia should not present much difficulty of differentia- tion from pellagra owing to the main seat of the eruption (palms and soles) which is rare in the latter disease, the original marked hyperesthesia followed by anesthesia, and the usual short course and favorable outcome. Pellagra has undoubtedly often been mistaken for syphilis, especially before pellagra was recognized in this country. The characteristic location of the skin lesions, the absence of history or evidence of a chancre or enlarged glands, and finally the negative Wassermann test (certainly in the vast majority of cases) will serve to differentiate the two conditions. Scurvy and leprosy have been mistaken for pellagra and vice versa but these conditions should offer little or no difficulty in dif- ferentiating when a careful history and examination are made. Gastro-intestinal Symptoms. — There are very few conditions other than pellagra in which the classic gastro-intestinal symp- toms are observed. 372 ENDEMIC DISEASES OF THE SOUTHERN STATES In sprue is found a gastro-intestinal syndrome which in many respects very closely resembles that of pellagra. There is more or less stomatitis, gastric indigestion with distention and diarrhea. In a well-marked case of sprue it is impossible to differentiate the stomatitis from that of pellagra except by observing the other symptoms. The diarrhea is also of a similar nature to that of pellagra, except that it maybe the stools are more copious and of a so-called yeasty consistence and the movements occur more frequently in the morning, the patient being undisturbed during the remainder of the day. This is usually not the case in pellagra, where the diarrhea is as marked during the afternoon and night as in the morning. Of course, where a characteristic skin eruption exists the dif- ferential diagnosis will be easy, but if no such eruption is ob- served and no history of such can be obtained, in short, if a true pellagra sine pellagra exists, the diagnosis may be most difficult. One distinguishing feature which may be of value is the leucocyte count which in sprue is nearly always low (6,000- 2,800, Castellani and Chalmers), while in pellagra it is usually increased. Finally, if a patient with pellagra be instructed to sit in the sun for a couple of hours with the backs of the hands exposed the characteristic eruption will usually develop. Dysentery, both amebic and bacillary, may be mistaken for pellagra, and in the absence of skin manifestations in the latter may present some difficulty in differentiation. The dysenteries usually present little or no stomatitis, and as a rule are ac- companied by more or less rise of temperature. Of course the finding of the ameba in the stools, while not proof positive that the patient is not suffering from pellagra, in the absence of skin manifestations and typical mouth find- ings, should be strong presumptive evidence that the disease is dysentery without pellagra complication. The same may be said of the cultural isolation of the dysentery bacilli. It is possible that the characteristic odor of the pellagrous stool might serve as a differentiating feature, but too much stress should not be laid upon this. In these conditions, again, the diagnosis may be cleared up by placing the patient in the sun. PELLAGRA 373 Nervous Symptoms. — Although nervous symptoms develop in a large percentage of cases of pellagra, there are none which are typical and which in the absence of other findings would justify a diagnosis. Further, they are usually found in the later course of the disease when other symptoms will be manifest or at least a history of such other symptoms may be obtained. Thus we find disturbances of the lower tendon reflexes, ankle clonus, tremors, pain, vertigo, etc., in many other conditions than pellagra. Mental S3miptoms. — From what has been written in the chapter on clinical history it is evident that there is no typical mental picture in pellagra, that we may have symptomatic depressions or delirious pictures due to the pellagrous toxin or toxins, in short, intoxication psychoses which are in no way characteristic of pellagra but may be brought about by other intoxications. Further that certain definite psychoses, manic- depressive disorders, dementia prsecox, paranoid developments, etc., may occur in certain predisposed individuals with the pel- lagra acting as an exciting cause but in no way differing from these conditions in non-pellagrins. And finally certain mental disorders due to definite brain changes, arteriosclerosis dementia, senile dementia, presenile psychoses and paresis, may be present with pellagra merely as a complication. It is therefore im- possible to make a diagnosis of pellagra on the mental symp- toms alone, and even in the presence of symptomatic depression or delirium with the absence of other pellagrous symptoms the examiner must look for another cause than pellagra. It should here be reiterated that the diagnosis of pellagra on one symptom alone usually cannot be made, that the whole history and clinical findings must be considered and a diagnosis made only when the various symptoms can be reconciled to the symptom-complex of pellagra. It must also be remembered that pellagra is very frequently complicated by other diseases, both those that resemble it in some respects and those that do not, which condition will render the diagnosis more difficult. CHAPTER XXn PROGNOSIS OF PELLAGRA Spontaneous Recovery. — That a disease so protean in its manifestations and varying so in the degree of its severity may undergo spontaneous cure is not beyond the range of possibility, although we are unable to find any evidence of its occurrence in this disease. In fact, on the contrary, Lavinder and Bab- cock^"^ state that untreated pellagra " advances inexorably until finally with marked involvement of the central nervous system little can be hoped for from treatment." That pellagra may vary in its severity in different localities and the prognosis be more favorable in one district than in another is undoubted. It has for some time been considered by most American observers that the disease in this country runs a more fatal course than in Italy, although there is a tendency at the present time among American pellagrographers to consider that the severity of the disease here is gradually decreasing. There seems to be some difference in the prognosis of pellagra in various races; thus Grimm-^- graphically shows the death rate from pellagra in the negro to be 44.5 per cent, against 27 per cent, in the white race. This seems to us to be more on account of the usual differences in sanitation between the two races than to a racial difference, for, as will be pointed out later, in those living under insanitary conditions the prognosis is worse than in those living under good sanitary conditions, and as the negro as a rule lives in poorer sanitary surroundings than the white we would expect a worse prognosis in the former. The prognosis of pellagra in children is as a rule good, as the disease usually runs a milder course. On the other hand, in elderly people the prognosis is bad, the severity of the disease depending to a greater or less extent upon the debilities of the patient incident to old age. 374 PELLAGRA 375 It has been pointed out that women are more frequently affected by pellagra than men and the death rate is higher also. According to Grimm^^- the death rate for white females is 28 per cent, and white males 26 per cent., while in the negro race there is more difference, the death rate for females being 51 per cent, against 38 per cent, for males. Occupation. — The only consideration in the prognosis in regard to occupation of the individual is found in the amount of work he has done. Those who have led lives which have debilitated them to a more or less extent are more susceptible to the ravages of this disease. As stated above, the prognosis in pellagra is less favorable in those living under insanitary surroundings, and as this condi- tion is found to a marked degree associated with poverty it would be expected that in those of poor circumstances the prognosis would be worse than in those better off. Of course it may be contended that this is due to a large extent to the fact that those of affluent circumstances can better afford the services of physicians and can receive better nursing than those of poorer classes. While this undoubtedly is true to a certain extent, it would seem that the surroundings of the individual with regard to sanitation have more bearing upon the subject. It has been pointed out that the majority of cases of pellagra develop in the spring of the year, and it is also a fact that the advent of cold weather has a favorable effect upon this disease; therefore it would seem, although we have no figures to sub- stantiate this statement, that cases developing in the fall would have a better prognosis than those developing in the spring. That the occurrence of previous diseases in an individual may have a bearing upon the prognosis of pellagra can be easily imagined. It has been pointed out above that pellagra not infrequently follows such diseases as typhoid fever, malaria, etc., and it would seem that individuals contracting pellagra following diseases of a debilitating character would give a less favorable prognosis than those in whom the disease developed without previous illness. 376 ENDEMIC DISEASES OF THE SOUTHERN STATES The knowledge of the habits of an individual is of more or less importance in making a prognosis. Alcoholics and those who have indulged in venereal excesses are of necessity less resistant to any form of disease than those who have lived tem- perate lives, and therefore in the former class of individuals the prognosis is more grave than in the latter. It is natural to consider that the complication of pellagra by other diseases would tend to make the prognosis more grave. This is indeed the case, and we find that the chances for recovery in pellagra are less when this disease is associated with other maladies. The associated infection of intestinal parasites, such as hook- worm and amebae, with pellagra undoubtedly renders the prog- nosis more grave, partially, at least, owing to infecting organ- isms attacking the intestines which are the seat of so much of the pathology of pellagra. Niles^"^ states that pellagra when found in hard drinkers almost invariably runs a speedy and fatal course. This un- doubtedly is generally true, but one case seen by one of us is an exception. This patient, a man of 39 years of age, developed the symptoms of pellagra in the spring of 1914 with the char- acteristic findings — stomatitis, diarrhea and dermatitis on the backs of the hands. He was at that time consuming a quart of whiskey per day and also taking 25 to 30 grains of morphine in the twenty-four hours. Under treatment the symptoms and lesions of pellagra cleared up with only a slight recurrence of the dermatitis in the spring of 1915, which lasted but a short time and disappeared. When last seen he was still consuming the above-mentioned amount of whiskey and had no evidence of pellagra. The complication of pellagra by tuberculosis, whether of the lungs or of other portions of the body, is nearly always rapidly fatal. The development of nearly any of the infectious fevers, such as typhoid, in pellagrins nearly always makes the prog- nosis extremely grave. Most observers state that when pellagrins show nervous and mental symptoms the prognosis is rendered less hopeful. This undoubtedly is true of those psychoses due to the pellagra PELLAGRA 377 toxin or toxins, the symptomatic depressions and delirious pictures, and also no doubt of those psychoses due to changes in the brain — arteriosclerotic dementia, senile dementia, paresis, etc. — and perhaps also of idiots and imbeciles in whom pellagra develops, but we do not believe pellagra associated with de- mentia praecox or paranoia, for example, need prove any more fatal than pellagra in normally mental individuals. There is one exception to this statement, however, and that is the more frequent suicidal intent of insane individuals than those of normal mentality. The prognosis of pellagra in pregnant women is more grave than in non-pregnant women. This is due, partially, at least, to the liability of pregnant pellagrins to abort as pointed out above. The gravity of the skin lesions seems to have little or no effect on the prognosis, those with the most severe skin mani- festations often making complete recoveries. This is more especially true of the "dry" lesions, as the "wet" type usually are associated with more serious general symptoms. The appearance of so-called typhoid pellagra is to be considered as of most grave import, as most cases go on to a fatal termi- nation. The development of fever in the course of the disease presents a grave condition and should be looked upon with concern. Continued and severe diarrhea is one of the gravest symptoms as it usually leads to marked emaciation. The appearance of nervous symptoms such as tremors, absence of knee Jerks, ankle clonus, etc., is of grave import and, according to Wood,-"^ the appearance of a coarse clonic contraction of the muscles of the forearms is the most positive indication of the approaching end. As in nearly all other diseases the prognosis depends considerably upon the promptness of the diagnosis. The earlier the diagnosis the earlier treatment may be insti- tuted, and certainly more treated cases recover than un- treated ones. It must be considered, however, especially in our present state of knowledge of pellagra, that any outbreak of this 378 ENDEMIC DISEASES OF THE SOUTHERN STATES disease, no matter how mild, is not to be considered lightly, and that the most diligent methods of treatment are some- times of no avail. Mortality. — As pointed out, the death rate from pellagra in this country is higher than in Italy, although according to some observers it is decreasing. Lavinder^^* quoted Lombroso as stating that in 1883 there were treated in 866 Italian civil hospitals 6,025 pellagrins of whom 923 died, while in 1884. there were 6,944 cases treated in 993 hospitals, 790 dying, making in a large number of cases a death rate of about 13 per cent. Wollenberg^*^ reports a total of 55,029 cases of pellagra in Italy in 1905 with a total mortality of 2,359, which is a little over 4 per cent. Sandwith'" states that of his cases at Kasr el Ainy 18 were cured, 72 relieved, 6 unrelieved and 4 died, making a mortality of 4 per cent. Statistics in this country are based largely upon insane hospital cases in which the mortality is very high in spite of the fact that in these institutions better facilities for treatment are usually found than outside them. This high death rate of hospital cases is no doubt due to the fact that pellagra cases do not as a rule enter hospitals until they have reached the less hopeful stages of the disease. According to the Illinois Pellagra Commission, '^^ in 258 cases at the Peoria institution there was a death rate due to the pellagra per se of 49.6 per cent. Searcy'°" reported 88 cases occurring in the Mount Vernon Insane Hospital in 1906, of which 57 or 64 per cent. died. Harrington^^^ states that of 32 cases occurring in the State Hospital for the Insane of Rhode Island 12 died, giving a mortality of 37 per cent. Of the 91 cases seen by one of us at the Arkansas State Hos- pital for Nervous Diseases, 57 or 63 per cent. died. The Thompson-McFadden Pellagra Commission^'^ gives the following table of cases and deaths, as far as could be determined, occurring in Spartanburg County from 1894 to 191 2 inclusive: PELLAGRA 379 Year Number of deaths Number of cases Per cent, of deaths 8l I I 2 2 I I 2 14 . \ 25 114 115 28s 376 1898 22 1909 28 54 47 19 This shows that the number of cases is increasing but the percentage of deaths is decreasing. Grimm^'- of a total of 1,426 cases gives a death rate of 30.2 per cent., while Lavinder^"* reports 19,915 cases with 8,085 deaths, or a mortality of 40.59 per cent. BealP^^ states that the prevalence of pellagra in the United States is decreasing, although he estimated the death rate to be over 25 per cent. CHAPTER XXm PROPHYLAXIS OF PELLAGRA The methods of prophylaxis proposed for pellagra are many and are based to a large extent upon the theories of etiology as upheld by those proposing them. In Italy, where the spoiled maize theory is almost universally accepted, the most thorough and extensive prophylactic measures have been in- stituted with this theory as a basis. These measures are directed against the sale or use of spoiled corn. According to Sambon'^" these measures are: 1. The inspection of maize, the seizure of unsound grain and its products. 2. The exchange of deteriorated maize for good maize. 3. The providing of drying apparatus for damp maize. 4. The providing of suitable ovens in rural districts for the proper baking of maize bread. 5. The abolition of late varieties of maize which do not ripen properly. 6. The compulsory notification of all cases of pellagra. 7. The obligation, in all affected districts, upon the municipal authorities to supply free meals to all their pellagrins twice every year for periods of not less than forty days. 8. The institution of special retreats, "pellagrosari," for the housing, feeding and treatment of the more advanced cases. 9. The dispensation of free salt to all pellagrins and their families. This author continues with statistics and conclusions of Professor G. Sanarelli, Under-Secretary of State for Agriculture, of Italy who claimed that beneficial results were seen almost immediately after the application of the law of 1902, stating that the pellagrins within the kingdom were reduced to barely 55,000 in 1905, showing a reduction of over 17,000 in the last six years. Further figures by Sanarelli show that the victims 380 PELLAGRA 381 of pellagra in Italy in the three years 1897-99 were 10,284; in igoo-02 they fell to 9,219; in 1903-05 they declined to 7,267; while in the three years 1906-08 the number was only 4,649. More comforting to Sanarelli was the fact that in 1907 4,950 new cases were notified, while in 1908 only 2,846 were reported, and that before the application of the present law the yearly mortality from pellagra reached or exceeded 3,000, while immediately after 1902 the number of deaths only just exceeded 2,000, in 1907 were 1,635, ^^^ i^ 1908 were only about 1,000. The conclusion reached is that these measures have reduced the number of pellagrins by 50 per cent., and that if the law of 1902 "had only been fully and vigorously enforced in all the forty-four provinces of the kingdom more or less severely affected by the fatal disease, at this hour (1909) the whole of Italy would be entirely free." Sambon then attempts to prove that instead of the law of 1902 bringing about the results claimed by Sanarelli, it "failed to produce any results at all." He states that the decline in the number of cases and deaths had already begun in a very striking manner some years before the law was enacted, and further that the law of 1902 did not come into effect until three years later. Then Sambon quotes the remarks of Sanarelli made upon an- other occasion in which he directly contradicts himself, after giving statistics, by remarking: "A legitimate doubt, therefore, arises as to whether it be right to ascribe the gradual decline of pellagra throughout the kingdom to the measures contained in the law of 1902." Following this Sambon goes into the details of the prophy- lactic propaganda of the Italians and proves, to his own mind at least, that they have failed entirely to prevent pellagra. While the bulk of evidence is against the theory that corn is responsible in any way for the spread of pellagra the evidence is negative, and certainly no other theory has been proven cor- rect. And further since spoiled maize is unquestionably not suited for human consumption, whether or not it has anything to do with pellagra, an effort should be made to have only sound corn used for food. While Sambon has advanced and defended the theory of the 382 ENDEMIC DISEASES OF THE SOUTHERN STATES transmissian of pel'lagra by the Simulium, he has not, as far as we are aware, proposed any definite measures of prophylaxis. Wood,-'^ who considers this theory the most interesting one at this time, states that as the buffalo fly is a field pest its control would be most difficult if not impossible. However, should the Simulium finally be proven guilty of being the intermediary host of pellagra, such measures as screening, destruction of larvae, etc., could be instituted. The spread of the knowledge of the connection of this insect with pellagra would in itself make those who come into contact with it wary of its bite and certainly lessen the number of cases. Should the stable fly {stomoxys calcitrans) prove to be the intermediary host, as suggested by Jennings and King,^^^ the prophylaxis of pellagra would become comparatively simple, first by screening and second by the destruction of the larvae and eggs of this insect in manure. The contagiousness of pellagra has been discussed in the chapter on etiology, and as no evidence has been produced to show that this disease is contagious the quarantine or isolation of pellagrins would be unwarranted at this time. However, owing to the possibility of pellagra being infectious, we consider that such close contact as kissing of pellagrins should be avoided, and further, owing to the rather strong evidence that if pellagra is an infectious disease the primary location of the infecting organism is in the gastro-intestinal tract, we consider the effective disposal of the excreta of pellagrins of importance. Also we consider the destruction of the scales and flakes of epidermis which come from the skin lesions during the des- quamating stage as not out of place. At least such proceedings can work but little hardship upon either the patient or his attendants and possible sources of the spread of the disease will be removed. The removal of secondary or alleged predisposing causes of pellagra in endemic districts would certainly not be out of place. One of the most important of these, as pointed out above, is alcoholism, which, even if it is not a predisposing cause of pellagra, is a bane upon civilization and should be destroyed. Other predisposing causes mentioned are other previous and PELLAGRA " 383 concomitant diseases, such as malaria, typhoid, hook-worm, etc. ; so measures instituted against these diseases might in a measure, at least, react against pellagra. The theory of Allesandrini and Scala that pellagra is due to certain silica compounds contained in drinking water, while brilliant in conception, lacks confirmation. If, however, it should be proven correct, the prophylaxis of the disease would be most simple, namely, the substitution of a water free from these substances. Goldberger,-^! whose deficiency diet theory has been dis- cussed in the chapter on etiology, states that "the prevention and eradication of pellagra will depend essentially upon the substitution of a mixed, well-balanced, varied diet for the restricted, one-sided diet that the individual will be found to have consumed prior to the development of symptoms." He further states that the amount of corn or other starchy foods should be reduced. The most important change in the diet, however, is an increased consumption of fresh (lean) meat, milk, eggs and legumes ("beans and peas, fresh or dried but not canned"). This should be carried out especially in the late fall, winter and early spring months. The poor, especially the poor of the South, should be en- couraged to cultivate beans and peas and preserve them by drying for winter consumption. Goldberger states that at orphanage "B. H." there were seventy-five cases of pellagra in the spring of 19 13, following ap- parently milder outbreaks in 1911 and 1912. A modification of the diet along the lines mentioned was instituted and not a case was known to have developed in the spring and summer of 1914 among a total of 234 children of the orphanage. He further states that there is reason to believe this experience is not unique. In the insane hospitals care must be taken to see that not only is a well-balanced, mixed and varied diet furnished to the patients, but that they actually eat it. Whether or not Goldberger's theory is proven true, we con- sider his tenets as to diet sound, and especially in the absence of proof of any other etiologic theory they should be carried out. 384 ENDEMIC DISEASES OF THE SOUTHERN STATES The public health aspect of pellagra assumes the proportions of a colossus. The disease should be made reportable where it is not so, and in every state where it is endemic appropriations should be made for the carrying on of study of it; not only an attempt to ascertain the etiology, but a study of the epidemi- ology, symptomatology, prophylaxis and treatment should be made. The laity should be informed of what we already know of the disease, both by pamphlets and lectures, and should be en- couraged in instituting such prophylactic measures as are outlined above. CHAPTER XXrV TREATMENT OF PELLAGRA The methods of treatment of pellagra are as varied as are the theories of its etiology, and as may readily be imagined many of them are of no avail. The methods of treatment may be discussed under three headings, namely: hygienic treatment, specific treatment (so called), and symptomatic treatment. Hygienic Treatment. — The first requisite in the treatment of pellagra is that the patient be placed under sanitary surround- ings. If he is ambulatory he should take a certain amount of exercise daily, but should avoid the direct sunHght except in certain nervous and mental conditions where no skin lesions have been manifest for several years, in which sunlight seems beneficial. In all acute cases and those with fever the patient should be put to bed, in which case, or if he is already confined to bed, his room should be well ventilated but with the light subdued. It goes without saying that bed patients should receive the best of nursing and their beds kept clean and fresh. Change of climate has been noted by many observers to be very beneficial to pellagrins, the change from a warm climate to a cold one being most recommended, although it would seem that a change of surroundings, per se, is helpful. In this connection Bass^*- has recommended an artificial refrigerated ward, which he states could be equipped for $3,000 and main- tained at an expense of $1 per day per patient in addition to the regular expense. Hydrotherapy of various forms has been recommended in pellagra. Sufi&cient bathing for cleanliness is of course to be carried out in all cases. Other hydrotherapy must be governed by the condition of the patient. In children and in elderly individuals warm baths should be employed. In weak individuals the treatment should 2S 385 386 ENDEMIC DISEASES OF THE SOUTHERN STATES be begun with a warm bath of short duration and the tem- perature reduced and the time prolonged with the improvement of the patient. Massage during the bath is often beneficial. The use of salt baths or rubs is often recommended, from which children derive the most benefit. The patient should be placed in a tub of warm water and after the body is wet all over should stand up in the tub and the attendant, after wetting the hands, takes a handful of salt (any good fine cooking salt will do) and thoroughly, but not roughly, rubs the entire body with the salt for fifteen to twenty minutes, after which the patient Hes down in the water, the salt is washed off and if the patient is sufficiently robust a cold douche is given, after which he is put to bed for a time. A shower bath is perhaps more satis- factory than a tub for this purpose. Medicated baths of vari- ous kinds, such as arsenic and sulphur, are some<:imes used, but are of doubtful value. Baths in water with radio-activity, such as at the Hot Springs of Arkansas and Virginia, have proven beneficial in certain cases. These baths should of course be controlled by the condition of the patient, and should be given in conjunction with other methods of treatment. Whether or not we accept the teachings of Goldberger con- cerning the etiology of pellagra, the diet he recommends as treatment is far from undesirable. It has long been recognized that, inasmuch as pellagra is usually found in the undernourished, one of the first and most essential procedures in the treatment is to prescribe good, wholesome, and nourishing food. The diet recommended by Goldberger^^' is as follows: Milk. — Fresh milk, alone or in alternation with buttermilk, should be given freely. An adult should be urged to take not less than a pint and a half to two pints in twenty-four hours. Eggs. — Fresh eggs should be allowed freely. In addition to the milk and meat, an adult should take not less than four eggs a day. In certain of the severer forms it may be necessary to give the eggs in the form of albumin water. Meat. — The meat should be fresh lean meat. Whether all fresh meats are equally valuable in treatment we do not know; future studies will have to determine this. Our experience has PELLAGRA 387 been with beef alone. This may be served as scraped beef, as a roast, or as steak. Where mastication is painful, meat juice may be given instead. An adult should be urged to take at least a half pound of lean meat a day in addition to the milk, eggs, and legumes. It may be necessary in some in- stances to work up gradually to the point where these quan- tities can be taken. Legumes. — We have been much impressed with the favorable results following the use of beans and peas alone. The beans and peas should be fresh or dried, not canned. A palatable pea or bean soup should be prepared and may be given freely. In addition to or in alternation with the soup the beans or peas should be served and eaten in any one of the other well-known forms. To this diet of Goldberger we feel that little can be added. We wish to say, however, that in view of the absence of proof as to the etiology of pellagra and out of deference to the zeist theory, although we do not subscribe to it, we are accustomed to advise our pellagra patients to abstain from eating corn in any form. This can work but little hardship and adds an element of safety until the exact etiology is learned. Specific Treatment. — The so-called specific treatment of pellagra consists of the empirical administration of various medical substances upon the theory that they are specifics for the hypothetical microorganism of the disease; the practice of transfusion of blood and the administration of blood serum from cured pellagrins upon the theory that "antibodies" against the hypothetical microorganism are being introduced; and finally, the practice of auto-serum therapy. Lavinder and Babcock^"^ quote Holland as having written in 181 7: "In short, it appears certain that mere medicine has done very little for the relief of pellagra; and Strambio frankly confesses that he never saw a case distinctly cured by the remedies that were employed." These writers then state that it was Lombroso who first em- ployed arsenic in the treatment of pellagra. The idea of the great Italian was not, however, that arsenic is a true specific for the disease, that it did not cure all cases, but that it was a 388 ENDEMIC DISEASES OF THE SOUTHERN STATES valuable remedy acting as a sort of antidote for the toxins of spoiled maize. Lombroso's method of administration of arsenic, according to Lavinder and Babcock, was in the form of Fowler's solution in dosage of 5, 10, 15, 20, and 30 drops, or as pure arsenous acid (arsenic trioxide) dissolved in slightly alcoholized water, in doses of }io to }4o milligram, increasing according to tolerance to o.ooi, 0.002, or 0.003 gram and very rarely even o.oi gram. The drug is discontinued for a few days from time to time. Lombroso cautions against certain untoward effects of the arsenic and mentions certain types of the disease which are benefited by the treatment and certain types which are not. Symptomatic and dietetic treatment are also recommended by the Italians. Other methods of administering arsenic in pellagra than by mouth have been employed by many investigators. Thus Babes, according to Wood,^^^ was the first to use atoxyl in the treatment of this disease. The latter writer has had a wide experience in the use of this drug, recommending its use in dosage of 5 to 7 grains every fourth day in the beginning and later increasing the length of the interval. The untoward effects sometimes seen, such as chills, faint- ing, headache, ^blindness from retrobulbar neuritis, colic, loss of appetite, albuminuria, etc., have not been observed by Wood, although expected and looked for. He attributes this to the careful preparation of the solution of the drug without the use of heat which it is claimed will decompose it. Wood reported very favorably upon the use of atoxyl, but. stated that he was instituting the use of soamin because it is said to be less toxic. Soamin has been used very extensively by many investigators with more or less satisfactory results. Martin^^^ reported its use in six cases of pronounced pellagra and five of suspected pellagra. In the latter the suspicious symptoms were promptly relieved by a few injections of soamin, and of the six pronounced cases all but one, who died within a week after the institution of treatment, made apparent recoveries. Martin injected this drug in 3- to s-grain doses on alternate days, giving 100 grains as a maximum for one course of treatment. PELLAGRA 389 Probably no other drug has ever received the attention that Ehrlich's saharsan or "606" has, and it is natural to suppose that a drug which contains arsenic and is said to be less toxic than any other so far produced should, in view of the results obtained with other arsenical preparations, be given a trial in pellagra. As far as we are able to determine, Nice, McLester and Tor- rance'*^ were the first to report on the use of salvarsan in the treatment of pellagra. These workers reported apparent re- coveries in three cases. Cole and Winthrop'*'' collected the reports of twenty-one cases of different investigators with only 33 J 3 per cent, im- provement lasting seven or more days. King and CrowelP** reported nineteen cases in which as a rule three doses of salvarsan were administered ten days apart with apparent recoveries in all but one case. Cranston'^^ administered salvarsan to eleven pellagrins in 1911 with the following rather discouraging results: Two left the hospital clinically cured; one was considered well until nausea developed a few days before the report was made and was therefore considered suspicious; three relapsed and were treated a second time; one was unimproved and four died. Probably the most enthusiastic supporter of salvarsan in the treatment of pellagra is Martin'^* who considers this drug a true specific for the hypothetical microorganism of the dis- ease. This investigator has used salvarsan in a great many cases (he does not state how many) and contends that one may confidently expect to cure over 80 per cent, of cases by the use of soamin or salvarsan or both. Martin's method of procedure is to administer salvarsan intravenously in doses of o.i gram per 20 pounds of weight, at weekly or ten-day intervals until no so-called endotoxin reaction occurs. He claims perfect cures in favorable cases (he states he is unable to say why favorable) after three or four doses, but considers that six, eight or ten doses will usually be required. Martin states that occasionally salvarsan seems to cause a recrudescence of the disease, and that several days following the first or second dose the mouth becomes red, diar- 3 go ENDEMIC DISEASES OF THE SOUTHERN STATES rhea begins and new skin lesions occur. This, Martin thinks, is an indication that a specific drug has been used, though in insufficient dosage. In a comparatively small experience with salvarsan in the treatment of pellagra we are forced to the conclusion that it does not act as a specific. One case treated by one of us in the spring of 1911 is very much to the point. This patient, a man of forty-nine years, had suffered with diar- rhea for two summers, accompanied by a breaking out on the backs of the hands. When examined there was a characteristic eruption on the backs of the hands extending about 4 inches up the forearm. Marked diarrhea was present, there being an average of fifteen bowel movements per day. Three doses 0.6 gram of salvarsan were administered intravenously ten days apart with absolutely no improvement. The patient grew steadily worse and died three weeks after the administration of the last dose of salvarsan. We are of the opinion that arsenic in any form, which exerts no untoward effect, is to be recommended in pellagra. This we do not consider as acting so much in the nature of a specific as in the nature of a tonic and alterant, although we are not prepared to say that it does not have specific action. We have found that sodium cacodylate has given the best results in our hands. This is administered intramuscularly, usually in 3- grain doses daily. The dosage may, however, be increased, we having given as high as 9 grains daily without any untoward effects. A number of investigators have reported favorable results from the use of hexamethylamine. Other drugs, sodium chloride, gelsemium, potassium permanganate, thyroid extract, calcium sulphide, castor oil, nitric acid, opium, etc., have had their advocates, but do not seem to offer much. Dyer^'^ advocates very strongly the use of quinine hydro- bromate and considers it as much of a specific as any drug so far proposed. It is given in doses of 2 to 5 grains three times a day in mild cases, and as much as 10 grains every two to three hours in severe cases. Dyer states that he has given as much as 10 grains every three hours night and day for four to five PELLAGRA 391 days and that he has never lost a case of pellagra treated entirely and throughout by himself. Recently Page^-" has advocated the use of ichthyol, and states that one or two 5-grain pills three or four times a day for three weeks seems to cure the average case. We have had experience with this drug used in this manner in but one case, but have been informed that at the Arkansas State Hospital for Nervous Diseases, it was used in several cases with apparently no beneficial results. According to Cole and Winthrop^^^ Antonini and Marianni secured curative results in pellagra by the injection of blood serum from cured pellagrins. Cole^'" early in 1909 published the results of blood trans- fusion from a cured pellagrin into a case which was considered absolutely hopeless, but which completely recovered. In 1910 Cole with Winthrop^^^ reported six recoveries in eleven cases. These investigators considered that if the blood serum of cured pellagrins contained specific antibodies the whole blood would also contain them, as well as help replenish the impoverished blood stream of the patient. They point out four dangers of transfusion, aside from the technic difficulties, as follows: the transmission of disease, hemolysis, agglutination and acute dilatation of the heart. Later these workers"^ reported twenty cases of pellagra in whom transfusion was performed with twelve recoveries. At this time, however, they stated that it seemed to make no difference whether the donor was a cured pellagrin or any other healthy individual. According to Castellani and Chalmers^^- a most unique method of treatment has been devised by Nicolaidi. This consists of horse-serum together with all the organic and mineral salts of the blood, in a solution saturated with carbon dioxide gas, which is then rendered radioactive. The preparation is administered by injections until twenty or twenty-five are given. Neither dosage nor the method of injection is stated. Remarkable improvement is reported by Nicolaidi and accord- ing to Castellani and Chalmers his results are supported by several eminent authorities. 392 ENDEMIC DISEASES OF THE SOUTHERN STATES Palmer and Secor"^ after a short review of the literature of auto-serotherapy in other diseases report the treatment of seven cases of pellagra by this method with most gratifying results. Two cases, according to these authors are well, having passed a spring and fall season without recrudescence of the disease. Two others are apparently well but as yet have not passed the critical seasons, while the other three showed marked improve- ment but have been lost track of. The technic employed is to apply a piece of cantharides plaster ij-^ inches square, smeared with olive oil, to the chest at bedtime. In the morning a blister will be raised. Without entirely removing the plaster a hypodermic needle is thrust into the blister from an upper corner, i c.c. of serum withdrawn and injected into the arm. No visible reaction should occur. Palmer and Secor state that their therapy is based upon the theory that the beneficial effects derived from the old-time blister in pneumonia were not entirely due to the counter- irritation but that antigens were produced in the serum and reabsorbed, thus stimulating the production of antibodies. We have seen this method tried in one case with apparently good results, although this patient Avas at the same time under treatment with sodium cacodylate. We consider this treatment rational and as it is very simple and devoid of much pain and discomfort to the patient, should be given a thorough trial. Instead of cantharides plaster, however, we recommend the application of cantharides collodion. Symptomatic Treatment. — The skin lesions are treated according to their severity, and it is best to err on the side of too little treatment rather than too much. In the beginning when there is nothing but an erythema a dressing of boric acid solu- tion is quite sufficient. Later when the eruption has started to desquamate zinc oxide ointment should be applied. The main requisite in this condition to our minds is to exclude the light, for which purpose zinc oxide has been found by one of us best suited. By coating photographic plates with various substances, zinc oxide, ichthyol, bismuth subnitrate and bella- donna ointment, exposing them to the light for several minutes, removing the coating and developing, those covered with the PELLAGRA 393 zinc oxide showed almost absolute exclusion of the light while the other substances permitted more or less light to penetrate. For the so-called "wet" lesions ordinary surgical treatment should be employed. Moist dressings of bichloride (i to 5,000) or I per cent, p eric acid are good. If there is secondary in- fection with pyogenic organisms the parts should have hydrogen peroxide applied in dilute solution once daily and aristol or some similar powder dusted over them. Of the gastro-intestinal symptoms the anorexia and nausea are usually relieved by nux vomica, condurango or some other bitter. Leroy^^^ has recommended a mixture of cerium oxalate, chloretone and bismuth subnitrate in troublesome vomiting. For the stomatitis if ulceration exists daily application of silver nitrate solution (4 per cent.) will be of benefit. An as- tringent mouth wash such as the following should be used: ^. Potassii chloratis 3ii Tinct. myrrhse f 5 ss Mellis depurati f S ss Aquas camphors q.s. ad fSviij Sig. — Shake; use as mouth wash, t.i.d. If salivation exists atropin J 200 grain every four hours until checked, may be used. For the gastric symptoms when there is a deficiency of hy- drochloric acid, this drug may be administered 10-15 drops of the official dilute t.i.d. after meals. Pepsin also may be given. Many drugs have been advocated for the diarrhea, bismuth in some form being most frequently used. Ergot, albumin tannate, and salol are also extensively employed. j)ygj.373 states that the quinine hydrobromate he recom- mends as a specific will control the diarrhea usually within the first five days. Tablets of B. bulgaricus have been used by one of us for the control of the diarrhea but without very flattering results. When all other means fail opium in some form may be given. Where constipation is present instead of diarrhea it may best be controlled by castor oil. Phenolphthalein or sodium phos- phate may also be employed. Of the nervous symptoms insomnia will usually be overcome 394 ENDEMIC DISEASES OF THE SOUTHERN STATES by the administration of chloretone in doses of 3 to 5 grains. Trional, veronal or sulphonal may be used. For the pains and burning sensation phenacetin, aspirin or some other salicylate may be administered. The various mental symptoms can be treated satisfactorily only in a hospital for the insane. The depressed conditions improve with the general condition. For the delirium small doses of deodorized tincture of opium is best. The other mental conditions associated with pellagra but not directly due to the toxins must be treated as if the pellagra were not present. An important part of the treatment of pellagra is that which is carried out between attacks. The patient should be under observation and the general condition should be made as good as possible, with careful diet, exercise, tonics, etc. A careful record of the weight should be kept as the season approaches for the attack, the development of slight symptoms should be noted and treated at once. If possible a change to a colder climate is highly to be recommended. It goes without saying that concomitant diseases should be recognized and treated. Thus in the advent of malaria, quinine should be given, hook-worm should be treated with salol, and cases with amebiasis should receive emetine. All major surgical procedures, except those absolutely necessary, should be postponed until the symptoms of pellagra subside. AMEBIC DYSENTERY CHAPTER XXV INTRODUCTION Amebic dysentery is an infectious disease, caused by a specific protozoal microorganism, the Endamceba histolytica, charac- terized clinically by abdominal pain, diarrhea and tenesmus, anatomically by ulceration of the colon, sigmoid and rectum, with a tendency to recurrences and chronicity and to the forma- tion of hepatic abscess. Amebic dysentery is also known as amebic enteritis, amebic colitis, amebiasis, tropical dysentery, amobenruhr, dysenteric amibienne and dysenterie a amibes. History. — The history of amebic dysentery may well be said to begin with Lambl"* who in 1859 discovered a minute, motile, unicellular organism in the intestinal mucus removed at necropsy of a child dead of diarrhea. Lambl described the organism as being roughly spherical in shape when at rest, of 0.009 mm. by 0.016 mm. in size, but assuming an elongated shape when in motion. Motility was attained by throwing out club-shaped pseudopodia which were of the same substance as the body. Lambl observed vacuoles in the body of the pro- tozoon and occasionally very minute ones in the nucleus. The peculiar vibration of the granules in the protoplasm was noted. Both classes of movement were stated by this investigator to be very marked at first but to cease gradually within a few hours. While Lambl did not definitely incriminate the organism he described as the cause of dysentery he did state that its impor- tance should not be underrated. The importance of Lambl's work was unrecognized and in 1870 Lewis and Cunningham^''^ described quite fully certain amebas found in the feces of cholera patients but ascribed to them no pathologic significance. 395 396 ENDEMIC DISEASES OF THE SOUTHERN STATES In 1875 Loesch'^^ published an account of the findings of ameba in the feces of a patient with dysentery. This patient had been suffering intermittently with the disease for two years and finally succumbed. Just before death the organisms were absent from the feces but were found at necropsy in great num- bers in the intestinal contents and in ulcers of the colon and sigmoid. Loesch also did not definitely incriminate the amebse as the cause of the disease, considering that they possibly merely aggravated the condition. Nevertheless he injected rectally four dogs with some mucus containing amebffi, produc- ing in one instance a dysentery, recovered the amebse from the feces and found ulceration in the lower colon. Grassi^'^ also found amebee in the feces of dysenteric patients as well as in normal individuals. He, therefore, considered them as non-pathogenic. This worker described a cystic stage of the amebse which occurred more frequently when the organ- isms were forced to live under unfavorable circumstances. Following the work of Grassi numerous investigators re- ported the finding of amebee in the feces of both normal persons and those suffering from dysentery (Leuckart,^^" Sonsino,^^^ Perroncito^^^). Koch'^' in 1883, while studying cholera in Egypt described amebae as occurring in sections of the intestinal walls. While Koch considered these as of possible pathologic significance owing to his other investigations he did not pursue the work further at that time. However, stimulated by the work of Koch, Kartulis'^* under- took extensive investigations of this important subject and added greatly to the knowledge concerning it. This worker found the amebs in many cases of dysentery both during life and at autopsy and failed to find them in cases of typhus, typhoid, tuberculosis and Bilharzia disease. He therefore rightly concluded that the amebse were the cause of the disease. He attempted to cultivate the organism and to reproduce the disease in guinea-pigs but without success. He, however, showed the relationship of hepatic abscess to the amebas. The findings of Kartulis were very quickly confirmed by several investigators. AMEBIC DYSENTERY 397 Hlava'^'^ in Prague found the organism in sixty cases of dysentery and was able to produce the disease in cats and dogs by injection into the rectum of feces containing amebas. The first worker in America to report the finding of amebas in dysentery was Osler^^^ who in 1890 discovered these organisms in the feces and pus from an hepatic abscess of a patient who had returned from Panama. In a short time Musser'^*^ reported four cases and StengeP'* three from Philadelphia, while Dock^*' found amebse in twelve cases of acute and chronic dysentery in Galveston, which were the first reported from the South. In 1 89 1 Councilman and Lafleur'^" published a most com- plete description of the disease with a critical study of the literature. These authors concluded that a disease entity with definite pathologic findings was produced by the amebje and proposed the name "Amoeba dysenterise" for the organism. They, however, considered that other amebse, perhaps non- pathologic might be found. The work of Councilman and Lafleur created a stir both among zoologists and physicians and an extensive literature quickly sprang up, some investigators accepting the work and others rejecting it. Maggiora'^' in 1893 after reviewing the evidence at hand reached the conclusion that the ameba coH could not be con- sidered as the cause of any kind of dysentery. Gasser'^- injected garden mould into cats producing a colitis and recovered amebae from their feces apparently identical with those of Loesch and Kartulis. However, Quincke and Roos^^^ confirmed the work of Council- man and Lafleur and concluded that there were three varie- ties of amebse, one being very virulent and causing a marked dysentery, another being less virulent and causing only a mild dysentery, while the third was non-pathogenic. Their conclu- sions were partially based upon experimental evidence, their first organisms producing marked symptoms when injected into the rectum of cats while the other organisms so injected pro- duced no symptoms. Kruse and Pasquale,^'* working in Egypt, also confirmed and 398 ENDEMIC DISEASES OF THE SOUTHERN STATES extended the work of Councilman and Lafleur, finding a patho- genic and non-pathogenic type of ameba in the intestine. They also produced dysentery in cats by the injection of pus from an hepatic abscess bacteriologically sterile, but containing amebse, into the rectum. During the next ten years numerous investigators contributed to the study of the intestinal amebae of man, but it was left for the zoologist, Schaudinn, whose name will be immortal as the discoverer of the specific organism of syphilis, to differentiate scientifically the pathogenic and the., non-pathogenic species. The former he termed Entamozha histolytica and showed it to be the definite cause of amebic dysentery, while the latter was designated Entamceba coli. However, it would seem that the term Endamceba is the more correct as Leidy^'^ as far back as 1879 estabHshed the genus Endamceba for parasitic amebas. Schaudinn's untimely end was probably brought about as a result of his investigations into the amebs as he allowed himself to become infected by swallowing the developmental cysts of the organisms and suffered with intermittent attacks of dysentery until the time of his death in 1906 following suppura- tion around the sigmoid. Schaudinn's work was confirmed by many writers, among them Craig, ^^^ Sandby and Miller, ^^^ Kartulis^®' and others. In 1906 Viereck^^^ described an organism that he considered a third species and termed it Endamceba ietragena. This he thought the cause of a certain form of dysentery, but by most investigators Viereck's ameba is considered identical with the endamceba histolytica. Numerous other workers have described amebas which they considered as distinct species, but their findings have not been confirmed and are considered by most authorities as based upon insufficient evidence and that they will eventually be shown to belong either to the species of Endamceba histolytica ox Endamceba coli. Geographic Distribution. — The distribution of amebic dys- entery is widespread although as with most infectious diseases there are certain endemic centers in which it is found more prevalent than in others. AMEBIC DYSENTERY 399 In Europe the disease is less prevalent than in some of the other continents. It is endemic, however, in parts of Italy, Malta, Sicily and in the Balkans. It has been observed more or less frequently in Austria, Hungary, Germany and Russia. In 1901 Jagers^'^ reported an epidemic among the German troops of East Prussia. In England^'* and France sporadic cases have been reported from time to time, some of them in in- dividuals who have never been out of their native countries. We are unable to find the reports of any cases occurring in the Scandinavian countries. Many hot beds of amebic dysentery exist in Asia. Thus in southern China, India and Siam it is found most prevalent, but in northern and central China and Japan, while dysentery is found, the bacillary type is more frequent. In the East Indies and the Philippines are found extensive endemic centers. Africa is found to contain many endemic centers of amebic dysentery. In Egypt along the lowlands of the Nile it is prob- ably found more frequently than in any other country of the world, although in the upper portion of the country it is rare. It is found in the Mediterranean countries, Morocco, Tunis and Algiers, while in South and Central Africa it is more or less rare. In Australia and Polynesia it is endemic, and is of frequent occurrence. In South America, amebic dysentery is found quite frequently in Chili, Brazil, and Venezuela, but less often in the southern countries. Central America, Panama and Mexico contain many endemic centers. In the United States amebic dysentery is endemic in most of the Southern States while sporadic cases have been observed from New England to the Western Coast. Economic Importance. — It would be hard to estimate the economic importance of a disease so prevalent as amebic dysentery. According to Walker^""' this disease, with the pos- sible exception of malaria, is the most widespread of all the endemic tropical diseases. Walker quotes Gauducheau as stating that nearly half of the deaths of Europeans at Tonkin, 400 ENDEMIC DISEASES OF THE SOUTHERN STATES Indo-China, are caused by amebic dysentery and Walker thinks where the disease is not modified by sanitation about the same position of morbidity and mortality statistics is held by it in other tropical countries. CHAPTER XXVI ETIOLOGY OF AMEBIC DYSENTERY Season. — There seems to be some evidence that the incidence of amebic dysentery varies with the season. Thus, according to most observers, in the Philippines the disease is most preva- lent from June to September. In Egypt it is said to occur most frequently in the late summer and autumn, while in this country by far the most cases are observed in the warm months, that is, from May to September. Inundation. — Strong^" ^ states that following the great flood in Manila in 1904 amebic dysentery became almost epidemic, while Brown '"'^ states that numerous observers in Egypt have pointed out the relation of the frequency of the disease to the annual overflow of the Nile. Following the overflow of the Mississippi River in 191 2 one of us had medical charge of 3,000 flood refuges, a large percentage of them being accommodated in tents and amebic dysentery was very prevalent. Altitude. — Many observers have noted the apparant effect of altitude on amebic dysentery, it being largely confined to the low lying countries, along the seashore and the valleys of great rivers and rarely encountered in the uplands. Race. — Strong"*"^ states that while the natives of the Philip- pine Islands, owing to their mode of hfe, are more exposed to infection with amebic dysentery they are not nearly so fre- quently affected as Americans or Europeans; that while the ratio of white to native patients at the Government Civil Hospital has been as 2.5 to i, that of amebic dysentery has been as 9 to i. In direct contradiction to this statement Walker^°° concludes that there is no definite evidence of racial immunity of the native Filipino to this disease. In the South there seems to be no difference as to susceptibility between the black and white races, and while amebic dysentery is probably more frequent in the negro than the white this is undoubtedly due to more frequent exposure. 26 401 402 ENDEMIC DISEASES OF THE SOUTHERN STATES Sex. — That males are much more frequently affected with amebic dysentery than females is the observation of all inves- tigators. That this is due to the more active life led by the former and not to any greater susceptibility is also conceded by all. According to Strong"""^ at the Government Civil Hospital of 401 cases the ratio of males to females was 4.1 to I, while of 200 personal cases he states only 23 were females. Age. — Musgrave^"' is of the opinion that children present a partial natural immunity to infection with Amoeba histolytica. He states that not only are children more frequently exposed and less frequently infected, but when infection does occur it is usually less severe than in adults. This investigator also con- siders that the aged are also partially immune, but states that when attacked the aged are usually more severely affected. DeBuys*"* does not agree that children possess any natural immunity, but considers the less frequent occurrence of the disease in children to be due to their less frequent exposure. He is of the opinion that perhaps owing to the usual mild character of the infection in children it is often overlooked. The youngest case observed by Musgrave"*"^ was six months, while other observers have reported cases in children as young as ten months. Occupation. — The occupation of an individual seems to play a certain role in the development of amebic dysentery, those whose occupation leads them into the open being affected more frequently than those who remain within doors the greater part of the time. This seems to be especially true of field laborers. j Other Predisposing Causes. — It would seem that such factors ■as eating of indigestible foods, chilling of the body, over-indul- gence in alcohol, etc., may act as predisposing causes of amebic dysentery. Also the existence of hemorrhoids, malaria, typhoid fever and other diseases may serve to render the individual more susceptible to infection with Amoeba histolytica. Iminimity. — As stated above there is some difference of opinion as to the relative immunity of children and different AMEBIC DYSENTERY 4O3 races. We are inclined to agree with Musgrave that children probably are less susceptible to infection, but do not consider that there is any racial immunity. Epidemics. — While amebic dysentery does not occur in widespread epidemics, such as have been known in many other infectious diseases, numerous small epidemics have been ob- served in non-endemic centers. Such an epidemic was reported by Allen'"'^ in which a number of persons were infected, sup- posedly from water from a well used in common with a man suffering from amebic dysentery. Parasite. — Amebic dysentery is now recognized to be a morbid entity caused by a specific microorganism, the Endamceba histolytica. The biologic position of the organism of amebic dysentery is of importance for a thorough understanding of its life history and relation to disease. The Endamceha histolytica is of the protozoa, a subkingdom of the animal world. The protozoa are divided into four orders: the Infusoria, the Flagelata, the Sporozoa and the Rhizopoda. It is to the latter order, which is the lowest of the protozoa, that the organism under discussion belongs. The Rhizopoda (ptfa, root -|- tovs (iro5) foot) consists of single cells which move by the extrusion of so-called pseudo- podia or parts of the cell substance and maintain their existence by enclosing food in a similar manner. Of a very extensive list of suborders into which the Rhizopoda are divided only one, the Amceba, contains organisms which are parasitic to man. The order of Amoeba is composed of three genera : Chlamy- dophrys, Leydenia and Amoeba. Schuadinn divided the genus Amceba into two subgenera: Amceba and Endamceba, and finally as stated above, the endamceba into Endamceba coli, a non- pathogenic intestinal parasite, and Endamceba histolytica the causative agent in amebic dysentery. For purposes of biologic study as well as of diagnosis it is well to compare Endamceba histolytica with Endamceba coli. Endamceba Histolytica. — The average diameter of Endamceba 404 ENDEMIC DISEASES OF THE SOUTHERN STATES histolytica in the vegetative stage is from 25 to 40 microns, thus averaging larger \haiiEndamwha coli. Some specimens measure as much as 70 microns in diameter. In color the ectoplasm is glassy, while the endoplasm is light gray, or when blood is present in the feces it may have a slight greenish tint. At rest the organism is roughly spheric or oval. In locomo- tion it becomes irregular or fantastic, dependent upon the extrusion of pseudopodia. In young amebcC it may be difficult to distinguish the endo- plasm from the ectoplasra, but in large organisms, especially in motion the differentiation Is easy. The endoplasm comprises about two-thirds of the protoplasm and is coarsely granular, more so than that of E. coli. The ectoplasm comprising one- third of the protoplasm is hyaline and lightly refractive. In fresh specimens it is frequently very difficult to distinguish the nucleus. It is situated to one side of the center of the endo- plasm. The average diameter is 5 microns. In shape it is circular or when located at the periphery or at the junction of the endoplasm and ectoplasm may be slightly flattened. The nucleus contains less chromatin than that of E. coli. The great variations in stained specimens in the appearance of the nucleus of this parasite were largely responsible for the former division of the species into E. histolytica type of nucleus. The nuclear membrane is delicate, the chromatin granules are few and lie upon the inner side of the nuclear membrane, the karyo- some is very small and appears as a dot of chromatin near the center of the nucleus, and there is no centriole. In the so-called tetragena type of nucleus the nuclear membrane is thicker and better defined, the chromatin is more abundant and lies upon the inner side of the membrane or between the membrane and the karyosome. The latter is comparatively large and appears as irregular or circular masses of chromatin, and a well-marked centriole is often present. The endoplasm always contains one or more non-contractile vacuoles. There may be as many as ten or more. When numerous they vary in size and are apt to be small. When single they are frequently large. It is thought to be dissolved hemoglobin within the vacuoles that give the endoplasm a PLATE 111 'L^i '^h ■mXt^ Endamoeba histolytica, i. Living organisms. Note absence of nucleus. All three of the parasites contain red blood-corpuscles. 2. Living organisms. Note nucleus in upper organism. The three lower specimens contain red blood-cor- puscles. (Bulletin No. i, Medical Department, U. S. Army.) AMEBIC DYSENTERY 405 greenish tint. When the parasite is at rest the vacuoles are spheric in shape, but in motion they may become elongated. Endamceha histolytica is much more actively motile than in Endamceba coli. Locomotion takes place by the protrusion of pseudopodia. The clear granular endoplasm follows, pouring in until it appears filled. The pseudopodia are larger and more distinct than in the non-pathogenic parasite. Motion without locomotion consists of the extrusion of pseudopodia and the ebb and flow of endoplasm. Endamceba histolytica is actively phagocytic. Within the endoplasm are engulfed bacteria, crystals and amorphous granules, and in contra-distinction to E. coli this parasite normally envelops red blood-cells. As a rule from two to six are present, but the parasite may appear markedly distended by the number of erythrocytes which it contains. In the cystic stage this ameba measures from lo to 20 microns in diameter and is spheric in shape. The outer contour of the organism is particularly distinct in stained specimens but in fresh specimens may appear double. The chromatin is arranged in large spindle-shaped masses. The cystoplasm appears uni- form, phagocyted bodies having been extruded before encysta- tion begins. The nucleus elongates, becomes constricted and then divides. Each of these two nuclei then divides, forming four daughter nuclei. The four-nucleated cyst is characteristic of E. histolytica. In fully developed cysts the chromatin is not infrequently found to have disappeared. In the vegetative stage the only known method of reproduc- tion is by simple division. In this process the nucleus elongates, becomes constricted and divides, to be followed by a corre- sponding process in the cytoplasm, resulting in the formation of two organisms. Degenerative forms of E. histolytica are not infrequently observed. They may appear entirely filled with vacuoles, the nucleus may appear almost entirely filled by the karyosome, or the nucleus may be broken and scattered through the cytoplasm. The staining reactions for E. histolytica are similar to those of E. coli. 4o6 ENDEMIC DISEASES OF THE SOUTHERN STATES Endamceba Coli. — The limits of size of Endamtsba coli may be put at from 6 to 50 microns in diameter. The average, however, is from 15 to 25 microns. While the largest Endamceba coli is larger than the average Endamceba histolytica, the average size of the former is smaller than the average of the latter. A differentiation should not be made, therefore, upon size alone but, taken with other morphologic data, is an aid. At rest this ameba is spheric in shape. In motion it varies in form with the protrusion of the pseudopodia. The color of Endamceba coli is uniformly dull grayish yellow. This color is independent of the composition of the feces, whether bloody or otherwise. It is ordinarily impossible to differentiate between the endo- plasm and the ectoplasm of E. coli, almost the entire pro- toplasm being endoplasm, and this is a valuable point in the determination between the two parasitic species in man. The endoplasm appears as finely granular in structure. In E. coli; unlike E. histolytica, a well-defined nucleus may nearly always be determined. Its position is usually to one side of the center. In size it is from 5 to 8 microns in diameter. The nucleus is commonly spheric, sometimes oval, in shape and contains numerous refractive granules and shreds of chromatin and one or more small nucleoli. Vacuoles are not commonly present in this ameba and when found are single. In common with the other parasitic species in man this vacuole is never contractile. It is usually indistinct and of small size. Endamceba coli is only slightly motile as compared with E. histolytica. Motion in the resting position may be detected by the flow of the granular protoplasm and the protrusion of minute pseudopodia. Locomotion is performed by means of small rounded pseudopodia. It is very slow compared to that of E. histolytica and ceases altogether after the specimen has stood at room temperature for half an hour. This ameba frequently engulfs bacteria and crystals, but very rarely red blood-cells. Even when blood is found in the feces it is rare to find the corpuscles phagocyted by this ameba AMEBIC DYSENTERY 407 and then only one or two, whereas with E. histolytica several corpuscles are frquently found in a single organism. Cysts of E. coli are about a third smaller than the vegetative forms. They possess a limiting wall of double outline and are motionless. The protoplasm is hyaline and contains nothing but the nucleus, bacteria and crystals having been extruded before the formation of the cyst wall. Reproduction takes place in the vegetative stage by two methods: by simple division, resulting in two daughter amebse; and by schizogony, resulting in eight daughter amebas. In reproduction by simple division the nucleus elongates, its membrane thins and the chromatin collects at each pole. Next a constriction appears near the center, narrowing in hour- glass form until complete separation occurs and two nuclei are formed. While this is taking place a corresponding constriction and division of the protoplasm occurs and two amebae are the result. Schizogonic reproduction is less common than that by simple division. In schizogony the nucleus becomes swollen and the quantity of its chromatin is greatly increased. The chromatin next collects in eight hemispherical masses within the nucleus. The nuclear membrane then disappears and the eight chromatin bodies are free in the protoplasm of the ameba. The chromatin masses become surrounded with nuclear membrane, thus forming daughter nuclei arranged with more or less regularity throughout the cytoplasm of the parasite. The cytoplasm then divides in proportion to the number of daughter nuclei and new organisms are formed. During reproduction within the cyst, the nucleus elongates, becomes constricted and finally divides much after the manner described for simple division. The further process of autogamy is obscure, but after division from two to eight nuclei are ob- served within the cyst, eight being the normal number for this ameba and less than eight denoting that the organism is still in the act of reproduction. More than eight nuclei, some- times as many as sixteen, are occasionally observed. The daughter nuclei are spheric in shape and have a distinct nuclear membrane. Degeneration forms are sometimes observed. These are 4o8 ENDEMIC DISEASES OF THE SOUTHERN STATES characterized by poorly defined cystic membranes, coarse granulation of the cytoplasm, shreds or lumps of chromatin, and distortion or disappearance of the nuclei. Vacuoles may almost entirely replace the endoplasm. In the vegetative stage stained with hematoxylin there is no distinction between endoplasm and ectoplasm, while the nucleus takes a dark purple color. With Wright's or Giemsa's stain the ectoplasm stains light blue and appears structureless, while the endoplasm is darker blue and appears granular. On account of its chromatin the nucleus takes a bright red or crimson. The nucleolus stains dark violet. Cultivation of Organisms. — Numerous investigators have attempted the artificial cultivation of the infective organism of amebic dysentery, and many reports of its accomplishment have been published. Thus Musgrave and Clegg*"^ considered that they had been successful in obtaining growth oiAmaha histolytica on a medium of bouillon and agar, i per cent, alkaline to phenolphthalein, plus a trace of peptone. They were unable, however, to ob- tain the organism in pure culture, but upon the addition of some bacterial form, 5. cholerw asiatica being best suited, they obtained good development at room temperature. Lesage^"^ considered that he had obtained cultures of E. histolytica but that E. coli could not be grown artificially. Whitmore,""** Craig'"'^ and others after thoroughly investigat- ing the matter have reached the conclusion that the organisms which have so far been cultivated are not the parasitic amebse, but are free-living species which have gained entrance either in the cystic stage with the food and passed through the intestines or as contaminations of the culture media. Inoculation Experiments. — One of the first to attempt to transmit amebic dysentery to the lower animals was Loesch.^^^ Since his time numerous investigators have performed inocula- tion experiments on various animals and in man, both by feed- ing and by rectal injections, and in one instance'"'" intra- venously, of feces containing amebse and of pus from liver abscess. In the classic experiments of Schaudinn^'" he fed kittens both AMEBIC DYSENTERY 4O9 with feces containing E. coli and those containing E. histolytica, and showed conclusively that the former was harmless while the latter produced typical amebic dysentery. He further showed by an ingenious experiment that E. histolytica is infectious only when spores are present. Craig*^^ found that amebic dysentery developed in 50 per cent, of young kittens injected per rectum with feces containing E. histolytica, and in 65 per cent, of those fed with that material. This investigator considers that the negative results obtained were due to the feces containing the organisms only in the vegetative state and without spores. In 1913 Walker and Sellards"^ published the results of most exhaustive feeding experiments on human beings. The work was carried on with long-term prisoners at the Bilibid prison, all of whom were volunteers, fully understanding the nature of the experiments and having signed an agreement to the conditions. The experiments were most carefully controlled by previous fecal examinations for parasites, by controlling the food and water supply, etc. The first series of experiments consisted of 20 feedings of cultures of 13 strains and 8 species of amebte to 10 different men. It was found that the amebas could be cultivated from the feces on Musgrave and Clegg's medium for a few days follow- ing the feeding, but never later. The amebas could not be recognized microscopically by examination of the feces. No dys- entery developed. These investigators therefore concluded that cultivable amebse will not live as parasites in the intestinal tract of man, are not pathogenic, and when obtained in cultures from stools are derived from cultural contamination or from encysted amebae which have been ingested with water and food and passed unchanged through the intestinal tract. The second series of experiments consisted of 20 feedings of 5 strains of Endamceba coli given to 20 different men. Of these 20 men 17 became parasitized at the first feeding, while 3 did not. In the 17 the Endamceba coli was found microscopically in every case, while cultures on Musgrave and Clegg's medium were invariably negative. None of the men developed dys- 4IO ENDEMIC DISEASES OF THE SOUTHERN STATES entery. From these experiments Walker and Sellards con- cluded that the Endamwba coli is a strict parasite, non-cultivable on Musgrave and Clegg's medium and non-pathologic. The third series of experiments consisted of 20 feedings with Endamceha histolytica. Of the 20 men 17 became parasitized after the first feeding, i after 3 feedings, while the other 2 were reserved as controls. Of the 18 men who became parasitized 4 developed endamebic dysentery. The organ- isms were recovered by microscopic examination in all who became parasitized, but cultures on Musgrave and Clegg's medium were invariably negative. Encysted "Endamceha tetragena" was obtained exclusively in the stools of men who ingested Endamceba histolytica only. Motile Endamwba histolytica were observed exclusively from men who ingested "tetragena" cysts only. From the above experiments these authors conclude that Endamceba histolytica is also a strict parasite and cannot be cultivated on Musgrave and Clegg's medium; that Endamceba tetragena and Endamceba histolytica are identical; that Endamceba histolyticaisthe essential etiologic factor in endemic tropical dysentery. Sellards and Baetjer"*^^ in 1914 introduced the procedure of direct inoculation into the cecum for the experimental produc- tion of amebic dysentery in cats. Their method was to perform a laparotomy under general anesthesia and inject the material with a sterile needle directly into the cecum. By this method they were able to produce dysentery in all of ten animals with the use of eight strains, two of which were from distinctly atypical cases. These authors consider that their method of inoculation is of value for the propagation of a strain of amebas through a series of animals for a period of at least several months ; that it may be used to determine the etiology of some obscure diarrheas; and that it is of value for the study of the morphology of some atypical amebas of low virulence. Mode of Infection. — As the life history of the Endamceba histolytica outside the human body is unknown, it is rather diffi- cult to determine the source of infection. All authors are agreed that practically the only method of infection in amebic dysen- tery is by the ingestion of the organisms. It is a somewhat AMEBIC DYSENTERY 41I moot point, however, whether or not drinking water is the sole source of infection. It is well within the range of possibility that the infective organism may be present on various kinds of uncooked food such as lettuce, cress, etc. Brown*"^ states that a case developed following the use of cold water enemas for constipation. While such cases are obviously possible they must be exceedingly rare. Pathogenesis. — The question as to the role of the amebae found in the intestinal canal of man in causing dysentery has been a greatly mooted one and many views have been ex- pressed. Cassagrandi and Barbagallo''^'' considered that amebae were not only harmless but that they actually combated disease, while Musgrave and Clegg'*"^ consider that all amebae are, or may become, pathogenic. Other views are that the amebae are infectious only in the presence of bacteria, that they may prepare the soil, as it were, for the action of certain bacteria, or vice versa. The view is becoming more and more prevalent that the Endamceba histolytica is the true and only cause of the disease ; however, this can be proven definitely only after the successful cultivation of the organism free from contamination, the reproduction of the disease in animals, and the recovery in pure culture of the amebae. Even the successful accomplishment of this experiment may be open to the objection that the bacteria always found in the intestinal canal of animals may in some manner be partially responsible for the production of the disease. This objection might be overcome after the successful cul- tivation of the organism has been accomplished by removing animals at term by Cesarean section, keeping them in a sterile ] chamber supplied with sterile air and fed on sterile food until old enough for experimental purposes, and then injecting with pure cultures of the organisms. It is generally conceded that the usual portal of entry of the amebae into the tissues is by way of the glands of Lieber- kiihn. This is shown to be the case by examination of the intestine early in the course of infection, when the organisms may often be found lying free in the lumen of the glands and the 412 ENDEMIC DISEASES OF THE SOUTHERN STATES epithelial lining remaining intact. Later they are found to have thrust themselves between the lining cells which to a large extent degenerate as a result. The orgam'sms soon penetrate the basement membrane and spread out on either side of it. Here they develop and push on into the submucosa and feed upon the tissue cells, red blood-cells and perhaps the leucocytes. In fresh tissues which are cut with a warm knife, movements of organisms in the tissue can be watched for several hours. The amebae may enter the radicles of the portal vein and be carried to the liver where they may cause hepatic abscess. CHAPTER XXVn PATHOLOGY OF AMEBIC DYSENTERY The morbid anatomy of amebic dysentery is confined mainly to the large intestine, the sigmoid and rectum, though oc- casionally the lower end of the ileum may be involved by extension through the ileocecal valve, and the appendix has been found affected. There are also certain complications which may arise, causing pathologic processes in other loca- tions than the bowels. The pathologic anatomy as observed in the large intestine in amebic dysentery presents many features which are charac- teristic of this disease. This is especially true of the chronic protracted cases, but as may readily be imagined the condition will depend largely upon the severity of the infection, and in very acute cases when death results early, the lesions may not present typical findings. In the latter type of cases the colon shows evidence of marked inflammation, the mucous membrane being hyperemic and inflamed with but little change in the submucosa. It is swollen, of a dark bluish or purple color, and presents many extravasations from congested vessels. Ulceration is infrequent, though small superficial areas of necrosis are noted. Diphther- itic-appearing membranes are often seen, composed of the ex- cessive mucous secretion and portions of the mucosa which have separated from the intestinal wall. The whole picture presents a marked resemblance to that observed in acute bacil- lary dysentery. This, however, is not the case in the more chronic type of amebic dysentery. In such cases of moderate severity the peritoneum is found more or less injected, contains some fluid, but otherwise presents little that is abnormal. The large intestine is bright in color, smooth and shows patches of con- gestion. The mucosa is seen to possess an excess of secretion 413 414 ENDEMIC DISEASES OF THE SOUTHERN STATES and presents some points of hyperemia and ecchymosis. The enamebce usually first enter the crypts of Lieberkiihn and penetrate the epithelial lining by boring between the cells with their pseudopodia and after passing through the base- ment membrane enter the submucosa. Here they multiply rapidly and are reinforced by others from the lumen of the intestine. By their presence in the submucosa, areas of congestion are formed; the mucosa is covered by a more or less copious secretion of viscid mucus and in severe cases with a diphtheroid membrane. It is, however, in the submucosa that the principal changes take place. There are evidences of acute inflammation and proliferation of the fibers of the con- nective tissue. Small tumors of adenoid tissue are formed which may be seen on the surface of the mucosa. Later these sup- purate in the center and present one of the characteristic lesions of the disease. In the early stage, also, are seen small erosions and areas of necrosis. They are in the beginning superficial and separate, but they gradually extend, deepen and are joined together and cover rather large areas of the surface. These erosions later constitute the typical ulcers of the disease. Be- tween them the mucosa appears normal except for the congested vessels. Two types of ulceration are seen: First, the typical under- mined amebic ulcers which in the early stages, as has been pointed out, are seen as small erosions on the mucosa. As the process continues, a pocket is formed in the submucosa which is extended in all directions parallel with the surface. The base of the ulcer rests upon the circular muscular coat with overhanging edges of mucosa. The size of the ulcer varies from I mm. in diameter to 8 or lo cm. As may be expected, the submucosa becomes markedly thickened and edematous, and usually the muscular and serous coats are somewhat in- volved in a like manner. It is not unusual in severe cases for two or more ulcers to coalesce either in the submucosa alone, forming tunnels under the mucosa, or by sloughing away of the mucosa itself. In very severe cases the muscular coat may be involved, necrosis or even perforation taking place and the peritoneum or omentum forming the AMEBIC DYSENTERY 415 base of the ulcer. The ulcer may perforate into the subperi- toneum where it may remain circumscribed, may burrow widely, or may cause general peritonitis. The second type of ulcer seen in amebic dysentery is the so- called type of Harris. These ulcers are rarer than the typical or undermined ulcer but are not infrequently seen, especially in early and rather acute cases. The Harris ulcers are in the beginning confined mainly to the mucosa, and for this reason there is some doubt as to their exact connection with amebic dysentery. They may extend into the submucosa, but rarely penetrate it and never extend into the muscular coat. The edges of the ulcer are abrupt, thickened and congested. They are sometimes described as of punched-out appearance. The base of the ulcer is clean, edematous and of a grayish color. Histopathology. — The mucosa between the ulcers generally presents little abnormality upon microscopic examination. Near the ulcers the mucosa may be hypertrophied, with some mucoid degeneration and occasionally cyst formation. Often the cells lining the glands are seen to have separated from the basement membrane and amebae may be found among these cells. In the beginning the most noticeable condition is a marked congestion, and often capillary hemorrhages are seen beneath the mucosa. The submucosa may also show congestion with thickening due to edema. There is an infiltration of lymphoid cells into the interglandular tissue. Later in the disease a slight superficial necrosis is seen and the glands surrounding the lesions show hypertrophy and mucoid degeneration. There is more infiltration and more congestion. Within the interglandular connective tissue amebae are seen in the blood-vessels and lymph spaces. As the process advances the submucosa is seen to be more affected. Congestion and edema are more pronounced and amebae are seen to be more plentiful. Sometimes there is an infiltration of polymorphonuclear leucocytes which seems to be accom- panied by activity of bacteria. The ulcer contents in uncom- plicated cases are composed of a granular base with degenerated cells, amebae, bacteria and erythrocytes. 4l6 ENDEMIC DISEASES OF THE SOUTHERN STATES Amebic ulcers show a marked tendency to heal. After the necrotic area has sloughed, red granulations are seen in the base of the ulcer. These granulations are unstable-and break down easily, and as long as amebtC are present no permanent repair takes place. In small ulcers complete repair may occur, but in large ones scar tissue is formed followed by more or less marked contraction. Complications. — The most important complication of amebic dysentery is hepatic abscess. According to Brown*"- there are four routes by which the amebae may gain access to the liver as follows : (i) Directly from the lumen of the intestinal canal; (2) transperitoneally from the intestinal wall; (3) by the portal vessels; (4) by the general circulation. Infection of the liver by way of the portal circulation is by far the most frequent route. According to Craig"^ Roux in 639 collected cases of hepatic abscess found the location to be as follows: 435, or 70.8 per cent., in the right lobe; 85, or 13.3 per cent., in the left lobe; and 2, or 0.3 per cent., in the lobus Spigelli. It was formerly considered that hepatic abscess of amebic origin are usually single but of recent years it has been shown that this is usually not the rule and that multiple abscesses are observed at least as frequently as in 50 per cent, of cases. The size of liver abscesses varies greatly. They may be so small as to be microscopic or they may attain a size so large as to fill almost completely the abdomen. The first change noted in beginning hepatic abscess is the formation of one or more small irregularly spheric nodules which appear like commencing coagulation necrosis and to some degree resemble the lesions observed in the intestinal tract. The nodules are solid and upon being cut appear of a cheesy consistency, the lobular markings being obliterated. Later the patches may coalesce and begin the breakdown. The process may be stopped at this point and occasionally found as de- scribed. As a rule the breaking down continues and liquefac- tion takes place, followed by the formation of a cavity which is filled with viscous fluid. This fluid is usually dark red in color AMEBIC DYSENTERY 417 and of gelatinous consistence. It may, however, be of a green- ish color owing to the mixture with bile. As the process ad- vances the contents become more liquid and necrotic tissue may be found floating in the mass. There is usually no lining mem- brane of the cavity especially when of large size but occasionally the small abscesses may have clearly defined smooth walls. It may be that the vascular structures are not destroyed and are seen crossing the cavity. Microscopically the contents of liver abscess are seen to be made up of disorganized liver cells, red blood corpuscles and granular matter. Fat globules, choles- terin, Charcot-Leyden crystals and hemotoidin are recognized. Pus cells are usually not present. The amebs are found if the abscess is not old. They are, however, found in the walls of practically all abscesses. The liver cells show hyaline and granular destruction. If the abscess is contaminated by pyo- genic bacteria the tissues will show many leucocytes. Other complications of the liver that are frequently noted are fatty degeneration and cirrhosis. The spleen is frequently the seat of cirrhosis; infarcts are occasionally seen, while splenic abscess has been reported. The route of infection is probably usually the blood stream although the infection may extend from the splenic flexure of the colon. Chronic gastritis is not a rare complication of amebic dys- entery and is usually of a rather severe character. Chronic enteritis is often seen, while, as pointed out above, acute peritonitis may occur and amebic appendicitis is not uncommon. The kidneys are very often the seat of nephritis, usually of a chronic character. In the heart, valvular disease is rarely seen, while edema of the pericardium is occasionally observed. Arteriosclerosis is some- times found. The lungs are quite frequently found to be the seat of bron- chopneumonia. This is in all probability mainly due to the fact that the patient remains in a recumbent position for so long a time. This complication is almost always fatal. Lobar pneumonia is occasionally seen and usually ends with death. 27 41 8 ENDEMIC DISEASES OF THE SOUTHERN STATES Empyema may occur, due to the perforation into the pleural cavity from an hepatic abscess. Brain abscess is a rather rare compHcation of amebic dys- entery and usually follows hepatic abscess. The abscesses are usually small and may even be microscopic in size. The amebae are readily demonstrable in the pus and the walls of the cavity, and bacteria of various kinds are usually present. CHAPTER XXVIII CLINICAL HISTORY OF AMEBIC DYSENTERY The clinical course of amebic dysentery varies greatly. It may be ushered in with a chill, nausea and vomiting, and pass on with acute griping pain and diarrhea followed by pros- tration, exhaustion, collapse, cardiac failure and death. Or after such an acute attack either with or without treatment the system may overcome the infection and after four or five days improvement begin. Complete recovery is rather rare and a tendency to relapse and chronicity may continue. On the other hand, the onset of the disease may be insidious and persist for years with only mild disturbances, such as ir- regularity of the bowels, occasional abdominal discomfort, and gastric derangement. This type of the disease may develop acute symptoms at any time and terminate in death or recovery. The period of time elapsing from the ingestion of E. histolytica until they could be found in the stools microscopically in the experimental cases of Walker and Sellards*^^ varied from one to forty-four days with an average of nine days. Of the four cases which developed dysentery the incubation periods until the advent of symptoms were respectively, twenty, fifty-seven, eighty-seven and ninety-five days. These authors consider that it is at least probable that the number of organisms in- gested accounts for the varying incubation periods. In the experiments of Sellards and Baetjer*'^ on cats the incubation period of animals injected from acute and chfonic amebic dysentery varied from six to ten days, while in the animals injected with atypical strains the incubation period was one month. In the acute form of the disease there may be some prodromal symptoms such as malaise and headache. After three to five 419 420 ENDEMIC DISEASES OF THE SOUTHERN STATES days marked nausea, which vomiting does not altogether re- lieve, is usually noted. A distinct rigor may be the first marked symptom or the nausea and vomiting may be accompanied by chilly sensations. In a short time diarrhea with severe grip- ing pain develops. The pain is at first of an intermittent acute character most marked in the umbilical regions; later this is less acute but continuous and is located in the region of the sigmoid. At first the stools are copious and watery but later are scanty and composed mainly of mucus, blood and cast-off fragments of intestinal epithelium. The movements become more fre- quent, sometimes as many as fifty a day, and urgent, and are attended with burning and tenesmus. Following defecation there is no relief and even though the rectum be almost entirely empty the desire to defecate remains and violent efforts are made to do so. Not only is rectal tenesmus present but very fre- quently vesical tenesmus is one of the most distressing symp- toms. In the malignant cases there is a continued increase in the severity of the symptoms. The pain and loss of sleep often cause mental symptoms, either depressions or delirium, to develop. There may be severe hemorrhages of the bowels. Exhaustion soon appears and in a few hours death results from cardiac failure and collapse. If the system is able to throw off the infection, or sometimes under proper treatment the acute stage is followed in four or five days by beginning recovery. The pain becomes less, the bowel movements less frequent, but contain more fecal matter. Complete recovery is unusual and the disease passes into either the chronic or the intermittent form. In the former the stools vary from 2 or 3 to lo or 15 per day with more or less pain. As the disease progresses there is loss of weight, anorexia, indiges- tion and flatulence. Extreme emaciation may result with great exhaustion. Death may follow from exhaustion or inter- current infection. In the intermittent type there are periods of diarrhea, more marked in the mornings, consisting of two to four semifluid stools without much mucus and little pain. The diarrhea lasts for one to six or eight days and is followed by a. period of constipation. These alternate periods of diarrhea AMEBIC DYSENTERY 42 1 and constipation may last for many years and the patient die of intercurrent disease or an acute exacerbation may lead to a fatal outcome. That mild cases of infection with Endamosba histolytica, in which there are no dysenteric symptoms, do occur has been pointed out by many observers. Thus Musgrave*^^ reports a series of fifty cases in which characteristic amebic lesions were present at autopsy but in which dysentery symptoms were absent. Such symptoms as abdominal "aching," more pro- nounced at night and early in the morning, flatulence and constipation are noted. The constipation is usually resistant to the ordinary doses of the usual cathartics, or their actions may be unusually severe and prolonged. Loss of weight is often noticed but this may not result, and the patient may even gain in iiesh. Anorexia is often first noticed at breakfast time and is frequently accompanied by nausea and accumula- tion of mucus in the mouth and throat during the night. One of the most frequently noted S3anptoms is excessive perspira- tion, especially of the palms of the hands and the soles of the feet. Often, as Musgrave points out, the whole chain of symp- toms, dullness, headache, loss of memory, weakness, desire for sleep, etc., is noted in these mild infections. The disease often begins insidiously and passes into a slightly more accentuated form which may persist for months or years. This type of infection is similar to the chronic type following an acute out- break and may develop at any time an acute attack. Physical Signs. — By physical examination in amebic dysen- tery little or nothing distinctive may be learned. During acute attacks there is more or less tenderness over the large intestine, especially over the sigmoid. The liver is usually enlarged and in some cases of hepatic abscess enormously so. At first the abdomen is more or less distended with gas but later is flat and the abdominal muscles are flaccid. Temperature. — The temperature in amebic dysentery varies from normal or subnormal in the mild cases to 104° to io5°F. in the severe attacks of acute onset. Just before death in the acute cases the temperature may drop to subnormal. In un- complicated cases even of moderate severity there is usually 42 2 ENDEMIC DISEASES OF THE SOUTHERN STATES no rise in temperature, but in cases of secondary infection the temperature may be high. In the acute attacks, which occur during the course of a chronic case, even if of marked severity, the temperature is usually not so high as in the attacks of acute onset. Ptilse and Respiration. — The pulse and respiration as a rule follow the variation in temperature. In the mild cases and those of chronic character the pulse may be normal, while in moderately severe cases the pulse changes from 80 to 100. In the acute cases the pulse rate may run as high as no to 120, and in those of fatal termination 120 to 140 and more have been noted. The respirations as a rule increase with the pulse, except as collapse occurs in which they are shallow and in- frequent. The blood pressure in amebic dysentery depends upon the general condition of the patient; where there is emaciation and cachexia the blood pressure is low, while in mild and even in some chronic cases it may be normal. In cases complicated by other conditions such as nephritis and arteriosclerosis the blood pressure may be high. As a rule there are no symptoms referable to the heart, though pathologic changes in this organ may occur. The blood stream in amebic dysentery shows nothing which is typical. In those cases of acute onset there is nothing ab- normal seen, the erythrocytes show no alterations in shape or numbers, and the hemoglobin is of normal percentage. There may be a slight leucocytosis. In the more chronic cases there is a secondary anemia de- pending in degree upon the severity and length of the infection. The red blood-cells are decreased in numbers to as low as 1,500,- 000 or less, while poikilocytes, normoblasts and megaloblasts may be found. The hemoglobin is diminished in amount in a proportion greater than the reduction of the erythrocytes. It may be as low as 20 to 30 per cent. There is usually a moderate leucocytosis in the later stages of the disease depending to a large extent upon the amount of secondary infection. The relative numbers of the various types of leucocytes are usually normal. There is rarely an eosinophilia in cases uncom- plicated by other intestinal parasites, although as pointed out AMEBIC DYSENTERY 423 by Amberg''^^ in children this condition is very frequently encountered. All symptoms observed which are referable to the lungs occur as complications. The gastro-intestinal symptoms are most marked in amebic dysentery. Thus nausea and vomiting are early symptoms in acute attacks, and as pointed out above in those mild in- fections without dysenteric symptoms the only symptoms may be those referable to the stomach. The appetite varies with the severity of the condition. In mild and chronic cases it may be normal while in the more severe cases there may be complete anorexia. As pointed out above, the intestinal symptoms may vary all the way from constipation to the most marked diarrhea of the dysenteric type. It is not at all to be inferred that the pathologic findings are to be interpreted in the light of the clinical evidence for it not infrequently occurs that cases show- ing marked dysenteric lesions come to autopsy without having shown dysenteric symptoms. Macroscopically the stools of amebic dysentery show nothing characteristic of this disease. They vary in consistence from solid and semi-solid in the mild and chronic conditions to watery in the acute. When formed stools are passed there may or may not be a coating of mucus. The fluid stools show the most marked variations. There may be little present but blood, mucus and intestinal debris, or there may be noted particles of undigested food. Again they often assume a watery consistence with little mucus. When ulceration is present the stools may contain blood clots and portions of intestinal mucosa. The odor of the amebic feces is usually very offensive and accord- ing to Musgrave''" "all but characteristic." This author further states that the odor is so nearly characteristic that diagnostic importance may be attached to it. The nature of the blood as passed in the feces is of importance both as an indication of the severity of the pathologic process and the location of the lesions. If no blood is present macro- scopically, it is an indication that ulceration probably has not taken place. This is not invariable as in very acute cases 424 ENDEMIC DISEASES OF THE SOUTHERN STATES perforation may take place before ulceration. If the blood is of dark brown or black color, it is an indication that the cecum is the chief seat of the infection. If the blood is fresh, bright red and clotted, it may be assumed that the lower end of the colon is most affected, while if the blood is intimately mixed with mucus and fecal matter and the stools are of a dark red or reddish-brown color, it is probable that the bleeding is taking place above the sigmoid flexure. Microscopically the appearance of the feces in amebic dysen- tery varies with the stage of the disease and the severity of the infection. Red blood-cells are practically always found and more or less epithelium. There are varying quantities of food particles, epithelioid and pus cells, bacteria and the distinguish- ing feature, Endamceba histolytica. It must be remembered that Endamceba coli are also frequently present as well as the ova of certain other intestinal parasites; The urine in amebic dysentery shows nothing characteristic. The amount is usually greatly diminished during the acute attacks, but may be normal during the intervening periods. The specific gravity corresponds to the amount secreted and the reaction is usually acid. Retention may occur in the severe cases when the reaction may become alkaline. Albuminuria is seen only when the disease is complicated by nephritis. Al- bumoses have been noted and may be indicative of hepatic abscess. Indican is usually present in considerable quantity, depending on the severity of the pathologic processes. It has been noted that the chlorides are diminished or absent during acute attacks, especially when the diarrhea is severe and the stools watery. Microscopically may be found hyaline and granular casts, if nephritis is present, and epithelial cells and various crystals. Complications. — As stated in the chapter on pathology the most important complication of amebic dysentery is hepatic abscess. This may occur early in the disease but is usually a later complication. Cases have been reported in which liver abscess preceded other manifestations of amebic infection but this is undoubtedly rare. In cases of acute onset hepatic abscess may be found AMEBIC DYSENTERY 425 within a week of the onset of dysenteric symptoms, but as a rule is not noted till about the sixth week. In chronic cases, however, this complication may not develop for months or even years after the initial attacks. In one case reported by Brown''"^ the patient developed hepatic abscess nine years after the last attack of dysentery. According to Manson*^^ Europeans are more liable to develop hepatic abscess than natives of tropical countries (India) although more dysentery is seen in the natives. He further states that while European women contract amebic dysentery as frequently as European men they rarely develop hepatic abscess and children hardly ever. One of us has operated on half a dozen cases of amebic abscess in adult negroes, all but one being males. The onset is usually insidious and may last for a considerable length of time without any symptoms. Symp- toms of perforation may be the first indication. Pain usually develops some time in the course of the disease and is usually dull and aching but may be sharp. The pain may be over the hypochondrium or epigastrium, or, as is very frequently the case, it may be reflex and observed in the region of the right scapula. If pain is absent, it may sometimes be elicited by pressure over the liver. A rise in temperature is usual but not constant. The morning temperature may be nearly normal and in the evening a rise to ioo° to ioi°F. be noted. On the other hand, a temperature of 103° to io4°F. is not infrequent. The temperature is usually intermittent but it may be continuous for a long time with slight morning remissions. Chills and excessive perspiration may occur. The pulse usually corre- sponds to the temperature and may run as high as 140 or more. Marked jaundice is rare, although the conjunctivae are fre- quently tinged with yellow. Vomiting is not usual and anorexia is the rule. The tongue is usually coated. Physical examination will reveal an enlarged liver and if the abscess is located anteriorly and of very large size fluctuation may be noted. If it is located under the vault of the diaphragm, there will be bulging upward and an area of dullness will be noted in the thorax. The intercostal spaces may be obliterated and protrude. 426 ENDEMIC DISEASES OF THE SOUTHERN STATES The blood in hepatic abscess usually shows a leucocytosis, although this condition is by no means constant. The total number of leucocytes may run as high as 30,000 or 40,000 mainly due to an increase in the polymorphonuclears. If the patient is not operated upon and lives long enough, spontaneous rupture may occur. This most frequently is into the right lung, less often into the peritoneum and pleural sac, and rarely into the colon, the stomach, small intestine, bile ducts, vena cava, pericardium, kidney, or through the skin in the lumbar or right hypochondriac region. Manson*^^ gives the following table of 563 cases of hepatic abscess collected by Rendu in which rupture occurred in 159: Rupture occurred into the pericardium in i case, 0.13 per cent. Rupture occurred into the pleura in 31 cases, 5.5 per cent. Rupture occurred into the lung in 59 cases, 10,5 per cent. Rupture occurred into the peritoneum in 39 cases, 6.9 per cent. Rupture occurred into the colon in 6 cases, i per cent. Rupture occurred into the stomach and duodenum in 8 cases, 1.4 per cent. Rupture occurred into the bile duct in 4 cases, 0.7 per cent. Rupture occurred into the vena cava in 3 cases, 0.5 per cent. Rupture occurred into the kidney in 2 cases, 0.3 per cent. Rupture occurred into the lumbo-iliac region in 6 cases, i per cent. One of us has recently treated a case in which rupture of an abscess occurred into the right lung. Ten months later, though pus was being expectorated freely, the abscess pointed just to the right of the second lumbar vertebra where it was evacuated through an incision. Peritonitis may occur as a result of rupture of an hepatic abscess into the peritoneum or following perforation of the intestine. This condition usually proves fatal. Other Diseases. — Amebic dysentery is very frequently com- plicated by other diseases, such as malaria, pellagra, hook-worm and other intestinal parasites, which complications will cause variations in the symptomatology. We have seen pyorrhoea alveolaris complicating amebic abscess of the liver. CHAPTER XXIX DIAGNOSIS OF AMEBIC DYSENTERY The absolute diagnosis of amebic dysentery upon clinical findings alone is usually impossible, although certain symptoms are very suggestive. A disease of acute onset with nausea and vomiting and griping diarrhea, especially in endemic centers of amebic dysentery, must be looked upon with suspicion. Again, a disease of insidious onset with chronic diarrhea, ema- ciation, etc., should be considered at least possibly amebic dysentery. It is, however, upon the microscopic examination of the feces or pus from a hepatic abscess for the Endamceba histolytica that the final diagnosis must rest. In collecting feces for examination for the infecting organism most writers enjoin the giving of a purgative beforehand. However, as Walker'''- has pointed out, if a purgative is given, the Endamceba histolytica, if present, will be found in the preen- cysted state when it most resembles Endamceba coli, and that if the stools are formed, the organisms are usually found in the encysted state when they may most certainly be differentiated from Endammba coli. The examination of dysenteric or diar- rheal stools should be made as soon as possible after passage, as entamebas in these stools are motile but quickly lose their motility. If the surrounding temperature is much below that of the body it is well to collect the stools in a glass jar of some description and place this in a vessel of water at a temperature of about ioo°F. This is not necessary with formed stools as the entamebas are in the encysted state and preserve their characteristics for several days. If the fluid stools are to be examined for the organisms in the fresh state, a platinum loop full of the material is placed upon a microscope slide and covered with a cover- glass. Gentle pressure should be applied to spread the material in a thin layer. If particles of mucous or bloody material are 428 ENDEMIC DISEASES OF THE SOUTHERN STATES present, preparations of them also should be made. Naturally it is more easy to recognize the endamebas when they are still motile but after some experience they may readily be recognized after motility ceases if disintegration has not commenced. A rapid survey with a low-power objective should be made and all suspicious-looking objects examined with the oil im- mersion. When motility is present even the inexperienced should have little or no difi&culty in recognizing the organisms. If, however, motility has ceased, amebas may be distinguished from other bodies found in the feces by their size which, even when smallest, is larger than pus cells and other protozoa except Balantidiiim coli, by their refractiveness which is greater than pus cells or epithelial cells, and by their distinctness of outline. The nucleus of the ameba is also characteristic in that it is usually ring shaped and relatively small. If the developmental characteristics of the entamebse are to be studied, it is well to employ a warm stage. In examining the solid stools for the organisms a small por- tion of stool is rubbed up on a slide with a drop of water or salt solution and covered with a cover-glass as described above. In these stools the amebse are found in the encysted state, when they are round or slightly oval, more refractive than when in the vegetative state, and the cyst wall is usually distinctly seen. The cysts will be observed to contain from two to eight nuclei depending- upon the species of entameba and the stage of development. While for diagnostic purposes it is usually best to examine the feces for the amebce in the fresh state, it is sometimes de- sirable for preparing permanent specimens and for bringing out some of the details of the nuclei to stain them. A simple method which is sometimes employed is to add a few drops of a weak aqueous solution of acid fuchsin or methy- lene-blue which will stain epithelial cells and debris, leaving the endameba almost free from stain. The vapor of osmic acid applied to an air-dried film of feces for twenty minutes, followed by washing in water, is another simple and satisfactory method of staining. AMEBIC DYSENTERY 429 Staining by one of the Romanowsky modifications is largely used and gives very satisfactory results. The following method, originated by Darling and described by Deeks,'*^^ has given very good results in our hands. A small portion of material is smeared on a slide by covering with another slide and drawing the two apart lengthwise, and dried in the air. The slide is then fixed for five minutes with undiluted Hast- ing's stain, after which distilled water is added until no more will stay on the slide. The staining is continued for one hour. More water and stain may be added from time to time to pre- vent drying, or it may be covered with a small bell jar. When the staining is completed the slide is rinsed in tap water and dried, following which it is placed in any good Giemsa solution. The one used by us is prepared by mixing 5 c.c. each of o.i per cent, aqueous solution of yellowish eosin and Azure II and diluting with 40 c.c. of distilled water. The slide is stained in this solution over night, after which it is rinsed in tap water, dried and differentiated by dipping a few times in 60 per cent, alcohol containing i per cent, aqueous solution of ammonia. Methods of dry fixation, however, are not as satisfactory, owing to the distortion of the nucleus, as certain wet fixation methods. For this purpose we have found Mallory's chloride of iron-hematoxylin stain as modified by James and described by Craig*-^ most satisfactory. 1. Thin smears of material are immersed without drying into Schaudinn's sublimate-alcohol solution and fixed for two to five minutes. (Schaudinn's solution was originally composed of one part of absolute alcohol and two parts of saturated aque- ous solution of bichloride of mercury. It has been modified to contain one part absolute alcohol to two parts of normal salt solution saturated with bichloride, plus 2.5 per cent, glacial acetic acid.) 2. After fixing, the smears are hardened in 80 per cent, alcohol for ten minutes. 3. Smears are washed in 50 per cent, alcohol and then in distilled water. 430 ENDEMIC DISEASES OF THE SOUTHERN STATES 4. Smears are flooded with a mordant which consists of freshly prepared 10 per cent, aqueous solution of chloride of iron. 5. After pouring off the mordant the smears are flooded with freshly prepared solution of hematoxylin made by adding crystals of hematoxylin to 250 c.c. of warm distilled water, until a deep port wine color is produced. The stain is added to the slides until the hematoxylin is precipitated, which is shown by the smear appearing through the solution. The staining is continued for five to twenty minutes. 6. Following the staining the smears are washed in at least ten changes of distilled water. 7. They are then decolorized with freshly prepared 0.5 per cent, solution of chloride of iron in distilled water. 8. Smears are washed in tap water over night. 9. They are next dehydrated in 95 per cent, followed by absolute alcohol. 10. Cleared in xylol. 11. Mounted in neutral balsam. The cytoplasm of the endamebse stains a grayish blue, the nuclear membrane and chromatin a deep black, while the struc- ture of the nucleus is beautifully brought out. While it is necessary to differentiate amebas from certain other cells and artefacts which appear in the feces, the main point in the diagnosis in amebic dysentery is the differentiation of Endamoeha histolytica from Eiidamosha coli. As far as we are aware no one has reported the finding of Endamceba huccalis in the feces, but it seems at least possible that in severe cases of Rigg's disease these organisms might be observed in the feces and perhaps mistaken for Endmnceba histolytica. The following table shows the main differentiating features between Endamceba histolytica and Endamceba coli: AMEBIC DYSENTERY 431 E. coli E. histolytica Size Variable, average 15 to 25 mi- crons in diameter, in vegeta- Variable, average 25 to 40 mi- crons in diameter. tive stage. Shape Spheric at rest. Dull greenish yellow. Roughly spheric or oval. Ectoplasm hyaline, endoplasm light gray or greenish tinted. Color Structure Ordinarily impossible to differ- Differentiation of endoplasm entiate between endoplasm and ectoplasm easy, Endo- and ectoplasm. Protoplasm plasm coarsely granular. finely granular. Nucleus Well defined, to one side of Poorly defined, average diame- center, 5-8 microns in diarne- ter 5 microns. ter, one or more nucleoli vis- ible. Vacuoles Generally absent, generally al- Always present, may be nu- ways single, usually small and merous, distinct. indistinct. Motility Sluggish, pseudopodia rounded Active, pseudopodia rounded and very small. or finger-like, larger and more distinct. Phagocytosis . . Bacteria and crystals, rarely In addition to bacteria and blood-cells. crystals, red blood-cells often present. Cysts A third smaller than vegeta- tive forms, limiting wall of double outline, protoplasm hyaline, no phagocytosis, eight nuclei. Four nuclei. Reproduction . . In vegetative stage by binary In vegetative stage by binary fission and by sporulation, in fission, in cystic stage by pro- cystic stage by formation of duction of four daughter cells. slight daughter cells. In staining the amebae in tissues the following method of Mallory''^- gives very satisfactory results: 1. Harden in alcohol. 2. Stain sections in a saturated aqueous solution of thionin three to five minutes. 3. Differentiate in a 2 per cent, aqueous solution of oxahc acid for one-half to one minute. 4. Wash in water. 5. Dehydrate in absolute alcohol. 6. Mount in xylol balsam. 432 ENDEMIC DISEASES OF THE SOUTHERN STATES By this method the nuclei of the amebas, the granules of the amebas and the granules of the mastzellen are stained a brownish red ; the nuclei of the mastzellen and of all other cells are stained blue. Differential Diagnosis. — There are a few conditions which closely resemble amebic dysentery and must be differentiated from it. The most important of these is bacillary dysentery, which, while its tendency is much more to assume an acute form than amebic dysentery, is usually without microscopic examination impossible of differentiation from the latter. In amebic dysentery the stools will almost always be found to contain Endaniosha histolytica upon microscopic examination. If this organism is not found it might be well to attempt animal inoculation as suggested by Sellards and Baetjer.''^^ In bacillary dysentery the B. dysentericB can usually be recovered from the feces by cultural methods, and in all but very mild cases the blood serum of patients suffering with bacillary dysentery will agglutinate either the Shiga bacillus or the Flexner bacillus after seven or eight days. Hemorrhagic typhoid may be mistaken for amebic dysentery, especially in the tropics where it usually runs an atypical course. In the absence of amebic in the stools a positive blood culture would clear up the diagnosis. Later a Widal test would be of service. Not infrequently malaria may simulate amebic dysentery, but an examination of the blood should make it impossible to confuse the two conditions, even in the absence of amebae in the stools. Tuberculosis of the intestines is sometimes mistaken for chronic amebic dysentery and when amebse cannot be found in the feces may be difficult of differentiation. A diagnostic point is that in tuberculosis of the intestine tenderness is usually more marked in the right iliac fossa, while in amebic dysentery it is usually more marked over the sigmoid. The various tubercuhn tests may be of value, while the finding of the tubercle bacillus in the feces will be conclusive. Malignant involvement of the sigmoid and rectum, may be mis- taken for amebic dysentery, and especially in old people the AMEBIC DYSENTERY 433 rectum should be examined, when httle difficulty should be encountered in arriving at a correct diagnosis. The invasion of the alimentary tract by other intestinal parasites, such as hook-worm, may cause symptoms simulating amebic dysentery, but microscopic examination of the feces should clear up the diagnosis. The diarrhea of pellagra has been mistaken for amebic dysen- tery, but here again even in the absence of the typical eruption of pellagra the diagnosis should be easy upon examination of the feces. It must be remembered that it is not only possible for amebic dysentery to be complicated by any of the above-mentioned conditions, but that such complications as malaria, pellagra and hook-worm are by no means rare. The physician should therefore be upon his guard to recognize such complications by careful examinations not only of the feces but also of the blood. Therapeutic Test. — Since the introduction of emetine into the therapy of amebic dysentery, the injection of this drug may be of importance in clearing up the diagnosis of obscure cases. If the symptoms improve under such treatment it would be strong presumptive evidence that the disease is amebic dysen- tery. If they do not improve the reverse would be the case. Hepatic Abscess. — This condition following amebic dysentery may usually be diagnosed by increase in size of the liver, by pain, which if not present can be elicited by pressure, by the temperature and leucocytosis. Or, as a last resort, aspiration with a needle may be performed. Of course the finding of pus by aspiration does not prove the abscess to be of amebic origin and a search for the organisms should be made. This may be done by similar methods to those described above for feces. The endamebas are found in the aspirated pus of hepatic abscess in only about 50 per cent, of cases, but can be found in all cases by scraping the wall of the abscess. CHAPTER XXX PROGNOSIS OF AMEBIC DYSENTERY Death in amebic dysentery may occur from the gravity of the intestinal lesions, from exhaustion in long-protracted cases, from severe complications, such as hepatic abscess, peritonitis due to perforation, etc., from severe intestinal hemorrhage, from terminal infection, or from intercurrent disease. The severity of the intestinal lesions and hepatic abscess are the most frequent causes of death. Musgrave*^® gives the following as the causes of death of fifty fatal cases of intestinal amebiasis without diarrhea : Three from peritonitis following perforation of the appendix — two of these produced by amebic ulceration, the other by an unknown cause, not amebic. Four from liver abscess — one perforating into the right pleura, one into the abdominal cavity, and two without perforation. One from acute pericarditis. Eight from pulmonary tuberculosis, and in three of these abdominal tuberculosis was also present. Two from chronic estivo-autumnal fever. Five from perforation of amebic ulcers in the large intestine — four times in the cecum and ascending colon, and once in the transverse colon. Seven from acute beriberi. Twenty from lobar pneumonia. Mortality. — The mortality in amebic dysentery varies with the severity of the infection, the time of beginning treatment, the resistance of the patient, and the method of treatment. Duncan*-^ states that among sixty cases in the Niger Protec- torate, of those treated with ipecac the mortality was 32 per cent., while of those treated with magnesium sulphate the mortality was only 2.9 per cent. In the Malay States, of 337 cases the mortality with ipecac treatment was 31.1 per cent., 434 AMEBIC DYSENTERY 435 with saline treatment 23.6 per cent., while with boric acid treatment the mortaUty was 18 per cent. In the Nigri-Sembilin Hospital the mortality sank from 34.2 per cent, to 17.88 per cent, after the introduction of the boric acid treatment. Of 100 cases treated by Musgrave"'' in private practice, including all types and stages of the disease, ninety-six per- manently recovered without leaving the Philippines, one died and three returned to the United States. Prognosis. — In making a prognosis of amebic dysentery the fact of the great tendency of this disease to recur must be kept in mind. In children, as a rule, the prognosis is good, while in the aged it is bad. It has been stated that alcoholics are less liable to infection. This we do not believe to be the case as the chronic gastritis so frequently observed in alcoholics predisposes to the disease, and certainly the prognosis in this class of individuals is not good. Good general physical condition and previous good health make for a favorable prognosis. According to Musgrave''^^ the location of the lesions is im- portant as a prognostic indication. Thus the higher up the lesions the less favorable the prognosis. The outlook in cases with acute onset is always grave, while if the onset is gradual and the condition recognized early the prog- nosis is good. Complications will, of course, render the prognosis less favor- able; thus in hepatic abscess the chance for recovery is lessened, depending upon the size of the abscess. Strong''^'' states that in twenty-seven cases reported by Futcher there were nineteen deaths. Of these cases seventeen were operated upon with only five recoveries. In his own cases Strong reports twelve cases of abscess with three recov- eries after operation. One of us has operated on six cases with no death. CHAPTER XXXI PROPHYLAXIS OF AMEBIC DYSENTERY Since the Endamwba histolytica is primarily an inhabitant of the intestinal canal and is passed with the feces of the vast majority of patients suffering from amebic dysentery, obviously one of the most important measures of prophylaxis is the dis- infection of the stools in all cases. This is best done by the use of chloride of lime. Bichloride of mercury, i— i,ooo, or lo per cent, phenol is very satisfactory. The so-called "carriers" are a source of danger. It is these individuals, in whom the organisms exist in the encysted state without any active manifestations of the disease, that should as far as possible be sought out and treated. It is obviously impossible to make examination of the feces of all persons to detect carriers, but with certain units of population, such as in eleemosynary institutions, hospitals, prisons, etc., it is not only possible, but very desirable to make such examinations. It goes without saying that the excreta of such individuals should be carefully disinfected. While the life history of the Endamceba histolytica outside of the human body is unknown, inasmuch as certain animals, especially the cat, are known to be capable of artificial infection, it is well within the range of possibility that they may become infected without the intervention of artificial means. It there- fore seems to us that cats as household pets should be eradi- cated from endemic centers of the disease. As stated above, all authors are agreed that practically the only source of infection is by the ingestion of the infective organisms, and in all probabiUty the main source of these is drinking water. It therefore becomes an essential to the pre- vention of the disease that nothing but water free from the amebse be used for drinking purposes. Obviously in endemic centers of amebic dysentery it is impossible to secure a raw 436 AMEBIC DYSENTERY 437 water that is absolutely above suspicion. It is therefore advis- able to boil all water before use, and to store it in as nearly a sterile condition as possible. It is well also to prepare only a sufficient quantity for use for a short time at once, to avoid possible contamination during storage. Of course in endemic centers the use of distilled water or bottled and carbonated waters is to be recommended where possible. However, care should be exercised that they come from reliable sources. The eating of raw foods such as lettuce, cress, etc., is not to be recommended. The use of raw milk is also to be looked upon as a possible source of danger in endemic centers, and unless the most rigid sanitary inspection is exercised over the source of the milk supply, this should be boiled before use. Alcohohcs are perhaps more susceptible to the disease than other individuals, therefore the use of alcohol as a beverage should be interdicted. It goes without saying that the general health of individuals, especially those residing in endemic centers of amebic dysen- tery, should be kept as nearly perfect as possible and that all measures of prophylaxis of other infectious diseases should be used. And, finally, it is well to remember the case cited above in which infection followed the use of cold water enemas and guard against such a possibility. CHAPTER XXXII TREATMENT OF AMEBIC DYSENTERY The treatment of amebic dysentery consists of hygienic measures, general and symptomatic treatment, surgical pro- cedures, and specific treatment. To these may be added the surgical and specific treatment of hepatic abscess. Hygienic Treatment. — In the acute attack of amebic dysen- tery the patient should be placed in bed and should not be permitted to get up to urinate or go to stool, using the urinal and bed pan. The room should be well ventilated, but chilling ■draughts of air which may increase congestion of the internal viscera should be avoided. In the chronic course of the disease it is not necessary for the patient to remain in bed, in fact is not desirable. A certain amount of exercise, depending upon the general condition of the patient, should be taken, although over-exertion and fatigue should be avoided. Care should be taken to avoid exposure to cold and dampness, and the clothing should be sufficient to keep the body warm at all times. The diet is of the utmost importance in treating amebic dysen- tery. During the early acute stage it should consist of nothing but albumin water. Later, when the symptoms have shown some improvement, chicken or beef broth may be given. Milk is usually contra-indicated owing to its tendency to form bulky residue. As improvement continues soup and eggs may be eaten, while minced chicken, fish, etc., can usually be allowed within a few days. The diet in chronic amebic dysentery should be sufficient to restore the body weight, yet it should not be excessive and should contain as little residue as possible. A diet composed largely of meat is very desirable. There is little residue in such a diet and it furnishes a large amount of nourish- ment; further, meat stimulates a flow of the gastric and intes- tinal juices. In prescribing a meat diet care must be taken to change fre- quently the kind of meat used, as well as the method of cooking 438 AMEBIC DYSENTERY 439 it. Eggs, tea, small amounts of toast and butter are permissi- ble, as well as fresh stewed fruits and small quantities of fresh cooked vegetables. General and Symptomatic Treatment. — In the acute stages of the disease when griping is intense and rest is imperative the use of morphine is to be recommended. This drug should be pushed to the physiologic limit if needed. Enemas of lauda- num may be given. As the symptoms improve Dover's powders may be substituted. Nausea and vomiting when troublesome may usually be controlled by the alkaline carbon- ated waters. Pepsin, hydrochloric acid and pancreatin may be employed for the dyspepsia seen in the chronic stages. If abdominal pain is severe it may usually be relieved by turpentine stupes, hot fomentations or the ice-bag. It may be necessary to administer opium in some form for the pain. Bismuth was formerly given quite extensively for the diarrhea, but its use is not to be recommended. In the beginning of treatment, whether in the acute or chronic stage, the administration of a dose of castor oil is usually ad- visable. This clears the bowel, and in a measure, at least, assists in removing the infecting organisms. The use of any purgative, however, is contra-indicated where the diarrhea is severe and the stools thin and bloody. The number of drugs which have been recommended in amebic dysentery is legion, and only the most important of them can be mentioned. Copper sulphate and opium have been recommended in chronic dysentery. Oil of turpentine has also been used very extensively. Salol, benzosol, benzoyl-acetyl-peroxide, salophen and many other similar preparations have been recommended and have had more or less extensive use. The use of rectal injections of various drugs for their ame- bacidal action has been widely recommended. After a pre- liminary douche of warm water to cleanse the lower bowel the injection of the drug at a temperature of about 96°?. is made. Solutions of quinine have been extensively employed for this purpose since the time of Loesch. This drug is usually used in a i to 1,500 dilution and about i liter injected. Argy- 440 ENDEMIC DISEASES OF THE SOUTHERN STATES rol has been highly recommended in i per cent, solution, while thymol, potassium permanganate, silver nitrate, protargol, boric and tannic acids, creosote, etc., have had more or less vogue. Surgical Treatment. — Several surgical procedures have been advocated in the treatment of amebic dysentery. For the most part, however, they have been recommended only in the most severe cases and those which have not yielded to other methods of treatment. According to Herrick,^-'' White, in 1895, was the first to suggest surgical treatment in this disease. This worker recommended making an artificial anus on the right side for the purpose of giving the colon rest and to ad- minister local treatment in severe cases of ulcerative colitis. Later other writers advocated cecostomy and appendicostomy with lavage of the colon with various antiseptics, such as argyrol, silver nitrate, potassium permanganate, etc. In certain extreme cases of amebic dysentery where the struc- ture of the colon has been very extensively destroyed and the patient almost moribund, the excision of the entire colon has been performed. Specific Treatment. — While, as mentioned above, certain drugs such as quinine, salol, etc., have been injected rectally for the purpose of destroying the infecting organisms, they are not considered true specifics. Ipecac, however, has been employed as a specific for dysentery for over two centuries. This drug was first known in Europe in 1672, having been brought from Brazil where it was used by the natives as an emetic.^^^ John Helvetius, grandfather of the famous author of that name, used it so successfully in the treatment of the Dauphin that he was given a large sum of money and public honors by Louis XIV upon the condition that he make the nature of his treat- ment public. While in Europe the use of ipecac fell into dis- repute, it was employed with considerable success in India, and in 1858 Docker, an English army surgeon, brought it again into prominence by advising its use in comparatively large doses. It has since that time been used with varying success in nearly all countries where amebic dysentery is known. The usual method of procedure in administering ipecac is to instruct the patient to abstain from food for three or four hours, and about AMEBIC DYSENTERY 44I twenty minutes after giving a dose of ten to twenty drops of laudanum to give 20 to 60 grains of the powdered ipecac root, usually in capsules. After this the patient is instructed to lie on his back in bed, absolutely quietly for at least four hours. Should nausea and vomiting of the drug be caused within an hour he should receive another dose as soon as the nausea ceases. The main objection to the ipecac treatment of amebic dysen- tery has been that in doses sufficiently large to exert any specific action nausea and vomiting are almost sure to occur. Even the pills coated with substances insoluble in the stomach do not entirely overcome this effect. The real specific treatment of amebic dysentery may be said to have begun with the introduction of emetine for this purpose. This drug is one of the alkaloids of ipecac discovered in 1867 by Pelletier and has the formula C15H22NO2. It is a white amorphous powder with a melting point of 6o°C. With the halogens and with nitric acid it forms crystaUine salts. It is readily soluble in chloroform, ether, benzol or alcohol. Its solution in the latter gives no coloration with ferric chloride. Emetine is insoluble in solutions of caustic or carbonated alka- lies, but is soluble in acetic acid in which latter it effects no substitution. The most frequently employed salt of emetine is the hydrochloride (C15H22NO2CI2H2O). The first use of emetine in amebic dysentery is accredited to Walsh,*^' who in 1891 employed it in combination with Mayer's reagent. He reported 34 cases diagnosed clinically, treated in this manner, of which 32 were clinically cured in an average of 4.9 days, one was unimproved and one died. It was not until twenty years later that any scientific work was done to determine the action of emetine on the amebae. In 191 1 Vedder,"*^^ working with cultures of the free living amebas, showed that ipecac in dilutions of i to 10,000 to i to 50,000 was amebecidal, and deematized ipecac in dilution of i to 5,000 was not amebecidal, while emetine in dilution of i to 100,000 killed the amebcC. To Rogers, *^^ however, is due the credit of applying emetine, clinically to amebic dysentery. This worker first found that solutions of emetine hydrochloride in normal saline in dilutions 442 ENDEMIC DISEASES OF THE SOUTHERN STATES of I to 10,000 immediately killed the active pathogenic amebae (£. histolytica) present in mucus, and that in dilutions of i to 100,000 they were rendered inactive and were apparently killed. After these experiments Rogers tried the drug hypodermically in cases. of amebic disease and reported most favorably upon it. In twenty-four cases treated in this manner twenty were cured, two moribund patients died within three days after admission to the hospital, and two died from other diseases following the cure of the dysentery. The average time in the hospital was 7.2 days, while the average time until the stools became normal was 2.35 days. Following the brilliant results of Rogers many investigators have used emetine in the treatment of amebic dysentery, with such generally favorable results that there can be no doubt that this drug should rank as a specific with quinine in malaria and mercury and salvarsan in s3^hiUs. The dosage employed by Rogers was )^ to i grain of the hydro- chloride dissolved in about i c.c. of salt solution administered hypodermically. This amount has been increased by various workers up to 5-6 grains. Baermann and Heinemann''^'' rec- ommend the subcutaneous or intravenous injection of one or two doses of 2^3 to 3 grains, followed in the next eight or ten days by four or five subcutaneous injections of i3^-2 grains given at intervals of two or three days according to the results of examination. According to these authors this after-treatment should be repeated at intervals of three or four weeks and the stools should be examined carefully for amebs at frequent intervals for several months. We consider that for ordinary cases such doses are too large and prefer to give not more than i grain daily, best in two in- jections, one in the morning and one at night. This seems as effective as the larger doses and much less irritating. In administering emetine intravenously the dose, not to exceed 0.25 gram (3.8 gr.) per 60 kilograms (132 pounds) of body weight, should be given in about 100 c.c. of normal salt solution. This, to our minds, is the method of choice in acute cases. Emetine may be given by mouth, but is neither as effective nor as pleasant to take, as nausea and vomiting are AMEBIC DYSENTERY 443 much more liable to occur. And further, the drug is more or less irritating to the intestinal mucosa. Nausea and vomiting are rare following the subcutaneous and intravenous injection of emetine except in very large doses (s-6 grains). Depending upon the size of the dose there is some local reac- tion at the point of injection when the subcutaneous route is used, and a general urticaria has been noted. Hepatic Abscess. — If the hepatic abscess be small, it will probably usually yield to the general emetine treatment alone. Rogers^-^ early reported the aspiration of liver abscess and the injection of the cavity with i grain of emetine dissolved in i ounce of normal salt solution. This with small and medium sized abscesses is usually sufficient, but with large abscesses a radical operation may be necessary, although Cantlie^" con- siders" cutting" operations, " overheroic " and that better results are obtained by the use of a large trocar and canula. A recent case treated by one of us was promptly cured after evacuation of the pus and daily injections of J^ grain of emetine. The operations most frequently employed are the abdominal and transthoracic. The former is employed when the abscess is in the lower portions of the liver and the latter when it is found in the superior portions or extends into the thorax. The abdominal operation is performed by placing the patient on his back or if a lateral incision is necessary on his left side. A sand bag is placed under him to raise the liver up as close to the abdominal wall as possible. An incision 8 to lo cm. in length over the most prominent part of the swelling is made through the skin and superficial fascia and is deepened to the peritoneum. If adhesions exist between the abscess wall and the peritoneum, walling off the abscess from the peritoneal cavity, the abscess may be opened at once. If, however, no adhesions are present, a series of sutures are made between the capsule and some of the liver substances and the parietal peritoneum and part of the rectus muscle. The peritoneum is walled off with a thick layer of gauze, after which an incision is made into the abscess cavity and the pus allowed to escape. Some authorities advocate the use of a cautery, but this is usually unnecessary. After the 444 ENDEMIC DISEASES OF THE SOUTHERN STATES evacuation of the pus the abscess cavity may be washed out with normal salt solution followed by 2 or 3 grains of emetine dissolved in several ounces of salt solution. A large drainage tube is now inserted and anchored with two stitches to the skin. In performing the transthoracic operation an incision 8 to 10 cm. in length is made along the rib under which the abscess seems to be. This incision should separate skin, fascia, muscle and periosteum. The latter is separated from the bone with a periosteal elevator for about 8 cm. and the rib cut at either end of the incision with bone forceps or a saw. The same care must be taken not to contaminate the pleura as was advocated for protection of the peritoneum. The remainder of the opera- tion is performed in a similar manner to the abdominal operation. Other complications, such as severe hemorrhage, a perito- nitis, and intercurrent disease must be met and dealt with as if the amebic infection did not exist. HOOK-WORM DISEASE CHAPTER XXXni INTRODUCTION Uncinariasis, ankylostomiasis, tropical chlorosis, tunnel workers' anemia, brickmakers' anemia, mountain cachexia, miners' anemia, dirt-eating disease, etc. History. — Uncinariasis is a parasitic infestation with certain species of hookworm and is characterized by the discharge of ova and worms in the feces, progressive anemia, and digestive and nervous phenomena. There is to be found in the Ebers papyrus, written by the Egyptians about 1550 B. C, a reference, thought by Joachim and Sandwith, to relate to hook-worm infection. The authen- ticity of this reference must of necessity remain doubtful owing to the incompleteness of the chnic picture. The earliest undoubted accounts of this disease are those of Piso, in Brazil, in 1648, Pere Labot of Guadeloupe in his travel narratives in 1742, and Bryon Edwards in 1793, in his history of the British Colonies in the West Indies. The latter who was a planter in Jamaica for many years attributed a large propor- tion of the deaths among the negroes to this disease. Following these were numerous reports by English, French and Danish practitioners in the West Indian Islands and in Guiana. The etiology of the condition was completely dark until the paper of Dubini in 1843. From 1838 this observer at several autopsies had discovered these little worms to which he attrib- uted the production of chronic diarrhea. Castaglioni found the parasite in Milan in 1844. Pruner in Egypt mentioned, in 1846, that he had found it in cachectic, scrofulous and dropsical adults, but he failed to note any etiologic relationship. 445 446 ENDEMIC DISEASES OF THE SOUTHERN STATES Bilharz discovered independently the worms in Egypt in 1852, and it was with him that Griesinger estabHshed the fact that the hook-worm caused the disease which he declared affected one-fourth of the population of Egypt. Wucherer in Brazil in 1866 called attention to the prevalence of the disease in that country and succeeded in arousing some interest. In Italy Paletti and Maliverria, in 1877, suggested that brickmakers' anemia was due to hook-worm infection and in the same year recognized in the feces the typical ova of the parasite, and attributed grave results to the blood-sucking propensities of the parasite. The epidemic occurring in 1879 among the workers of the St. Gothard tunnel marks an epoch in the prophylaxis of the disease. Hundreds of these laborers sickened and many died; no cause was known, and gases, faulty ventilation and lack of sunshine were advanced. Colormiatti found i ,500 uncinarias in the intes- tines of one of the dead laborers. As a result of the investi- gation which followed the true cause was determined, and to Perroncito and Bozzolo is given the credit for the campaign against the epidemic. Profiting by the lessons of this epidemic, investigations were then made into the anemia of mines and brickyards of Europe with the uniform result of finding the hook-worm responsible. For more than 100 years anemia has been recognized as the scourge of Porto Rico. On August 8, 1899, a hurricane swept a part of the island. Ashford, of the Army Medical Corps, was ordered to establish a provisional hospital for the care of some of the sick natives who were thronging the streets. Blood exami- nations of these natives showed an eosinophilia which led to an examination of the feces disclosing the ova of the parasites responsible for the trouble. On November 24, 1899, Ashford wired the chief surgeon of his findings. This culminated in the appointment of the Porto Rico Anemia Commission, which has contributed much toward the eradication of the infection from the island and toward the scientific study of the disease. In the United States the earliest reference which seems to allude to hook-worm infection is that of Pitt, in 1808, writing of HOOK-WORM DISEASE 447 the Roanoke Valley in North Carohna. Chalbert, in Louisiana, in 1832, Cotting, in Georgia, in 1836, Le Conte, in Georgia, in 1845, Little, in Florida, in 1845, ^.nd Duncan, in Louisiana, in 1850, refer to what was probably uncinariasis. Blickhahn, of St. Louis, in 1893, is apparently the first in this country to observe and recognize as such, a case of hook-worm infection. His patient was a German brickmaker who had been in America but seventeen months, and it is probable that the infection was imported. In 1893, Allen J. Smith, of Galveston, Texas, found ova of hook-worm in a specimen of feces but was unable to locate the patient. Cases were reported from Buffalo, N. Y., by Mohlau in 1897; from Richmond, Va., by Gray in 1901 ; from New Orleans, by Tebault in 1899; from Galveston, Texas, by Smith in 1901; from Washington, D. C, by Clayton in 1901 ; from St. Louis, by Dyer in 1901; from Georgia, by Claude Smith in 1902; and by Harris in 1902. The credit, however, for the discovery that hook-worm is endemic in the Southern States belongs to Stiles. Upon the evidence of specimens from Washington, D. C, from Porto Rico, sent by Ashford, from Cuba, sent by Guiteras, and from Galveston, sent by Smith he stated positively in a paper pub- lished September 25, 1902, that there existed in the United States an endemic uncinariasis, which had been generally over- looked. He was thereupon commissioned by the Public Health and Marine Hospital Service to investigate, and after a prelimi- nary survey in Virginia, North Carolina and South Carolina he reported, October 22, 1902, that the disease was resulting in loss of wages, loss in productiveness of the farms, loss in the school attendance of the children, etc. He announced also that the parasite was a new species which he termed uncinaria americana. Stiles' observations were abundantly confirmed from many sections and great interest was aroused, the matter being- dis- cussed pro and con in the lay press. The concern culminated in the organization on Oct. 26, 1909, of the Rockefeller Sanitary Commission, financed by John D. Rockefeller, for a campaign against the endemic in the South. 44o ENDEMIC DISEASES OF THE SOUTHERN STATES Geographic Distribution. — Uncinariasis does not occur north of latitude 52°, and north of 47°, it is found only in the hospitable warmth of mines. Thus it is a disease of tropic and subtropic countries, but there are countries with endemic foci in more northerly climes. In Germany the Westphalia mining districts are heavily infested. The disease prevails also in localities in Rhenish Prussia. Cases have been reported from other parts of Prussia. In Austria and Hungary the disease has been known to be prevalent for many years, particularly among miners, but among other classes as well. From Limburg in Holland several cases have been recorded. The Belgian mines are hot beds of infec- tion where public measures have been directed against the sup- pression of the disease. In France, Auzin, Vallenciennes, Com- mentry, Lyons and St. Etienne are centers of infection. Uncin- ariasis is said to occur in the Spanish mines and in Servia' and Bulgaria. In Italy, Sicily, and Sardinia the disease prevails extensively. In the Dolcoath coal mine in Cornwall, England, nearly 20 per cent, of the miners have been found infested. In Asia a number of the Indian Provinces, particularly Bengal, Madras, and Travancore are scourged. It has been stated that in Ceylon the ravages of the hook-worm exceed those of cholera. Siam, Indo-China, Korea, and portions of China are intense foci. In Japan the mountainous regions of the island of Kiou-Siou are said to be intensely infested. The disease prevails in the Malay States and is found in the Province of Bagdad. The continent of Africa, especially the coast regions are foci of hook-worm infection. Parts of Egypt are heavily scourged. Abyssinia, German East Africa, Nyassaland, British Central Africa and Orange Free State show a high infection index. British South Africa, parts of Cape Colony, and Madagascar are infested. In the north, besides Egypt, Tunis and Algeria habor the disease. On the west coast it prevails from the Senegal River to the Congo River. In AustraHa the infection is known upon the west coast particularly in Queensland. Other islands where the disease HOOK-WORM DISEASE 449 is known to be endemic are the Leeward Islands, Comore Islands, Mauritius, New Guinea, Borneo, Java, Sumatra, Fiji, Sandwich Islands, West Indies, Samoa, Formosa, Philippines and Guam. In South America the disease has been studied particularly in Brazil. Paraguay and northern Argentine are endemic foci. Other South American States where the infection prevails are Bolivia, Peru, Ecuador, Columbia, Venezuela and Guyana. Central American States from which cases are reported are Panama, Costa Rica, Nicaragua, Salvador, Guatemala, and British Honduras. Cases have been found in southern Mexico and in Lower California. In the United States the disease is endemic in all the states south of the Ohio and Potomac Rivers, and in Arkansas, Louisiana and Texas. Autochthonous cases have been re- ported from Oklahoma, Nevada, California and Missouri and it is probable on clinical grounds that the disease exists in Maryland. To illustrate the extent of infection in some of the Southern States the following is quoted from the 1912 Report of the Surgeon General of the U. S. Pubhc Health Service: "Hook-worm infection has been demonstrated in 93 of the 100 counties in Virginia; in 99 of the 100 counties in North Carolina; in 140 of the 146 counties of Georgia; in every county in South Carolina; in 66 of the 67 counties in Alabama; in 77 of the 79 counties in Mississippi; in 27 of the 59 parishes of Louisiana; in 57 of the 75 counties in Arkansas; in 95 of the 96 counties in Tennessee; in 22 of the 119 counties in Kentucky. The foregoing statistics include the reports up to December 31, 191 1, as reported by the state boards of health in question. Of the 884 counties in these ten states, infection has been dem- onstrated by the state boards of health in 719; the remaining 156 counties had not been surveyed when these statistics were summarized." The comparative degree of infection at all ages in eleven states is shown in the following table from the 1913 Report of the Rockefeller Sanitary Commission: 29 450 ENDEMIC DISEASES OF THE SOUTHERN STATES Alabama Arkansas Georgia Kentucky Louisiana Mississippi Nortii Carolina. South Carolina. Tennessee Texas Virginia Total. 25,821 17,169 31,251 64,485 35,472 110,007 247,870 47,692 32,432 38,913 49,622 700,734 11,204 4,151 I9,°34 22,862 17,533 42,722 77,625 16,386 10,369 13,447 12,888 S,22I The new-world hook-worm, Necator americanus, besides being the parasite of the disease in the United States, has been found in Porto Rico, Cuba, Guam, Panama, Brazil, Philippine Islands, Australia, Ceylon, Mysore, Burmah, Assam, Cochin China, China, Egypt, Rhodesia, Gold Coast, Uganda, and South Africa. Imported cases have been recorded in Italy and Spain. CHAPTER XXXIV ETIOLOGY OF HOOK-WORM DISEASE Climate. — As has been stated hook-worm disease is one of tropic and subtropic climates with occasional endemic foci in temperate climates, these latter being chiefly in mines. It has been determined that temperatures from 78.5° to 95°F. are best adapted to the hatching of ova and that while they still matured below 7i°F. their numbers were few and many perished. Direct exposure to sunlight inhibits the development of the ova. Altitudes from the sea level to 3,000 feet are had by endemic areas. Season. — In cold weather larval life and activity are dimin- ished or abolished and the hook-worm larva is no exception. Freezing prevents ova from hatching but they may develop after gentle thawing out. Infection in temperate chmates is commoner in the summer months. Moisture. — Moisture is necessary for the development of both ova and larvae. Complete desiccation destroys both ova and larvae. The ova will not develop in water but Lambinet-"' has shown they will then enter a resistant state and hatch later under favorable circumstances. Bruns'-"" experiments show that (i) in undiluted feces the larvas appeared in four days but in ten days all were dead; (2) the best cultures were obtained from a dilution of from i : 10 to 1:100; (3) dilutions of from 1 : 1 ,000 to 1 : 2 ,000 killed the larvae and prevented the ova from developing after six days. Soil. — The character of the soil exerts an important influence on the distribution of the disease. Stiles^"' has shown that in the South the infection prevails chiefly upon sandy soils. My experience in eastern Arkansas was that alluvial soil did not afford a favorable environment and this conclusion is further strengthened by the work of the Rockefeller Sanitary Com- mission. The Porto Rico Anemia Commission-"- found that 4SI 452 ENDEMIC DISEASES OF THE SOUTHERN STATES sandy regions were not those which contributed the majority of their cases on that island. Race. — It was shown by Zinn and Jacoby" that the negro possesses a relative immunity to the effects of hook-worm in- fection. It is probable, however, that negroes in the Southern States are more frequently infested than whites. Hence the carrier problem is, as in malaria, a weighty one. No immunity other than racial is known. Sex. — Stiles-"* believes the infection to be commoner in females than in males in the South. In Egypt Sandwith^"^ found only i per cent, of his cases in females. Of 89,219 cases examined by the Porto Rico Anemia Commission 52.10 per cent, were males and 47.90 per cent, were females.-"^ Age. — In the Southern States the disease is commoner in the young, 58.5 per cent, of Stiles'-"'* cases being in children under sixteen years old. Two years experience of the Porto Rico Commission-"' gave the following age distribution: Under 10 years 15,622 10 to 20 years 50.924 '21 to 30 years 36,589 31 to 40 years 18,254 41 to 50 years 8,796 51 to 60 years 3,841 Over 60 years 1,413 Of 18,865 cases found by this Commission-"* in 1905 there were 240 under five years of age. Sandwith's-"^ youngest patient was four years old, Giles'-"'' four years old, and Stiles reports one in a child of three. Occupation. — Those occupations which necessitate intimate relations with the soil predispose to hook-worm infection. Miners and brickmakers are the classes chiefly infested in Europe. In the South the agriculturists are especially predis- posed, particularly those who go into the fields barefoot or poorly shod. Dock and Bass^"' mention cases occurring in charcoal burners and turpentine dippers. The cotton mill operatives through the South are heavily infested, but this is probably due more largely to the insanitary condition of their homes than to the occupation. HOOK-WORM DISEASE 453 Social Condition. — While no class is exempt from infection those who use concrete sidewalks and modern sewerage are far less frequently infested than those who walk the fields and defecate in the fence corners. Uncinariasis is chiefly a disease of poverty, ignorance and bad hygiene. Surface closets and soil pollution are largely responsible for the dissemination of the disease, hence its over-whelming prevalence in the rural districts. Mode of Infection. — There are two routes by which the para- sites gain access to the host, through the mouth and through the skin. There is no doubt that the former method is more common than is supposed by some authorities. Infection through un- clean vegetables, fruits and drinking water, and soiled hands undoubtedly occurs. A considerable proportion of hook-worm patients in this country deny having had ground itch, and while some of these may have been unaware of an existing dermatitis, it cannot be denied that many of them are correct. In 1898 while working in his laboratory in Cairo Looss inad- vertently allowed a drop of water containing more than i,ooo hook-worm larvae to fall between the fingers. This was im- mediately followed by burning and redness. To be sure that the symptoms were due to the fluid he permitted another drop to fall upon another part of his hand and this was followed by the same results. Examining the fluid remaining upon his hand he found that most of the larvte had disappeared leaving behind a few sluggish ones and numerous empty sheaths. In due time ova were found in the feces and anemia and debility ensued necessitating prolonged treatment with thymol. Looss' next experiment was upon the leg of a boy, one hour before the leg was amputated. After thorough cleansing a drop of fluid containing larvae was placed on the skin. After amputation the skin was removed, hardened and sectioned. The larvce were found in the skin having penetrated through the hair follicles. Another experiment was made upon a volunteer nurse who was infected through the forearm. Ova were found in the 454 ENDEMIC DISEASES OF THE SOUTHERN STATES feces seventy-one days later. Looss succeeded in infecting puppies in a similar manner. These experiments with ankylostoma duodenale were con- firmed by Schaudinn in Germany, Herman in Belgium, and others. The same mode of infection was proven for Uncinaria ameri- cana by Claude Smith of Atlanta. A mixture of soil and feces containing larvae was bound upon the wrist of a volunteer. In five minutes a sharp stinging sensation was complained of. During the night and the next day the itching was severe, and the area was covered with vesicles. These crusted and des- quamated and by the eighth day had disappeared. By the middle of the sixth week ova were found in the feces. After piercing the skin through the hair follicles the larvae gain entrance to the circulation and are carried through the heart to the lungs. Here they leave the blood-vessels, entering the air cells, traverse the bronchi to the larynx, and down the esophagus through the stomach to the intestine. From the entrance into the skin until ova appear in the feces averages from five to ten weeks. The dermatitis produced by the entrance of the larvae into the skin is known as "ground itch." Its commonest location is upon the feet and ankles, oftenest between the toes, but may occur upon any part of the body exposed to infection. Turner^^" states that in the South African mines the miners sitting on damp wood contracted the sores on their buttocks. The Parasite. — While Looss succeeded in infecting dogs with human hook-worms both through the skin and through the mouth, this parasite is not known in nature to infest any host but man. Uncinariasis is known to occur in many domestic and other animals but their parasites are not communicable to man. The new-world hook-worm, Uncinaria americana, or Necator americanus, has a cylindrical body, narrowed anteriorly and of a light reddish or grayish color. The male measures from 7 to 9 mm. in length, and 0.3 to 0.35 mm. in diameter; the female 9 to II mm. in length by 0.4 to 0.45 mm. in diameter. The buccal capsule is small, presents an irregular border and is pro- HOOK-WORM DISEASE 455 vided with a ventral pair of prominent semilunar plates, there being dorsally a pair of slightly developed chitinous plates. The dorsal tooth projects prominently into the buccal cavity. The four buccal lancets are situated deeply. The tail of the Fig. 86. — Ova of uncinaria americana, enlarged. male flares into an umbrella-like caudal bursa, composed of dorsal and ventral lobes and prominent lateral lobes supported by rays like the ribs of an umbrella. Two barbed spicules proceed from the bottom of the caudal bursa and the genital organ lies at the bottom. The tail of the female is conical. The vulva is situated slightly an- terior to the middle of the body. The eggs are symmetrically oval and vary from 64 to 76 microns in length by 36 to 40 microns in breadth. They are laid in a state of segmentation, the number of segments being most commonly four. The old-world hook-worm is longer and broader, the mouth is heavily armed bearing two pairs of ventral teeth, curved like worm larva, Infective stage, enlarged. 456 ENDEMIC DISEASES OF THE SOUTHERN STATES Fig. 88. — Uncinaria americana, male, enlarged. Fig. 89. — Uncinaria americana, female, enlarged. ( ) Fig. go.^Showing natural size of hook-worms, a, Male; b, female. HOOK-WORM DISEASE 457 hooks, and one pair of dorsal teeth, the buccal capsule is larger, and the ova are smaller. The ova never hatch in the intestine, but pass out with the feces. The ova hatch under proper conditions in from one to three days or less, into rhabditiform larvae, measuring about 0.2 mm. in length. In a few days the larvae attain a length of 0.5 to 0.6 mm. and moult. On the fifth to the ninth day a second moult or ecdysis occurs and the larvffi are in the infec- tive stage or stage of encystation, and measure 0.65 mm. long by 0.025 to 0.027 mm. broad. The larvae may live for months in this stage but cannot reach maturity except in the intestine of man. They arrive at maturity from four to six weeks after infection. The third stage in the evolution of the larva marks the beginning of its parasitic existence. Its sojourn in the stomach is said not to exceed fifteen hours. During the fourth stage the mouth parts are further elaborated, a provisional buccal capsule appearing, and the sexes are differentiated. In the fifth or adult stage all the organs become maturely developed. These parasites infest the small intestine, chiefly the duo- denum and jejunum, but the ileum may also harbor them. The number of parasites varies greatly and is not necessarily in ratio to the severity of the disease. In 40 cases of the Porto Rico Commission-"* in which the worms expelled were counted, they varied from 96 to 4,395. Of a series observed by Leichtenstern-^^ in 9 cases the parasites were less than 100, in 14 cases between 100 and 500, in 3 cases over 500, num- bering respectively 991, 1,066, and 2,763. Turner-^- states that in his experience in South Africa it was exceptional to collect 50 specimens from one body. Of 58 cases reported from North Carolina by Stiles-'^^ the greatest number of worms was 2,277, the smallest number, i, the average 135. With reference to the proportion of sexes of the parasites existing in given cases, Bilharz found the proportion of males as I to 3; Leichtenstern as 10 to 24; Lutz as 2 to 3; Schulthess as I to 6;^^^ Sandwith-"^ reports that in about 50 cases the pro- portion of males to females was 56 to 44. Stiles-'^ observed 102 cases from which 13,080 parasites were obtained; 46 per 458 ENDEMIC DISEASES OF THE SOUTHERN STATES cent, of the specimens were males and 53 per cent, females. Of the 102 cases, 37 presented an excess of males, 9 presented an equal number of males and females, and 56 presented an ex- cess of females. Pathogenesis. — A satisfactory explanation of the proximate cause of the symptoms of uncinariasis is yet lacking. There are three factors which may be concerned in the pathogenesis: (i) The abstraction of blood by the parasite and hemorrhage subsequent thereto; (2) mechanical injury to the intestinal mucosa followed by infection; (3) the production of a toxin. 1. The structure of the mouth parts, the habit of the worms clinging to the mucosa, a portion of which it partially swallows, and the finding of blood in the alimentary canals of the para- sites renders it certain that the hook-worm is a blood sucker. It is furthermore possible that the worm injects a substance at the site of feeding to prevent the coagulation of blood to cause it to flow more easily as the leech and mosquito are supposed to do. This is rendered probable by the finding of visible and occult blood in the feces, by the appearance of the mucosa, and by experiments of Loeb and Smith. -"'■' It seems hardly possible that the amount of blood merely consumed by the parasites in certain cases of light infection could account for the symptoms present so that subsequent bleeding or some other factor must be at work in these cases. Looss claims that the mucous membrane itself is the food of the hook-worm and that the abstraction of blood is only accidental. 2. The mechanical wounding of the intestine and ensuing infections may possibly play a role in the pathogenesis of hook- worm disease but nothing definite is known. 3. The belief that a toxin is produced "by the parasite and is responsible for the symptoms is widespread. The reasons for this theory are: (a) The blood changes, eosinophilia, almost or quite normal red cell count with low hemoglobin percentage. (b) Nervous symptoms out of proportion to the anemia and which may improve before the anemia has been com- pensated. HOOK-WORM DISEASE 459 (c) The relative immunity evinced by certain individuals and races. {d) Analogy to other helminth infestations. (e) The appearance of symptoms before the parasites have reached the suctorial phase. (/) Symptoms in some cases out of proportion to the number of worms. {g) Deposits in liver and kidney cells giving reaction of hema- toidin. {h) Results of experiments. The question of the existence of a toxin, however, is far from settled. A toxin is said to have been demonstrated by the experiments of Bohland-"^, Lussano,^^' Micheli,-"^ Crisapilli,-"^ de Renzij-o^ Preti,2«2 Tenholt and Peiper,^" Arslanj^^^ Battis- tiner^^ Gabbi and Vadala.^os Goldman,^''^ Muller.^es Rieder,^^^ Gappert,2«=' Ehrlich,2«3 Leichtenstern^es and Herman,^*"' while Loeb and Smith, ^o^ and Whipple, 2*'' on the basis of their ex- periments deny the existence of a toxin. CHAPTER XXXV PATHOLOGY OF HOOK-WORM DISEASE Even in severe cases the body usually shows no emaciation. The skin is pallid and anemic. The subcutaneous fat is well preserved and of a light yellow color. Edema is commonly present, ascites is shown in greater or less degree, hydrothorax and hydropericardium are often found and the condition may amount to general anasarca. The muscles appear anemic and may be atrophied or normal in development. The stomach is often dilated and sometimes the seat of gas- tritis. Hemorrhagic erosions of the mucosa have been observed. Hook-worms are occasionally found in this organ either free or attached. Important changes are shown in the intestine. The duode- num, jejunum, and part of the ileum are in a catarrhal condition, thickly coated with mucus in which the worms are embedded. This part of the bowel may be studded with erosions produced by the bites of the parasites. Sometimes these may be visible to the naked eye and sometimes they may show through the serosa. There are usually more erosions than parasites. Free blood is rarely found in the bowel but the mucus may be blood stained. The majority of the parasites appear in the upper and middle third of the jejunum. Interstitial inflammation, infil- tration of the solitary follicles and Peyer's patches, and atrophy of the valvulae conniventes are microscopic findings in many cases. The liver is commonly of normal size. In color it is very pale being of a light brownish-yellow color. On section it is soft, greasy and friable. These changes depend upon fatty degeneration which is present in practically every case. The outer third of the lobule is chiefly affected where the entire lobule is not involved. Yellow pigment and dilated capillaries have been found in a few cases. Amyloid degeneration is a rare phenomenon. 460 HOOK-WORM DISEASE 46 1 The pancreas is anemic but further changes are not constantly found. The spleen may be slightly enlarged but is more often normal in size or atrophied. In the Porto Rico Commission's^"^ autop- sies microscopic sections revealed a great reduction of lymphoid elements and a decrease in the protoplasm of the cells. The size of the Malpighian corpuscles was greatly reduced, the cells were scanty and widely separated, and the central artery showed hyaline degeneration. The increase of connective tissue was only relative and apparent. Pigmentation is rare. Changes in the hemolymph glands, particularly those about the bifurcation of the abdominal aorta, have been described. These are larger than normal, of a dull reddish hue and on section show mitosis and phagocytosis of red cells. The marrow of the long bones presents changes similar to those of pernicious anemia, being reddish and soft, and in ad- dition showing groups of eosinophiles and an abundance of myeloplaxes. Cardiac hypertrophy is a common post-mortem finding. Flabby musculature and fatty degeneration predispose to valvular incompetency. An increase in the pericardial fat is not infrequent. Arteriosclerosis is often found. In the lungs extreme pallor and edema are almost constant changes. Passive congestion is a finding in many cases. Pleu- ral effusion is present in the majority of cases. Practically all cases show chronic parenchymatous or diffuse nephritis. The kidneys are usually slightly enlarged. The convoluted tubules show the most marked changes consisting of fatty degeneration and desquamation of epithelium. Yel- low pigment is a rare finding. The brain usually shows an intense anemia and effusion into the ventricles of a clear, pale yellow fluid. CHAPTER XXXVI CLINICAL HISTORY OF HOOK-WORM DISEASE Classifications of clinical forms of hook-worm disease are purely arbitrary and rest solely on differences of degree. Lutz-*^ has proposed the following rather complicated schedule : I. Stage of exclusively local symptoms. (a) Acute form. (b) Chronic form. In the two forms the symptoms are simi- lar and characterized by disorders of digestion; no pallor nor acceleration of pulse. II. Stage of anemia. (a) Acute form. i. First degree: the vessels of the con- junctiva are visible, the nails and the lips are pale, the pulse is frequent, no anemic murmur. 2. Second degree: conjunctiva colorless, nails and lips pale, pulse always accelerated, anemic murmur. (b) Chronic form. Anemia more or less intense, cardiac hypertrophy and dilatation, valvular insufficiency rare, pulse rapid. III. Dropsical stage. (a) Acute form. Profound anemia, rapid pulse, anemic murmur, edema and serous effusion. (b) Chronic form. Symptomsof organic dissolution, arrhyth- mic heart, myocarditis, asystole, cyanosis, anasarca, marasmus, death. Ashford and King's'-"^ division into slight, moderate, and marked cases, and Stiles'-"' into light, medium, and severe are much simpler and more satisfactory. Light cases are those in which the feces contain a few ova, but symptoms, if present, are slight. Anemia is not particularly noticeable, but fatigue is out of proportion to exertion and there may be slight uneasiness in the epigastrium. 462 HOOK-WORM DISEASE 463 Moderate cases are those in which there are definite anemia and digestive disorders with their resulting symptoms. In severe cases symptoms of the first two forms are intensely exaggerated, the heart weakens, and edema and ascites super- vene. A not altogether fanciful classification of the stages of hook- worm disease is into primary, secondary and tertiary, after the stages of syphilis. The primary stage is the stage of the initial Fig. 91. —.1. Delia Carder, tlrant County, Arkansas, aged sixteen, practically an invalid from childhood, treated for malaria and tuberculosis, found heavily infected with hook-worms, treated. B. Delia Carder as she is today. (Rocke- feller Sanitary Commission.) lesion or port of entry of the organisms into the host — ground itch. The period of incubation of this stage is from a few hours to a few days. This is followed by a secondary period of incu- bation, as in syphilis, during which time the parasites are imma- ture and unable to produce marked symptoms. The secondary stage begins after the parasites have reached the alimentary 464 ENDEMIC DISEASES OF THE SOUTHERN STATES canal, have matured, and have begun to produce ova in the feces, anemia and digestive disorders. As tertiary symptoms may be designated evidences of organic changes in other organs resulting in heart weakness and anasarca. General Description. — It is ordinarily from five to ten weeks from the time the larvae enter the skin until ova appear in the feces. The symptoms are essentially those of anemia and impaired digestion. A slight uneasiness in the epigastrium is often the first symptom, or the patient may complain of indigestion. Pressure often increases the uneasy sensation or causes actual pain, while it may be relieved by food. The appetite is not radically affected early but is apt to be capricious. Gastralgic pains may be complained of. Meteorism appears in many cases and abdominal tenderness is not infrequent. The bowels are constipated or regular, occasionally loose. In mild cases nausea and vomiting are not early symptoms. A certain degree of pallor, as evidenced by bloodless conjunctivae and pale mucous membranes, is observed in all but mild cases. The skin is dry and inactive. Headache is a common complaint and dizziness is frequent. The patient is subject to palpitation and shortness of breath on slight exertion and. this, with muscular weakness, gives him an aversion to labor. In chronic cases the mentality is substandard, initiative and ambition are lacking, and the victim is insensitive to the stimuli of the daily routine of life. Hence it is that the hook-worm has been called the "germ of laziness." In severe cases the pulse is accelerated and weak, the blood pressure is low, and the anemia reaches a low degree. An anemic murmur is often heard over the precordia and the heart may be dilated. There are pains in the thorax and joints. The appetite becomes perverted and the patient eats earth, chalk or soot. Sometimes blood is passed from the bowels. The face becomes puffy, the ankles swell and fluid may collect in the serous cavities. Hook-worm disease in childhood, if neglected, results in re- tarded mental and physical development. The children are over-age in school. Puberty is delayed. Sandwith-"" found that 100 infested men weighed 17.5 pounds HOOK-WORM DISEASE 465 less than normal. Dock and Bass-"'' report that fifty-six grown men affected with hook-worm disease averaged 8}^ pounds lighter and 2^3 inches shorter than normal. The duration of the disease in untreated cases is governed by two factors, the opportunity for reinfection and the life of the worm. It is evident that there is no limit to the number of reinfections nor the duration of cumulative infections in the absence of prophylaxis. As to the life of the parasite it is certain that this may be as long as twelve or fifteen years. The cause of death is most commonly exhaustion. Inter- current affections play a prominent role. Fatty degenerations are frequent as secondary factors. Exodus may occur from intestinal perforation. Temperature. — This is normal, subnormal or elevated. I have noted nothing characteristic in its occurrence or course. In Porto Rico, fever at the onset of the disease is said to be a fairly constant symptom.-"^ In Ceylon, Castellani-^^ observed fever in about 25 per cent, of the cases of medium gravity and in 50 to 75 per cent, of those of a serious nature. Sandwith-"^ in Cairo found that one-third of his patients had a normal temperature during their stay in the hospital and that two- thirds had a distinctly subnormal range. In cases having fever it rarely exceeds 102°. Skin. — Ground itch, known also as dew poison, toe itch and water itch, is usually the first evidence of the disease. It occurs of tenest between the toes and on the sides and tops of the feet, but may appear upon the hands, buttocks, or indeed upon any portion of the skin. Its commonest site is explained by the habit of going barefoot, and squeezing mud between the toes. Its first appearance is of small macules or papules which soon proceed to vesiculation and pustulation. Scratching and mechanical irritation follow, producing crusts and scabs. It is highly probable that bacterial infection occurs both with the entry of the larvffi and later when the lesions are scratched. The exudate from the ruptured lesions is sticky and causes the stockings or bandages to adhere tightly. The average duration of ground itch is one or two weeks, but deeply ulcerated lesions, particularly between the toes, sometimes take weeks in healing. 400 ENDEMIC DISEASES OF THE SOUTHERN STATES The pallor of the skin varies from a fish-belly white through yellowish to tan. True icterus is rare. It should be borne in mind that it is impossible to determine the degree of anemia by the appearance of the skin. Edema is present in many moderate and most severe cases. In the absence of heart and kidney lesions its frequency is in direct ratio to the degree of anemia. It is commonest in the lower extremities, then in the face. The entire body may be water-logged in severe cases. Of the serous cavities the peri- toneal is oftenest involved. Injuries of the skin usually heal slowly and may result in ugly ulcers. Diminished activity of the skin, indicated by lack of perspira- tion, is a common manifestation. Atrophy of the skin results from chronic infections. Petechias are occasionally observed in those of low vitality. Urticaria is an infrequent symptom. Pruritus is not uncom- mon. Digestive System. — A vague uncomfortableness in the epigastrium is rarely absent except in the mildest cases. Sen- sations of weight and distention after eating are the rule. Gnawing pain is frequently complained of and gastralgia is sometimes present. Not infrequently the epigastric region is tender to pressure, a sign of significant diagnostic import. The tongue is furred, enlarged and shows the imprints of the teeth. Not infrequently a purplish smear is observed on each side of the tongue as if a pencil had been sucked. This ap- peared in nearly 5 per cent, of a series of cases reported from Porto Rico.^"^ These phenomena are attributed to engorge- ment of the veins. Pharyngitis may occur early. Catarrhal stomatitis is occasionally observed. The appetite is very variable. It is said to be frequently greatly increased in the beginning, but in cases seen in practice it is usually capricious or diminished. In severe cases it is nearly always diminished. One of the most striking features of the disease is geophagy or dirt-eating. This runs the scale from the desire for coarse food to actual dirt-eating. It was formerly thought to be the cause of the anemia. Among the many articles which may be HOOK-WORM DISEASE 467 eaten are coffee, chalk, ashes, soot, brittle wood, paper, earth, mortar, clothing, sand, etc. I have known subjects to walk 12 miles and back to obtain a small box of a certain kind of earth. I am convinced, however, that this is not pathog- nomonic of uncinariasis and that it is a habit which is widely prevalent among the negro women of the South. Flatulence and heart-burn are common complaints. Nausea is infrequent in mild cases but common in severe infections. Vomiting may occur in severe cases. Hematemesis is occasion- ally reported. Yoshida^"^ states the results of his observations upon loi sub- jects as to the acidity of the gastric juice as follows: 1. The content of free hydrochloric acid in the gastric juice in uncinariasis is usually normal, then follows hypochlorhydria, then hyperchlorhydria. 2. The greater the intensity of the anemia the lower the con- tent of free hydrochloric acid. 3. The appetite is usually in the most intimate relation to the content of free hydrochloric acid. The bowels are usually constipated or irregular, often normal, occasionally loose or even dysenteric. Blood is not often ob- served macroscopically in the feces. Of over 22,000 speci- mens of feces examined by the Porto Rico Commission,-"' only six contained blood and five blood and mucus from a naked- eye inspection. Microscopically blood is occasionally noted. Charcot-Leyden crystals are not infrequently found. The chief characteristic of the feces in these cases is of course the presence of hook-worm ova. These vary greatly in numbers and may be present in every field, or several slides may have to be examined before finding a single specimen. Leichtenstern'^ states that it is not unusual for a single stool to contain four mil- lion ova. The number of ova in the feces is a guide to the number of parasites in only a very general way, if at all. Adult parasites are very exceptionally found in the feces except after the administration of a proper anthelmintic. Circulatory System. — In mild cases the only symptoms from the circulatory system are palpitation and acceleration of the pulse on exertion. Pain in the precordial region is common in 46b ENDEMIC DISEASES OF THE SOUTHERN STATES the more severe cases. This pain may be lancinating or may be dull. In the mildest cases the pulse rate may not depart from the normal except after exertion, but in moderate and severe cases it is always accelerated. It is usually soft and compressible, even dicrotic, and later may become small and irregular. The blood pressure is low. In mild cases the apex beat is normal in location and force. Later it is apt to be dis- placed downward and to the left, and diffuse and weak. Pulsation in the epigastrium is often observed. Acute dilata- tion and cyanosis have been observed. An anemic murmur is the rule when the hemoglobin per cent, is markedly reduced. Insufficiency from dilatation also may cause characteristic murmurs. Dilatation is not uncommon in chronic infections and hypertrophy may result. Pericardial effusion often occurs in the cases with anasarca. Exaggerated pulsations in the neck and throbbing in the supraclavicular spaces may be detected at a distance. The superficial abdominal veins are often dis- tended. Uncinariasis in childhood predisposes to organic heart lesions in later years and probably also to arteriosclerosis. Upon the blood is spent most of the force of the infestation. In mild cases there may be no reduction of red cells. Dock and Bass^°'-.examined forty university students who were hook-worm carriers and found the average number of red cells to be 5,246,- 322. However, there is usually a reduction of these cells. The average count is around three millions, though it may run in severe cases below one million. The most frequent qualitative changes in the erythrocytes are polychromatophilia, poikilocytosis, and the appearance of microcytes and macrocytes. Nucleated red cells are not rarely present. Notwithstanding these changes occur, they are not as prevalent as in primary anemia. The hemoglobin falls more rapidly and to a lower degree than the red cells so that the color index is nearly always below nor- mal. It is occasionally noted that the color index is high, even as high as 1.35 having been observed. In the mildest infections there may be little or no reduction. The average in this country is perhaps between 40 and 60 per cent. The Porto Rico Com- mission report one case in which it was as low as 9 per cent., and HOOK-WORM DISEASE 469 they record it that persons with as low as 1 6 to 20 per cent, can and do keep at their accustomed labor. -"^ The white cells range from 5,000 to 10,000 per cubic milli- meter. Leucopenia is common in cases of long standing and leucocytosis may usually be accounted for by complications. The increase in the eosinophiles is the only characteristic change in the leucocyte formula. This is the rule in mild and moderate cases, but eosinophilia is usually lacking in severe and fatal cases. Ehrlich and Leichtenstern-^^ report a case where these cells were 72 per cent, of the total leucocytes. The highest count of Dock and Bass^"' was 34 per cent., mine was 26 per cent. Fifteen per cent, is not uncommon for moderate cases. Regarding the variation of the eosinophiles the Porto Rico Commission draw the following conclusions: 1. Very severe chronic cases with poor resisting power and exhausted blood-making organs have little or no eosinophilia. 2. A rise in eosinophiles is generally found in cases which progress favorably and should influence the prognosis. 3. If very severe cases presenting little or no eosinophilia fall in their eosinophile percentage without improving in their gen- eral condition, the prognosis for such a case is less favorable. Under appropriate treatment the eosinophiles rise to a vary- ing degree, then gradually fall to normal. Extreme blood changes are much less frequently found in the negro race than in the white. Respiratory System. — Symptoms on the part of the respira- tory system are few. Dyspnea is very common and usually in proportion to the anemia. Hydrothorax often occurs in ana- sarca cases and edema of the lung may supervene. Bronchitis is mentioned by some observers as an early symptom and at- tributed to the passage of the larva: through the air cells and bronchi, but I have had no experience with this symptom. So far as I am aware larvae have not been found in the sputa. Urinary System. — In cases of edema or anasarca attended with grave anemia it is often difficult to determine how much of the former are attributable to the anemia and how much to the kidneys. That nephritis does play a role is credible from both clinic and urinary findings. 470 ENDEMIC DISEASES OF THE SOUTHERN STATES In the early stages the quantity of urine is normal; later it becomes diminished. The Porto Rico Commission^"^ deter- mined that one-fourth of cases of all grades have albuminuria. Casts are not very frequent and when present are in relatively small numbers. The kinds of casts found are in the order of frequency hyaline, granular, fatty and epithelial. Urobihn and indican are common findings. Biliary coloring matters are not common. Generative System. — Puberty is delayed in both sexes. The male organs are apt to remain undeveloped. Impotence is very common. In the Porto Rico-"'' cases 58.5 per cent, of the males were completely impotent, and 9.7 per cent, were par- tially so. In Sandwith's-"" series 63 per cent, were completely impotent and 13 per cent, were partially so. The age at which menstruation begins is often postponed several years. Irregularity of the menses is very common. Total suppression of the menses is not uncommon in moderate cases and is the rule in severe ones. Sterility is frequent. Stiles^^^ showed that of thirty-four pregnancies in hook-worm subjects 8.1 per cent, terminated in miscarriage. Still-births are said to cause havoc among the women of Porto Rico. Lactation may be impaired or suppressed in severe cases. Musciilar System. — The muscles are weak and lack tone. Fatigue on exertion is due not only to dyspnea but to muscular weakness. To this weakness is largely attributable the reputa- tion for laziness which the subjects of uncinariasis have. Pains in the joints and bones, especially in the sternum, are very common. Neirvous System. — Headache is one of the commonest symp- toms and many patients complain of vertigo. Neuralgia is sometimes very annoying. Tingling and formication are the commonest paresthesias present in these cases, and many of the subjects complain of over-sensitiveness to cold. The patel- lar reflex is diminished in many cases and abolished in some severe infections. After the infection has persisted some time, neurasthenia not infrequently develops and outbursts of hys- teria and hystero-epilepsy may supervene. Drowsiness is almost constant except in mild cases but insomnia is very com- HOOK-WORM DISEASE 47 1 monly met with and night terrors are not rare. Edema of the brain sometimes occurs in cases with a tendency to anasarca. The expression is usually dull and stupid. Lack of ambition and intellectual laziness are psychic characteristics. Children are retarded and over age in school. There is difficulty in concentration and delay in answering questions which must ofttimes be repeated. Apathy exists to a marked degree. Defective memory is common. Melancholia and other psy- choses may develop. Green-^* believes that hook-worm infec- tion is in many cases the direct or indirect cause in the production of a distinct psychiatric entity, the principal symptoms being psychic retardation, irritability, depression, lackadaisicahsm and blunting of the higher sensibilities. The moral perversions dependent on uncinariasis are among the most interesting of the aspects of the disease. Macdon- g^j(j»g269 observations show that the infection is responsible for disobedience, cunning, lying, stealing, forgery, and sexual per- versions, which are cured by thymol. Special Senses. — Tinnitus aurium is a frequent manifesta- tion. The conjunctiva of the lids shows anemia. The pupil is readily dilatable. Stiles-"' describes a symptom which was present more constantly than almost any other: "If the patient is directed to stare intently into the observer's eyes there will be noticed a symptom which is difficult to describe, but which I have found more constant than almost any other noticed, namely: after a moment, the length of time apparently varying slightly according to the degree of the disease, the pupils dilate and the patient's eyes assume a dull, blank, almost stupid, fish- like or cadaveric stare, very similar to that of extreme alcohoh'c intoxication." This sign is not thought by other observers to be pathognomonic of hook-worm disease. Blurred vision and specks before the eyes are frequent complaints. Cataract was common and corneal ulceration occasional among the Porto Rico cases. Examination of the fundus shows the retina pale, occasional hemorrhages, and pulsation and convolutions of veins. Other eye manifestations which have been described are nystagmus, diplopia, amblyopia, neuritis, asthenopia, restriction of the visual field, and chemosis of the bulbo-palpe- 472 ENDEMIC DISEASES OF THE SOUTHERN STATES bral fold. From observations on the eye changes, especially cataract, in hook-worm infections in the South, Calhoun^^" be- lieves that the former are due directly to the disease, while Jervey-^^ concludes that these lesions are only indirectly' de- pendent upon the infection, and that they are in no sense suffi- ciently distinctive or characteristic to be of any diagnostic value. Latent Infections. — There are many cases of hook-worm in- festation which cannot be classified as either mild, moderate, or severe, inasmuch as symptoms are entirely absent. Such a host is known as a " carrier." From a public-health standpoint these cases are the most important of all since they do not seek treatment for their parasites, hence are difficult to locate. When such a person is a soil polluter he may spread the infection broadcast without being suspected. Complications and Sequelae. — It is, of course, possible that almost any disease may be found associated with uncinariasis. In the majority of instances this association is merely a coinci- dence. The Porto Rico Commission-"^ record 657 complica- tions in 17,354 cases. The most common were diarrhea, dysen- tery, malaria and tuberculosis. Other than intercurrent dis- eases hook-worm infection may bear an etiologic relation to gastritis, dilatation of the stomach, enteritis, and dysentery. As sequellse disturbances dependent on fatty degeneration of the heart, kidneys and liver may be mentioned, and nervous dis- orders have been attributed as sequelje. Pernicious anemia and leukemia are supposed to bear a direct relation to hook-worm infection in some cases. In the Southern States infestations with other intestinal parasites is extremely common in hook-worm disease. The commonest worms associated with hook-worms are ascaris lumbricoides, trichiiris trichiura, and hymenolepis nana. CHAPTER XXXVn DIAGNOSIS OF HOOK-WORM DISEASE While it is as easy in hook-worm disease to examine the feces and obtain the signs of certainty as it is to examine the patient for the signs of probability, it is as a rule true that the disease must first be suspected before any examinations are made. The symptoms which should cause any one to suspect hook-worm disease are especially anemia, weakness, digestive disorders and a history of ground itch. Many cases come to the physician to be treated for heart disease and some for dropsy. The following conditions should invariably lead to an exami- nation of the feces : anemia not due to malaria or other obvious cause, a history of ground itch, fatigue out of proportion to exertion, and the presence of eosinophilia. In many instances the diagnostic clue is obtained from the blood examination. However, it should be borne in mind that the absence of eosino- philia does not exclude uncinariasis nor does even the presence of malaria parasites. Too much stress should not be laid upon geophagy as a diag- nostic sign particularly in the female negro. In an investigation which I made upon this point in eastern Arkansas the result was that of the female negroes who came to me for troubles other than hook-worm disease, about 80 per cent, confessed to having been dirt or soot eaters. Occupation, social position and sanitation of surroundings may be taken into consideration in the probable diagnosis but it is to be remembered that only the detection of the ova in the feces is decisive. When requesting a specimen of feces the physician should explain to the patient that only a small quantity is necessary and should furnish a container, otherwise he is apt to be brought an entire stool in a large jar or a portion of liquid stool in a match box. Small wide-mouthed bottles such as those for vase- line and quinine are suitable. 473 474 ■ ENDEMIC DISEASES OF THE SOUTHERN STATES The best slides for this purpose are said to be the 2 by 3-inch slides but I have always used the i by 3 -inch. A drop or two of water should be placed in the center of the slide and a quantity of feces the size of a match head thoroughly mixed to the proper consistency and spread well over the slide except for a narrow margin along each edge. A tooth pick serves the purpose of mixing and spreading. A cover-glass should not be used. A i-inch eyepiece and ^g-inch objective are best adapted to this work. A mechanical stage is a great convenience but not an es- sential. A moderate degree of illumination is most appropriate. While this method of examination will certainly detect mod- erate or severe infections it is well known that even the most careful scrutiny of a single slide will fail to detect ova in many cases of light infection. Stiles--" holds that a negative opinion cannot be given until at least ten such slides have been examined, consuming from thirty minutes to one hour, and Dock and Bass-"' have shown that in some cases twenty-five slides may have to be examined before detecting ova. The time necessary for this would, of course, preclude such examinations by the general practitioner, and as the importance of detecting these mild infections is of the greatest degree from a public-health stand- point, it becomes necessary to use some special method of con- centrating the eggs for examination before pronouncing the patient free from infection. Pepper's method is to mix the feces thoroughly with water and then centrifugalize. The supernatant fluid is poured off and fresh water added, mixed well and again centrifugalized. This process is repeated half a dozen times and in this way the bacteria, free coloring matter, light vegetable and other matter are eliminated and only the ova and heavy particles remain in the bottom of the tube whence they may easily be removed by means of a pipette. Pepper further showed that ova of the hook-worm thus placed on a slide after being allowed a few mo- ments in which to settle would adhere to the glass when the water was drained off and would even withstand the slide being rinsed in water. Additional drops may be placed on the slide, the iJuid drained ofT and if this process is frequently repeated the glass becomes studded with ova. HOOK-WORM DISEASE 475 Bass' method is a most valuable one. It is as follows: It is known that the specific gravity of the hookworm egg is between 1,050 and 1,100. A quantity of the feces is diluted with about ten parts of water and strained through gauze to eliminate coarse matter. This filtrate is centrifugaKzed and the fluid poured off. This is repeated several times to wash thoroughly. A fluid of heavy specific gravity is then added and again cen- trifugalized, the ova remaining in the top of the liquid. A nine- tenths saturated solution of sodium chloride, or a solution of calcium chloride having a specific gravity of 1,250 maybe used for this. A small amount of the top fluid is then poured off into a centrifuge tube, water added and when centrifuged the ova go to the bottom. Dock and Bass-"' state that without the adoption of this method, of 104 cases of intestinal parasite infection, 47 per cent, were found by the usual technic and 53 per cent, were missed until the centrifuge technic was employed. It is of course in the mild infestations that it is of such great service. For making permanent specimens of ova I have sedimented them in 2 per cent, formalin, and after making a cell of damar varnish by means of the turntable, filled the cell with the pre- servative containing the ova, applied a circular cover-glass while the varnish was still soft and ringed again with damar. Reference to the chapter on other intestinal parasites will assist in differentiating between hook-worm ova and those of other helminths. Besides these the beginner may confound vegetable cells and other food remnants with hook-worm ova. A striking characteristic of the ova of most intestinal parasites is their uniformity and when once recognized, or even when good plates are studied there should be no difficulty in their determination. Attempts to estimate the number of parasites from the num- ber of ova detected on examination have been made. It is estimated that a vigorous female will lay between two and six thousand eggs in twenty-four hours. Leichtenstern's-"^ method of making this estimate is to divide the number of ova found in I gram of feces by 47. Lutz's-"^ method is to make a 25 per cent, suspension of the feces in water and by a specially 476 ENDEMIC DISEASES OF THE SOUTHERN STATES ruled counting- chamber to estimate the number of ova in the entire stool. Grassi and Parona-"^ estimate that 150 to 200 ova per centigram of f eces indicate 1,000 uncinarise, three-fourths females and one-fourth males. The Porto Rico Commission, ^"^ however, maintain that no more shifting ground can be assumed than that one can judge of the number of uncinariae inhabiting an intestine save in a general way. Stiles-"^ proposed as a rough diagnostic method the blotting- paper test, which he claims is useful in the absence of a micro- scope examination. An ounce or more of the fresh stool is placed on a piece of white blotting paper; after being allowed to stand from twenty minutes to an hour the stool is removed and the color of the stain is examined. A reddish-brown stain is suggestive of uncinariasis. This test has not found wide favor. Herman-''^ endeavored to apply the method of serodiagnosis to uncinariasis but the result of his experiments was completely negative. The therapeutic test is occasionally advocated as a diagnostic measure. This consists of administering a dose of anthelmintic and examining the stool for worms. Inasmuch as it is now readily possible in most Southern States to have feces examined free of charge there is rarely any justification for the therapeutic test. There are several diseases from which uncinariasis may have to be diagnosticated. In malaria there can often be elicited a history of typical paroxysms, splenic enlargement may be detected, and herpes is sometimes present. The blood examination may show the presence of malaria parasites, a mononuclear leucocytosis, a relatively high color index, and the absence of eosinophilia. Malaria is usually amenable to quinine. The examination of the feces should settle the diagnosis. In pernicious anemia the color index is high, the blood con- tains megaloblasts as well as normoblasts and poikilocytes. Eosinophilia is not present. The skin may show icterus or even pigmentation. The fecal examination is negative. In leukemia the blood examination on one hand shows an HOOK-WORll DISEASE 477 enormous increase in the leucocytes with the advent of abnormal cells together with splenic enlargement, and on the other hand the examination of the feces should render the diagnosis certain. In chlorosis the anemia and the sometimes perverted appetite may cause temporary uncertainty. The blood examination and the color of the skin together with the microscopic examina- tion of the feces should clear all doubt. In many cases of uncinariasis heart disease is suspected. Careful examination of the heart, however, with the examina- tion of the feces will usually settle the diagnosis. Bright's disease, tuberculosis, syphilis and enteritis may be diflerentiated from hook-worm disease by the history, physical examination and the microscopic investigation of the feces. CHAPTER XXXVin PROGNOSIS OF HOOK-WORM DISEASE While the majority of cases of uncinariasis tend to recover spontaneously it is known that the worms may live for years and that reinfection is extremely common. Under favorable conditions the prognosis of hook-worm dis- ease is good because the disease is usually chronic, affording time for diagnosis and treatment, because reinfection is pre- ventable, and because we possess a specific for its treatment. The prognosis depends largely on the severity of the disease, the presence or absence of complications, and on the age of the patient. In the presence of organic changes resulting directly from the infection and in the event of intercurrent diseases the outlook is less favorable. The prognosis is more favorable in the young because the blood-making organs are commonly more active and complications in vital organs are less likely to supervene. No case of hook-worm infection should be treated lightly on account of the depletion of vitality due directly to the disease and of the predisposition to and aggravation of other diseases. Pregnancy, miscarriage and labor are unfavorable complica- tions. Even after all worms are expelled some cases will die from lack of recuperative power. Contra-indications to specific treatment render the prognosis very grave. According to the Porto Rico Commission-"^ good resistance to the toxin of uncinaria is expressed by eosinophilia and they conclude : 1. Very severe chronic cases with poor resisting power and exhausted blood-making organs have little or no eosinophilia. 2. A rise of eosinophiles is of good prognostic import. 3. If very severe cases, presenting little or no eosinophilia, 478 HOOK-WORM DISEASE 479 fall in their eosinophile count, the prognosis is not generally The cause of death is most commonly from exhaustion, diar- rhea, intercurrent affections, fatty changes in the heart, kidneys or liver, or complications of pregnancy and labor. Intestinal perforation has been observed as a cause of death. It is very difficult to determine the true mortality of uncina- riasis for unquestionably many cases never come under the observation of any physician. Furthermore it is doubtful if, as in the Porto Rico Commission figures below, all cases can be traced to termination by cure or death. The following figures show a mortality of twenty- three hundredths of i per cent.: Porto Rico Commission'"'^ 287,568 cases, 473 deaths. Canal Zone Reports'*' 445 cases, 3 deaths. German Protectorate Reports'^'.. . 1,158 cases, 200 deaths. Total 289,171 cases, 676 deaths. Of Sandwith's-"^ hospital cases 89.5 per cent, were cured or greatly relieved, 2.5 per cent, were unrelieved, and 8 per cent, died. CHAPTER XXXIX PROPHYLAXIS OF HOOK-WORM DISEASE Hook-worm disease is preventable. Caused as it is by a para- site having also an extracorporeal phase of development and for which there exist specific remedies it may be attacked in both phases by several methods. The following table of deaths from anemia demonstrates the results obtained through the campaign of the Porto Rico Commission-"': 1900-01 11,875 1901-02 6,284 1902-03 6,830 1903-04 6,179 1904-0S '. 4,963 1905-06 3,769 1906-07 1,134 1907-08 1,785 The methods to be employed against hook-worm disease fall naturally into three classes: (i) The sterilization of carriers; (2) the prevention of soil pollution; and (3) the prevention of access of larvae, by mechanical means or by destruction. For success in any method education in the methods of causation and prevention is a sine qua non. There are many who will follow if intelligently led, though there will remain a few who must be forced even after they have been informed and the policy of any campaign should be education for the willing and legislation for the unwilling. I . If every person who has hook-worms could be treated to a radical cure the disease would be exterminated. Most of those seeking medical advice are so cured but there are very many who have the disease who do not take treatment, and there are many more who are infested but have no symptoms which lead them to suspect it. These carriers are a greater source of danger than actual cases of the disease for the latter sooner or later are compelled to take treatment, while the former rarely 480 HOOK-WORM DISEASE do. It is impossible to force hook-worm patients to accept competent treatment, and with the carrier there is the double difficulty of first locating him and then sterilizing him. It is, of course, the duty of every physician treating a hook-worm pa- tient to explain to him the importance of complete cure. It is, furthermore, the duty of physicians to seek out carriers and to educate their clientele in hook-worm etiology and prophylaxis. Fig. 92. — An insanitary privy, found too frequently on our farms. Notice how the animals are spreading soil pollution. (Public Health Reports.) If each physician, expecially in the rural districts, would con- stitute himself health officer among his patients the hook-worm problem would solve itself and the collateral benefits ensuing, the prevention of typhoid fever and other diseases, would be almost incredible. As to guides in the search of carriers, residence in an endemic area, other cases in the family or neighborhood, and a history of ground itch, must be regarded in those lacking symptoms. 482 ENDEMIC DISEASES OF THE SOUTHERN STATES In industrial concerns it would be advantageous if employees were periodically inspected for hook-worm infection as is done in some European mines. 2. Since it is largely through infected earth that uncinariasis is propagated it is evident that any scheme of prevention which ignores the significance of soil pollution will work in vain. Fig. 93. — Sanitary privy designed to prevent soil pollution. Galvanized pails may be used instead of tubs. (Public Health Reports.) Throughout the rural districts of the South soil pollution is the rule rather than the exception. In relatively thickly popu- lated communities and along main roads there is usually an ex- cuse for a privy, but in more remote districts there is often none, and the observance of the hygienic rules against soil pollution does not equal the instinct of the cat or the hygienic knowledge of the time of Moses. Only a very small percentage of such privies as exist prevent HOOK-WORM DISEASE 483 to any degree whatever soil pollution. They are surface closets, open at the back with nothing to prevent the access of flies and domestic animals. <^''^'"^ticanyclo,,-njUcl_ ^inc lined 60, Fig. 94. — Mechanism of the Lumsden- Roberts-Stiles privy. (Public Health Reports.) There are five requirements for a sanitary privy: 1. The feces must not lie upon the ground. 2. Domestic animals must be excluded. 3. Washing rains must be guarded against. 4. Flies must be excluded. 5. The receptacle must be easily accessible and capable of being cleaned. A simple and at the same time efficient privy is illustrated in 484 ENDEMIC DISEASES OF THE SOUTHERN STATES Fig. 93. A small quantity of earth or sand in the bottom of the receptacle facilitates cleaning. Several methods of disposing of night soil have been proposed ; heat, chemicals, burial, fermentation, etc. While burial is perhaps not the ideal method, it is reasonably safe if properly done and by far the most practical of all. The excreta should be buried at least 18 inches deep and at least 100 yards distant, and down hill from any source of water supply. They should never be thrown into any stream or spread upon the surface for fertilizer unless absolutely sterilized. The Lumsden-Roberts-Stiles^^^ privy illustrated in Fig. 94 is ideal for rural homes. The device consists of the following parts: 1. A water-tight barrel serving as liqueher. 2. A covered water-tight barrel, can or other container to re- ceive the efiiuent. 3. A connecting pipe about 2!^ inches in diameter, about 12 inches long, and provided with an open "T" at one end, both openings of the "T" being covered by wire screens. 4. A tight box, preferably zinc lined, which fits tightly on the top of the liquefying barrel ; this is provided with an opening on the top for the seat, which has an automatically closing lid. 5. An anti-splashing device consisting of a small board placed horizontally under the seat and i inch below the level of the transverse connecting pipe; it is held in place by a rod, which passes through eyes or rings fastened to the box, and by which the board is raised and lowered. The liquefying tank is filled with water up to the point where it begins to trickle into the effluent tank. A thin film of oil should be poured upon the surface of the liquid in each barrel. The devisers claim that the following requirements are met: 1. It solves the fly and mosquito problems so far as the privy is concerned. 2. It liquefies fecal matter and reduces its volume so that it may be safely disposed of more easily and cheaply than night soil. 3. It reduces odor. HOOK-WORM DISEASE 485 4. It reduces the labor of cleaning the privy and makes this work less disagreeable. 5. It is of simple and inexpensive construction. The location of the privy is important. When inaccessible or even when too public it is not used. It should be placed within easy reach of the house. Proximity encourages its use and care. 3. Chemical and physical means of destroying ova and larvae are not practical, and in the European mines where they have been so thoroughly tried they have been abandoned in favor of the restriction of soil pollution and of the protection of the feet. Since it is known that the skin route of infection is the usual one, and that ground itch is commonest on the feet, the wearing of shoes in infected areas has been shown productive of good results. This means, of course, the annihilation of the barefoot boy immortalized by Whittier and not a few artists, but serves to translate the whistled tunes, red lips and sunshiny face from the realm of poetry to reality. Ashford-'^ mentions the case of a planter in Porto Rico, em- ploying a large number of laborers, who provided them all with shoes at his own expense and declared that he never made a better investment, since the increase in efficiency repaid him many fold. As this writer states, the providing of shoes for the poor should receive the attention of educationalists and philanthropists. In this connection Manson-^* cites an interesting incident: "A planter from Trinidad, West Indies, told me some time ago that he was at one time seriously inconvenienced by coolie itch among his field hands. He remarked that the attack of coolie itch was often followed by profound anemia, and he also remarked that the anemia occurred only or principally among the coolies who either passed through or who worked in certain fields. He argued that in these fields were certain germs that, coming into contact with the legs and feet of the coolies, pro- duced the dermatitis and, on subsequently entering the body, the specific anemia. He knew nothing about the ankylostoma; the observation was made long before Looss' discovery. The planter had some knowledge of bacteriology and he, like many 4»6 ENDEMIC DISEASES OF THE SOUTHERN STATES Others, thought that the germ in question was a bacterium, and that by some antiseptic and protective procedure he could either kill the germ or prevent its access to the skin. In casting about for a means to effect this he bethought him of a practice he had seen in operation in a certain part of- Germany during one of the annual pilgrimages he made to that country in search of health. In that particular part of Germany geese are raised in large numbers. The goose market is a long way from many of the goose farms, so that the birds, when ready for sale, have to be delivered for many miles over the hard roads. To enable their feet to stand the journey the farmer provides each of his birds with a pair of close-fitting socks and sandals. This he fits on in this wise : He fills a shallow trough with tar and through this trough he drives the geese onto a piece of ground covered with fine sand. The tar sticks to their feet and the sand to the tar; the birds are shod for the road. Thus provided they perform the long journey without injury. Acting on this hint the planter made his coolies, on their way to their work in the morning, dip their feet and legs in a bucket of Barbadoes tar and then walk across a layer of sawdust or sand. The result was excellent. Coolie itch and coolie anemia almost disappeared from the plantation." Children should constantly be drilled to keep the fingers out of their mouths. It is impossible to keep their hands clean, and diseases other than hook-worm are frequently conveyed in this manner. Those who till the soil or handle the products of the soil should be taught to wash the hands frequently. In many European mines shower baths have been installed for the miners. Bathing in common tubs by those exposed to hook-worm infection is conducive to the spread of the disease. After all is said and done in the prophylaxis of uncinariasis the results will not be proportionate to the efforts until a popular demand for sanitation is created throughout the rural districts. This must be accomplished through a campaign of education beginning with the children. The Rockefeller Sanitary Com- mission has, in a few years, come nearer this end than all other combined agencies throughout the past. CHAPTER XL TREATMENT OF HOOK-WORM DISEASE Hook-worm disease is a curable affection, there being one or more specifics for its relief. It is true that patients die of hook- worm infection even under treatment, but if appropriate treat- ment is begun reasonably early and persisted in practically all these cases' recover promptly. The most efficient remedy for uncinariasis is thymol, first used for this disease by Bozzolo'^'' in 1879. Thymol consists of large colorless, translucent, hexagonal crystals, with an aromatic odor and pungent taste. It is obtained from the volatile oils of thymus vulgaris, thymus monarda and carum ajowan. It is soluble in 1,100 parts of water, and in less than one part of alcohol, ether or chloroform, it is readily soluble in glacial acetic acid, carbon disulphide and in fixed and volatile oils. It liquefies when triturated with equal quantities of camphor, menthol or chloral. When liquefied by fusion it is lighter than water. Thymol has poisonous properties, but in proper dosage ad- ministered with due precautions, it is a very safe drug. It is neither uncertain nor unreliable, and so far as I am aware espe- cial idiosyncrasies toward it are not common. It is a powerful antiseptic, said to be ten times less toxic than carboKc acid; indeed it is not unhke the latter in some of its systemic effects as well as in chemical nature. The commonest symptoms following thymol administration are nausea, depression, burning in the epigastric region and vertigo. It is ehminated principally by the lungs and kidneys, and the urine may become very dark and increased in quantity. These symptoms are usually aggravated by getting out of bed. Everything possible should be done to prevent the absorption of the drug, as it is not the patient that is to be treated but the worms, and the more of the medicine absorbed by the host the less his parasites receive. When absorbed, nausea and vom- 487 400 ENDEMIC DISEASES OF THE SOUTHERN STATES iting, diarrhea and tremors may occur. The temperature is frequently lowered, the pulse may be rapid and weak and dysp- nea and cyanosis may develop. Profuse sweating and collapse have been observed, and convulsions and delirium may ensue. The drug is said to irritate the kidneys in some cases. The heart symptoms are due to the effect of the thymol on the heart muscle and to the lowered blood pressure. Stiles and Boatwright-^^ have recently studied the subjective effects in 464 administrations of thymol to 243 patients. The results of their observations are recorded in the following tabulation : Total treatments Ill effect absent Ill effect present (as follows) Sickness at the stomach Weakness Burning in the stomach Dizziness (including also "giddiness," "drunk" "staggery' Headache Vomiting Burning in throat Pain in stomach Drowsiness or sleepiness Sick after discharge from treatment Chill apparently not due to treatment Dyspnea Irregular heart following thymol Fainted Deaths 464 259 205 66 62 4S 100. 55- 0.64 Stiles and Leonard"^ state that they know of at least eleven deaths in this country, due, so far as it has been possible to determine, either to following thymol with castor oil instead of with salts, or to carelessness in respect to following out the usu- ally adopted procedure. Bozzolo,^^' ThornhilP^ and others report cases of fatal poison- ing by thymol. Thymol poisoning should be treated systematically. Mor- HOOK-WORM DISEASE 4S9 phine and atropin are usually indicated, and digitalis, ergot or strychnine may be needed. Hot coffee should be avoided as it is a solvent of the drug. External warmth is not to be used. Thymol is contra-indicated in great debility, advanced old age, organic heart disease, nephritis, gastritis, dysentery, and pregnancy. In some such cases, however, it may be deemed safer to administer the drug than to withhold it. The Porto Rico Commission sometimes treated pregnant women with thymol to save Kfe, and on several occasions nursing mothers were given the drug without bad effect to either mother or child. The American school is inclined to regard with disfavor the large doses of thymol, even up to 120 grains, advocated by the Europeans. In gauging the dose of thymol the apparent age, real weight and degree of debility should be the determining factors rather than the real age. There are few diseases in which the real and apparent ages have such a wide degree of variation and the latter must be taken into consideration. Subjects with contra-indications to thymol should, if treated, be given small doses and repeated; they should be "fractionally sterilized." The following scale of dosage is recommended by Ashford and King, and widely used in the Southern States: Under 5 years old, in size 7}^ grains. S to 10 years old, in size 15 grains. 10 to IS years old, in size 30 grains. 15 to 20 years old, in size 45 grains. 20 to 60 years old 60 grains. Over 60 years old 30 to 45 grains. The parasites lie in the small intestine, many of them with head and neck imbedded in the mucosa. They are covered with the normal mucus of the gut, together with that produced by mechanical irritation. In addition the food contents of the bowel envelops the worms. It can be seen that under these circumstances a dose of anthelmintic might kill none and sicken and dislodge only a few parasites. Hence it becomes imperative to prepare the intestine for the medicine. The patient should eat sparingly the day before treatment and take only liquids for the evening meal. At bedtime a purge should be administered. Sulphate of soda and the sulphate of magnesia are the most 490 ENDEMIC DISEASES OF THE SOUTHERN STATES suitable ; the former especially seems to liquefy and remove the protecting mucus. On the day of treatment the patient should remain in bed and should not be allgwed any nourishment until through with the treatment. Especially should no milk, butter, other oils or fat, alcohol, turpentine, ether or chloroform be permitted, as these are solvents of thymol. The thymol should be thoroughly triturated with an equal quantity of sugar of milk to prevent packing. It may be given in capsules or in cachets. To children who cannot swallow these it is usually given suspended in syrup or mucilage of acacia. The dose selected is ordinarily divided into two parts and administered two hours apart, say at 8 a.m. and at lo a.m. At noon another dose of the saline is given and in an hour the patient may be allowed nourishment, excluding rigidly the solvents of the drug. The directions to the patient should be given in the minutest detail, and should be reduced to writing. The patient should be instructed to save the stool for inspection. He should not be obliged to walk to a privy or water closet, but should use a bed pan or vessel at the edge of the bed. As Stiles suggests, Sun- day is a convenient day for treating working people and school children. Although thymol is a specific for hook-worm disease, this does not mean that cures are always accomplished by a single dose, a Iherapia sterilisans magna. On the other hand, while at least three-fourths of the parasites are expelled at the first treatment, usually several repetitions are necessary to effect a radical cure. In many cases a single dose expels so many worms that the patient is greatly improved clinically, but is not sterilized and remains a carrier to infect others. Sandwith^"^ found that an average of 2.6 treatments were necessary to cure hospital cases. His observations on 184 cases are as follows: One dose cured 42 patients. Two doses cured 58 patients. Three doses cured 42 patients. Four doses cured 25 patients. Five doses cured g patients. Six doses cured 4 patients. Seven doses cured 2 patients. Eight doses cured 2 patients. HOOK-WORM DISEASE 49I Ashford, King and Igaravidez-"- recorded in 3,630 patients the number of treatments necessary to effect a complete cure, averaging 2.04 doses per patient: Number of doses Number of patients Number of doses Numbe: r of patients I i,5iS 7 19 2 1,166 8 6 3 S18 9 3 4 247 10 I 5 104 II I 6 47 While most authorities recommend at least three doses for all patients as routine, I am of the opinion, inasmuch as many patients are radically cured by one dose, that repetitions after the first dose be based solely upon microscopic evidence of more parasites in the intestines. These examinations should be made at weekly intervals and should be repeated at least three times, because a dose of thymol which may not destroy all worms may suspend ovulation for a week or two. Weekly intervals are the most suitable intervals also for the repetition of treatment should it be necessary. To recover the parasites from the stools I have found useful a large flat baking pan, known in the South as the "biscuit pan. " This should be painted black and In one end about an inch from the bottom should be punctured a row of small holes so that the diluted feces may be retained or released by tilting without agitating. Straining through gauze is also a very satisfactory method. After treatment patients usually begin to show unmistakable evidence of improvement in from three to five days. Improve- ment depends largely upon the intensity of the infection and the resistance of the patient, considered under Prognosis. In certain cases thymol does not give the good results anticipated. In some of these it is because the alimentary canal has not been properly prepared and the drug does not gain access to all the parasites. In other cases the thymol be- comes lumped in the alimentary canal and passes through like a marble. There remains a small group of cases in which the only explanation seems to be that the worms are of a thymol-resistant 492 ENDEMIC DISEASES OF THE SOUTHERN STATES strain. Analogies are found in other parasitic diseases, notably the quinine-fast parasites in certain resistant cases of malaria. Of other drugs for the specific treatment of uncinariasis heta-naphthol introduced by Bentley"' in 1904 is the most serv- iceable. Bentley used it in several thousand cases with ex- cellent results and prefers it to thymol. It is used in half the dose of thymol and is very much cheaper. It is less depressing than thymol but more irritating to the kidneys, a serious draw- back in view of the frequency of albiminuria in the disease. The treatment preparatory to beta-naphthol is the same as that for thymol. The Porto Rico Commission-"^ made a compara- tive study of the value of thymol and of beta-naphthol as shown by the percentage of the total number of parasites expelled by successive doses of each drug. Their observations may be sum- marized as follows : Doses Thymol Beta-naphthol One Two 76.84 + 92-39 + 97-56 + 99-07 + 99-80+ 72.24 + 88.13 + Three 93.68 + Four Five 98.75 + This shows that thymol is somewhat more efl&cient than beta- naphthol in the treatment of uncinariasis. Even a slight degree of difference is important in the prevention of carriers as a result of lack of complete cure. Male Jem has been used largely and successfully in Europe for the treatment of infection with the old-world hook-worm, but seems to be relatively inert against the new-world species. Herman's mixture, consisting of chloroform 3 grams, oil of eucalyptus 2 grams, and castor oil 40 grams, to be given in two divided doses an hour apart, has been used successfully and has the advantage for research purposes of expelling the worms alive. It is said to be a nauseous dose and will hardly supplant thymol in popularity. Oil of chenopodium has recently come into repute as a remedy for hook-worm disease. Liquid diet and a saline should be used HOOK-WORM DISEASE 493 preparatory to the drug. The next morning three doses of the oil are given at two hourly intervals. The following individual doses have been recommended: From 6 to 8 years 8 drops. From 9 to 10 years 10 drops. From ii to 16 years 12 drops. Over 16 years 12 to 16 drops. It is not disagreeable to take, is not accompanied by unpleas- ant symptoms and is said to be very effective. The number of other drugs advocated for the specific treat- ment is almost legion, but none possess any particular virtues. Archibald has recently suggested an autogenous vaccine pre- pared from bacteria of the colon group on the theory that the intoxication is largely due to the absorption of the to.xins of these germs. Uncomplicated ground itch is not often seen by the physician, but secondary infection may cause the patient to seek medical aid. Pustules should be opened, crusts removed and the parts soaked in a hot antiseptic solution and then dressed with wet antiseptic dressings. The treatment of uncinaria infection before ova have ap- peared in the stools is futile inasmuch as the encysted larvce are very resistant to treatment. The majority of patients should receive aid to the blood- making organs to restore the lost blood. Proper hygiene, air, sunshine and nutritious food are of prime importance. Iron is usually indicated, and the preferable forms are Blaud's pills and the peptonate of iron and manganese. CHAPTER XLI OTHER INTESTINAL PARASITES It is probable that the pathogenic importance of intestinal parasites other than hook-worm and the dysenteric ameba has been as frequently under- as over-estimated. There is a marked tendency on the part of the laity to magnify the importance of these worms, and all the symptoms in the category of disease have been attributed to them. On the other hand, most physi- cians who have not paid particular attention to this branch of the pathology of our Southern States are apt to minimize their significance and regard them as innocent commensals of their host. The numerous cases of mechanical injury caused by intestinal parasites, as in obstruction and appendicitis, as well as the many instances in which toxins have provoked trouble, forces on us the realization that they are potential factors for evil. Every child infested with intestinal worms is more or less handicapped and most adult hosts are at least less eifiicient. Something of the bearing these parasites have on the predis- position to, and aggravation of other diseases, may be gathered from the fact that after quarantining the prisoners in Bilibid prison who were entertaining intestinal worms the death rate fell from 75 per 1,000 to 9 per 1,000.-"'^ Stiles and Garrison Canal Zone Hook-worm Ascaris lumbricoides 6,219 3-792 2,846 19 1,503 95 62 39 15,137 6,359 Hymenolepis nana Oxyuris vermicularis Tffinia saginata Strongyloides intestinalis 9 26 53 3,149 97 250 I 496 ENDEMIC DISEASES OF THE SOUTHERN STATES The different helminths occur with great variation in fre- quency in different localities. In the foregoing tabulation the first column is the result of a compilation by Stiles and Garrison-^* of results by observers in many parts of the world. The second column shows the finding of the laboratories of the Canal Zone as recorded in the reports from 1907 to 1913. Since the inauguration of the work of the Rockefeller Sani- tary Commission the relative frequency of the various parasites of the Southern States is determinable, and the magnitude of their figures probably eliminates any large degree of error. Below are given the results of the work of this commission as well as of other investigators. Stiles and Garrison (214) Kohl- heim (2S7) Rockefeller Sanitary Com., 1911-1913 Rockefeller Sanitary Com., 2nd qtr. 1914 (258) Total Hook-worm Ascaris lumbricoides... . Trichuris trichiura Hymenolepis nana Oxyuris vermicularis . . . Taenia saginata Strongyloides intesti- 36 17 266 12 45 2 ■ 8 269 21 17 15 5 29,743 18,820 5,757 1,879 177 102 S3 3 56,543 25,873 8,330 2,424 806 581 23 23 55,941 27,188 8,447 2,714 818 125 89 3 95,325 Total 386 327 31,588 From the beginning of the work of the commission in Arkan- sas to June 30, 1914, the following results were obtained :-°' Number persons examined 43,528 Infected with hook-worm 9,434 Ascaris Hymenolepis. . Trichuris O.^yuris T. saginata. . . Strongyloides . Cercomonas. . Flv larvse. . . . 138 193 13 34 16 Mixed infections are common. The combinations do not seem to depend on any particular affinities or elements of sym- OTHER INTESTINAL PARASITES 497 biosis but are in direct ratio to the frequency of single infections by the particular species concerned. Negroes are much more susceptible to infection than are the whites. Indians are said to be infrequently the hosts of hel- minths.^*" Females are more frequently infested than males. Children entertain most varieties of intestinal worms much more frequently than adults. While the inhabitants of cities are not immune to the inva- sion of parasites, they are much less frequently infested than residents of rural districts. The diagnosis of intestinal helminthiasis rests solely on the discovery in the feces of worms or their segments or ova. The determination of the various ova is among the simplest of microscopic procedures and with a little experience should sufJBice to enable one to make an accurate diagnosis. A small bit of fecal matter the size of a match head should be rubbed on a glass sHde with sufficient water to spread it well and examined with a 2^-inch objective. TMmA SAGINATA The beef tapeworm, the fat tapeworm, T. mediocanellata, T. inermis. While the tapeworms have been known from the earliest times, Fig. 95. — Ovum of tenia saginata, enlarged. it was Kuchenmeister, in 1852, who first distinguished between the unarmed Tania saginata and the armed Tmnia solium. The geographic distribution of the parasite comprises all continents and in most localities is the commonest of the larger cestodes infesting man. In Abyssinia infestation is said to be 498 ENDEMIC DISEASES OF THE SOUTHERN STATES well-nigh universal owing to the prevailing practice of eating uncooked beef. In the United States Tania saginata is far com- moner than Tania solium but rarer than the dwarf tapeworm. Of 56,543 cases of intestinal parasites recorded by the Rocke- feller Sanitary Commission there were 102 of Tcenia saginata. It is stated that this tapeworm is found in Jews far oftener than is the pork tapeworm. The negro is not immune. In my experience males are more often infested than females. Stiles and Garrison-" found infestation in females more than twice as prevalent as in males. Of Hosier and Peiper's-" cases there were eighty-eight men and twenty-four women. The age of most hosts is from twenty to forty-five years, Fig. 96. — Scolex of tenia saginata, enlarged. though no age can be said to be exempt. My youngest patient was nine years old and he had then harbored the worm for sev- eral years. Schloss^^^ reports five cases in children from six to twelve years of age. The beef tapeworm in the adult state is found only in man. Cattle serve as intermediate hosts for the larvae which are imbedded in the tongue and other muscles. The source of infection in man is the eating of raw or insuffi- ciently cooked "measly" beef, that is, beef infected with the cysticercus bovis, or larvffi of Tcsnia saginata. The beef tapeworm is usually from 12 to 30 feet in length, but specimens up to 36 and even 74 meters long are recorded. OTHER INTESTINAL PARASITES 499 The proglottides average from i,ooo to 1,300111 number. The head is subcubical and from 1.5 to 2 mm. in diameter. There are no booklets. The suckers are circular and about 0.8 mm. in diameter. The rostellum is rudimentary being replaced by a sucker-like organ. The neck is long and narrower than the head. The proglottides gradually increase in size, when sexually ma- ture measuring 4 to 6 mm. long by 8 to 10 mm. broad. Gravid segments measure 12 to 20 mm. long by 4 to 7 broad. The uterus has from 20 to 35 dichotomous branches on each side of and shorter than the median trunk. The eggs are subglobular and if the shell remains intact one or two filaments are found. The six-hooked embryo is surrounded Fig. 97. — Segments of tenia saginata, natural size. by a radially striated capsule. The ova are transparent or bile stained and measure 30 to 40 microns by 20 to 30 microns. Abnormalities in the morphology of this parasite are not rare and monstrosities of scolex and proglottides are reported. Symptoms. — The majority of persons infested with the beef tapeworm do not complain of symptoms, at least until after they discover the presence of the parasites. When symptoms are present there is nothing characteristic about them. The old idea that tapeworm patients have enormous appetites is in a measure erroneous. The appetite is capricious in many cases and anorexia or buhmia occur in a few. Dyspeptic symptoms, increased flow of saliva, belching and nausea are complained of in some cases. Colickypains in the epigastrium orhypogastrium are sometimes felt. Constipation may be present and diarrhea is an occasional symptom. Nervousness may be marked, especially in young patients. Poor and disturbed sleep are not 500 ENDEMIC DISEASES OF THE SOUTHERN STATES infrequent. Vertigo, tinnitus, palpitation, anal and nasal pru- ritus, and malaise sometimes appear. Syncope, convulsions and visual disturbances are rare symptoms. Some patients complain of being conscious of the movement of the worm. Segments may be passed in defecation or may escape spontane- ously and may be found in the clothing or bedding or about the room. The blood examination usually shows an increase in the eosino- philes and the feces may contain Charcot-Leyden crystals. It is not known how long the beef tapeworm may live in the intestines but since certain of the cestodes may hve as long as thirty-five years it is probable that taenia saginata may survive a number of years. From the time of swallowing the cysticercus until segments appear in the stools is about sixty days. The average daily growth of the parasite is said to be 7 cm. Infection with a single parasite is the rule but as many as fifty- nine are recorded in one patient.^^^ The diagnosis can be made only by the passage of segments or the finding of ova in the feces. The differentiation between taenia saginata and t^nia solium may be made by examination of the scolex or of mature pro- glottides. If the scolex is armed with hooks the specimen is taenia solium. Proglottides should be examined pressed be- tween glass slides. In the beef tapeworm the lateral uterine branches number from twenty to thirty-five, while in the pork tapeworm they are usually less than fifteen. The prognosis is favorable but the beef tapeworm, of all the cestodes, being the most resistant to anthelmintics, several treatments may be necessary before the scolex is removed. The prophylactic measures consist of the prevention of soil pollution, and efficient system of meat inspection, cold storage for three weeks, or thorough cooking of beef. In the treatment of tapeworm infection the preparatory treat- ment is of scarcely less importance than the specific medication. Directions to the patient should be minutely detailed and re- duced to writing. The patient should subsist upon liquids only during the entire OTHER INTESTINAL PARASITES 50I day preceding the administration of the specific. At bedtime half an ounce of magnesium sulphate is given. The next morn- ing no breakfast is allowed and the anthelmintic is given on an empty stomach. The best remedy against the beef tapeworm is a fresh prepa- ration of the oleoresin of male-fern. An average dose is i dram. In children from five to ten years old I have given from twenty to thirty drops. It may conveniently be administered in several large capsules. The parasite is not killed by anthel- mintics, but merely stupefied and it must be removed by a purgative. Two hours after giving the male-fern is the proper interval and the sulphate or citrate of magnesia are suitable. Castor oil should not be used for this purpose. Pomegranate is an efficient taeniafuge in many cases. It should be used in the form of the fluid extract, dose half a dram. Pelletierin is a mixture of the alkaloids of pomegranate. An average dose is lo grains. This as well as all other anthelmin- tics should be preceded and followed by brisk purgatives. Pumpkin seed is a safe and fairly efficient remedy. One or 2 ounces of the ground seeds should be given in sugar and water. Cusso, kamala and turpentine are rarely used at the present day. As the worm is about to be passed the patient should be seated on a vessel containing warm water over which gauze or coarse cloth is suspended to receive the parasite. Care should be taken to avoid breaking the worm and no traction should be made. If the bowels cease to move before expulsion is complete an enema of warm water should be given. Search should be made for the head. On account of its small size, however, failure to find it does not necessarily indicate that it has not been passed. In the latter event proglottides will reappear in the feces within three months. T./ENIA SOLIUM The pork tapeworm, the armed tapeworm. While Tania solium is almost cosmopolitan and in certain locahties the commonest cestode, it is far rarer in the South than either the beef tapeworm or the dwarf tapeworm. There are 502 ENDEMIC DISEASES OF THE SOUTHERN STATES no cases of this parasite recorded in the reports of the Rocke- feller Sanitary Commission. In the adult stage this parasite inhabits the small intestine of man only. In the cysticercal or larval stage the common host is the domestic swine, but it is known also in the wild boar, man. Fig. 98. — Scolex of tenia solium, enlarged. certain species of monkeys, bears, the dog, rat, sheep, cat and deer. The mode of infection in man is eating pork infested with the larvae of the pork tapeworm. a b Fig. 99. — Ripe proglottides of a, tenia solium and b, tenia saginata. Tcenia solium does not attain the length of saginata, averaging from 6 to 10 feet and consisting of 800 or 900 segments. The scolex is subglobular, 0.6 to i mm. in diameter. The short, OTHER INTESTINAL PARASITES 503 thick rostellum is armed with a double wreath of hooks, 22 to 32 in number, oftenest 26 or 28. The 4 circular suckers are 0.4 to 0.5 mm. in diameter. The neck is slender. The pro- glottides increase gradually in size, mature ones measuring 10 to 12 mm. in length by 5 to 6 mm. in breadth. The uterus is composed of a median stem with 7 to 10 lateral branches on each side. The eggs are globular, 30 to 36 microns in diameter, the shell radially striated, and the oncosphere contains 9 hooks. The symptoms of infestation with the pork tapeworm do not differ from those of the beef tapeworm. The anatomic differ- entiation has been made under Tcenia saginata. The length of life of the pork tapeworm is not definitely known, but it may infest man for fifteen years or more. Multiple infections are much more common with this worm than with the beef variety. Hosier and Pfiefer-'^ recount infections with 18, 21, 21, 33, and 41 parasites. The prophylactic measures against the armed tapeworm are identical with those against Tmnia saginata excepting that in the former the meat concerned is pork. On account of the danger of somatic teniasis in case of infec- tion with the pork tapeworm, treatment should be instituted immediately. It is possible for the patient to infect himself with cysticercus by swallowing the eggs of his own parasite or by eggs gaining access to the stomach by reverse peristalsis. This does not occur in the case of the beef tapeworm. The treatment is the same as laid down for Tcenia saginata. HYMENOLEPIS NANA The Dwarf Tapeworm, Tasnia murina, Taenia nana, Taenia agyptica, Diplacanthus nanus, Hymenolepis murina The dwarf tapeworm was found in man for the first time by Bilharz in Cairo, Egypt, in 1851. He recovered a "countless number" of them at a post-mortem on a boy who had died of meningitis. Besides in Egypt, this parasite has been found in England, Italy, Servia, Russia, Germany, Siam, Japan, North and South America. Until 1909 only thirty-three cases had been reported in the United States, seven of these having been reported by me. These cases may be tabulated as follows: 504 ENDEMIC DISEASES OF THE SOUTHERN STATES Philadelphia, 1872, Spooner^" i Galveston, Texas, 1902, Moore^'* i Charleston, S. C, 1902, Stiles^'" i Macon, Ga., 1902, Stiles--" 3 Washington, D. C., 1903-04, Hygienic Laboratory-'* 12 Amarillo, Texas, 1903, Magnenat--' 4 Fort Porter, N. Y., 1904, Hallock'^J 2 Statesville, N. C, 1906, Stiles and Garrison-''' i Marianna, Ark., 1906, Deaderick--' 4 Brooklyn, N. Y., 1906, Lambert^^'i i Marianna, Ark., 1907, Deaderick^^^ i Marianna, Ark., 1909, Deaderick"* 2 Within the past four years the dwarf tapeworm has been shown to be the commonest cestode in the South. During the three years, 1911-1913 of 56,543 infections found by the Rocke- feller Sanitary Commission 1,879, '^^3-3 P^r cent., were Hymeno- lepis nana. It has been found in all Southern States surveyed by this Commission. Schloss^^" reports twenty cases in 280 con- secutive examinations in New York. Negroes are affected as well as whites. Males are affected more frequently than females. Children from live to ten years of age are most susceptible to infestation, but no age seems exempt, cases being recorded past fifty years of age. The only intermediate hosts yet determined are the rat and probably man; the definitive hosts are man and a certain species of rats and mice. Direct infection from man to man seems possible. In sup- port of this are the two cases of Stiles--" in an orphan asylum, members of the staff of the Hygienic Laboratory-" finding five cases in the same ward of an insane asylum/ Magnenat's--^ four cases in the same family, and my--® two cases in the same house- hold. In all of Schloss'--'' cases, with one exception, more than one child in each family was infected. Venuti^' found twenty- three cases among 214 boys examined in an institution in Catania, while no cases could be found among 100 boys of the general population. The usual mode of infection seems to be the ingestion of food soiled by the excrement of infested rats and mice. The length of my specimens of Hymenolepis nana has been OTHER INTESTINAL PARASITES 505 from 8 to 18 mm. ; the breadth of mature proglottides from 0.33 to 0.58 mm.; and the number of segments approximately from 100 to 200. In a specimen measuring 15 mm. in length there were 185 segments. The head is subglobular, elongated, possessed of a retractile rostellum surrounded by a single row of booklets, numbering from twenty-two to thirty, and has four suckers. The average length of the head with rostellum pro- truded was 0.34 mm., with rostellum retracted 0.27 mm., and the width of the head 0.27 mm. The diameter of the suckers averaged 86 microns. The booklets averaged 14 microns in length. The neck is slender and unsegmented. In a specimen measuring 15 mm. the distance from the tip of the rostellum to the first segment was 1.18 mm.; the breadth of the neck 0.14 mm. The segments of the strobila gradually increase in breadth toward the posterior extremity, the last fifteen to forty proglottides being usually stuffed with ova. Occa- sionally a sterile segment is seen between two fertile ones. The genital pores are single, near the anterior border of the segment, and usually on the left side. Each oviparous seg- ment may contain from 80 to 180 ova. The mature ova are round or slightly oval, averaging in my cases: outer mem- brane 50 by 42 microns, inner membrane 32 by 30 microns. Between the outer membrane and the inner one which en- closes the membrane is a hyaline substance which surrounds the latter like a wide halo. Within the embryo can be dis- tinguished six booklets lying parallel or radially. A few very delicate filaments may commonly be detected arising from opposite poles of the inner membrane and permeating the hyaline substance. I have examined the ova in my last three cases with reference to Foster's-^^ interesting observations on the movements of the embryo within the ovum, but have not been able to verify them. The symptoms are similar to those of infection with the beef tapeworm, strikingly exaggerated in children. In one of my cases abdominal pain, diarrhea and vomiting were prominent; in another nausea, vomiting, dizziness, headache and dyspnea; in a third vomiting, abdominal pains, headache, dyspnea, dizzi- 5o6 ENDEMIC DISEASES OF THE SOUTHERN STATES Fig. I02. — Scolex of hymenolepsis nana, enlarged. Fig. 103. — Hooklets from hymenolepis nana, enlarged: a, lateral aspect; b, view from edge. Fig. loi. — Hymenolepis Fig. 104. — Proglottides of hymenolepis nana, nana, enlarged. enlarged. OTHER INTESTINAL PARASITES 507 ness and diarrhea. A boy aged eleven developed edema of the hands, feet and legs up to the knees, of the eyelids and upper lip. A young girl had convulsions every time she had a slight fever; this was promptly stopped by removal of a large number of dwarf tapeworms. Many cases are symptomless. The appetite may be increased, decreased or otherwise per- verted. Abdominal pain is frequent, so are nausea and Fig. 105. — Hymenolepis nana, proglottides containing ova. vomiting. Gnawing and crawUng sensations are occasion- ally complained of. The bowels may be loose, regular or constipated. Nervousness and disturbed sleep are not infrequent manifes- tations. In children choreic movements and convulsions have been recorded. A slight degree of anemia is not uncommon. In seven of my cases the eosinophiles varied between 7.8 and 26 per cent. Of fourteen cases of Schloss'^-' seven showed eosinophilia ranging from 6.5 to 22 per cent., while in the remaining seven cases these cells were normal. I have not found Charcot crystals in the feces of any of my cases, but in mounted specimens of the parasite, have frequently 5o8 ENDEMIC DISEASES OF THE SOUTHERN STATES noticed the formation of these crystals at points where the worm was lacerated or contused. Multiple infestation is the rule, as many as several thousand occasionally being present in the same individual. Mixed infestations are common, the combination with hook- worm being the most frequent. One of my cases showed in addition to Hymenolepis nana, Ascaris lumbricoides and Tri- chomonas intestinalis. The infection may persist for several years if untreated. The diagnosis depends solely upon the detection of the ova or parasites in the feces. The ova are likely to be confounded with no others excepting the rare parasite Hymenolepis diminnta. The latter may be distinguished by the somewhat larger size, the presence of two other membranes with delicate radial stria- tions between, and by the absence of filaments in the hyaline substance. Preventive measures consist of treating promptly and radi- cally infested persons, guarding against pollution of food or hands with feces of infested persons and the protection of food stuffs from rats and mice. Treatment. — The most efficient vermifuge in these cases is male-fern. It should be given as for the treatment of the beef tapeworm. While the worms are readily expelled by this agent, an analysis of the cases in which the results of treatment by male- fern were verified by subsequent microscopic examination of the feces shows that more than one treatment is usually neces- sary. There are twenty-two cases in which the results were thus followed up. Of these there are only five cases in which no ova were found after one treatment with male-fern; in six cases two treatments were necessary; in five cases three doses were needed; in one case four or five treatments were adminis- tered; in four cases after one dose the ova were still present but no further treatment is recorded; in one case after several treatments the ova persisted in the feces; and in two of the cases in which three doses were given the ova were yet found after the last dose. The drug should, of course, be given only after thorough purgation with salines. OTHER INTESTINAL PARASITES 509 HYMENOLEPIS DIMINUTA Taenia diminuta, Taenia leptocephala, Hymenolepis flavopunctata, Taenia flavopunctata, Taenia flavomaculata, Taenia minima, Taenia varesina In 1858 Weinland first described a case of Hymenolepis dimi- nuta occurring in man. The parasites were recovered in 1852 from a healthy infant nineteen months old. Two fragments labelled as coming from man were found in the museum at Alfort, France, by Raillet before 1810, and were identified as Hymenolepis diminuta by both Raillet and Zschokke. The following is a synopsis of cases which have thus far been reported in man:--^ Alfort, France, by Raillet, before 1810 i case. Boston, 1842, Weinland i case. Philadelphia, 1884, Leidy i case. Varese, Italy, 1884, Parona i case. Catania, Sicily, 1887-8, Grassi i case. San Paulo, Brazil, 1893, Lutz i case. Pisa, Italy, 1895, Sonsino i case. Rio Janeiro, Brazil, i8g6, Magalhaes i case. Centuripe, Sicily, 1900, Previtera 2 cases. Philadelphia, 1900, Packard i case. Marianna, Ark., 1906, Deaderick^^^ i case. Hanley Falls, Minn., 1906, Nickerson^^' i case. Of the above thirteen cases four were in males, five in females, and in four the sex is not recorded. Fig. 106. — Ovum of hymenolepis diminuta, enlarged. The ages were 16 months, 19 months, 20 months, 2, 2, 3, 8, 11,12 and 40 years, the ages of four patients not being recorded. According to Ransom^-^ the number of worms present in each individual varied from one to four. In my case there were three Sio ENDEMIC DISEASES OF THE SOUTHERN STATES or four specimens, while in Nickerson's^^^ there were about twenty-five. No marked symptoms have been recorded in any of the cases. Increased appetite, nausea, and pain in the epigastrium were the complaints in my case. Slight "peevishness" was noted by the mother of the child in Nickerson's case. In my case the eosinophiles were 7 per cent. This parasite in the adult stage inhabits the intestine of certain species of rats and mice. It is probably accidental in Fig. 107. — Hymenolepis diminuta, natural size. Fig. 108. — Scolex of hymeno- lepis diminuta, enlarged. man. The larva occurs in the meal moth, the earwig and cer- tain species of beetles. Recent experiments of Nickerson-^' implicate certain myriapods, Fontaria and Julus, as interme- diate hosts in America. Hymenolepis diminuta is from 20 to 60 cm. in length and up to 3.5 to 4 mm. broad. The segments number from 600 to 1300. The head is club shaped, 0.2 to 0.5 mm. in diameter, and has a rudimentary unarmed rostellum. There are four suckers. The ova resemble those of Hymenolepis nana. The average of ten measurements of ova in my case gave: outer membrane 35 by 40 microns. Some were slightly bile stained, others perfectly OTHER INTESTINAL PARASITES 51I clear. The outer membrane appears thickened or doubled and may be radially striated. No filaments are found in the hyaline substance as in the ova of the dwarf tapeworm. The diagnosis is made by the discovery of segments of the worm or its ova in the feces. Prophylaxis of infection with this parasite consists of guard- ing against contamination of food by the meal moth, rats, mice, and other hosts. Fig. 109. — Hymenolepis diminuta, proglottides containing ova, enlarged. Treatment. — Any anthelmintic or merely a cathartic is usually successful in expelling the parasite. In the thirteen cases santonin was used twice, male-fern three times, calomel once, the worm was expelled without medicine once, and the anthelmintic used is not recorded in six cases. STRONGYLOIDES rNTESTINALIS Anguillula intestinalis, Anguillula stercoralis, Rhabdonema strongyloides, Rhabdonema intestinalis, Leptodera stercoralis, Leptodera intestinalis In 1876 Normand treated a number of French soldiers re- turned to Toulon from Cochin China suffering severely from diarrhea. A large number of small nematodes in the feces were SI2 ENDEMIC DISEASES OF THE SOUTHERN STATES identified as strongyloides intestinalis . Both Normand and Bavay, who made a careful study of these parasites, regarded them as the causative factors of Cochin China diarrhea. The geographic distribution at large seems strikingly in con- formity with that of hook-worm. The reports of the Rockefeller Sanitary Commission for the years 1911-1913 record cases in Mississippi, North Carolina, Tennessee, Alabama and Georgia. Cases were observed in Baltimore by Strong-^^ and Thayer,^^* and in Tennessee by Brush.^^^ I observed a case in eastern Arkansas, and the State Director of Sanitation in this state^'^ informs me that his field men have found twenty-one cases in this state to June 30, 1 9 14. Simon^'^ records it in Louisiana. Besides man the only other host for this parasite appears to be the monkey. The modes of infection by Strongyloides in- testinalis are two: by the mouth with infected food or water, and by the skin after the manner of hook-worm infection. It is maintained by Fulleborn and Torgau-^^ that even those larvae which are swallowed must pass through the stomach wall into the vessels and by way of the right heart, lungs, trachea and esophagus back to the stomach and intestines. The complicated life cycle of this parasite is, according to Stiles,-^® as follows: I. (a) The parasitic adults, inhabiting the intestine, are parthenogenetic females measur- ing 2.2 to 3 mm. long by 34 to 70 microns broad. The eggs are deposited in the intestinal lumen of the host or in galleries in the intestinal mucosa made by the females, and develop into (b) Rhabditiform embryos 200 to 240 microns long by 12 microns broad which may grow to 450 to 600 microns long by 16 to 20 microns in diameter by the time they are discharged with the feces. These embryos develop within two or three days into Fig. no.- — Larva of strongyloides in- testinalis, enlarged. OTHER INTESTINAL PARASITES 513 II. (c) Free-living dioecious adults. The males measure 0.7 mm. long; the tail is curved ventrally to form a hook; the spicules are curved and 38 microns long. The females measure I mm. long; thevulvais situated slightly posterior to the equator of the body. Each female develops thirty to forty eggs which may or may not segment in the uterus; these eggs develop forming the (d) Free-living rhabditiform embryos which measure 220 microns long; when they attain a length of 550 microns they moult and become (e) Filariform embryos. This is the infecting stage which enters man by the mouth or through the skin, reaches the duo- denum and upper part of the jejunum and develops directly into {a) The parthenogenetic females. Instead of the cycle a-b-c-d-e-a an abridged cycle a-b-e-a may occur. Strongyloides intestinalis may be cultivated by adding sterile water to the feces and placing in the sunlight. The parthenogenetic females are found only in the upper part of the small intestine. The pathogenic equation of this worm has long been debated and is still unsolved. Earlier writers on the subject were con- fident of an etiologic association with diarrhea. Of recent years the tendency is increasingly to belittle this relation. In many cases in which the parasite is associated with diarrhea, enam^ebas and other organisms have been found. It is not infrequently associated with hook-worm. It is probable that its pathologic status is not important, though in some cases it appears to excite a catarrhal enteritis. The diagnosis is possible only through the discovery of the rhabditiform embryo in the feces. Occasionally after free purgation strings of eggs may be found. Treatment. — No known anthelmintic is of any particular value in the treatment of infection with this parasite. Thymol is most frequently recommended, but the results are far from satisfactory. 514 ENDEMIC DISEASES OF THE SOUTHERN STATES ASCARIS LUMBRICOIDES Round Worm, Eel Worm, Lumbricoid Worm This worm is practically cosmopoKtan. The only country on the globe in which it is not endemic is said to be Iceland. It is second only in frequency to the hook-worm in the South, one- third of all infection found by the Rockefeller Sanitary Com- mission for the years 1911-1913 being the round worm. The negro race is more often infested than the white. In some sections of the South it is a common custom for the little negroes to be "wormed" (treated for round worms) regularly every year. While seasons are not known to influence the frequency of their occurrence, in my experience they are more evident in the summer and fall. The fact that this is the malarial season is probably responsible for this, since febrile conditions cause the wandering and expulsion of the parasites. Females seem more prone to infestation than males. Chil- dren are more frequently the hosts of these worms than are adults. Miller"^ reports an interesting case in a child of three weeks. After the separation of the cord ulceration of the um- bilicus occurred leading to perforation of the intestine, and from the resulting fistula a round worm 18 cm. long was discharged. Stiles and Garrison^" report a case in a patient over eighty years old. These writers have collected 534 cases in which the age was given and which are distributed as follows: 0-15 years 444 15-30 years 3° 30-50 years 35 More than 50 years 5 Ascaris liimbricoides is known to occur in man only. An intermediate host is not concerned in the dissemination of the infection. After passing out with the feces the ova in the course of a month or more develop embryos within. When these ova are swallowed the contained embryo develops directly into the adult stage. Freezing, if not too prolonged, and drying of the ova at ordinary temperatures do not destroy the embryo, and they may be blown about as dust. Infection OTHER INTESTINAL PARASITES 515 Fig. III. — Ovum of ascaris lumbricoides, enlarged. through water, vegetables or soiled hands are the usual methods. Stiles^ beUeves that flies may carry the ova in their intestines and thus spread the infection. The worms are reddish or gray- ish yellow in the fresh condition. The oval cavity is surrounded by three papillae, one dorsal and two ventral. The body is round and tapers toward both extremities. The male is 15 to 25 cm. in length and about 3 mm. in diameter. The posterior end is flexed ven- trally. The females are 20 to 40 cm. long and about 0.5 cm. in diameter. The posterior extrem- ity is straight. The vulva is an- terior to the middle of the body. The ova are elliptical, 50 to 70 microns in length by 40 to 50 microns broad. The external covering is thickly set with proc- esses and usually bile stained. The ova are deposited before segmentation. Fig. 112. — Ascaris lumbricoides, female, natural size 5l6 ENDEMIC DISEASES OF THE SOUTHERN STATES It is probable that the pathogenic power of ascaris lumbri- coides depends, besides mechanical disturbances, upon a toxin. Goldschmidt-^" records the symptoms experienced by himself and others while dissecting fresh ascaris. The first dissection often caused no symptoms, but a repetition was followed by tenderness, irritation of the respiratory tract, sneezing, coryza, conjunctivitis and typical asthmatic attacks recurring period- ically, strikingly resembling hay fever. These suggest ana- phylactic phenomena. By the intraperitoneal injection of an aqueous extract of Ascaris lumbricoides Herrick-'*^ produced a notable eosinophilia after previous sensitization, and shows that the substance causing such an eosinophile increase is a protein. Flury-^^ has shown that the tissues and excreta of these worms contain numerous compounds capable of inducing local hyper- emia, inflammation and necrosis. Multiple infections are the rule, from two to six being the usual number. However, large numbers may be present. I have felt masses of these worms through the abdominal wall. Raines-"*- describes the unique case of a child of twenty months who discharged 834 worms in one day, 634 the next, and within a short period 1,992 in all. Fauconneau-Dupresne-'^ observed the case of a twelve-year-old boy who passed 5,126 of these worms in less than three months. Many cases present no symptoms. On the other hand, the symptoms may be alarming. The commonest manifestations are fretfulness, restless sleep, dreams, itching of the nose and anus, gritting the teeth, meteorism, nausea and vomiting. There may be perversion of hearing, taste, sight and smell, vertigo, hysteria and convulsions. Other digestive symptoms are dyspepsia, griping pains in the abdomen, irregular bowels, diarrhea, constipation, increased, deficient or perverted appetite, malnutrition and jaundice. I have seen severe dysenteric symptoms subside after riddance of round worms. Anemia is present in some cases, and if symptoms are present the blood shows eosinophilia. At times infestation with eel worms assumes dangerous sig- nificance. This is especially true when the parasites are in such numbers as to cause intestinal obstruction, or when they pene- OTHER INTESTINAL PARASTIES 51 7 trate communicating passages or cause perforation. Febrile conditions cause the parasites to become active, and it is often under such circumstances that these accidents occur. The worms may escape spontaneously from the anus, mouth or nose, or may be vomited. Perforation into the thoracic or abdominal cavity may result, or the parasite may enter the Eustachian tube or cause suffocation by entering the trachea. ' It is stated that there are recorded about ninety cases in which round worms have entered the bile ducts, nine cases into the pancreatic duct, and over twenty cases into the urinary passages." Over eighty cases are recorded in which the worms have escaped through the body wall at various points. The following unique case occurred in my practice: A colored boy, aged nine years, shot himself while playing with a 41-caliber Derringer. I saw him several hours after the accident occurred. The ball entered the abdomen in the median Hne immediately above the symphysis and could be felt beneath the skin a little to the left of the anus. There was some abdominal rigidity; he had vomited once and his bowels had moved twice with blood in both actions. He had urinated once and the urine contained one or two small clots of blood. The temperature was 102, pulse 120, otherwise good. The insanitary surroundings and lack of facilities and the belief that the course of the bullet was extraperitoneal led me to treat the case expectantly. His condition did not get any worse nor did he pass more blood from the bowel or bladder. A week or ten days after the ac- cident he began to have difficulty in starting the flow of urine, which would sometimes be interrupted suddenly after having been started — typical " stammering urination." This difficulty continued until the fifteenth day after the accident, when a large living lumbricoid worm made its exit from the bladder through the urethra. The boy made an uneventful recovery. The diagnosis is easily made by the detection of the ova in the feces or the expulsion of the worms. The longevity of Ascaris lumbricoides is not known. Eggs may be found in the feces about a month after infection. Prophylaxis consists of abstaining from contaminated food and water, infection by soiled hands, and exclusion of flies. 5l8 ENDEMIC DISEASES OF THE SOUTHERN STATES Treatment. — The cure of this infection is easy, santonin being practically a specific. The dose for a child under one year is }i to H grain; for a child one to five years of age, i or 2 grains; for older children, 2 or 3 grains. It is well to combine calomel with the vermifuge, and preliminary diet and purge should be prescribed as for teniasis. The treatment is usually repeated once or twice at forty-eight-hour intervals. The feces should be examined periodically to ascertain whether the cure has been radical. OXYURIS VERMICULARIS Ascaris vermicularis, Fusaria vermicularis, Pin Worm, Seat Worm, Thread Worm, Maw Worm These worms are practically cosmopolitan. Even in Iceland, where the round worm is not endemic, oxyuris is enormously frequent. In the Southern States they do not seem to be as common as they were in former years. The Rockefeller Sani- tary Commission has found them in each of the states surveyed, and it is probable that they occur with greater relative frequency than their figures indicate, since statistics based on ova findings under-estimate pin worms as their ova are not as numerous in cases of infection as is the case with many other parasites. More cases are observed in spring and summer than in other seasons. Males are less frequently infested than females. Infections are found from early childhood to old age. Heller-''^ observed a case in a child of five weeks. A number of cases compiled by Stiles and Garrison'^'* may be arranged according to age as follows: 0-15 years 305 cases. 15-30 years 20 cases. 30-50 years 16 cases. More than 50 years 3 cases. Oxyuris vermicularis is not known to occur in any other animal. No intermediate host is concerned in the transmission of this parasite from one person to another. The ova gain access to the alimentary canal of man through infected hands, food, or drink. Reinfection of an infected individual is common after . OTHEE INTESTINAL PARASITES 519 Fig .113. — Ovum of oxyuris vermicularis, enlarged. scratching the anus and putting the hands to the mouth or nose. It is possible that flies may carry the ova. The worm is white in color. The female is about I cm. in length and 0.6 mm. in diameter, and has a long sharp-pointed tail. The vulva is in the anterior half of the body, the anus in the posterior half. The male is 3 to 5 mm. in length, the body curved ventrally. The males die early and are not often seen in the feces. For a long time it was not known. The eggs are oval, flattened on one side, and average 50 by 20 microns. The sexes are usually present in equal numbers. The worms may be from a very few to so many that the mucous membrane of the gut looks like fur. Symptoms are usually due to the nocturnal wanderings of the worms. These consist chiefly of irritation of the anus, disturbed sleep, gritting the teeth, and itching of the nose. Pain in the lower part of the abdomen is common and there may be meteorism, nausea, Fig- 114-— Ox- ,. , . . ,-^_ . , yuris vermicu- diarrhea or constipation, ihe appetite may be laris, adult fe- deficient, increased or irregular. Genital irrita- °^^'^' enlarged. tion leading to masturbation is observed in some cases, and the worms may enter into the vagina. Enuresis is occasionally caused by pin worms. Loss of weight, headache, anemia, convulsions and chorea may exist. 52C ENDEMIC DISEASES OF THE SOUTHERN STATES Eosinophilia above 5 per cent, existed in seventeen of Schloss'^^^ twenty-two cases. Numerous cases are recorded in which the appendix has been invaded by pin worms with resulting appendicitis; indeed it was at one time erroneously supposed that the appendix was the nornial habitat of these parasites. A diagnosis of this infection cannot be made on symptoms alone and usually rests on the discovery of adult females dis- charged from the rectum. The ova may be found in the feces in the majority of cases, but a negative result does not exclude infection. Since reinfection is common it is impossible to determine the length of life of the individual worms. Infection may persist for a number of years, however. The males are short lived. Prophylaxis. — Since infection is carried from the anus to the mouth by the fingers, the hands should be washed after defecation and the nails kept trimmed and clean. Food should be guarded against contamination and flies should be excluded. In outhning the treatment it should be considered that the normal habitat of oxyuris is the cecum, and only impregnated females descend to the rectum to ovulate; hence the treatment should be continued for several weeks. Internal treatment should at the outset be combined with irrigations, and santonin, given as recommended for ascaris, is the most useful drug. Quassia is an effective irrigation. It should be used as an infusion using two tablespoonfuls of the chips to a pint of hot water. No more should be injected than can be retained and it should be given with the buttocks elevated, or in the knee- chest position. In the cases where this has failed me I have usually had success on obtaining a fresh supply of quassia. Strong salt water used in the same manner is often effective. For the anal pruritus weak mercurial ointment or zinc oxide ointment should be applied locally at night. Reinfection should be guarded against and the treatment persisted in until the cure is radical. OTHER INTESTINAL PARASITES 52 1 TRICHURIS TRICHIURA. Trichocephalus dispar, Trichocephalus trichuris, Trichocephalus hominis, Ascaris trichiura, Whip-worm The whip-worm is said to be cosmopolitan. It ranks third in frequency among the infections found by the Rockefeller Sanitary Commission. I failed to find ova of this parasite in about 500 examinations in the Mississippi River "bottom" in eastern Arkansas. Infections are commoner among negroes than among whites. The frequency of this parasite is sometimes regarded as an index to the sanitary condition of a community. Females are more frequently infested than males. Fig. 115. — Ovum of trichuris trichiura, enlarged. Infections have been found from the age of less than three months until old age. Stiles and Garrison-''' collected from the literature a number of cases, which fall according to age in the following limits: 0-15 years 4°° iS-3° years 41 30-50 years 66 More than 50 years 16 Besides in man the whip-worm is found in certain monkeys and lemurs. No intermediate host is necessary in the propagation of infection, the partially developed ova being swallowed with contaminated water or food. The whip-worm has a thick club-shaped body which tapers radially into the long thread-like neck. The male is 40—45 52 2 ENDEMIC DISEASES OF THE SOUTHERN STATES mm. in length, the female 45-50 mm., about three-fifths being comprised by the anterior portion of the body. The anus is terminal and the vulva is situated near the commencement of the posterior portion of the body. This part of the body in the male is spirally rolled up. The ova are very characteristic. b Fig. 116. — Trichuris trichiura. a, Male; b, female, enlarged. They are barrel-shaped, possessed of a thick brownish shell and perforated at the poles. They measure about 50 microns in length by about 23 microns in breadth. There are usually about a dozen worms present, but thousands have been found at autopsy. The cecum is the normal habitat. This parasite can no longer, as formerly, be regarded as a harmless commensal of man. Various theories have been adduced to explain its pathogenicity, such as that the worm is OTHER INTESTINAL PARASITES 523 a blood sucker, that it produces a toxin or hemolysin, or that it causes mechanical injury, but none of these is satisfactory. It is known that the whip-worm transfixes the mucous mem- brane, embedding beneath it the anterior portion of the body and producing hyperemic or even eroded areas, but these are not sufficiently extensive to be pathogenic. This worm has been accused of a part in the infection with typhoid fever but the evidence is not convincing. While many cases present no symptoms there may be anemia, severe nervous symptoms and gastro-intestinal dis- turbances, shortness of breath on slight exertion, dyspeptic manifestations, vomiting, diarrhea, nervousness, insomnia, and even convulsions and coma are symptoms. There is rarely any eosinophilia in these cases, contrary to the case in most helminthic infections. There are a number of fatal cases on record. Metchnikoff^*^ emphasized the importance of these parasites in the production of appendicitis. Accurate diagnosis can be made only by examination of the feces. It is not known how long infection with whip-worms may persist. Prophylaxis. — The prevention of soil pollution and care against contamination of food are the requisite prophylactic measures. Treatment. — It is proverbially difficult to rid the bowel of these unwelcome guests. Many anthelmintics bring away part but none is known to be specific. Thymol perhaps has the best reputation. High enemas of solutions of benzene have recently been used with apparent success and this treatment deserves further trial. BALANTIDroM COLI Paramoecium coli, Holophyra coli Infections with Balantidium coli have been found in Russia, Sweeden, Finland, Germany, Italy, North and South America, Cuba, Africa, Sunda Isles, Cochin China and the Philippines. In the United States, Bel and Couret-'*" reported a case in Louisiana, Gray-^^ three cases in Arkansas, I observed one 524 ENDEMIC DISEASES OF THE SOUTHERN STATES case in eastern Arkansas, Sistrunk-"" one in Minnesota, and the Rockefeller Sanitary Commission-^^ two cases in North Carolina and one in Mississippi. Altogether less than 150 cases have been recorded in man. Males are twice as frequently infested as females. Adults are far more frequently subject to this infestation, but two cases having occurred in children. Association with pigs or the preparation of sausage predispose to infection. Fig. 117. — Balantidium coli, enlarged. Four cases have been reported in the same household. -^^ Besides man, the domestic pig and certain species of monkeys serve as hosts for halantidiuni. It is possible to acquire this infection through food or water infected with the feces of pigs or through eating infected hog meat. The body of this infusorium is nearly oval, one side being usually somewhat longer than the other. The length is from 0.06 to o. I mm. and the breadth from 0.05 to 0.07 mm. The an- terior end shows the short, broad, funnel-shaped peristome. The anus is terminal at the posterior end. There is a distinct ectosarc thickly set with ciha. The endosarc shows ordinarily two contractile vacuoles and phagocyted particles. The nucleus is commonly bean-shaped. Reproduction occurs through binary fission and budding conjugation is known in OTHER INTESTINAL PARASITES 525 this parasite, and encystation is known to occur. The organ- isms are highly motile. Bel and Couret-^^ were unable to cultivate them. The habitat of this parasite in man is the large intestine. The organisms invade the coats and vessels of the gut, produc- ing ulcers, hyperemic or a hemorrhagic condition of the in- tervening mucosa, and swelling of the mesenteric glands. Nearly all infested patients suffer with diarrhea or dysentery. The feces are liquid and contain undigested food, mucus or blood. Tormina and tenesmus are frequent symptoms, and in persistent cases there may be anemia, loss of weight and edema. Eosinophilia is present in many cases. The diagnosis is impossible without the detection of the characteristic organisms in the feces. The duration of the infection may be as long as fifteen years. The mortality in in cases collected by Strong^"*^ was 30 per cent. Prophylactic efforts should be directed against infected pigs. Treatment. — The list of drugs recommended for the treat- ment of the condition indicates that there is no specific. Ene- mas of quinine solutions are perhaps more highly recommended than other measures. Enemas of tannic acid, silver nitrate, iodine, acetic acid, salicylic acid, and boric acid have been used. Internal treatment has so far been unavailing. Em- etine should be given a trial. MYIASIS INTESTINALIS In 1902 Schlesinger-"" was able to find in the literature some 100 cases of intestinal myiasis. Since then a number of such cases have been recorded. I have observed two cases in Arakansas.-^^ Most of the cases are reported in adults, but children of one year or under may be affected. As is well known, the larval stage of some diptera is neces- sarily passed in the alimentary canals of mammals and other animals, for instance, the bot-fly of cattle, but fly larvae must be regarded as accidental parasites of man. 526 ENDEMIC DISEASES OF THE SOUTHERN STATES The following species may give rise to intestinal myiasis in this chmate: Musca domestica, the common house-fly, deposits its eggs on horse manure, occasionally on that of the cow, or even in human feces, rarely on decaying animal or vegetable matter. Musca voniitoria, the blue bottle meat fly, deposits its ova by preference upon decaying animal matter. Anthomyia canicularis, the little house-fly, deposits ova upon decaying vegetable matter. Chrysomyia macellaria, the screw-worm fly, deposits ova in wounds or on decaying flesh. Sarcophaga carnaria, the green flesh fly, larvs placed on de- composing animal matter, possibly also on human feces. Piophila casei, the cheese fly, deposits its ova upon human feces. Eristalis tenax, the drone fly, the larvas are found on decaying animal and vegetable matter, in soft mud and in foul water. These creatures may gain entrance to the body either as ova or as larvae. Probably the most common mode of infec- tion is through eating food containing ova or larvae, though the anus may be the port of entry. Wirsing-"- believes that in- fection occurred through the anus in the case of a breast nurs- ing infant taking an air bath in an open window. In the case reported by Finlayson^^^ due to Anthomyia canicularis, it ap- pears that the ova were not swallowed but were deposited at the anus while the patient was defecating and were taken up within the bowel after defecation. Nicholson^^'' reports three cases of infection with larvae of Musca domestica in which it seems probable that infection was by way of the anus. Pro- lapse, hemorrhoids and external lesions predispose to such infections. It is possible that infestation may occur through the swallowing of pregnant viviparous flies, as sarcophaga. Among the species of this order of insects whose larvae occur in man as pseudoparasites there are two modes of reproduction, the oviparous and the viviparous. The former is the more frequent among the species in question, but the latter is usual among the sarcopagids especially with Musca domestica; each female lays about 120 eggs; the duration of the egg stage is OTHER INTESTINAL PARASITES 527 about eight hours, of the larval stage about five days, and the pupa stage the same. These figures vary with the cUmate and season. The symptoms produced by these loathsome creatures are abdominal pains, nausea, diarrhea, dysentery, nervousness, abdominal tenderness, crawling sensations in the bowels, mi- grain, neuralgia and even hysterical symptoms and convulsive seizures. The longevity of intestinal maggots is not known, but in- fection may persist for years. One case is recorded of twelve years' standing. ^°^ The broad diagnosis of intestinal myiasis is easy to any one familiar with the ordinary parasites, but a specific determina- tion should not be attempted by any one but an expert. In all these cases it is well to breed out the maggots to mature insects as determination is much easier in the adult state. A little earth in a pot covered by gauze is all that is necessary for this experiment. P*rophylaxis consists of prevention of access of flies to food and avoidance of defecation in the open, especially by those predisposed by anal or rectal disease. The treatment which is usually successful is castor oil, alone, or given with santonin. The oil should be given on an empty stomach, one dose for three successive days. In one of my cases, an infestation with Chrysomyia macellaria, I used an enema of a pint of cotton-seed oil with a satisfactory result. 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"'* King, Popular Science Monthly, Sept., 1883. ■•^^ Moore, Jour. Trop. Med., Mar. 15, 1902. ''" Curry, Boston Med. and Surg. Jour., Nov. 23, 1899. "' Charity Hospital Reports, New Orleans, 1906, 1907. "^ Thayer and Hewetson, The Malarial Fevers of Baltimore, Baltimore, 1895. ■'■'" Kendall, Jour. Am. Med. Assn., xlvi, 1270. ''■" Gray and Low, Brit. Med. Jour., Jan. 25, 1902. *" Gorgas, Ann. Rept. Dept. Sanitat., Isthmian Canal Commis., 1907-08 "^ Koch, Deutsch. med. Wchnschr., Feb. 2, 1899. "« Koch, Ibid., Sept. r4, 1899. "^ Cardamatis and Diamessis, Grece M^d., Nov. 1-15, 1906. ^^15 TSbUow, Malaria, i, 75. ^■" Atti della Soc. per gli Studi della malaria, Rome, 1901-08. 448 Wright, The Malarial Fevers of British Malaya, London, 1902. ^'^ Craig, Jour. Trop. Med., June 15, 1904. «" Hope, Ibid. 451 Williamson, Brit. Med. Jour., Sept. 14, 1901. "^ Koch, Deutsch. med. Wchnschr., Apr. 26, 1900. ■"' Chamberlain, Jour. Am. Med. Assn., xlvi, 304. ■•^^ Buchanan, Mai. Fever and Mai. 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"' Moffat, Brit. Med. Jour., May 4, 1907. "• Crespin, Precis du Paludisme, Paris, 1905. "' Hitte, These de Montpelier, 1902. "* Holt, Diseases of Infancy and Childhood, New York, 1908. ^'^ Economous, Bull, de la Soc. d'Obstet., x, 70, 1907. "^ Bel, Jour. Am. Med. Assn., U, 1993. *" Jeffries, Med. Rec, New York, Ivii, 654. "* Daniels, Brit. Med. Jour., Jan. 26, 1901. "^ Thompson Yates Laboratory Reports, v, i. ^^° Galli-VaUerio et De Jongh, Manuel pour la Lutte, etc., Paris, 1906. ^^' Banks, Philippine Jour. Sc, Dec, 1907. 482 Austin, Practitioner, London, Mar., 1901. ^'^ Smith and KUbourne, Texas or Southern Cattle Fever, Washington, 1893. ■**' Giles, The Gnats or Mosquitoes, London, 1902. *** Pressat, Le Paludisme et les Moustiques, Paris, 1905. «" Eysell, Arch. f. Sch. u. Trop. Hyg., xi, 6. ^*' Woldert, Jour. Am. Med. Assn., 1, 1249. 488 Mitchel, Mosquito Life, New York, 1907. *8' Stephens, Ann. Trop. Med. and Parasit., i, Apr., 1914. *™ Rowley-Lawson, Jour. Exper. Med., xix. No. 6, 1914. ■"' Craig, Estivo-autumnal Malaria, New York, 1901. ^'2 Ewing, Jour. Exper. Med., Mar. 25, 1901. *^' Mannaberg, Die Malaria Parasiten, Vienna, 1893. ^^* Schaudinn, Arb. a. d. k. Gsndtsamte, 19, 2. «5 Maurer, Centralbl. f. Bakteriol., Nov. 5, 1902. ^^^ Bluml and Metz, Arch. f. Sch. u. Trop. Hyg., xii, 249. ^" Craig, Internal. Clin., 17th ser., iii. ^'8 Ford, Jour. Am. Med. Assn., xlviii, 133. ^'' Rosenau et al, Exp. Stud, in Yellow Fever and Malaria, Wash., 1905. ^°° Brown, Jour. Exper. Med., xv.. No. 6, 1912. *"i Ewing, Am. Jour. Med. Sc, Oct., 1901. '"2 Craig and Nichols, Studies of Syphilis, Wash., 1913. '"' Boehm, Malaria, vol. i, p. 191. ™* Thayer, Am. Jour. Med. Sc, Nov., Dec, 189S. '"^ Anders, Jour. Am. Med. Assn., June 15, 1895. ^"^ Atkinson, Am. Jour. Med. Sc, July, 1894. 607 Wurtz and Thiroux, Diag. et Sem. des Malad. Trop., Paris, 1905. ™' Cohen, Am. Jour. Med. Sc, cxxxvi, 344. *"' Rist and Boudet, Pres. Med., Dec. 4, 1907. "° Berl. klin. Wchnschr., Aug. 24, 1885. KEFERENCES 539 "1 Goth, Zeitschr. f. Geb. U. Gynak., vii, i, 1881. SI- Bonfils, Paludisme et Puerperalite, Paris, 1885. 613 Williams, A Text-book of Obstetrics, New York, 1903. s'* Winfield, New York Med. Jour., Aug. 2, 1902. ^'■' Anders, Pliila. Hosp. Repts., iv, 1895. ''* Loeffler, Deutsch. med. Wchnschr., 1901, No. 42. s^'' Henson, Malaria, St. Louis, 1913. s'^ Fornario, Deutsch. med. Wchnschr., Jan. 22, 1903. • *!' McElroy, Memphis Med. Month., Nov., 1902. s-° Atti della Soc. per gli Studi deUa Malaria, Rome, 1902. s^' Plehn, Weiteres iiber Malaria, etc., Jena, 1901. S22 Delaney, Brit. Med. Jour., Mar. 28, 1903. s-^ Cardamatis, Bull. Soc. Med. de Gand., Feb., 1901. '''* Ross, Lancet, London, Nov. 17, igo6. ^-'' Ross, Ibid., Sept. 28, 1907. 526 Med. and Surg. History of the War of the Rebellion, iii, Med. Vol. s" Hagen, Arch. f. Sch. u. Trop. Hyg., iv, iii. s^' Jour. Trop. Med., vol. xi. '" Haw, Jour. Trop. Med., Oct. 16, 1899. ^^Laveran, Bull. Acad. Med., Ixix, 32. s'l Erni, Arch. f. Sch. u. Trop. Hyg., June, 1899. s'2 Annual Reports, U. S. P. H. and M. H. S., 1905-07. ^'^ Medizinal Berichte iiber die Deutsch. Schutzgeb 1903-06. ^'^ Wood, Practical Medicine, Phila., 1847. 5^5 Atti della Soc. per gli Studi deUa Malaria, Rome, 1901. "* Ibid., 1904. 5" Cardamatis, Bull. Soc. Med. Gand., Nov., 1900. "8 Billet, Rev. de Med., Dec, 1902. 52' Maurel, Maladies Paludeennes a la Guyana, Paris, 1883. 5*° Charity Hospital Reports, New Orleans, 1906-07. 5" Neer, Jour. Am. Med. Assn., 1, 1890. ''2 Atti della Soc. per gli Studi della Malaria, Rome, 1908. 5" Ibid., 1904. "' Bacelli, Gaz. degli Osp., Feb., 1890. 5*5 Guttmann and Ehrlich, Berl. klin. Wchnschr., 1891, 39. "* Carpenter, Med. Rec, New York, Ixx, 165. 5" Goldbetger, Public Health Reports, Nov. 12, i9r5. INDEX Abdominai. forms of malaria, ii6 Abortion and malaria, 131 Abscess of liver, 424, 433, 443 and malaria, 161 Acute malaria, 97 Age and amebic dysentery, 402 and blackwater fever, 230 and hookworm disease, 452 and malaria, 36, 137 and pellagra, 291 Algid malaria, 116, 165 Altitude and amebic dysentery, 401 and blackwater fever, 233 and malaria, 28 and pellagra, 288 Ameba in pellagra, 308, 312 Amebic dysentery, clinical history, 419 diagnosis, 427 etiology, 401 geographic distribution, 398 history, 395 pathology, 413 prognosis, 434 prophylaxis, 436 treatment, 438 Anaphylaxis and blackwater fever, 245 Anemia in malaria, 85 Ankylostomiasis. See Hookworm Disease. Anopheles crucians, 61 maculipennis, 60 mosqiiitoes, 50 Ardent fever, 115 Ascaris lumbricoides, 514 Autoserotherapy in pellagra, 392 Bacteria in pellagra, 303 Balantidium coli, 523 Banti's disease and malaria, 164 Bass' method in hookworm disease, 475 Beta-naphthol, 492 Bilious pernicious malaria, 118 Biology oi malaria parasites, 66 Blackwater fever, a disease sui generis, 243 and malaria, 235 clinical history, 250 ■ diagnosis, 262 etiology, 229 geographic distribution, 226 history, 219 pathology, 247 prognosis, 265 prophylaxis, 270 treatment, 272 Blood in amebic dysentery, 422 in blackwater fever, 256 in hookworm disease, 468 in malaria, 106, 125, 142, 157 in pellagra, 349 Bone-marrow in malaria, 93, 96 Bowels in amebic dysentery, 423 in malaria, 92, 96, 109, 125 in pellagra, 372 Brain in amebic dysentery, 418 in blackwater fever, 249 in malaria, 93 Breeding places of mosquitoes, 50 Cachexia in pellagra, 349 malarial, 126 treatment of malarial, 211 Cancer and malaria, 137 Carriers in hookworm disease, 472 in malaria, 189 Cause of death in blackwater fever, 58 Cerebellum and malaria, 1 14 Cerebrospinal malaria, 112 Change of residence and blackwater fever, 233 and malaria, 39 Children and malaria, 137 542 Choleraic pernicious malaria, 117 Chronic malaria, 119 treatment, 211 Circulatory system and malaria, 123 Civil condition and pellagra, 292 Civilization and malaria, 40 Climate and hookworm disease, 451 Clinical history of amebic dysentery, 419 of black water fever, 250 of hookworm disease, 462 of malaria, 97 of pellagra, 324 Comatose malaria, 112, 164 Complications of amebic dysentery, 424 of black water tever, 259 of hookworm disease, 472 of malaria, 123 of pellagra, 362 Congenital malaria, 42 Contagion of pellagra, 302 Convulsions and malaria, 115 Corn in pellagra, 295 Cultivation of amebae, 408 of malaria parasites, 80 Diabetes and malaria, 136 Diagnosis of amebic dysentery, 427 of blackwater fever, 262 of hookworm disease, 473 of malaria, 140 of pellagra, 369 of pernicious malaria, 164 Diaphoretic pernicious malaria, 117 Diarrhea in pellagra, 341 Diet in pellagra, 295, 386 Differential diagnosis of 'malaria, 161 Digestive system in hookworm dis- ease, 466 Dirt eating in hookworm disease, 466 Duration of hookworm disease, 465 of pellagra, 361 Dwarf tapeworm, 503 Dysenteric malaria, 118 Dysentery and malaria, 125 Ear in malaria, 134 Emetine in dysentery, 441 Endamceba coli, 406, 431 hystolytica, 403, 427, 431 Endemic index and malaria, 37 Endocarditis and malaria, 162 Epidemics of amebic dysentery, 403 of malaria, 41 Estivo-autumnal fever, 102 parasites, 72 Etiology of amebic dysentery, 401 of blackwater fever, 229 of hookworm disease, 451 of malaria, 25 of pellagra, 287, 295 of pernicious malaria, 85 Experimental blackwater fever, 241 Exposure and malaria, 40 Eye in hookworm disease, 471 in malaria, 133 in pellagra, 348 Family predisposition to blackwater fever, 231 tendency to pellagra, 302 Feces in amebic dysentery, 423 in hookworm disease, 467, 473 in pellagra, 358 Flagella of malaria parasites, 70 Gametes, 70, 73 Gangrene and malaria, 135 Gastro-intestinal tract, 313 Generative system in hookworm dis- ease, 470 Genito-urinary organs and malaria, 130 Geographic distribution of amebic dysentery, 398 of blackwater fever, 226 of hookworm disease, 448, 466 of malaria, 21 of pellagra, 285 Goldberger's theory, 299 Ground itch in hookworm disease, 465 Heart in blackwater fever, 249 in hookworm disease, 467 in malaria, 93, 96, 123 in pellagra, 323 543 Hemoglobinuria, 253 Hepatic abscess in amebic dysentery, 424 Heredity and pellagra, 292 Hibernation of mosquitoes, 64 History of amebic dysentery, 395 of blackwater fever, 219 of hookworm disease, 445 of malaria, 17 of pellagra, 281 Hookworm disease, clinical history, 462 diagnosis, 473 etiology, 451 geographic distribution, 448 history, 445 pathology, 460 prognosis, 478 prophylaxis, 480 treatment, 487 Hymenolepis diminuta, 509 nana, 503 Hygiene and pellagra, 293 Hygienic treatment of malaria, 210 Idiosyncrasy and blackwater fever, 231 Immunity and amebic dysentery, 402 and malaria, 32 and pellagra, 303 Incubation in malaria, 97 in pellagra, 326 Individual predisposition in malaria, 88 Infectivity in pellagra, 301 Influenza and malaria, 136, 163 Inoculation experiments in amebic dysentery, 408 of malaria, 45 of pellagra, 308 Insanity in pellagra, 343 Intermediate host in pellagra, 305 Intestinal parasites, 495 and malaria, 125 and pellagra, 362 Intestine in amebic dysentery, 413 in blackwater fever, 249 in hookworm disease, 460 Intestine in pellagra, 315 Inundations and amebic dysentery, 401 and malaria, 30 Ipecac in dysentery, 440 Jaundice in blackwater fever, 254 Kidneys in blackwater fever, 248, 259 in malaria, 92, 95, 130 in pellagra, 323 Larva, anopheles, 54 Latent malaria, 84, 119 Length of residence and blackwater fever, 232 and malaria, 39 Leucocytes in malaria, 108 Leukemia and malaria, 164 Liver abscess in amebic dysentery, 424 in blackwater fever, 248 in malaria, 91, 94 in pellagra, 323 Lumbricoid worm, 514 Lungs in blackwater fever, 249 in malaria, 92, 96 in pellagra, 322 Localizations of parasites in malaria, 87 Macrogametes, 71, 75 Maggots, 525 Malaria, cachexia in, 126 clinical history, 97 chronic, 119 diagnosis, 140 etiology, 25 geographic distribution, 21 history, 17 pathologic anatomy, 90 pernicious, 1 11 prognosis, 166 prophylaxis, 172 treatment, 197 Malarial mosquitoes, 46, 50, 59 paroxysms, 97 Malignant tertian fever, 103 544 Masked malaria, 123 Mental symptoms in pellagra, 343, 373 Methylene blue in malaria, 214 Microgametocytes, 71, 75 Mode of infection in amebic dysen- tery, 410 in hookworm disease, 453 in malaria, 42 Moisture and hookworm disease, 451 Mortality of amebic dysentery, 434 of blackwater fever, 266 of hookworm disease, 474 of malaria, 168 of pellagra, 378 Mosquitoes and malaria, 46 destruction of, 177 Muscular system in hookworm dis- ease, 470 Myiasis intestinalis, 525 Negator americanus, 454 Negro and malaria, 138 Nephritis in blackwater fever, 259 in malaria, 130 Nervous system in hookworm dis- ease, 470 in malaria, iii, 112, 132 in pellagra, 342, 373 Number of parasites in malaria, 86 Occupation and amebic dysentery, 402 and blackwater fever, 334 and hookworm disease, 452 and malaria, 39, 375 and pellagra, 292 Ova of hookworm, 457 of mosquitoes, 51 Oxyuris vermicularis, 518 Parasites, frequency, in malaria, 151 of amebic dysentery, 403 of blackwater fever, 236 of hookworm disease, 450 of malaria, 64, 74 of pellagra, 298, 303 Paralysis in malaria, 114, 132 Paroxysms in malaria, 97 Parthenogenesis, 77 Pathogenesis of amebic dysentery, 411 of blackwater fever, 235 of hookworm disease, 458 of malaria, 82 of pellagra, 311 Pathology of amebic dysentery, 413 of blackwater fever, 247 of hookworm disease, 460 of malaria, 90 of pellagra, 313 Pellagra, clinical history, 324 diagnosis, 369 etiology, 287 geographic distribution, 285 history, 281 pathology, 313 prognosis, 374 prophylaxis, 380 sine pellagra, 361 treatment, 385 Periodicity in malaria, 140 Pernicious malaria, xi i diagnosis, 164 ■ etiology, 85 prognosis, 169 treatment, 216 Pin worm, 518 Plasmodium tenue, 65 Pneumonia and malaria, 116, 125 Pork tapeworm, 501 Prevention of blackwater fever, 270 of hookworm disease, 480 of malaria, 172 Pregnancy and pellagra, 364 Previous attacks of blackwater fever, 231 malaria and blackwater fever, 235 Prognosis of amebic dysentery, 434 of blackwater fever, 265 of hookworm disease, 478 of malaria, 166 of pellagra, 374 Prophylaxis of amebic dysentery, 436 of blackwater fever, 270 of hookworm disease, 480 545 Prophylaxis of malaria, 172 of pellagra, 380 Pseudopellagra, 364 Puerperal septicemia and malaria, 162 Pupa of anopheles, 58 Quartan fever, loi parasites, 71 Quinine, absorption and elimination, 197 action on parasites, 200 and blackwater fever, 224, 239 choice of preparation, 202 contra-indications, 201 dose, 208 in blackwater fever, 272 in malaria, 197 methods of administration, 203 prevention of malaria, 190 substitutes, 214 Quotidian estivo-autumnal, 105 Race and amebic dysentery, 401 and blackwater fever, 229 and hookworm disease, 452 and malaria, 32, 138 and pellagra, 289 Rainfall and malaria, 26 and pellagra, 288 Recurrences in pellagra, 364 Relapse in malaria, 84, 1 19 Relative frequency of malaria, 24 Respiratory organs in hookworm disease, 469 in malaria, 109, 124 Round worms, 514 Salvaesan in malaria, 216 Schizogonic cycle, 67 Season and amebic dysentery, 401 and blackwater fever, 231 and hookworm disease, 451 and malaria, 26 and pellagra, 287 Sepsis and malaria, 162 Sequels of blackwater fever, 259 of hookworm disease, 472 of malaria, 123 Sex and amebic dysentery, 402 and blackwater fever, 230 and hookworm disease, 452 and malaria, 36 and pellagra, 290 Skin and malaria, in, 134 and pellagra, 313, 327, 369 Smallpox and malaria, 137 Social condition and hookworm dis- ease, 453 and malaria, 40 and pellagra, 293 Soil and hookworm disease, 451 and malaria, 27 Sources of error in malaria, 149 Spinal fluid in pellagra, 359 Spleen in blackwater fever, 247 in malaria, 91, 94, 125 in pellagra, 323 rupture, 129 Spontaneous recovery in malaria, 166 in pellagra, 374 Sporogonic cycle, 76 Staining ameba, 428 Stains for malaria, 147 Stomach in blackwater fever, 249 in malaria, 92, 96, 109, 125 in pellagra, 315, 340, 356, 371 Stomatitis in pellagra, 339 Strongyloides intestinalis, 511 Surgery and blackwater fever, 278 and malaria, 139 Symptomatic t'eatment of malaria, 210 Symptoms of amebic dysentery, 419 of blackwater fever, 250 of hookworm disease, 462 of malaria, 97, 105 of pellagra, 324 Syphilis and malaria, 137, 163 T/Enia saginata, 497 solium, 501 Tapeworm, 497, 501, 503, 509 Technic of blood examinations, 142 Temperature in amebic dysentery, 421 in malaria, 105 546 Tertian fever, 99 parasites, 69 Therapeutic test in hookworm dis- ease, 476 in malaria, 159 Thoracic forms of malaria, 116 Thymol, 487 Topography and malaria, 28 and pellagra, 288 Toxin in malaria, 82 Transfusion and pellagra, 391 Trauma and malaria, 139 Treatment of amebic dysentery, 438 of blackwater fever, 272 of hookworm disease, 487 of malaria, 197 of pellagra, 385 Trees and malaria, 30 Trichocephalus dispar, 521 Trichuris trichura, 521 Typhoid fever and malaria, 135, 163 Typhoid pellagra, 360 pernicious malaria, 115 Typhomalarial fever, 135 Tuberculosis and malaria, 136, 163 Uncinaria americana, 454 Uncinariasis. See Hookworm dis- ease. Urine in blackwater fever, 252 in hookworm disease, 470 in malaria, 109 in pellagra, 355 Vegetation and malaria, 30 Wassermann reaction in malariai 108 in pellagra, 354 Whipworm, 521 Wind and malaria, 31 , Yellow fever and blackwater fever, 262 and malaria, 163 SAUNDERS' BOOKS Pathology, Physiology Histology, Embryology Bacteriology, Biology W. B, SAUNDERS COMPANY WEST WASHINGTON SQUARE PHILADELPHIA 91. HENRIETTA STREET COVENT GARDEN. LONDON Prentiss' Embryology Laboratory Manual and Text=Book of Embryology. By Charles W. Prentiss, Ph. D., Professor of Microscopic Anatomy, Northwestern University Medical School, Chicago. Large octavo of 400 pages, with 368 illustrations, 50 in colors. Cloth, $2,-7$ "^t. JUST ISSUED Prof. Prentiss' new work has many features that make it extremely valuable to students and teachers of vertebrate or human embryology. 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Pennsylvania Medical Journal " It is arranged in such a manner as to be easy of access and comprehension. To anj contemplating the study of histology and organography we would commend this work." SAUNDERS' BOOKS ON GET ifc • THE NEW THE BEST /\ 111 C r 1 C 8i II STANDARD Illustrated Dictionary Just Out— New (8th) Edition— 150O New Terms The American Illustrated Medical Dictionary. A new and com- plete dictionary of the terms used in Medicine, Surgery, Dentistry, Pharmacy, Chemistry, Veterinary Science, Nursing, and kindred branches ; with over 100 new and elaborate tables and many handsome illustrations. By W. A. Newman Borland, M.D., Editor of "The American Pocket Medical Dictionary." Large octavo, 1 137 pages, bound in full flexible leather. Price, ^4.50 net; with thumb index, $5.00 net. IT DEFINES ALL THE NEW WORDS— IT IS UP TO DATE The American Illustrated Medical Dictionary defines hundreds of the newest terms not defined in any other dictionary — bar none. These new terms are live, active words, taken right from modern medical literature. It gives the capitalization and pronunciation of all words. It makes a feature of the derivation or etymology of the words. In some dictionaries the etymology occupies only a secondary place, in many cases no derivation being given at all. In the American Illustrated practically every word is given its derivation. Every word has a separate paragraph, thus making it easy to find a word quickly. The tables of arteries, muscles, nerves, veins, etc., are of the greatest help in assembling anatomic facts. In them are classified for quick study all the neces- sary information about the various structures. Every word is given its definition — a definition that defines in the fewest pos- sible words. In some dictionaries hundreds of words are not defined at all, referring the reader to some other source for the information he wants at once. Howard A, Kelly, M. Yi,, Johns Hopkins University, Baltimore. ■■ The American Illustrated Dictionary is admirable. It is so well gotten up and of such convenient size. No errors have been found in my use of it." J. Collins Warren, M. D., LL.D., F.R.C.S. (Hon.), Harvard Medical School " I regard it as a valuable aid to my medical literary work. It is very complete and of convenient size to handle comfortably. I use it in preference to any other." PATHOLOGY Stengel O Fox's Pathology Pathology. By Alfred Stengel, M. D., Sc. D., Professor of Medi- cine, University of Pennsylvania; and Herbert Fox, M. D., Director of the Pepper Laboratories of Clinical Medicine, University of Pennsyl- vania. Octavo of 1045 pages, with 468 text-illustrations, many in colors, and 1 5 colored plates. Cloth, g6.oo net ; Half Morocco, $7.50 net. JUST READY— NEW (6th) EDITION, REWRITTEN This new (6th) edition is virtually a new work. It has been rewritten through- out, reset in new type, and a larger type page used. New matter equivalent to 175 pages has been added and some 75 new ilhistrations, many of them in colors. The work is a handsome volume of over 1000 pages. In the first portions, de- voted to general pathology, the sections on inflammation, retrogressive processes, disorders of nutrition and metabolism, general etiology, and diseases due to bac- teria were wholly rewritten or very largely recast. A new section on transmissible diseases was added ; the terata were included, with a synoptical chapter on terat- ology. The glands of internal secretion were given a separate chapter, and new chapters on the pathology of eye, ear, and skin ^txe, added. Stiles on the Nervous System The Nervous System and its Conservation. By Percy G. Stiles, Instructor in Physiology at Harvard University. i2mo of 230 pages, illustrated. Cloth, ^1.25 net. ILLUSTRATED You get chapters on the minute structure, elements of nerve physiology, re- flexes, anatomy, afferent nervous system, neuromuscular system and fatigue, autonomic system, the cerebrum and human development, emotion, sleep, dreams, causes of nervous impairment, neurasthenia, hygiene. Stiles' Nutritional Physiology Nutritional Physiology. By Percy Goldthwait Stiles, In- structor in Physiology at Harvard University. i2mo of 295 pages, illustrated. Cloth, ^1.25 net. ILLUSTRATED This new work expresses the most advanced views on this important subject. It discusses in a concise way the processes of digestion and metabolism. The key-word of the book throughout is " energy " — its source and_its conservation. " It is remarkable for the fineness of its diction and for its clear presentation of the sub- ject, relieved here and there by a quaintly humorous turn of phrase that is altogether delight- ful." — Colin C. Stewart, Ph. £>., Dartmouth College, SAUNDERS' BOOKS ON Jordan's General Bacteriology A Text=Book of General Bacteriology. By Edwin O. Jordan, Ph.D., Professor of Bacteriology in the University of Chicago and in Rush Medical College. Octavo of 650 pages, illustrated. Cloth, ^3.00 net. NEW (4th) EDITION Professor Jordan's work embraces the entire field of bacteriology, the non- pathogenic as well as the pathogenic bacteria being considered, giving greater emphasis, of course, to the latter. There are extensive chapters on methods of studying bacteria, including staining, biochemical tests, cultures, etc. ; on the development and composition of bacteria ; on enzymes and fermentation-products; on the bacterial production of pigment, acid and alkali ; and on ptomains and toxins. Especially complete is the presentation of the serum treatment of gonor- rhea, diphtheria, dysentery, and tetanus. The relation of bovine to human tuberculosis and the ocular tuberculin reaction receive extensive consideration. This work will also appeal to academic and scientific students. It contains chapters on the bacteriology of plants, milk and milk-products, air, agriculture, water, food preservatives, the processes of leather tanning, tobacco curing, and vinegar making ; the relation of bacteriology to household administration and to sanitary engineering, etc. Prof. Severance Burra^e, Associate Professor 0/ Sanitary Science, Purdue University. " I am much impressed with the completeness and accuracy of the book. It certainly covers the ground more completely than any other American book that I have seen." Buchanan's Veterinary Bacteriology Veterinary Bacteriology. By Robert E. Buchanan, Ph.D., Pro- fessor of Bacteriology in the Iowa State College of Agriculture and Mechanic Arts. Octavo, 5 16 pages, 2 14 illustrations. Cloth, ^3.00 net. THE BEST PUBLISHED Professor Buchanan discusses thoroughly all bacteria causing diseases of the domestic animals. He goes minutely into the consideration of immunity, opsonic index, reproduction, sterilization, antiseptics, biochemic tests, culture-media, isolation of cultures, the manufacture of the various toxins, antitoxins, tuberculins, and vaccines that have proved of diagnostic or therapeutic value. Then, in addi- tion to bacteria and protozoa proper, he considers molds, mildews, smuts, rusts, toadstools, puff"-balls, and the other fungi pathogenic for animals. B. F. Kaupp, D. V. S.» State AgricicUural College, Fort Collins. " It is the best in print on the subject. What pleases me most is that it contains all the late results of research. It fills a long felt want," EMBRYOLOGY. Heisler's Embryology A Text=Book of Embryology. By John C. Heisler, M. D., Pro- fessor of Anatomy in the Medico-Chirurgical College, Philadelphia. Octavo volume of 435 pages, with 212 illustrations, 32 of them in colors. Cloth, ^3.00 net. THIRD EDITION— WITH 212 ILLUSTRATIONS, 32 IN COLORS This edition represents all the advances recently made in the science of em- bryology. Many portions have been entirely rewritten, and a great deal of new and important matter added. A number 01 new illustrations have also been intro- duced and these will prove very valuable. Heisler' s Embryology has become a standard work. G. Carl Huber. M. D.. Professor of Embryology at the Wistar Institute, University of Pennsytania. " I find this edition of 'A Text-Book of Embryology,' by Dr. Heisler, an improvement on the former one. The figures added increase greatly the value of the work. I am again recommending it to our students." Bohm, Davidoff, and Huberts Histology A Text=Book of Human Histology. Including Microscopic Tech- nic. By Dr. A. A. Bohm and Dr. M. Vox Davidoff, of Munich, and G. Carl Huber, M. D., Professor of Embryology at the Wistar Insti- tute, University of Pennsylvania. Handsome octavo of 528 pages, with 361 beautiful original illustrations. Flexible cloth, $^.$0 net. SECOND EDITION, ENLARGED The work of Drs. Bohm and Davidoff is well known in the German edition, and has been considered one of the most practically useful books on the subject of Human Histology. This second edition has been in great part rewritten and very much enlarged by Dr. Huber, who has also added over one hundred original illustrations. Dr. Huber' s extensive additions have rendered the work the most complete students' text-book on Histology in existence. Boston Medical and Surgical Journal " Is unquestionably a lext-book of the first rank, having been carefully written by thorough masters of the subject, and in certain directions it is much superior to any other histological manual." SAUNDERS' BOOKS ON Wells' Chemical Pathology Chemical Pathology. — Being a Discussion of General Pathology from the Standpoint of the Chemical Processes Involved. By H. Gideon Wells, Ph. D., M. D., Assistant Professor of Pathology in the University of Chicago. Octavo of 6i6 pages. Cloth, ^3. 25 net. NEW (2d) EDITION Dr. Wells' work is written for the physician, for those engaged in research in pathology and physiologic chemistry, and for the medical student. In the intro- ductory chapter are discussed the chemistry and physics of the animal cell, giving the essential facts of ionization, diffusion, osmotic pressure, etc., and the relation of these facts to cellular activities. Special chapters are devoted to Diabetes and to Uric-acid Metabolism and Gout. Wm. H. Welch. M. D. Professor of Pathology , Johns Hopkins University. " The work fills a real need in the English hterature of a very important subject, and I shall be glad to recommend it to my students." Lusk's Clements of Nutrition Elements of the Science of Nutrition. By Graham Lusk, Ph. D., Professor of Physiology at Cornell Medical School. Octavo volume of 302 pages. Cloth, ^3.00 net. THE NEW (2d) EDITION— TRANSLATED INTO GERMAN Prof. Lusk presents the scientific foundations upon which rests our knowledge of nutrition and metabolism, both in health and in disease. There are special chapters on the metabolism of diabetes and fever, and on purin metabolism. The work will also prove valuable to students of animal dietetics at agricultural stations. Lewellys F. Barker, M. D. Professor of the Principles and Practice of Medicine, Johns Hopkins University. " I shall recommend it highly to my students. It is a comfort to have such a discussion of the subject in English." HISTOLOGY. Daugherty's Economic Zoology Economic Zoology. By L. S. Daugherty, M. S., Ph. D., Professor of Zoology, State Normal School, Kirksville, Mo., and M. C. Daugh- erty, author with Jackson of " Agriculture Through the Laboratory and School Garden." Part I: Field atid Laboratory Gtiide. i2mo of 237 pages, interleaved. Cloth, ^1.25 net. Part II: Principles. l2mo of 406 pages, illustrated. Cloth, $2.00 net. ILLUSTRATED There is no other book just like this. Not only does it give the salient facts of structural zoology and the development of the various branches of animals, but also the natural history — the life and habits — thus showing the interrelations of structure, habit, and environment. In a word, it gives the principles of zoology and their actual application. The economic phase is emphasized. Part I — the Field and Laboratory Guide — is designed for practical instruction in the field and laboratory. To enhance its value for this purpose blank pages arc inserted for notes. DrewV Invertebrate Zoology A Laboratory Manual of Invertebrate Zoology. By Oilman A. Drew, Ph.D., Assistant Director at Marine Biological Laboratory, Woods Hole, Mass. With the aid of Former and Present Members of the Zoological Staff of Instructors. i2mo of 213 pages. Cloth, gi.25 net. NEW (2d) EDITION The subject is presented in a logical way, and the type method of study has been followed, as this method has been the prevailing one for many years. Prof. Allison A. Smyth, Jr., N^rginia Polytechnic Institute " I think it is the best laboratory manual of zoology I have yet seen. The large number of forms dealt with makes the work applicable to almost any locality." SAUNDERS BOOKS ON Norris* Cardiac Pathology Studies in Cardiac Pathology. By George W. Norris, M.D., Associate in Medicine at the University of Pennsylvania. Large octavo of 235 pages, with 85 superb illustrations. Cloth, ^5.00 net. SUPERB ILLUSTRATIONS The illustrations are superb. Each illustration is accompanied by a detailed description; besides, there is ample letter press supplementing the pictures. Boston Medical and Surgical Journal " The illustrations are arranged in such a way as to illustrate all the common and many of the rare cardiac lesions, and the accompanying descriptive text constitutes a fairly continuous didactic treatise." McConneirs Pathology A Manual of Pathology. By Guthrie McConnell, M. D., As- sistant Surgeon, Medical Reserve Corps, U. S. Navy. i2mo of 523 pages, with 170 illustrations. Flexible leather, $2.50 net. NEW (2d) EDITION Dr. McConnell has discussed his subject with a clearness and precision of style that make the work of great assistance to both student and practitioner. The illustrations have been introduced for their practical value. New York State Journal of Medicine " The book treats the subject of pathology with a thoroughness lacking in many works of greater pretension. The illustrations — many of them original — are profuse and of exceptional excellence." McConnell's Pathology and Bacteriology ''°s.uda"n?] Pathology and Bacteriology for Dental Students. By Guthrie McConnell, M. D., Assistant Surgeon, Medical Reserve Corps, U. S. N. i2mo of 309 pages, illustrated. Cloth, ^2.25 net. ILLUSTRATED This work is written expressly for dentists and dental students, emphasizing throughout the application of pathology and bacteriology in dental study and prac- tice. There are chapters on disorders of metabolism and circulation; retro- gressive processes, cell division inflammation and regeneration, granulomas, pro- gressive processes, tumors, special mouth pathology, sterilization and disinfection, bacteriologic methods, specific micro-organisms, infection and immunity, and laboratory technic. HISTOLOGY. Dtirck and Hektoen's Special Pathologic Histology Atlas and Epitome of Special Pathologic Histology. By Dr. H. DURCK, of Munich. Edited, with additions, by Ludvig Hektoen, M. D., Professor of Pathology, Rush Medical College, Chicago. In two parts. Part I. — Circulatory, Respiratoiy, and Gastro-intestinal Tracts. 120 colored figures on 62 plates, and 158 pages of text. Part II. — Liver, Urinary and Sexual Organs, Nervous System, Skin, Muscles, and Bones. 123 colored figures on 60 plates, and 192 pages of text. Per part : Cloth, ^^3.00 net. In Saimders' Hand-Atlas Series. The great value of these plates is that they represent in the exact colors the effect of the stains, which is of such great importance for the differentiation of tissue. The text portion of the book is admirable, and, while brief it is entirely satisfac- tory in that the leading facts are stated, and so stated that the reader feels he has grasped the subject e.xtensively. William H. Welch, M. D., Proft'ssor of Pathology, Joktis Hopkins University, Baltimore. " I consider Diirck's ' Atlas of Special Pathologic Histology,' edited by Hektoen. a very useful book for students and others. The plates are admirable." Sobotta and Huber's Human Histology Atlas and Epitome of Human Histology. By Privatdocent Dr. J. Sobotta, of Wijrzburg. Edited, with additions, by G. Carl Huber, M. D., Professor of Histology and Embryology in the University of Michigan, Ann Arbor. With 214 colored figures on ?,o plates, 68 text-illustrations, and 248 pages of text. Cloth, ^4.50 net. In Saunders' Hand-Atlas Series. INCLUDING MICROSCOPIC ANATOMY The work combines an abundance of well-chosen and most accurate illustra- tions, with a concise te.\t, and in such a manner as to make it both atlas and text- book. The great majority of the illustrations were made from sections prepared from human tissues, and always from fresh and in every respect normal specimens. The colored lithographic plates have been produced with the aidof over thirty colors. Boston Medical and Surgical Journal "In color and proportion they are characterized by gratifying accuracy and lithographic beauty." 14 SAUNDERS BOOKS ON Bosanquet on Spirochaetes Spirochsetes : A Review of Recent Work, with Some Original Ob- servations. By W. Cecil Bosanquet, M.D., Fellow of the Royal Col- lege of Physicians, London. Octavo of 1 52 pages, illustrated. ^2.50 net. ILLUSTRATED This is a complete and authoritative monograph on the spirochsetes, giving morphology, pathogenesis, classification, staining, etc. Pseudospirocheetes are also considered, and the entire text well illustrated. The high standing of Dr. Bosanquet in this field of study makes this new work particularly valuable. Levy and Klemperer's Clinical Bacteriology The Elements of Clinical Bacteriology. By Drs. Ernst Levy and Felix Klemperee, of the University of Strasburg. Translated and edited by Augustus A. Eshner, M. D., Professor of Clinical Medicine, Philadelphia Polyclinic. Octavo volume of 440 pages, fully illustrated. Cloth, ^2.50 net. S. Solis-Cohen, M. D., Professor of .Clinical Medicine, Jefferson Medical College, Philadelphia. " I consider it an excellent book. I have recommended it in speaking to my students." Lehmann, Neumann, and Weaver's Bacteriology Atlas and Epitome of Bacteriology : including a Text-Book of Special Bacteriologic Diagnosis. By Prof. Dr. K. B. Lehmann and Dr. R. O. Neumann, of Wiirzburg. From the Second Revised and Enlarged German Edition. Edited, with additions, by G. H. Weaver, M. D., Assistant Professor of Pathology and Bacteriology, Rush Medical College, Chicago. In two parts. Part I. — 632 colored figures on 69 lithographic plates. Part II. — 511 pages of text, illustrated. Per part: Cloth, ^2.50 net. In Saunders' Hand-Atlas Series. PATHOLOGY, BACTERIOLOGY, AND PATHOLOGY 15 Durck and Hektoen's General Pathologic Histology Atlas and Epitome of General Pathologic Histology. By Pr. Dr. H. Durck, of Munich. Edited, with additions, by Ludvig Hek- toen, M. D., Professor of Pathology in Rush Medical College, Chicago. 172 colored figures on 77 lithographic plates, 36 text-cuts, many in colors, and 353 pages. Cloth, 55.00 net. Lt Saunders'' Hand- Atlas Series. American Text-Book of Physiology second Edition American Text-Book of Physiology. In two volumes. Edited by William H. Howell, Ph. D., M.D., Professor of Physiology in the Johns Hopkins University, Baltimore, Md. Two royal octavos of about 600 pages each, illustrated. Per volume: Cloth, ^3. 00 net; Half Morocco, 114.25 net. " The work will stand as a work of reference on physiology. To him who desires to know the status of modern physiology, who expects to obtain suggestions as to further physio- logic inquiry, we know of none in English which so eminently meets such a demand." — The Medical News, Warren's Pathology and Therapeutics second Edition Surgical Pathology and Therapeutics. By John Collins Warren, M. D., LL.D., F. R. C. S. (Hon.), Professor of Surgery, Harvard Med- ical School. Octavo, 873 pages, 136 relief and lithographic illustrations, 33 in colors. With an Appendix on Scientific Aids to Surgical Diagnosis and a series of articles on Regional Bacteriology. Cloth, 55.00 net; Half Morocco, 56-5° net. Raymond's Physiology New (3d) Edition Human Physiology. By Joseph H. Raymond, A. M., M. D., Pro- fessor of Physiology and Hygiene, Long Island College Hospital, New York. Octavo of 685 pages, with 444 illustrations. Cloth, 53. 50 net. " The book is well gotten up and well printed, and may be regarded as a trustworthy guide for the student and a useful work of reference for the general practitioner. The illustrations are numerous and are well executed." — The Lancet, London. l6 BACTERIOLOGY, PHYSIOLOGY, AND HISTOLOGY. Ball's BaCteriolO^ seventh Edition, Revised Essentials of Bacteriology : being a concise and systematic intro- duction to tlie Study of Micro-organisms. By M. V. Ball, M. D., Late Bacteriologist to St. Agnes' Hospital, Philadelphia. i2mo of 289 pages, with 135 illustrations, some in colors. Cloth, Ji.oo net. In Saunders' Questiofi- Compend Series. " The technic with regard to media, staining, mounting, and the lil-ies, "He has an excellent conception of his subject. . . It is one of the most satisfactory books of this class" — University of Pennsylvania Medical Bulletin. Leroy's Histology New (4th) Edition Essentials of Histology. By Louis Leroy, M. D., Professor of Histology and Pathology, Vanderbilt University, Nashville, Tennessee. i2mo, 263 pages, with 92 original illustrations. Cloth, gi.oo net. In Saunders' Question- Conipe?id Series. " The work in its present form stands as a model of what a student's aid should be ; and we unhesitatingly say that the practitioner as well would find a glance through the book of lasting benefit." — T/ie Medical World, Philadelphia. Barton and Wells* Medical Thesaurus A Thesaurus of Medical Words and Phrases. By Wilfred M. Barton, M. D., Assistant Professor of Materia Medica and Therapeutics, and Walter A. Wells, M.D., Demonstrator of Laryngology, Georgetown University, AVashington, D. C. i2mo, 534 pages. Flexible leather, ^2.50 net; thumb indexed, $3.00 net. American Pocket Medical Dictionary ^^^ (p^j,) Edition American Pocket Medical Dictionary. Edited by W. A. New- man DoRLAND, M. D., Editor "American Illustrated Medical Dic- tionary." Containing the pronunciation and definition of the principal words used in medicine and kindred sciences, with 75 extensive tables. 693 pages. Flexible leather, with gold edges, ^i.oo net; with patent thumb index, ^1.25 net. "I can recommend it to our students without reserve." — J. H. HOLL.\ND, M.. D., of the Jefferson Medical College, Philadelphia.