XVII. LEPROSY
DEFINITION AND SYNONYMS
=Definition.=—Leprosy is a very chronic, almost incurable disease, with a protracted period of incubation (two to ten years), which sets in with indefinite prodromata of malaise, and irregular febrile attacks associated with sweating and somnolence. In nerve leprosy there may be vague manifestations of neuritis as prodromata. There are two well-recognized types of the disease. The type characterized by granulomatous proliferations in corium and subcutaneous tissues, as well as lymphatic glands, is known as nodular or skin leprosy. It shows spots and nodular infiltrations, chiefly about lobes of ears, alae of nose and region of eyebrows, with falling out of hairs of eyebrows and bearded region, and also involves extensor surfaces of forearms, dorsal surfaces of hands and feet. The palms of hands and soles of feet are almost never invaded. The other type is known as nerve or maculo-anaesthetic leprosy and is characterized by nerve thickenings, flat anaesthetic spots, chiefly of the covered region of the body, muscular palsies and atrophies, with trophic changes leading to contractures and mutilations. When the two types are associated we have mixed leprosy.
The disease is caused by an acid-fast bacillus, which has not surely been cultivated or inoculated into animals with pathogenic result, and which is found in extraordinary abundance in the granulomatous subepithelial tissues of nodular leprosy and in scanty numbers or not at all in the perineurium and endoneurium of the ulnar, facial or perineal nerves.
=Synonyms.=—Lepra. Elephantiasis Graecorum. Leontiasis. Satyriasis. French: La Lèpre. German: Aussatz.
HISTORY AND GEOGRAPHICAL DISTRIBUTION
=History.=—There are those who consider India as the home of leprosy, a condition corresponding to the disease having been described in the Rig Veda, of date of 1400, B. C.
Others regard Egypt as the original focus, a disease similar to leprosy having been described in the “Ebers papyrus” of date of about 1300, B. C.
Any one reading chapter xiii, Leviticus, must be convinced that the disease there described as leprosy was of a different nature. We find statements to the effect that where the hair in the spot is white and the spot deeper than the skin of the flesh that it is leprosy; again, if there be a white or red rising it is not leprosy, but if lower than the skin it is leprosy.
According to Unna the term Zaarath had a theological rather than a medical meaning. At the same time other references in the Bible would indicate that leprosy was more or less prevalent among the Jews of that period.
It is very probable that the ancients confused leprosy with many other diseases where ulceration and nodular disfigurement were conspicuous features.
From the fact that leprosy was called the Phoenecian disease it would seem that Asia was the real home of the disease.
It is well established that leprosy was introduced into Europe, from Egypt, in the first century, B. C., by the returning legions of Pompey.
As a result of the crusades, leprosy was spread widely over Europe by the crusaders, so that in the 14th century the disease was so prevalent, that it required approximately 20,000 leper asylums to care for the lepers. In France alone there were about 2000 such leprosaria.
As a result of the most drastic measures of isolation the disease began to decrease in the 14th century and had practically disappeared from Europe, as a whole, by the 15th century.
=Geographical Distribution.=—With the exception of a limited and steadily diminishing number of cases in Norway and Sweden, with an uncertain number in the Balkan region and Turkey, leprosy has almost disappeared from Europe. Parts of Brittany and Provence in France show cases and there are a considerable number in Portugal and Spain.
Africa is heavily infected with the disease, especially in Central and East Africa. In certain portions of the Cameroons (Banyang) it is so common that one in every four persons suffers from leprosy.
Asia has many important leprosy centers, there being a very great number in China and India. There are about 100,000 lepers in Japan and about 3000 in the Philippines.
In 1902 there were 278 lepers in the United States, of which number 145 were native born. In 1912 there were only 146 distributed chiefly in three centers: (1) That of the Great Lakes, there being now 13 cases in Minnesota as against 27 in 1900; (2) among the Orientals of the Pacific Coast, and (3) in the Gulf region, especially about Louisiana and Florida.
There are 696 lepers in Hawaii and 28 in Porto Rico.
In South America, the disease is found in Columbia, Venezuela and Brazil as is also true of Mexico and Central America.
In Australia the disease is found in Queensland and New South Wales.
It also prevails in New Caledonia and the islands of the Pacific.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—Leprosy is caused by an acid-fast bacillus, Bacillus leprae, which rather closely resembles the tubercle bacillus morphologically as well as tinctorially. It was first discovered by Hansen in 1871 and fully reported in 1874. Much of our knowledge of its characteristics is due to Neisser (1879).
The leprosy bacilli are found in profusion in the granulomatous tissue of the corium and subcutaneous structures of the leprous nodules, chiefly within cells called “lepra cells” and also within endothelial and connective-tissue cells as well as lying free, packed in lymphatic channels, the so-called “globi.”
The leprosy bacillus may be distinguished from the tubercle bacillus by the following points:
1. The presence ordinarily of huge numbers of bacilli often grouped in packets like a bundle of cigars tied together.
It will be remembered that it is very difficult to find even a single tubercle bacillus in a skin lesion. Leprosy bacilli form palisade groups but not chains.
2. The leprosy bacilli stain more solidly and when granules are present they are coarser and more widely separated than the fine granulations of the tubercle bacillus.
3. They do not stand decolorization quite as well as the tubercle bacillus. With 20% sulphuric acid in water they hold their color almost as well as tubercle bacilli but with 3% HCl in alcohol they decolorize in about two hours as against twelve to twenty-four hours for the tubercle bacillus.
4. Leprosy bacilli have neither been surely cultivated nor surely inoculated with pathogenic results into guinea pigs or other experimental animals and it is by the negative results upon cultivating or animal inoculation that we have our surest method of differentiation from tubercle bacilli.
Leprosy bacilli are chiefly spread through the lymphatics, but in nodular leprosy, their occurrence in the blood stream during the febrile accessions is so constant that this route may also be of importance. Next to the corium they are most abundant in the lymphatic glands. They stain readily by Gram’s method.
A great amount of work has been done within recent years in attempting to cultivate the leprosy bacillus.
In 1900 Kedrowsky culturing material from 3 cases of leprosy obtained diphtheroids from two and a streptothrix from one. A rabbit was inoculated first intracerebrally and later intraperitoneally with this nonacid-fast streptothrix and, when killed six months later, showed peritoneal nodules, from which both diphtheroids and acid-fast bacilli, but not a streptothrix, were recovered culturally. Injections of cultures of the acid-fast bacilli and diphtheroids into rabbits and mice produced nodules which when cultured showed acid-fast organisms or diphtheroids.
In 1901 he cultivated a diphtheroid from a fourth case of leprosy.
Fraser and Fletcher working with Kedrowsky’s culture produced peritoneal nodules with the killed as well as the living organism. They were able to produce the same results with B. phlei. With emulsions of leprous nodules, rich in leprosy bacilli, they could not produce similar lesions in the experimental guinea pigs.
Rost obtained a culture on a salt-free medium from which he prepared his leprolin by a process similar to that used for old tuberculin. It was claimed that leprolin had marked curative power in leprosy. Recently Williams and Rost have cultivated a streptothrix on a medium containing milk.
Clegg, by inoculating his medium with cultural amoebae, obtained growth of a diphtheroid organism, with acid-fast tendencies, from the spleen pulp of lepers.
Duval, by using media containing amino-acids, as result of tryptic digestion, brought forward two organisms, one of which was a diphtheroid and grew luxuriantly while the other showed a slow scanty growth and was acid-fast.
Bayon, by using placental media, isolated an organism rather resembling that of Kedrowsky. These organisms alone responded to immunity tests when such were made by Bayon and they alone gave rise to tissue changes resembling those of leprosy when injected into animals.
Professor Deycke obtained a streptothrix-like growth from the granulomatous tissue of excised leprous nodules. The ethereal extract from this culture gave a neutral fat which he called nastin and which is the basis of a leprosy treatment.
Quite recently and after working for eighteen months, with material from 32 nonulcerative cases of nodular leprosy, not only with media as recommended by Duval, Rost and Bayon, but with blood and serum culture media, both by aerobic and anaerobic procedures, Fraser has been unable, in a single instance, to obtain any evidence of growth from this wealth of leprosy material.
As being opposed to the possibility of culturing the human leprosy bacillus, it may be stated that most of the experiments along this line with rat leprosy, a disease occurring naturally in rats and caused by an organism almost identical, as to lesions produced, with the leprosy bacillus, have been negative. Bayon, however, states that he has cultivated the bacillus of rat leprosy.
=Epidemiology.=—There is a consensus of opinion that every case of leprosy owes its origin to contact, direct or indirect, with some other case, but evidence as to the manner in which the disease is transmitted, or even the proof of transmission, is to a great extent lacking.
Every book refers to the inoculation experiment by Arning, of a freshly excised leprous nodule sewn into a skin incision of the arm of a condemned criminal. In this case a neuritis developed shortly after the inoculation and the patient showed fully developed leprosy three years later. Unfortunately for the value of the experiment the man was a native of Hawaii and had lepers in his own family. Against this experiment are the numerous instances where physicians have inoculated themselves and others with leprous material with invariably negative results.
Danielson inoculated himself and nine others with leprous material and later Profeta repeated the same, but without success in a single instance.
As regards those living for a long time in attendance on lepers there have been a very few instances of the contraction of leprosy as in the case of Father Damien at Molokai, and two instances in Sisters of Mercy. Such cases however are most exceptional, as the hundreds of attendants on the unfortunates continue their work for years without showing any signs of leprosy.
It is stated that there has never been an instance of transmission of leprosy to any attendant at the Saint Louis Hospital, Paris.
There are two cases which show that those who live in close relation to lepers may develop the disease; in one, a leper returned to Ireland and his brother, who had never been in a leprosy country, but who had occupied the same bed with the leper and worn his clothes, developed the disease in about five years. A similar case is reported from Germany.
As showing that even with intimate contact, infection is rare, it is stated that of 225 healthy Hawaiians, living in the same houses with lepers, only 4½% contracted leprosy. Even when married to lepers only 9 out of 181 healthy people contracted leprosy from their leprous mates.
In Japan, 7% of children of lepers contract the disease, 3.8% of those married to lepers and 2.7% of people living in the same house with lepers.
Just as with tuberculosis, in which all evidence points to the predominance of infection in early life and its infrequency in adult life, so does it seem to be true of leprosy. Among 10,000 lepers in the Culion leper colony, Denny notes that 35% were brothers and sisters, 27% were cousins, 11% were children of lepers, 7% parents of lepers, and only 1% husband and wife. This would indicate that the relationships involving intimate contact in childhood are etiologically most important.
One of the strongest proofs that leprosy is at least feebly contagious is that based on the disappearance of the disease following isolation of the lepers. The best instance is that of Europe, in the thirteenth and fourteenth centuries, where, with 20,000 leper asylums for isolation, the disease disappeared by the fifteenth century. In Norway, there were 2833 cases in 1856, while in 1907, there were only 438 left.
At the end of 1913 there were only 285 cases, 181 of these being interned and 104 in their own homes. The reduction is attributed to isolation.
This might have occurred without isolation because Hansen in investigating the descendants of 160 known Norwegian lepers, who immigrated to the North-western States of America, was unable to find trace of a single leper among their descendants.
This and other facts militate against the views that leprosy may be inherited and the idea is generally held that if a child be taken away from its leprous surroundings after birth there is little or no likelihood of its developing leprosy.
Again, it is a well-recognized fact that leprosy is more than twice as common among men than among women. It is probable that the greater opportunity for contact with lepers by man is the explanation of the greater frequency.
Views as to Mode of Transmission.—It may be stated that nothing definite is known. There has been an idea that itch mites might transmit the disease but no proof has been advanced. Lebouf found leprosy bacilli in the stomachs of flies, which had been feeding on leprotic ulcerations, and did not find acid-fast rods in flies which had fed on persons with nerve leprosy or upon those not showing open lesions. He thinks that flies may deposit faeces containing bacilli about the nasal orifices or upon wounds of well persons, bringing about thereby their infection.
Skelton was unable to find evidences of leprosy bacilli in bedbugs living in the beds of lepers. Paldrock also was unable to find any evidence of leprosy bacilli in bedbugs a few hours after feeding on leprous tissue, but did find acid-fast rods in cockroaches which had fed on leprosy nodules, even fourteen days after the feeding.
A. J. Smith fed bedbugs on Duval’s organism and recovered acid-fast bacilli for considerable periods. The question arises, however, as to the significance of Duval’s bacillus for leprosy.
Acid-fast bacilli have been reported from head lice and mosquitoes, when the insects have been feeding on leprous tissue, but little or no evidence of any multiplication has been obtained.
For many years Jonathan Hutchinson insisted that leprosy was caused by the eating of imperfectly cured or decomposing fish, a view which now has no supporters.
For a time it was considered that the initial lesions of leprosy were to be found in the nasal mucosa and especially in ulcerations of the nasal septum and that it was by the atrium of the nasal mucous membrane that infection occurred.
There is no question but that the examination of the nasal mucus for leprosy bacilli is of prime importance in diagnosis and it may be that cases showing ulcerations of the septum are especially dangerous when sneezing, but very few believe that leprosy is to any extent contracted through this channel. de Azevedo examined smears from the nasal mucosa in 59 persons who were in close contact with lepers without finding acid-fast bacilli in a single instance.
With a period of incubation covering from two to ten years it is of course manifestly difficult to arrive at any correct idea as to transmission but there is a growing belief that the free and frequent use of soap is a decided factor in preventing infection which may, like rat leprosy, be best brought about by continued contact with a skin surface more or less abraded. There has been a suspicion, but no proof, that sexual intercourse may bring about infection.
Rat Leprosy.—A disease occurring naturally among rats was first observed by Stefansky, in Odessa, in 1903.
There are two types: (1) Of skin and muscles, and (2) of the lymphatic glands. In the skin form areas of alopecia are present with thickening of the site invaded. These areas are most often on the back of the head. Just as in human leprosy the epithelium is unaffected, the corium however being filled with cells packed with acid-fast bacilli, exactly similar to the picture in human leprosy. Ulceration of these subcutaneous nodules is common.
In the glandular type the glands are enlarged and the lymph sinuses packed with the causative bacilli.
In rat leprosy it has been found that infection of other rats takes places as readily through slight abrasions of the skin as when material is injected subcutaneously.
The idea is that natural infection occurs by way of the skin and through the lymphatics. There is no evidence that insects play a part in transmission.
Rat leprosy prevails extensively in Europe, Asia and America. Although similar etiologically and pathologically there does not seem to be any connection between the disease in rat and in man, as is the case with human and rat plague.
The prevalence of rat leprosy in the various parts of the world varies greatly; thus in Odessa 4 to 5% of the rats are infected while in San Francisco only ⅕ of 1%.
PATHOLOGY AND MORBID ANATOMY
In whatever way introduced the leprosy bacilli tend to invade and multiply in the lymphatics of the corium and subcutaneous tissues. In response to irritation, cells of disputed type, possibly plasma cells, appear and phagocytize the bacilli in large numbers, so that eventually the outline of the cell, as brought out in acid-fast staining, is that of a mass of red bacilli.
These red-staining bodies are called lepra cells. In addition, endothelial cells phagocytize the bacilli and these with their bacilli, together with the free lying masses of bacilli in the lymphatic sinuses, make the so-called “globi” when seen in transverse section. The toxicity of the lepra bacillus is only slight so that we may have very large giant cells of the Langhans type and this probably explains the absence of caseation in leprosy. The arteries of the leproma, as the granulomatous mass is termed, undergo an arteritis with thickening of their walls.
The leproma is a mass of cells of varying sizes and types in a connective-tissue framework. The infiltrations are chiefly about the hair bulbs, sweat glands and arteries. The epidermis is separated from the leproma by a connective-tissue layer and is uninvolved except for a thinning out of the layer and obliteration of the interpapillary epithelial pegs.
Incision of a leprous nodule shows a smooth glistening cut of a yellowish to slate gray color.
In nerve leprosy the cellular proliferations in the region of the blood vessels and later in the perineurium and endoneurium cause pressure on the axis-cylinder with consequent degeneration. The affected nerves are swollen and reddish-gray in color. It is now thought that an axonal degeneration involves the cells of the anterior horns so that this, as well as the peripheral neuritis, is a factor in the muscular atrophies which are features of the disease. The sensory fibres are destroyed before the motor ones.
Leprous changes are common in the anterior part of the eye, as of conjunctiva, cornea and iris, but rare in the posterior eyeball. The mucosa of tongue, larynx and, pharynx is often involved. Cartilage and bone are destroyed through pressure of the granulomatous tissue.
The ovaries and testes may show connective-tissue increase.
Nephritis is rather common in leprosy but there is considerable doubt whether the lungs are invaded by leprosy, except most rarely.
Next to skin, mucous membrane and nerves, the lymphatic glands show the greatest involvement.
The liver not uncommonly in nodular leprosy and more rarely the spleen may show connective tissue or cellular infiltrations.
SYMPTOMATOLOGY
The period of incubation of leprosy is peculiarly prolonged and is at any rate from two to five years and may extend over many years, Hallopeau having recorded a case where the disease did not develop for twenty-seven years after the patient left the infected district. The early manifestations are vague and indefinite, consisting chiefly of malaise, weariness and mental depression.
There are often noted (a) irregular accessions of fever (leprotic fever), attended with rather profuse sweating, so that the onset may be mistaken for a malarial infection; (b) progressive weakness, the patient being easily fatigued with a tendency to somnolence; (c) alternating attacks of dryness and hypersecretion of the nasal mucous membrane, with frequent attacks of epistaxis, and (d) various neuralgic manifestations or paraesthesias as well as headache. These prodromal manifestations usually precede but may accompany the outbreak of the spots.
It is the prominence of the nasal manifestations that has caused Sticker to insist that the primary lesion of leprosy is of the nasal mucosa, the general view, however, being that this view is without sufficient foundation and as a matter of fact some have recently suggested that the disease first manifests itself in the lymphatic glands, punctures of such structures showing bacilli rather frequently, although in less proportion than upon examination of the nasal mucosa.
All authorities recognize two well-separated clinical types of leprosy, one the nodular, skin, hypertrophic or tubercular form and the other the smooth, nerve, maculo-anaesthetic or atrophic form.
These fairly distinct types tend to run into one another and in such cases we have the mixed form of the disease.
Following Manson I use the terms nodular and nerve leprosy. It is usually stated that in Northern climates nodular leprosy forms about 70% of cases while, in the tropics, the larger proportion is made up of nerve leprosy.
At one time a classification of the 239 lepers at San Lazaro Hospital, Manila, P. I., showed 97 cases of nodular, 42 of nerve and 93 of mixed leprosy, with two cases of doubtful nature.
NODULAR LEPROSY
A Typical Case.—After more or less indefinite and uncharacteristic prodromata the definite onset is by an outbreak of brownish red spots which later become pigmented and thickened. These spots are at first erythematous and tend to come out in crops, attended with attacks of irregular fever. They soon have the appearance of limited areas of sunburn. They vary in size from 1 or 2 millimeters to a blotch the size of the palm of the hand.
They are raised and have a preference for appearing on the lobes of the ears, the nasal alae, the forehead, eyebrows, cheeks and chin.
The extensor surfaces of the forearms, thighs and buttocks are also favorite sites for the indurated spots. The palms of the hands, soles of the feet, hairy scalp, groin and axillary regions are almost never attacked.
These spots may be hyperaesthetic at first but soon show loss of pain and temperature sense with retention of touch sensation (dissociation of sensation). These spots do not sweat, they remain dry even in a general perspiration.
Following successive febrile accessions and reappearances of spots we have developed reddish-brown nodular masses, usually on the sites of the spots.
When the nodules are grasped between the fingers one usually finds them elastic to touch. As the result of active sebaceous secretion these nodules have a greasy appearance.
These protruding nodules may give the face a leonine appearance, hence the name leontiasis, or that of a satyr, hence satyriasis. With the development of the nodules the hair falls out of the eyebrows and bearded face. Nodules develop in the mucous membranes of the nose, mouth and larynx, giving rise to foetid discharges and obstruction of the nares, difficulty in mastication as well as in breathing and a raucous voice.
The eye is involved with frightful frequency in this form of leprosy, there being infiltrations of the eyelids, conjunctivae, cornea and iris, with subsequent ulcerations and loss of sight.
The nodules on face, backs of hands, buttocks, etc., may disappear by resolution but the tendency is for them to ulcerate and produce various contractions and deformities.
The glands in the region of the lesions become enlarged but do not tend to suppurate.
Visceral involvements are not common but serious lesions of the liver have been reported.
The course of the disease is essentially chronic and if some intercurrent affection does not carry off the patient, the end comes in a cachexia in about ten years, the temperature gradually falling and a state of somnolence ushering in the end.
When nerve leprosy sets in upon a nodular type the life of the patient seems to be prolonged.
Nerve Leprosy
A Typical Case.—The prodromal manifestations are characterized by the results of irritation of the granulomatous tissue upon the nerve fibers and are chiefly neuralgic pains or signs of sensory disturbances as formication, paraesthesias, etc. In particular, are the ulnar, peroneal and facial nerves attacked, the process very rarely extending above the knee or elbow.
Anaesthesia of the region supplied by the ulnar nerve with contractures of the fourth and fifth fingers may be signs directing our attention to the true nature of the disease and in those cases where the appearance of smooth yellowish-brown spots precedes the neuritis manifestations we may here also find anaesthesia, provided the eruption has lasted for some time.
In brief the fully developed case of nerve leprosy shows anaesthetic spots, trophic lesions of the skin and bone, together with muscular palsies. The spots often appear singly and may be from ½ to several inches in diameter. They are not raised, have a sunburnt color and do not sweat. Instead of having a preference for the exposed parts they most frequently appear on the covered portion of the body or limbs as trunk, buttocks, scapular region, thighs or arms, although the first appearance of spots may be on the face.
These spots often look like ringworm lesions, as they have an erythematous border with a paler center, but they are oval in outline rather than round and there is no scaling. Bullous eruptions, which are most frequently noted about the knuckles, are rare manifestations of nerve leprosy. They are often followed by ulceration.
About this time the nerve trunks begin to enlarge, especially the ulnar at the elbow and the great auricular as it crosses the sterno-mastoid muscle. The characteristic nerve enlargement is spindle-shaped or beaded.
These nerve enlargements are at first tender but later become painless and we have extensive areas of anaesthesia and trophic changes of the skin and nails of fingers and toes such as felons, glazed skin, bullae, which latter on rupturing leave ulcers.
We also have absorption of the bones of the phalanges.
The phalangeal bones may be completely absorbed and a distorted nail cap the end of the metacarpal bone (lepra mutilans). Owing to the anaesthesia lepers often burn or injure their fingers and toes. Perforating ulcers are more common in leprosy than tabes.
Muscular palsies, atrophies and contractures are more common in the face and upper extremity than in the lower extremity. We may have changes quite similar to those of progressive muscular atrophy, the thenar and hypothenar, as well as the interossei, undergoing atrophy and resulting in the claw hand. There is extension of the first joint and flexion of the two distal joints of the fingers. Such hands may function quite well. Wrist-drop is not uncommon but foot-drop is rare. Rarely Charcot’s joint condition may be observed.
Of the facial muscles the orbicularis palpebrarum is most apt to show paralysis. The eyes are affected much less frequently in nerve leprosy than nodular, 45% as against 85% for nodular leprosy. The most common changes in nerve leprosy are ectropion of the lower lid and subsequent corneal ulceration.
=Mixed Leprosy.=—In mixed leprosy we simply have a combination of the manifestations of the two main types and as a matter of fact the majority of cases tend eventually to assume a mixed type.
SYMPTOMS IN DETAIL
Temperature Course.—On the whole leprosy runs an afebrile course except for the accessions of irregular fever at the time of the appearance of the successive crops of spots. This leprotic fever lasts for a few days or a week or so and then the course becomes afebrile. At such times sweating may be present and suggest malaria. In the final stages of leprosy the patient may run a high fever for long periods, associated with profuse sweating and loss of weight.
Skin.—The raised spots of nodular leprosy tend to come out in numbers on lobes of ears, over eyebrows and on cheeks, as well as backs of hands and forearms and on buttocks and feet. Soles of feet and palms of hands almost never show spots. In nerve leprosy the spots are often single and flat and often appear on parts of body covered by the clothing, as trunk, thighs or arms. The spots of leprosy are anaesthetic, often showing dissociation of sensation. The indurated spots of nodular leprosy are succeeded by tubercle-like growths. The hair falls out of the areas occupied by the spots.
Mucous Membranes.—The nasal mucosa is in particular studded with nodules which later undergo ulceration. An ulcer of the septum is often the first place from which leprosy bacilli may be obtained. The pharynx and larynx are also involved early.
Nervous System.—Besides the characteristic anaesthesia we have various manifestations of neuritis, especially involving the ulnar, facial and peroneal nerves. The affected nerves show a fusiform enlargement and are tender. Later we have trophic changes in skin, bone and nails of the fingers and toes. Absorption of bones and perforating ulcers are common. Muscle palsies and atrophies, especially the main-en-griffe, are common. The orbicularis palpebrarum is not infrequently paralyzed. The olfactory, optic and auditory nerves are rarely if ever involved. The reflexes are slightly exaggerated.
Patients often complain of a sensation of cold. Some authorities have called attention to the frequency of a mental and moral apathy in lepers.
The Circulatory System.—Honeij considers a high pulse rate, especially in the morning, as characteristic of progressive stages of leprosy.
The Eye.—In nodular leprosy eye lesions, chiefly leprotic nodules in conjunctivae or iris, with subsequent ulceration, are met with at some time in the course of the disease in almost 90% of cases. In nerve leprosy, corneal ulcerations, chiefly resulting from paralyses of the facial muscles, with ectropion, give eye symptoms in about 45% of cases.
Genito-urinary Symptoms.—Atrophy of the testicles with increase of connective tissue often result in males but data would indicate that the procreative power of the female is but little diminished. Lepers often die of renal complications, the kidney lesions being rather those of amyloid change. Bacilli may be eliminated in the urine during accessions of fever.
The Lymphatic Glands.—These tend to enlarge and show bacilli, but rarely suppurate.
The inguinal and cervical glands are most often enlarged.
The Blood.—The changes, other than those of a secondary anaemia as the disease progresses, are not characteristic. Bacilli are present in the blood of cases of nodular leprosy quite constantly but less so in that of cases of nerve leprosy. The bacilli are more apt to be found in the blood at the time of febrile accessions.
DIAGNOSIS
=Clinical Diagnosis.=—It must be remembered that leprosy is very slow in development, so that for months or even years there may be but slight indications of the disease, as an anaesthetic spot or the palsy of an orbicularis palpebrarum. One should always run over the lobes of the ears or region of the eyebrows to feel for shot-like nodules.
In the making of a diagnosis the information as to possible exposure to the disease is of first importance.
The leprous spots are at first rather oily from increased action of the sebaceous glands but subsequently become dry. In ancient times the hypersecretion of sebaceous material about the facial spots of nodular leprosy served as the basis of a test for leprosy, the suspected eruption being dashed with water. If the surface was not wetted it was a point in favor of leprosy. Of prime importance however is the pin prick for anaesthesia, which is the most important distinguishing characteristic, next to the finding of the bacilli, for a leprous spot. The anaesthesia is more marked in the center of the spot and may show dissociation of sensation. It is very important to examine for enlargement of the ulnar or great auricular and the earliest signs of a nerve leprosy may be anaesthesia and a slight contraction of the ring and little finger.
Of the general diseases, which may be confused with leprosy, we have the circumscribed form of scleroderma. Such spots however are dead white in color and are not anaesthetic. The prodromal manifestations with fever and sweatings simulate malaria. Elephantiasis and Madura foot have been confused with leprosy but the marked tendency to limitation to the lower extremities and absence of anaesthesia should differentiate. Probably the most difficult disease to differentiate from leprosy is syringomyelia. Morvan’s disease is only a form of syringomyelia in which the neuralgic pains, anaesthesia of the skin and painless whitlows, with tissue loss, are features. In fact Zambaco has advanced the idea that Morvan’s disease is leprosy.
In syringomyelia the dissociation of sensation is marked, as with leprosy. In syringomyelia, however, the upper extremities are, as a rule, alone affected and the muscular atrophy is more of the scapulohumeral type, with involvement of trunk muscles causing scoliosis, than of the thenar and hypothenar eminences, so that while the fingers may be more contracted and rigid than in leprosy we do not get the main-en-griffe. The anaesthetic areas of syringomyelia continue to sweat, and we may also get spastic symptoms and speech defects in syringomyelia.
Raynaud’s disease has also been confused with leprosy.
Of the skin diseases the most important confusing lesions are the cutaneous manifestations of tuberculosis and syphilis. In lupus the tubercles are very much smaller, show the apple jelly appearance, the lesion spreads peripherally, is rather purplish and is not anaesthetic. Syphilitic ulcerations are more punched out, do not affect the same sites and respond to syphilitic treatment immediately. You do not find nerve enlargements in syphilis.
There is great lack of agreement as to the frequency of the Wassermann reaction in leprosy, some reporting a positive test as common in nodular leprosy while others have reported negative findings where there was not ground for suspecting syphilis. Nerve leprosy does not often give a positive test.
Fletcher obtained 22% positives in 100 cases of leprosy—28% in nodular and 17% in nerve cases. One-third of the cases gave a history of syphilis.
Sutherland and Mitra obtained 17 positive Wassermann reactions in 34 nodular cases, 16 positives in 52 anaesthetic cases and 8 positives in 14 cases of mixed leprosy. The sera of 12 children of leprous parents were negative.
The luetin reaction is negative in leprosy.
Mycosis fungoides has not the characteristic location about the face and itches markedly and does not show anaesthesia.
Vitiligo shows an abrupt margin and is not anaesthetic.
=Laboratory Diagnosis.=—The usual procedure is to scrape a spot or nodule with a scalpel until the epidermis has been gone through and then smear out the serous exudate on a slide and stain by the Ziehl-Neelsen acid-fast method or by Gram’s stain. Twenty per cent. sulphuric acid is less apt to decolorize than the 3% acid alcohol, the leprosy bacilli being less resistant to acid alcohol decolorization than to aqueous acid solutions. There is a great variation in the resistance to decolorization of leprosy bacilli, a preparation from one case holding its color almost as well as tubercle bacilli, while material from another case may decolorize very easily.
I am partial to Tschernogabow’s technique. In this, one punctures the subepithelial granulomatous tissue with a capillary pipette, the end of which has been broken off by tapping the point in order to give a cutting point, and the serum which exudes is smeared out and stained.
Some prefer emulsifying a piece of the tissue and centrifuging and staining the sediment. Quite recently the antiformin method of treating leprous tissue, as for tuberculous tissue, has been used.
Many insist that the best method is to cut out small sections of the lesion, going well into normal tissue, and putting through paraffin and cutting thin sections and staining. Gram’s method, counterstaining with bismarck brown, gives beautiful preparations. For acid-fast staining first stain with haematoxylin to obtain a histological background and then steam with carbol fuchsin, decolorize very briefly with acid alcohol, then through absolute alcohol and xylol.
Of the greatest diagnostic value is the staining of the nasal mucus or scrapings from ulcerations on nasal septum for leprosy bacilli. These are often found in the characteristic cigar package bundles or engulfed in lepra cells. A standard procedure is to give 60 grains of iodide of potash to cause a drug coryza, in the secretions of which leprosy bacilli may be found. However, one will have better success if the nasal secretion be obtained at a time when a natural coryza exists.
Thibault examined the nasal mucus, gland juice and blood of 30 lepers. He obtained leprosy bacilli in the nasal mucus of 20, in the gland puncture juice of 18, and in the blood of 7.
Hollman detected leprosy bacilli in the nasal mucus of 90% of 58 nodular cases, of 67% of 6 mixed leprosy and of 45% of anaesthetic cases, after making 329 examinations.
Leprosy bacilli are apt to be found in the blood of nodular cases, especially at the time of the febrile accessions. The blood is best taken in 5 or 10 cc. quantities into 1% sodium citrate in distilled water. After centrifuging, the sediment is treated with 10% antiformin, at 37°C. for one hour. Again centrifuging, and washing, the sediment is smeared out on a slide and stained. The bacilli are not apt to be found in the blood of cases of nerve leprosy.
Smith and Rivas add 10 vols. of 2% acetic acid to 1 vol. blood, centrifuge and make smears.
Gland puncture has recently been considered as an important diagnostic procedure in leprosy.
It must not be forgotten that while the finding of leprosy bacilli is usually very easy in the nodules of nodular leprosy it is a painstaking and discouraging procedure with the spots of nerve leprosy. Even the affected nerves, at autopsy, often fail to show bacilli. For nerve leprosy the examination of nasal mucus is of prime importance.
The Roentgen ray has been utilized in the recognition of the very early, trophic changes in bone, showing the commencing absorption of phalanges. Neve has reported a case in which there were no satisfactory indications of leprosy other than slight deformity of toes and fingers but showing marked changes in the phalanges, even to disappearance of terminal phalanx of some toes when examined with X-ray.
PROGNOSIS
The progress of the disease is so slow that it is difficult to estimate improvement or cure. At present the possibility of a cure, with the new methods of treatment, is encouraging. There is no doubt but that many of the reported cures have simply been instances of remissions in the course of the disease for periods covering months or even three or four years. It would seem that the earlier treatment is instituted the greater the possibility of cure. There were 38 cases officially reported as cured, in Norway, from 1881 to 1885.
Nodular leprosy runs its course much more quickly than does nerve leprosy. It is in nodular leprosy particularly that intercurrent affections carry off the patients. Tuberculosis carries off about 23% of cases and nephritis almost 30%, while a combination of tuberculosis and renal disease about 10%. In the remainder, the cachexia or accidents of leprosy itself are responsible for a large portion of the deaths. Cases of nodular leprosy are more often carried off by kidney disease than those with nerve or mixed leprosy.
It must not be forgotten that lepers, especially those with the nerve form, may live for twenty to forty years.
PROPHYLAXIS AND TREATMENT
=Prophylaxis.=—As was noted under epidemiology there seems to be little evidence to show that insects play any part in the transmission of leprosy. Nevertheless it would seem advisable to prevent flies from becoming contaminated with the discharges from leprous ulcerations which so often teem with leprosy bacilli. This possible method of transmission would seem more deserving of attention than the question of the taking up of bacilli from the blood by mosquitoes, bedbugs or biting flies, as the leprosy bacilli are found in the blood of nodular leprosy chiefly during the febrile accessions and very rarely in the blood of cases of nerve leprosy. In all of the ordinary insects the bacilli seem to disappear in a very short time, with the exception of the cockroach, for which reason it would seem advisable to destroy these pests, which can be easily done by sprinkling around a little sodium fluoride.
There is some evidence that scabies favours infection so that this disease should be looked for and actively treated in endemic areas.
Leprosy tends to spread where there is marked personal uncleanliness and close contact with lepers in overcrowded quarters. Many authorities consider the free use of soap and water the most important means of avoiding infection. While segregation is generally considered the one proven prophylactic measure there are those who question its value. There does not seem to have been any very marked influence on the spread of leprosy among the native Hawaiians through the enforcement of isolation of such cases. Partial segregation at their homes has given very satisfactory results. Where a leper is not excreting bacilli, or where acid-fast organisms cannot be found after careful search there is no danger. Such patients, however, should report for examination every few months. Evidence as to contact indicates that all young children are particularly liable to the infection, as has been noted for children of lepers and brothers and sisters. Even if segregation of lepers is not carried out as regards adults, it should be the rule for children, so that infants and young children should be separated from their leper parents or parent. A very remarkable feature in connection with leprosy is the hysterical dread that many communities have of a leper, when they must know or could easily learn, that the contagiousness of the affection is so slight, that notwithstanding our efforts, we can scarcely point to a single instance to prove undoubted transmission of the disease from one person to another. At any rate knowing that immense numbers of the bacilli are given off from ulcerations and the nose, we should guard against the dissemination of leprosy bacilli from such sources.
=Treatment.=—Many so-called specific products, whether of the nature of extractives, as leprolin or nastin, or of bacterial vaccines, have been tried with results which have not tended to gain the confidence of conservative men. The product which has been given most general trial is nastin. This is a neutral fat, extracted from a streptothrix growth, obtained by Deycke from leprous nodules. It is combined with benzoyl chloride and is contained in ampoules containing from one-half to one-fifth of a milligram.
Wise and Minett treated 244 cases with nastin for periods of from one to two years, the treatment having been at first supervised by Deycke himself. It was stated that nodular cases did not seem to be improved and that anaesthetic leprosy was not apparently influenced.
Minett mentions the efficiency of a 2½% solution of benzoyl chloride as a nasal spray and as an application to leprous ulcers, this treatment causing the bacilli rapidly to disappear from the discharges of nose or ulcers. On the other hand Scott, in Assam, reports practically 50% of cures, or cases greatly improved, in patients treated with nastin for a year or more. He gave nastin B1 injected intramuscularly at two weeks intervals.
Salvarsan does not seem to have been of any value in leprosy.
The standard treatment for leprosy is chaulmoogra oil given internally, in capsules, in doses of 5 to 10 minims increased gradually, according to stomach tolerance, to 40 to 60 minims.
For hypodermic use Heiser makes a mixture of 60 cc. each of chaulmoogra oil and camphorated oil with 4 grams resorcin. Injections are made weekly, commencing with 1 cc. This dose is increased steadily according to tolerance, but in some patients marked reaction in the lesions, with fever, occurs after a dose of only a few cubic centimeters has been reached.
Rogers has for some time been giving subcutaneous injections of sodium gynocardate, the sodium salt of the lower melting-point fatty acids of chaulmoogra oil. Finding that large doses of sodium gynocardate could be administered to animals with safety he has recently given intravenous injections and has substituted this method for the subcutaneous one. For use in the treatment of leprosy he prepares a 2 or 3% solution in distilled water and, after sterilization in an autoclave, adds ½ per cent. carbolic acid. The solution should be quite clear. He starts with one-tenth of a grain and increases the dosage by one-tenth with each successive injection up to four-fifths of a grain. He states that this method has as great superiority over the subcutaneous one as that has over the administration of chaulmoogra oil by mouth. Rogers now uses a solution of 3% sod. gynocardate with 1% phenol and 1% sod. citrate. At first the intravenous injection is with 0.5 cc. thrice weekly, which dose is gradually increased up to as much as 5 cc.
It is possible that sodium morrhuate (cod-liver oil) may be as efficacious as the gynocardate salt. Rogers has used Hydnocarpus instead of the true chaulmoogra oil and thought he obtained better results. One explanation of the uncertainty of success with chaulmoogra oil is the difficulty of securing oil obtained from proper sources. The standard treatment of leprosy in Honolulu, as reported by McDonald, is the weekly injection of the ethyl esters of the entire fatty acids of the whole chaulmoogra oil, with 2% by weight of iodine, chemically combined. The treatment begins with 1 cc. injected intramuscularly, increased by 1 cc. at every second or third injection, until a dose of from 2 to 6 cc. is reached, according to age and weight of patient.
For internal use the mixed fatty acids, carrying 2½% iodine, chemically combined, are given in capsule. The dose by mouth is 0.25 grams per 100 lbs. weight, three times daily, an hour or two after meals. This is gradually increased every two weeks until a maximum dose of 1 gm. per 100 lbs. weight is reached.
Dyer combines hydrotherapy with the administration of chaulmoogra oil. He gives a daily bath as hot as can be borne, and, in addition to the specific treatment, gives 1/60th grain of strychnine three times daily.
Antileprol, a preparation of chaulmoogra oil, which is more satisfactory than oil, may be given in doses approximating 120 grains by mouth daily or 60 grains subcutaneously. Such drugs as arsenic salicylate of soda and bichloride of mercury have been used.
Thyroid extract has seemed to benefit cases of anaesthetic leprosy in rare instances. The high frequency current with the needle applied to the nodular lesions has been recommended by Unna. Radium and X-rays have also been employed. There have been reports as to the value of the antimony treatment in leprosy.
Leprosy is a disease in which improvement often occurs when the patient is placed under more favorable conditions as to food, climate, etc. Again, there is at times a tendency for the disease to abort or ameliorate without relation to treatment or environment.
Surgical treatment is frequently of use, as nerve stretching for the leprous neuralgias. Various eye operations are necessitated by the ectropion or leprotic iritis. The amputations of the area involved in perforating ulcer is recommended. Tracheotomy is often demanded for the laryngeal stenosis.
McCoy has combined carbon dioxide snow local treatment with chaulmoogra oil. The lesions showed decrease in size but remained bacteriologically positive.
SECTION III
FOOD DEFICIENCY DISEASES
XVIII. BERIBERI
DEFINITION AND SYNONYMS
=Definition.=—Beriberi is a food deficiency disease due to the absence from the dietary of a neuritis-preventing vitamine. It is particularly important among the people of the Orient whose diet is preponderatingly one of rice. In milling the grain the outer vitamine-containing layers are rubbed off and this polished rice, when the chief constituent of a dietary, is capable of causing, after a period of two or three months, a peripheral neuritis.
This neuritis not only involves the nerves of the extremities but, as well, the pneumogastric, and it is the manifestation of cardiac disturbances which best differentiate this form of neuritis from those due to alcohol or arsenic.
The disease is usually described under two types: (1) a wet or dropsical beriberi, in which the vasomotor nerves are affected with resultant general oedema and (2) a dry atrophic or paraplegic type, in which muscular palsies and atrophies are the leading features. Pathologically, we have a Wallerian degeneration of the peripheral nerves with possibly axonal degeneration of the cells of the neuron involved.
=Synonyms.=—Neuritis Multiplex Endemica, Polyneuritis Endemica, Hydrops Asthmaticus. Japanese: Kakke.
HISTORY AND GEOGRAPHICAL DISTRIBUTION
=History.=—While modern knowledge of beriberi may be said to date from the writings of Bontius, in 1642, yet the disease is distinctly described by Chinese writers of the seventh century and treated in writings of the second century and possibly referred to in writings as ancient as B. C. 2697. It is probable that the disease described by Strabo as occurring in a Roman army while invading Arabia, in 24 B. C., was beriberi. While mention of the disease may be found in Japanese writings of the ninth century it is thought by Scheube that this relates to the disease in China and that beriberi first appeared in Japan about the eighteenth century. Bontius described the atrophic form of the disease, Rogers, in 1808, the serous effusions, and Marshall, in 1812, noted two types, barbiers, when the paralysis predominated, and beriberi, when the dyspnoea and oedema were leading features.
In 1835 Malcolmson noted that cases of beriberi assumed the type of barbiers and vice versa, from this time the view has obtained that the two affections belong to one disease.
The disease seems to have first made its appearance in Brazil in 1866.
=Geographical Distribution.=—Reference to the chart will show 3 markedly endemic centers for beriberi, one embracing Japan, a second the Dutch East Indies (Java, Borneo, Sumatra), and a third, involving the Eastern coast of Brazil. In somewhat less degree the disease prevails in India, Indo-China, Malay Peninsula, Eastern China, and the Philippine Islands. It is also found in the regions of the East and West Coasts of Africa, and was devastating to the laborers on the Congo railway. It has been reported from many parts of the world among coolies from Asiatic countries. A disease of similar nature has been noted in asylums in England and America. Beriberi occurred among the British soldiers in Mesopotamia during the recent war—more than 300 cases in 1915. It is interesting to note that scurvy, and not beriberi, occurred among the Indian troops in Mesopotamia at this time. There was no scurvy in the British troops.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—There is probably no disease about which there exist so many views as to etiology as with beriberi. Many of those formerly advanced are so negatived by recent investigations that it would seem hardly worth while to mention them. While the cause is still unsolved attention is at present almost exclusively directed to some deficiency of a neuritis-preventing substance in the dietary and such studies have in large part centered about the question of such deficiencies in certain kinds of rice.
Reserving until the last the discussion of the rice theories we may briefly dismiss such views as those assigning bacterial or protozoal causes with the exception of those of Manson and Hamilton Wright.
Manson’s Theory.—Under conditions of overcrowding, filth, warmth, moisture and lack of ventilation, as would obtain in the forecastle of a ship carrying a native crew, the development of a hypothetical germ is favored. This germ in its growth gives off emanations which like alcohol act as toxins upon the peripheral nerves. The germ itself does not infect the patient.
Wright’s Theory.—According to this view a bacillus which was given off in the faeces was ingested and locating in the duodenal mucosa gave off a toxin similar to that of the diphtheria bacillus. Instead of developing its soluble toxin in the membrane of the region of the throat this action took place in the upper part of the small intestines.
Of the bacterial causes may be mentioned: (1) The coccus of Pekelharing and Winckler. This organism was supposed to be short lived in the body and repeated infections were necessary to produce the disease.
(2) Dangerfield held views somewhat similar to those of Pekelharing and thought a coccus in the alimentary canal the cause.
(3) Isuzuki regarded a coccus isolated from the urine as the cause.
(4) Okata and Kokubo thought a coccus obtained from the blood to be the infecting agent.
Various bacilli, other than that incriminated by Wright, have been brought forward as pathogenic agents but it may be stated without further discussion that the claims of the advocates of bacterial causes have not been verified and are solely of historical interest. The same statement will hold for the plasmodium-like protozoon of Glogner which was found in the splenic blood.
Of the chemical theories may be mentioned; (1) Arsenic poisoning. In an outbreak of arsenical neuritis in England, from arsenic contained in the glucose used in making beer, Ross diagnosed the illness as beriberi. Subsequently, arsenic was found in the hair of certain patients with beriberi, hence the theory which has never been substantiated. It may be stated that a careful study of this epidemic by Reynolds and Bury indicated that the alcoholic factor was also operative as persons taking an equal amount of arsenic but without alcohol, did not develop neuritis.
(2) Treutlein’s oxalate theory.—This was based on the fact that polyneuritis gallinarum could be produced in fowls by feeding them oxalic acid.
Of the food deficiency theories, the most prominent is (1) that of Takaki, generally designated the nitrogen deficiency theory. As the result of increasing the proteid constituents of the ration of the Japanese Navy from 109 to 196 grams, the disease was largely eliminated (from about 32% incidence to less than 0.5%).
In the old ration the ratio of N to C was as 1 to 17—32, in the new ration, 1—16. In looking over the constituents of the new ration the addition of about 100 grams of beans is noted. These are rich in vitamines.
(2) According to Fales the hypothetical germ of beriberi can only live in body fluids deficient in potassium carbonate. The high content of potash in potatoes made him greatly increase the amount of this vegetable in the dietary he recommended. Fales noted scurvy as well as beriberi in the Bilibid prisoners on a diet deficient in potash.
(3) Deficient fat. (4) Deficient phosphorus.—It was Schaumann’s idea that the phosphorus contained in the outer layers of the rice grain was essential in the prevention of beriberi. While it is now known that the beriberi-preventing substance does not contain phosphorus, yet the idea has proven of practical value as giving an index of beriberi-producing power of rice.
P{2}O_{5} Index of Beriberi-producing Rice._—If a rice contain under 0.4% of phosphorus pentoxide it is liable to produce beriberi.
Schaumann now considers that the antineuritic substance in rice polishings acts as an activator in the metabolism of phosphorus.
Vitamine Deficiency.—Grijns was the first to insist that beriberi was due to the absence in the diet of some substance essential to proper metabolism of the peripheral nerves. His views were along the line of our present vitamine deficiency ones. There are undoubtedly many different vitamines, varying as to nature of protective power, temperature at which destroyed, solubility, etc. McCollum emphasizes the importance of a fat soluble A and a water and alcohol soluble substance B for proper metabolism. This latter, usually designated “Water soluble B,” is generally considered the same as the anti-neuritis vitamine but there is recent evidence that this may not be the case. The antiscorbutic vitamine is water soluble C.
Food Poisoning as Cause.—There are other theories as to intestinal parasites causing the disease and in particular views as to relation of fish eating to the disease, which are (1) that it is caused by the ingestion of raw fish, or again (2) from the eating of certain poisonous fish.
Miura, who is the great advocate of a fish intoxication, believes that this comes about from eating fish belonging to the Scomberidae family. As proving this, he cites the absence of beriberi in prisons in Japan, where no fish is allowed. He does not recognize that it is the diet of barley 6 to rice 4 parts which is the prophylactic factor. Barley is rich in vitamines.
RICE AND BERIBERI
There are a few points in connection with rice which should be understood. The larger part of the rice grain is starch and covering this central starch core we have the rather thin aleurone layer containing the proteid and fat constituents of the grain. Externally there is an adherent layer, the pericarp, which varies in color from red to white according to the kind of rice. The pericarp contains the salts. The grain is covered by the husk which is always removed to render the rice suitable for food. Unhusked rice is called padi in India and palay in the Philippines. In the process of removing the husk (milling) the pericarp and more or less of the aleurone layer may be rubbed off the grain. When the milling process is carried to the extent that but little remains except the starch the rice is termed polished, highly milled, or white rice. A process of parboiling causes the husk to be more easily detached and the pericarp to adhere more firmly to the grain and when milled there is less loss of the anti-neuritis principle, which is contained in the outer layers. Such rice is called cured rice. The embryo also contains the anti-neuritis vitamine as well as the fat soluble A one. It is also lost in milling. The scale-like dust is termed rice polishings and has curative value for those who have developed beriberi under a diet of polished rice. When the milling process is less complete the rice so treated is called undermilled rice or red rice. Polished, highly milled or white rice contains as a rule less than 0.4% of phosphorus pentoxide while the beriberi-preventing rices contain more than 0.4% of this compound for which reason legislation has required rice to have more than 0.4% phosphorus pentoxide.
Siam rice is a polished white rice which contains about 0.25% phosphorus pentoxide and has more often been associated with severe outbreaks of beriberi than Rangoon rice, which has about 0.32%, this latter, however, being a well-recognized beriberi-producing rice. Unpolished rice contains about 0.55% of phosphorus pentoxide. Natives generally prefer the polished rice because it is clean and free from weevils, while the undermilled kind is dirty. Parboiled rice has a disagreeable odor.
Voegtlin has recommended a P_{2}O_{5} requirement of 0.5% for corn products and 1% for wheat ones. Thus whole wheat contained 1.12% while highly milled flour had only 0.114%. Fowls fed on this flour developed polyneuritis in twenty to thirty-two days.
Whole corn contains 0.76% P_{2}O_{5}, while highly milled corn grits has approximately 0.2%, and highly milled corn meal about 0.3%. These highly milled corn products produced polyneuritis within from thirty to thirty-five days.
With rock ground corn meal, containing 0.7% P_{2}O_{5} the fowls remained well.
Experiment of Fraser and Stanton.—While there have been numerous instances reported to show the connection between polished rice and beriberi, when such rice was the predominating article of diet, it will suffice to refer to the experiments of Fraser and Stanton and of Strong.
In 1909, Fraser and Stanton experimented with 493 Javanese coolies who were employed in building a road far removed from any village which might introduce the factor of bacterial etiology into the problem. They noted that the Javanese prefer white rice, and reference is made to the fact that many cases of beriberi occurred among these laborers in 1906, which outbreak ceased upon requiring them to eat parboiled rice at the suggestion of Doctor Braddon. They state that they informed the coolies of the danger of white rice but, notwithstanding, they all expressed a preference for the white rice over parboiled rice. For the purpose of comparison, only one-half were allowed the white rice diet. The two parties were quartered in virgin jungle and were isolated from each other by an interval of 7 miles. Of 220 individuals on white rice there were 20 cases of beriberi recorded while among 273, who lived on parboiled rice, no cases occurred.
Prolonged Continuation of Faulty Diet Necessary.—It appeared that a considerable period of continuance of white rice diet was necessary before the appearance of the disease (eighty-seven days). As against the infectious nature of the disease they note that contact of persons on a parboiled rice diet with the beriberi cases was without result. Substitution of parboiled rice for white rice brought about a cessation of the outbreak.
The Philippine scouts, numbering about 5000 natives, gave 618 cases of beriberi in 1908 and 550 cases in 1909. In 1910 undermilled rice was substituted for polished rice and they were required to eat 1-6 oz. beans daily. No other change in their mode of living was made. By 1913 beriberi had disappeared among them, although the disease still prevailed among the native population in contact with them.
Experiment of Strong and Crowell.—Strong and Crowell stated that the object of their study was to determine whether beriberi, as it occurs in the Philippines, is an infectious disease or whether it is one which has its origin in disturbances of metabolism, due chiefly to the prolonged use of polished rice as a staple article of diet.
The experiments were carried out in Bilibid prison. Prisoners, who had been condemned to death, were informed of the nature of the experiment and were told of the diet on which it was proposed to place them. They were also told that they might contract beriberi. Twenty-nine volunteered and each signed a statement in his own dialect that he undertook the experiment voluntarily.
In general, the groups were fed for the greater part of the time occupied by the experiments as follows: Group (1) “White rice and extract of rice polishings and special diet.” Group (2) “White rice and special diet.” Group (3) “Red rice and special diet.” Group (4) “White rice and special diet.”
Of 6 men on the Group 1 diet, 2 developed beriberi. The symptoms however, were not marked, being chiefly loss of weight, tachycardia, slight oedema of legs and tenderness of muscles of calves. Four of the 6 men of Group 2 developed beriberi and 6 out of 11, in Group 4, showed symptoms of beriberi. In Group 3, only 2 in 6 developed symptoms and these consisted in case No. 13 only in tenderness of epigastrium, paraesthesia, cardiac disturbance and marked diminution of knee jerk. In case No. 18 there was noted only slight cardiac disturbance and epigastric pulsation. In none of the cases was the complete picture of beriberi obtained except in those in which the white polished rice formed the staple article of diet, but in one case, fed on red rice, the diagnosis of beriberi was almost definite.
The results of their experiments with the addition of rice polishings to the diet would indicate that whatever may be the results obtained with extracts from this material in preventing polyneuritis of fowls or in curing it after it has developed it is not as efficient in man as the cheaper and more readily obtainable mongo or katjangidjo bean or yeast.
Evidently symptoms of beriberi may also sometimes occur in individuals fed on red rice as a staple article of diet when the diet is very monotonous, comprising few articles and continued for long periods of time. From the experiments it is evident that beriberi may be produced by the prolonged consumption of white rice as a staple diet. Of 17 individuals fed on such diet 8 developed beriberi, all with distinct loss of knee jerk, as well as with other marked symptoms of the disease. Symptoms appeared within 61 to 75 days after the commencement of the diet.
Vedder thinks that the red rice used in these experiments may not have been sufficiently undermilled, as it was found most difficult to obtain such a beriberi-preventing rice for the Philippine scouts. As regards the lack of success with extract of rice polishings the same author considers that a sufficient amount of alcohol for the extraction of the vitamines was not used in the above experiments, as he found it necessary to use 30 litres of alcohol to 5 kilos of rice polishings. Strong and Crowell used only 14 litres of 95% alcohol to 5 kilos of polishings.
Braddon’s views.—Prior to the investigations of Fraser and Stanton the importance of the rice factor in the etiology of beriberi was insisted upon by Braddon who thought that a poison was elaborated by some organism which poison was contained in the beriberi-producing rice. This development was thought to occur in rice stored in damp places, but Vedder has shown that storing undermilled rice in a damp place for a year does not cause it to lose its anti-beriberi-producing properties.
Endocrine Gland Disturbances and Beriberi.—We owe in particular to the researches of McCarrison our appreciation of the important rôle of the endocrine glands in deficiency diseases. With dietaries deficient in vitamines he noted in birds and other animals hypertrophy of the adrenals, atrophy of the thyroid, thymus, testicles and ovary. The pituitary was unaffected. Vitamine deficiency seems to impair the activity of the thyroid and to thus favor the action of products of intestinal bacteria. It is now accepted as important this secondary factor of bacterial infection in all types of food deficiency pathology. Dietaries rich in fats and proteins with sufficiency of vitamines bring about thyroid hyperplasia. In a diet too rich in carbohydrates and deficient in vitamines marked endocrine disturbances are noted.
The adrenals show hypertrophy on a vitamine-deficient diet and this hypertrophy is associated with increase of the adrenalin content of the glands. Oedema seems to be associated with adrenal hypertrophy. McCarrison believes the oedema to be associated with increased intracapillary pressure from the effect of adrenalin but others dispute the explanation. The adrenalin content of the enlarged adrenals varies; it is in excess with a diet rich in carbohydrates and deficient in proteins and vitamines, but is below normal when the diet is scurvy-producing. Butter, probably from its fat soluble A content, seems to protect against oedema.
Polyneuritis gallinarum.—The work of Eijkman in showing that polyneuritis could be produced in fowls by feeding them on polished rice and prevented when a diet of rice polishings was added to the neuritis-producing rice opened the way for a vast amount of experimental work. As regards the nature of the neuritis-preventing substance in the rice polishings it was soon found that it had no relation to the phosphorus content. Funk has isolated a substance he calls vitamine, a pyramidine base precipitated by phosphotungstic acid, which is present in rice polishings and seems to possess extraordinary curative properties in polyneuritis gallinarum. Heart muscle, egg yolk and yeast are rich in this anti-neuritis substance, which is also present in lentils and barley.
Various Vitamines.—The anti-neuritis vitamine is soluble in water and alcohol and is comparatively thermostable (destroyed by a temperature of 120°C. in two hours). It is affected by alkaline reaction but is stable in acid solution. The water soluble B vitamine does not seem to be destroyed by a temperature of 120°C. for two hours, hence it may be different from the anti-neuritis one. The antiscorbutic vitamines differ in being thermolabile, these factors in certain foods being destroyed by a temperature of 60°C. Another vitamine, fat soluble A, found particularly in butter, seed embryos and leaves of plants, is a food essential. Its absence from a diet causes xerophthalmia. Cod-liver oil and glandular organs of animals contain it.
Schaumann considers malt as richer in the anti-neuritis vitamine than any other article of diet, rice bran coming next. Many think that vitamines have not as yet been separated but that they are intimately combined with some mother substance in the food.
There is, in all probability, a large number of vitamines present in various animal and vegetable foods, the deficiency of which in a diet may lead to vague disorders or to well-recognized diseases, such as scurvy, ship beriberi, beriberi or pellagra.
Schaumann considers the curative principle to be of the nature of an activator. An increase in the ingestion of carbohydrates and necessarily in the vitamine as well seems to produce neuritis more rapidly than where a smaller amount is given, this indicating the importance of these vitamines in carbohydrate metabolism.
There are those who deny this carbohydrate metabolism function of vitamines and it is a fact that polyneuritis of fowls will develop on a diet from which carbohydrates are excluded.
In epidemics of beriberi it has been observed that those who eat most rice are more often attacked, thus men more frequently than women. A temperature of 120°C. destroys the vitamine. Owing to the absence of rice as a constituent of other than slightest importance in the dietary of Brazilian cases of beriberi, as well as from numerous reports of the occurrence of the disease in nonrice-eating persons, the view that is now entertained is that not only polished rice, but any predominating carbohydrate article of diet, which is deficient in the neuritis-preventing substance, can produce beriberi. Wellman and Bass have shown that such articles of diet as sago, boiled white potatoes, corn grits and macaroni practically parallel polished rice in the production of polyneuritis in fowls.
=Predisposing Causes.=—There does not seem to be any racial predisposition other than that associated with the more varied and the more neuritis-preventing diet of the white race. For the same reason beriberi is more prevalent among the poor than among the prosperous classes of countries where the disease exists extensively.
It is customary to consider as predisposing causes bad hygienic surroundings, such as occur in jails, camps, etc., as well as the influence of warmth and dampness of the atmosphere. Beriberi is more common among men than women and affects most commonly individuals between 15 and 30 years of age. Physical exhaustion, excessive grief, digestive derangements, abuse of alcohol and tobacco are considered to have a bearing in the production of the beriberi symptoms. Surgical operations may be followed by manifestations of the disease.
=Epidemiology.=—Inasmuch as the experiments of Strong force us to the conclusion that the disease is not infectious, the study of the prevention of the disease would appear to rest almost exclusively in the question of a neuritis-preventing dietary.
In this connection Heiser, in the Philippines, has reported that with a diet in which polished rice was contained the monthly death rate at the leper colony at Culion was approximately 100, the majority of these deaths being from beriberi. As a result of the substitution of unpolished rice, about 1909, the monthly death rate fell to less than 20 and of these none were from beriberi.
Toward the close of 1911 there was a great shortage of the rice crop and the Philippine government bought quantities of rice in order to protect the people from extortionate dealers. Much of this rice was polished rice. The use of this polished rice was commenced at Culion in November, 1911. In January, 1912, there were 35 deaths, of which 2 were from beriberi. In February 86 deaths with 36 from beriberi and in March 82 deaths with 60 from beriberi. In February the use of polished rice was discontinued and unpolished rice substituted. In April the deaths had fallen to 25 with 3 from beriberi and, subsequent to that month, deaths from beriberi cases developing at Culion ceased to be reported.
As regards the length of time necessary for the production of the symptom-complex, Strong’s experiments show that beriberi was produced in from sixty-one to seventy-five days. In Fraser and Stanton’s work no case developed under eighty-seven days and many of the cases did not develop for 120 to 160 days. Hamilton Wright considered that the incubation period for his toxin-producing bacillus was ten to thirty days.
PATHOLOGY AND MORBID ANATOMY
In polyneuritis gallinarum, Vedder and Clark are of the opinion that there may be two vitamines involved, the absence of one from the dietary causing the neuritis, while that of the other leads to general prostration and cardiac degeneration, so that there may be other factors in the production of beriberi than the degeneration of the peripheral nerves and involvement of the vasomotors.
Furthermore, extract of rice polishings rapidly cures the cardiac condition as well as the dropsy, but not the paresis; while Funk’s vitamine base, which will cure the paralysis, will not affect the cardiac disorder.
The blood of beriberics in the acute stage, has been shown to contain a substance capable of profoundly influencing the vasomotor functions, causing venous engorgement and a fall of blood pressure.
In deaths from wet beriberi the tissues are very moist so that incisions tend to fill with fluid. There are generally present pleural and in particular pericardial effusions. Serous fluid in the abdominal cavity may also be present. The lower end of the stomach and the upper portion of the small intestines, in particular the duodenum, show marked congestion with more or less abundant haemorrhagic extravasations. Some authorities do not admit the existence of this duodenal congestion so insisted upon by Wright.
The oesophagus is usually congested as may be also the pharynx and the larynx.
Next to the peripheral nerve degenerations, to be later considered, the most important lesions are found in connection with the heart. All chambers of the heart show a dilatation with hypertrophy as well as dilatation of the right ventricle in cases that have lasted for some time. The heart muscle has the faded-leaf appearance indicative of fatty degeneration. Microscopically there are segmentation and vacuolation of the fibres. The lungs show congestion and at times present the characteristics of pulmonary oedema. The kidneys are congested but show only exceptionally parenchymatous or interstitial changes. As would be expected, the back pressure in the right heart gives a dilatation of the central vein of the liver lobules which at times is productive of atrophy of the adjacent liver cells. The muscles supplied by the affected peripheral nerves show more or less atrophy according to the duration of the disease.
Microscopically, the affected fibres show a loss of striation with a colloid degeneration. These changes are more marked in beriberic residual paralysis. The key to the disease is in the changes present in the peripheral nerves. While these may appear normal yet histological examination shows varying nerve degenerations from slight medullary degeneration in a few fibres to complete destruction of the nerve, giving a Wallerian degeneration (vacuolation and formation of myelin droplets in the medullary sheath with fragmentation of the axis-cylinder).
While it is usually stated that the central nervous system (brain and cord), remains uninvolved yet we note axonal degeneration in the cells of the nuclear centres of the affected peripheral nerves as shown by convexity of the cell sides, dislocation of the nucleus and disappearance of the tigroid substance. The striking feature of the pathology of beriberi is the involvement of the vagus nerve and there is evidence of degenerative changes in the cells of the vagal origin in the floor of the fourth ventricle.
Various investigators have shown that in fowls marked peripheral neuritis can exist long before clinical manifestations appear and that typical cases of beriberi may show striking improvement following vitamine administration, notwithstanding the continued existence of peripheral nerve degeneration. For such reasons Vedder thinks the more important changes to probably belong to cells of cord and brain.
McCarrison has noted striking changes in the endocrine glands in avian polyneuritis, particularly hypertrophy of the adrenals and atrophy of the other glands of internal secretion. He attributes the oedema to increase in adrenalin content. Shimbo has reported adrenal hypertrophy in 14 human cases of beriberi.
SYMPTOMATOLOGY
It is well to remember that beriberi is but a form of multiple neuritis which in many cases shows only motor and sensory disturbances of the lower portions of the upper and lower extremities.
In fact an extensive epidemic of arsenical neuritis, or, to be more exact, a neuritis in which both alcoholic and arsenical factors were operative, was regarded by eminent authorities as beriberi.
The key to beriberi, however, is the peculiar and striking selection of the vagus nerve in the degenerative processes as well as those of the peripheral nerves of the extremities. It is vagal involvement, giving disturbances of heart particularly and lungs in less degree, which chiefly differentiates beriberi from other forms of multiple neuritis.
Another peculiarity of beriberi is the tendency to vasomotor involvement as shown in the patchy areas of oedema.
Epidemic Dropsy.—Beriberi is typically a nonfebrile disease. There is, however, a disease with fever, called epidemic dropsy, which seems to have a similar etiology to beriberi. It also shows the symptoms of a peripheral neuritis plus cardiac disturbances. In fact Pearse has maintained the identity of the two diseases. Greig considers epidemic dropsy as resembling ship beriberi.
The first record of epidemic dropsy was during a famine in Southern India in 1877. Outbreaks again occurred in 1902 and 1907. The fact that it is a disease which often shows a house infection has caused the advancing of a theory that the bedbug transmits the disease.
While greatly resembling beriberi clinically the following points of difference are usually noted by those who hold that it is a distinct disease entity.
1. The presence of fever, which rarely exceeds 102°F. and is usually only about 99° to 100°F.
2. An erythematous rash upon the oedematous portions of the extremities.
3. The frequent generalized oedema, which suggested the designation dropsy for the disease, cannot be differentiated from wet beriberi.
4. The neuritis manifestations are slight or absent. There may be formication of the feet but anaesthesia is wanting. The vagal involvement gives cardiac disturbances. There is anaemia.
Infantile Beriberi.—There is also a condition in nursing infants which would be difficult to recognize if unaware of the existence of this type of beriberi. It is called infantile beriberi.
In 1898 Hirota first noted the existence of a condition in infants nourished by beriberi mothers which has more recently been carefully studied by McLaughlin and Andrews and to which the name infantile beriberi is now generally given. In the Philippines it is called “taon.” Clinically there is restlessness, vomiting, altered voice, increased heart action, oedema and cyanosis. After death there is found a marked hypertrophy and dilatation of the right side of the heart with no change of the left side. The peripheral nerves also show the lesions of beriberi of adults but of less intensity.
The disease most often shows itself in an acute form, the child rather suddenly being seized with great pain, crying constantly and soon becoming cyanosed. Death, which may occur in a few minutes or hours, is often thought to be due to meningitis, although there is no fever or true convulsions. There is only rigidity of the body. Less frequently the disease appears in a chronic form in which vomiting and constipation are most marked. There is often a history of the loss by the mother, who herself may have only a rudimentary beriberi, of several children from this disease.
The infants improve rapidly when other infant feeding is substituted for the mother’s milk. An extract of rice polishings gives striking results in these cases.
Asylum Beriberi.—The beriberi outbreaks which have frequently been reported from European and American camps, prisons and asylums do not differ from the cases one may see in the classical distribution of the disease among the rice-eating populations of the Orient. The cause is the same, a deficiency in beriberi-preventing vitamines, and the symptoms are similar. These vitamines may be deficient in the rice or other cereal or proteid food supplied. Again they may have originally been present in sufficient quantity but later destroyed by too great heat or otherwise.
=Types of Beriberi.=—The ordinary clinical division of beriberi is into (1) wet or dropsical beriberi and (2) dry or atrophic beriberi. At the same time, in a typical case, we find such a combination of the vasomotor disturbances which lead to the oedematous or dropsical manifestations of wet beriberi, and likewise of those of peripheral nerve involvement causing more or less development of muscular palsies or atrophies, as seen more strikingly in dry or atrophic beriberi, that it does not seem advisable to employ such a division.
In fact typical cases of wet or dropsical beriberi after a profuse diuresis may change in a short time, as Manson has so aptly stated, from a bloated carcass to little more than skin and bones and assume all the appearance of a case of dry or atrophic beriberi.
Even Vedder, who states that from a theoretical standpoint wet and dry beriberi may be considered separate pathological processes (deficiency in the anti-cardiac degeneration vitamine rather than the anti-neuritis one), is inclined to believe it inadvisable, from a clinical standpoint, to consider the one type apart from the other.
One sees cases which combine the features of dry and wet beriberi which can best be designated typical beriberi. Again we see cases where the vagal and vasomotor involvement is so marked that the patient resembles a man with acute nephritis plus all the evidence of extreme cardiac decompensation. Such cases may be designated fulminating, pernicious or better cardiac.
Again we observe cases which from the start show little if any oedema and very slight cardiac involvement, but with marked motor disturbances as shown by muscular atrophies and palsies. The sensory changes are not so marked as the motor ones. Complete anaesthesia is rarely present, it is rather paraesthesia and blunting of sensation which characterize the sensory phenomena. This is usually designated the atrophic or paraplegic type.
Rudimentary or Larval Beriberi.—Scheube recognizes a rudimentary type and it must have been the experience of every one in the tropics that these indefinite types of beriberi are quite common.
In such cases there may be nothing more than some weakness of the legs with vague manifestations of blunting of the sensation or variation of the reflexes. At times there may be marked anaesthesia in the region over the shin bones.
Many of these cases show cardiac palpitation on exertion and at times we may note slight evidences of oedema about the lower part of shin bone or dorsum of the foot. It is the frequency of such cases that causes physicians in the tropics to consider almost any affection showing neurological manifestations as of beriberi nature. A careful study of the neurological features of cases in the tropics will show that many of these cases are not beriberi but rather the common cosmopolitan diseases of the nervous system.
=A Typical Case of Beriberi.=—The patient first complains of weakness and heaviness of the legs, particularly after fatiguing work. There is also noted a sense of fullness and tenderness in the epigastric region. The slightest exercise brings about cardiac palpitation and more or less dyspnoea.
As the symptoms of peripheral neuritis become more prominent we have hyperaesthesia of the calf muscles so that squeezing these muscles gives rise to rather marked pain. The thenar muscles or those of the forearm may also be more or less hyperaesthetic. Attention has been called to a circumoral anaesthesia.
An examination at this time will probably show an active patellar reflex, some oedema over the shin and malleoli, possibly extending to the dorsum of the foot, with partial anaesthesia in the oedematous areas. It is a blunting of sensation as though a layer of cotton were interposed between the skin and the examining instrument. Other favorite sites for the oedema are the sacral and sternal regions. Occasionally sharply defined oedematous patches may be observed, particularly on the arms.
The exercise attendant upon the physical examination will probably cause a rather marked cardiac palpitation. The pulse is usually rapid and its rate is markedly affected by the slightest exertion. The systolic pressure is low.
The anaesthesia noted in the lower extremities soon tends to show itself about the back of the hands and the finger tips, so that it may be difficult for the patient to button his coat. There is also weakness of the grip. The temperature is normal and the mind is entirely clear. The results from a blood examination are practically negative, although later on there is the blood picture of a secondary anaemia.
In cases where the oedema is more marked and generalized and when pericardial or other effusions are developing we find a diminution in the amount of urine, but with an absence of albuminuria.
Later the case may show a dropsical condition more or less resembling nephritis, but with only slight scrotal oedema. At the same time there will be found a dilatation of the right heart with blowing systolic murmurs and equal spacing of the heart sounds. There may be marked pulsation of the veins of the neck. At this time the patellar reflex may be diminished and the anaesthetic areas more extensive.
This condition of wet, dropsical or oedematous beriberi may be fairly rapidly succeeded by a disappearance of the oedema with, as a result, the making more striking of the muscular atrophy incident to the neuritis of the peripheral nerves. In this, the atrophic, dry or paralytic beriberi, the jongkok test is of value. With the hands over the head the patient squats down on the calves of his legs and attempts to rise—something impossible for the beriberic. At this time the patellar reflex probably cannot be elicited and later on there will be found foot and wrist-drop with atrophy of muscles. With complete foot-drop, the reactions of degeneration will be found.
A combination of the dry and wet types of beriberi is often described as the mixed type.
It must always be remembered that the course of the ordinary case of beriberi is essentially chronic, running over months or years.
=Acute Pernicious Beriberi.=—This is the fulminating type of beriberi in which the marked involvement of the vagus overshadows the other but less manifest phenomena of the disease. In some cases the signs of peripheral neuritis may be quite prominent before the fulminating onset of the cardiac manifestations, there being almost a total lack of disturbance of the vasomotor system. Again we may have slight if at all demonstrable motor or sensory disturbances but with marked oedema. It should be borne in mind that this development of cardiac disturbance with its fatal tendency may develop even in a case of rudimentary beriberi. It is a common experience that cases considered as mild types may, in a few hours, show cardiac involvement and terminate fatally with striking suddenness.
There is apt to be marked epigastric tenderness or even distress coming on with the onset of the acute cardiac involvement. It may be so extreme that the patient dreads the slightest palpation of his epigastrium. From a marked palpitation and praecordial distress evidences of the dilatation of the right heart become prominent. Indications of tricuspid insufficiency are seen in the pulsating jugulars and cyanosis. The cardiac dullness is greatly increased to the right and various abnormalities of sounds and rhythm may be observed. There is also dyspnoea and a sensation of constriction of the chest (beriberic corset). These are the cases which give as horrible a picture of death as one ever sees. In the final struggle for breath and praecordial agony of the last stages of decompensation in old heart lesions we have a more gradual course in a more asthenic patient. Acute pernicious beriberi may run its course in a strong, vigorous patient in a few hours. In some cases we have paralysis of the diaphragm.
=Paraplegic and Rudimentary Types.=—The rudimentary type has already been considered and it would be impossible to draw a line between slightly developed paraplegic cases and rudimentary ones. The paraplegic cases show the weakness of feet and hands going on to wrist and foot-drop. There is also marked blunting of sensation of feet and hands which gives one the impression of ataxia when the patient tries to button his coat.
There is atrophy of muscles so that the grip of the patient is enfeebled. This partial anaesthesia also accounts for the pseudoataxic gait in which the element of muscular weakness is prominent as opposed to the vigorous heel stamping gait of the ataxic tabetic. The patient drags the toes and leans forward on a cane when walking, thus suggesting the tripod.
It is the typical steppage gait of degeneration of the lower motor neurones. It is a flaccid, atrophic paralysis of the muscles.
There is no involvement of the sphincter.
Beriberic Residual Paralysis.—Hamilton Wright has used the term beriberic residual paralysis to indicate cases which, in the course of convalescence and favorable regeneration of axis-cylinders and more or less return to a normal condition, become subject to some factor lowering the vital forces and body resistance and experience a return of the beriberi manifestations. To use a common expression the patient has a set-back and the favorable progress to complete recovery is temporarily in abeyance.
Symptoms in Detail
Nervous Symptoms.—The most common symptoms are those connected with degenerations involving the peripheral nerves of the extremities. The motor nerves are more involved than the sensory ones, there being rarely complete anaesthesia, but rather a blunting of sensation as though a piece of cloth were interposed between the examining instrument and the skin. At first there is weakening of the muscle power as shown by the grip of the hand or weakness of foot muscles. In more advanced cases we may have foot and wrist-drop. Hyperaesthesia of the muscles is prominent, especially that of the calf muscles. The unsteadiness of gait is not true ataxia as the patient does not clearly show the Romberg sign. It is muscular weakness rather than incoördination.
The Argyll-Robertson pupil is absent. The gait is the steppage one of peripheral neuritis, the patient walking as if extracting one foot after the other from clinging mud. Later on, when other muscles than the foot extensors are involved, the gait becomes a shuffling one. The mind is entirely clear. The vasomotor phenomena are often marked as shown by patchy or most extensive development of oedema and serous exudates. The knee-jerk is usually absent. Fibrillary twitchings may be observed in beriberi as well as in progressive muscular atrophy. The extensors of arms and legs are more markedly affected than the flexors. The cardiac symptoms are really connected with vagal involvement.
The Cardio-respiratory Symptoms.—Owing to involvement of the vagus the inhibitory apparatus is deranged so that we have palpitation and rapid pulse rate both of which are markedly increased by the slightest exertion.
The blood pressure is below normal. Shortness of breath is the earliest feature of respiratory trouble. This may go on to marked thoracic oppression and dyspnoea.
Aphonia may be present in acute pernicious beriberi and probably indicates laryngeal palsies. Such cases are usually fatal.
Pulmonary congestion and oedema always accompany the terminal right side dilatation of the heart which is responsible for the cyanosis, pulsating jugulars and various murmurs. The pulmonic second sound is accentuated and may be reduplicated. The rhythm of the heart sounds is replaced by the equal spacing of embryo-cardia. The diaphragm may be paralyzed as may also happen to the intercostal muscles.
Digestive and Urinary Symptoms.—Those who considered beriberi as an acute infectious disease were disposed to note frequently evidences of toxaemia as manifested by nausea, vomiting and epigastric distress. As a matter of fact these symptoms only become very prominent in pernicious beriberi and may well be connected with the cardiac decompensation. However caused vomiting is of unfavorable prognostic import.
The amount of urine is markedly decreased when oedema is advancing but is succeeded by a polyuria when this diminishes. If albumin should be present it is not connected with beriberi but some other condition.
Other Features.—There is nothing characteristic about the blood other than a slowly developing anaemia.
Oedema is the most striking feature of wet beriberi. When slight this oedema may only involve the pretibial-region or sternum. Circumscribed areas of oedema may be present on the upper parts of the body as neck and trunk.
Hydropericardium is the most frequent of the exudates into serous cavities. Fever is almost always absent except in epidemic dropsy.
DIAGNOSIS
When the case is one of mixed type with the oedema, cardiac involvement and signs of peripheral neuritis the diagnosis is readily made. A diagnosis of nephritis is often given the wet type of beriberi and locomotor ataxia the dry form, by those who have not in mind the possibility of the disease existing in an oriental crew after a long voyage.
The urine in beriberi is as a rule normal and there are no peripheral nerve disorders in nephritis. Chagas has noted that a quartan form of malaria gives rise to oedema about the ankles and is often mistaken for beriberi by the physicians of the Amazon region.
The cardiac manifestations of beriberi differ from those of valvular disease in that the murmurs are muffled and there does not exist the definite areas for the location of the murmurs of the various valvular lesions. The rapid development of a pericardial effusion is also against valvular heart disease.
The absence of lancinating pains, typical Romberg sign and Argyll-Robertson pupil should differentiate from tabes.
The tripod gait of beriberi takes its name from the wide separation of feet and use, with the hands, of a cane in front. It is a steppage gait instead of the ataxic one of tabes. On account of the lack of power to raise the toes in walking, the beriberic lifts the hip and swings to one side in order to avoid scraping his toes.
In progressive muscular atrophy the palsy attacks the hand first and in a more advanced case showing the main-en-griffe there would also be deltoid involvement. Of course beriberi may show the main-en-griffe characteristic but the greater involvement of the feet with vagal phenomena differentiates.
Ship Beriberi.—A disease of importance on Scandinavian sailing ships to which the designation “ship beriberi” has been given resembles beriberi in that we have oedema particularly of the lower extremities and at times generalized so that a case would appear to be one of wet beriberi.
More or less dyspnoea and cardiac palpitation are features of the disease as of beriberi. In fact death often is the result of acute cardiac paralysis. The striking point of difference is the generally reported absence of manifestations of neuritis and Nocht in an autopsy of a case failed to find evidence of degeneration of the peripheral nerves.
Another point of distinction is that once the ship arrives in port and a diet of fresh meat and vegetables is substituted for the one of sterilized canned meats and desiccated and preserved vegetables, the patient recovers rapidly so that in one or two weeks there is no sign of the disease remaining. Beriberics improve at once when put on a curative diet but the damage done the peripheral nerves makes complete recovery a matter of weeks or months. Nocht is of the opinion that ship beriberi is closely related to scurvy as he found sore gums and haemorrhages into muscles in some of his cases. He also notes that even in true scurvy there may be cases of dropsy without the spongy gums and haemorrhages. Dropsy plus sore gums is not infrequently noted in the beriberi-like affection of the men of the French fishing fleet off the Newfoundland banks.
Schaumann believes that ship beriberi is due to an acute deficiency in phosphorus, a chronic deficiency causing beriberi. It is probable that this disease is caused by a deficiency in certain vitamines, these being destroyed in the sterilization of canned meats or by drying vegetables.
Scurvy.—It will be remembered that in scurvy, which is the classic food deficiency disease, we have spongy, swollen gums, loose teeth, oedema about ankles and, in particular, haemorrhages into skin at site of hair follicles and tumor-like haemorrhages into subcutaneous and muscular tissues. Haemorrhages into the mucous membranes are not uncommon. The heart shows marked palpitation and weakness.
The scurvy vitamine is much less stable than the beriberi one. It is contained in fresh foods only, drying destroying it.
In connection with the question of multiplicity of vitamines monkeys fed on rice will develop beriberi while if fed on a bread deficiency diet they develop scurvy.
In Mesopotamia the Indian troops suffered greatly from scurvy but not from beriberi while the British troops had many cases of beriberi. From July to December there were 11,445 cases of scurvy among the Indian forces and 104 cases of beriberi among the British. During this period the British ate white biscuits, tinned meats and horse flesh. This latter protected them from scurvy but the Indian troops would not eat the fresh meat but ate barley flour instead. The antiscorbutic vitamines are sometimes designated as water soluble C vitamines.
Rand Scurvy.—In investigating the endemic scurvy on the Rand, in South Africa, Darling noted hypertrophy and dilatation of right heart. Such cases often showed vagal degeneration. Pathologically, these cases were closely related to beriberi, but clinically, they showed spongy gums, and haemorrhages elsewhere. The knee-jerks were always exaggerated.
Infantile Scurvy.—As differing from infantile beriberi, we have in infantile scurvy, which is attributed to the use of sterilized milk instead of fresh milk, a tendency to separation of the epiphyses from the shafts of the bones and extreme sensitiveness to any movement particularly of the legs. A markedly anaemic and asthenic condition is also characteristic. The chief lesion is a subperiosteal blood extravasation.
Milk contains several vitamines some of which, as the growth vitamine, are, destroyed in boiling; others, however, are not destroyed until subjected to a temperature of about 120°C.
War Oedema.—In those areas of Europe where famine conditions were approached during the great war a condition of weakness and oedema was noted by many observers and to this symptom-complex various designations were applied such as war dropsy, war oedema, etc. The oedema was more marked than would be true in ordinary cases of starvation so that such factors as consumption of large amounts of water and salt in the thin soups so prominent in the dietary, plus hard work, must have been additional causes.
The oedema was most common in the feet and legs, at times extending to the thighs and trunk, and in about one-half the cases involving the face. Marked muscular weakness and alimentary disturbances were common. There was dyspnoea on slight exertion with a slow pulse, but cardiac disturbances were not features of the disease. The urine was pale, of low specific gravity and free of albumin. There was reduction of red cells and a tendency to leukopenia. These cases showed marked emaciation upon the disappearance of the dropsy. As is well known the deficiency in fats was marked in Central Europe so that it was to be expected that ocular manifestations should be frequently noted, deficiency of fat soluble A being the exciting cause of xerophthalmia. The cases tended to recovery under proper diet and hospital care.
Probably the most important conditions to consider in differentiation of beriberi are the peripheral nerve involvements caused by alcohol and arsenic.
In alcoholic neuritis there is the history of alcoholic excesses, long-standing digestive disorders and tremors of hands, lips and tongue. Chiefly characteristic, however, is the mental involvement, such cases almost always showing loss of memory and defective mental concentration.
Mental symptoms and tremors are practically absent in beriberi and we have here the marked feature of vagal involvement plus vasomotor phenomena.
In arsenical neuritis we have an early puffiness under the eyelids and pigmentation of the skin which first shows itself in areas normally pigmented. A dysenteric syndrome may also be present.
There would be less chance of confusing lead palsy as this chiefly involves the upper extremity. Punctate basophilia, lead colic and the blue line on the gums should differentiate.
In diphtheritic palsies the muscles of the soft palate are involved in more than 75% of cases. Ocular palsies are also not infrequent.
In lathyrism we have a history of the eating of the chick-pea (Lathyrus sativus) or other vetches, as may occur in times of famine. Pain in the back, weakness of the legs and symptoms of spastic paraplegia appear. The spasticity differentiates. The heart is not affected.
It may be stated that there is no laboratory diagnosis for beriberi.
PROGNOSIS
There is no disease in which one should be more conservative in making a favorable prognosis than in beriberi. A case which seems to be progressing toward recovery may suddenly develop cardiac disturbances and die in a very short time.
We now know that a change to a beriberi-preventing diet is practically curative.
The mortality rate varies in different countries and in different epidemics, so that we have death rates varying from less than 2 per cent. to those exceeding 50 per cent. In acute pernicious beriberi the prognosis is almost surely fatal.
The epidemic of beriberi which prevailed at Manila in 1882 seems to have been attended by a great mortality, this having been as high as 60% during the early part of the outbreak.
PROPHYLAXIS AND TREATMENT
=Prophylaxis.=—It must be remembered that not only is rice, from which the neuritis-preventing vitamine has been removed by excessive milling, productive of beriberi but that the same applies to other cereals which have been similarly deprived of their vitamines.
The same result may be obtained by the employment of excessive sterilization for canning.
Fresh meat is as valuable as fresh vegetables in prophylaxis but if either kind of food be subjected to excessive heat, as is the case with tinned meats, etc., they not only do not prevent beriberi but in a negative way are beriberi-producing.
While boiled beef is heated throughout, with more or less complete destruction of vitamines, roast beef does not sustain a temperature above 70°C. in its interior, hence the greater portion of the vitamine content is present in such meat.
It is possible that moulds may deprive cereals of their vitamines so that spoiled cereals may be beriberi-producing. There have been many reports both from asylums and prisons which would indicate that the employed and the patients or prisoners lived on the same ration yet the guards or nurses failed to develop beriberi, which disease was prevalent among the inmates. Such statements rarely stand the test of investigation. The same is true of pellagra.
Many of the reported outbreaks of beriberi among those who were enjoying an abundant ration have been found to be connected with the almost exclusive consumption of expensive canned meats and vegetables.
As the beriberi vitamine is apparently important in carbohydrate metabolism, a greater ingestion of carbohydrates demands more vitamine, hence an increase in carbohydrates, without corresponding increase in vitamine-containing foods, may bring on beriberi where, before the increase in carbohydrates, there was an absence of beriberi.
In connection with the development of beriberi it must always be kept in mind that debilitating conditions such as unhygienic quarters and overexertion, as well as disease conditions (malaria, ancylostomiasis, etc.) are factors of importance. In military forces excessive drills should be stopped. The fatigue factor is to be kept in mind in this as in other food deficiency diseases.
A combination of barley, which is rich in vitamines, with the rice is important in oriental countries, thus a diet containing 6 parts barley to 4 parts rice and used in Japanese prisons, on account of its cheapness, not only prevented beriberi but cured the disease in beriberics entering prison.
There is no doubt but that legislation against rice which contains less than 0.4% of P_{2}O_{5} is a valuable measure of prophylaxis. Polished rice has lost in P_{2}O_{5} as well as in vitamines.
Heiser has proposed that an excessive tax be placed on polished rice with free entry for the unpolished article. The following suggestions of Vedder in connection with prophylaxis would seem to be worthy of consideration in pellagra as well as in beriberi.
1. In any institution where bread is the staple article of diet, it should be made from whole wheat flour.
2. When rice is used in any quantity, the brown, undermilled, or so-called hygienic rice should be furnished.
3. Beans, peas, or other legume, known to prevent beriberi, should be served at least once a week. Canned beans or peas should not be used.
4. Some fresh vegetable or fruit should be issued at least once a week and preferably at least twice a week.
5. Barley, a known preventive of beriberi, should be used in all soups.
6. If corn meal is the staple of diet it should be yellow meal or water-ground meal, i.e., made from the whole grain.
7. White potatoes and fresh meat, known preventives of beriberi, should be served at least once a week, and preferably once daily.
8. The too exclusive use of canned food must be carefully avoided.
McCarrison has noted the value of onions even in a diet in which protein and vitamine constituents are sufficient. The onions seem to inhibit the growth of putrefactive bacteria.
=Treatment.=—The most important treatment is that of the substitution of a diet containing the essential vitamines for the beriberi-producing one. In carrying this out regard must be had for the customs and tastes of the race concerned. Thus fresh beef may be excellent for some people but objectionable to others. Eggs, particularly the yolk, are very valuable as is also true of unsterilized milk. Extract of rice polishings has given splendid results in infantile beriberi but does not seem to have been as efficacious in the disease in adults. Yeast has great curative value. An extract of yeast known as marmite has achieved reputation when given in doses of 20 grains daily. Seidell has recently used an autolyzed brewers’ bottom yeast. By treating this material with Lloyds’ reagent he has extracted the vitamines so that instead of having to give 200 cc., a dose of 10 grams of the concentrated product suffices.
Malt extract is very rich in vitamines and liver seems to have a higher content than beef muscle. Fat soluble A vitamine is abundant in glandular organs but scarcely present in the beef of our markets—this is probably true of water soluble B. Heart muscle is about on a par with liver. Germinating wheat and beans seem to have special value in treatment as well as prophylaxis.
In the treatment of a case care must be had not to allow a patient with any cardiac involvement to sit up in bed as this may cause sudden death. Braddon considers atropine hypodermically as of value in cardiac types of cases.
Amyl nitrite inhalations or injections of 1% solution of nitroglycerine are indicated when there is evidence of extreme cardiac dilatation. Venesection is also to be kept in mind. Cardiac tonics are of less value than rest, diet and venesection.
In the feeding of such patients only small amounts should be given at a time to avoid epigastric distress. Again carbohydrates should be restricted as there is evidence that excess of carbohydrates as well as vitamine deficiency may be concerned in the disease. The bowels should be kept open with salines. Mineral oil tends to keep down intestinal putrefaction which is a factor of importance.
Strychnine is usually given as a routine treatment in the less acute cases. With muscular atrophy massage is of prime importance. Electrical stimulation is also usually employed. With the palsies there is great danger of contractures so that even the bed clothing should not rest upon the paralyzed feet. Even splints may be necessitated.
XIX. PELLAGRA
DEFINITION AND SYNONYMS
=Definition.=—For a time it seemed as if the old idea that pellagra was connected with a dietary defect, chiefly as regarded some factor in a preponderating diet of maize, had been replaced by one assigning as cause some infectious process, probably protozoal, possibly bacterial.
The important advances recently made in the study of beriberi have tended once more to swing the pendulum to the food deficiency etiology. The latest views assign to food deficiency the basic etiology, but regard some other factor, possibly an infectious one, as secondarily operative.
The disease is essentially chronic with periodic exacerbations but may run a rather acute course with a rapidly fatal termination. The trend of symptoms consists of (1) mild neurasthenic manifestations in the winter to be followed in the spring by (2) disturbances of the alimentary tract, consisting of stomatitis, burning sensations going up the oesophagus, gastric eructations and recurring diarrhoeas. (3) In addition to the neurological and alimentary tract symptoms we have the third and diagnostically the most important group, those of the cutaneous system. The pellagrous eruption is characterized by strikingly symmetrical, sharply delimited patches of erythema, resembling sunburn. The sites of preference are backs of hands, extending up the forearms, bridge of nose or neck. The neurasthenia tends to pass into a toxic psychosis or even a confusional insanity.
=Synonyms.=—Maidismus, Alpine Scurvy, Asturian Leprosy, Mal de la Rosa, Mal del Sole.
HISTORY AND GEOGRAPHICAL DISTRIBUTION
=History.=—Strambio considers some of the references of Hippocrates to refer to pellagra but Castellani and Chalmers state that after searching the writings of Hippocrates they have been unable to find any references to a disease showing a resemblance to pellagra.
The first definite description of the disease is generally credited to Casal who, in 1735, described the disease as it existed in the Asturias.
In his writings he notes that the peasants lived chiefly on corn and that they rarely had fresh meat.
Casal’s paper was not published until 1762 but Thitery, who visited Spain and was shown cases of pellagra by Casal, described the disease in 1755 and gave full credit to Casal for the recognition of the disease. The name of the disease was given it by Frapolli, in 1771, the derivation being from pelle—skin, and agra—rough. The disease had then existed in Italy for a considerable time.
Casal called the disease mal de la rosa.
In 1810, Marzari insisted that the two diseases, pellagra and Alpine scurvy, which had a few years previously been recognized as identical, were caused by the consumption of maize and from this time on the maize theory as to etiology has been supported in Italy.
Later on (1872 to 1909) Lombroso elaborated the maize theory of etiology and so strongly presented this view that it is impossible for us lightly to set aside the arguments of this great physician.
While the zeists, as the advocates of the maize etiology are termed, insist that pellagra made its appearance in Europe following the introduction of Indian corn, after the voyages of Columbus, there does not seem to be any evidence that pellagra ever existed among the North American Indians. In 1905 Sambon insisted that pellagra was a protozoal disease and in 1910 claimed that it was probably transmitted by a midge, Simulium reptans.
About 1907 pellagra was found to be an important disease of the Southern States of the United States and since that time the number of cases has steadily increased so that it is now estimated that there have been approximately 200,000 cases in the United States.
It is generally conceded that isolated cases of pellagra had occurred in the United States prior to 1907, but they generally were diagnosed differently.
=Geographical Distribution.=—In Europe it is most prevalent in Italy, Balkan States, Greece, Turkey, Spain and Portugal. In Roumania there were about 100,000 cases in 1906. The disease has decreased in incidence and virulence in Italy, there having been in 1910 only 33,869 cases, as against 104,607 cases in 1881.
The disease was first recognized in Egypt by Sandwith in 1893 and is now known to be widespread in Lower Egypt. It is rare in Upper Egypt where they live on millet instead of maize. It exists in Algiers.
It has been reported from India and the Straits Settlements and prevails extensively in the West Indian Islands as well as in Mexico and Central America.
The disease in the Southern States of the United States is of a more fatal type than elsewhere, the average mortality having been 39.10%. The death rate in the United States has fallen, thus the rate in Mississippi for the years 1914 to 1916 was only ten per cent.
At present the Italian mortality is only about 3% although formerly it was much higher.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—Like other diseases of unknown etiology the views in this connection are innumerable.
Zeists and Anti-zeists.—It is customary to divide the adherents of the different views as to the cause of the disease into two groups, the zeists, who advocate a connection between maize or Indian corn (Zea Mays) and the disease, and the anti-zeists, who claim that corn has nothing to do with pellagra.
Food Deficiency.—Before taking up the better known considerations noted above it may be stated that many now believe that pellagra, along with beriberi and scurvy, belongs to the group of “food deficiency” diseases. Just as beriberi is caused by the absence of a neuritis-preventing substance or vitamine in the dietary, so is the symptom-complex of pellagra brought about by the absence from the dietary of some vitamine or vitamines essential to proper metabolism. There are various ideas as to the factor which eliminates the pellagra-preventing vitamines.
Some claim that in the process of milling maize the vitamine-containing outer portion (bran) has been taken off just as with beriberi-producing white rice, from which the pericarp with its neuritis-preventing vitamine has been more or less completely removed.
From analyses of milled maize and millings Funk has recently suggested that pellagra in different countries is in relation to the degree of milling. Just as with rice and maize so does excessive milling of wheat get rid of vitamines, therefore, bread made from highly milled flour is dietetically deficient.
Again, as brought out by Voegtlin, alkalis tend to destroy any remaining vitamines in such bread. The practice of using sodium bicarbonate in preparation of bread is a further factor in the food deficiency problem. With the use of baking powder or buttermilk the alkaline carbonate of soda is neutralized so that there is no destructive effect on vitamine content.
The vitamine deficiency of highly milled flour and highly milled corn meal runs parallel with the phosphorus pentoxide content of such products. Whole wheat shows about 1.1% P_{2}O_{5}, while highly milled flour contains only about 0.1%. Whole corn has about 0.76% P_{2}O_{5}, while milled corn meal has only about 0.3%. Highly milled rice has under 0.4% P_{2}O_{5}.
Others think that as the result of bacterial or mould diseases of the corn grain these important vitamines are destroyed. Then too, as with rice and beriberi, the prevailing idea is that while there is a striking association between a maize dietary deficient in the pellagra-preventing vitamine and the occurrence of pellagra, yet this deficiency may be supplied by other foods.
Beriberi seems rather definitely to be associated with a deficiency in the anti-neuritis vitamine, which is probably the same as water soluble B., and in pellagra-producing diets a similar deficiency may be noted. More striking however is the deficiency in fat soluble A in such diets. This vitamine is abundant in butter fat and egg yolk, articles of diet of which pellagrins are deprived.
Leaves of plants contain it in abundance, while with seeds it is present in less degree and then contained in the embryo, which latter is lost in milling. Millet contains an exceptionally large amount of fat soluble A and it is well known that in Egypt those living on millet instead of maize escape pellagra. The protein of millet has a high biological value which is the reverse with that of maize. It should be noted that besides vitamine and protein deficiencies the lack of inorganic salts should be considered.
Protein Deficiency.—Animal protein is a superior protein and maize protein an inferior one. Wilson grades proteins according to their assimilability and taking meat protein as 1 he assigns to maize protein a relative value of 3.4, which means that one must consume 3.4 times as much maize protein as that of meat to obtain the necessary protein requirements. Thirty grams of animal protein daily is sufficient to maintain nitrogenous equilibrium but Wilson considers 40 as a minimum B. P. V. (Biological protein value). We should have to consume 136 grams of maize protein to obtain a B. P. value of 40. Where hard labour is required the B. P. V. should be 50 and when associated with chronic intestinal disease it should be as high as 60.
Wilson noted a B. P. V. of 23 for males in the diet which caused an outbreak of pellagra in Armenian refugees at Port Said. The diet of the pellagrous Turkish prisoners in Egypt had a B. P. V. of 33.5. It may be stated that zein, the protein of maize, is deficient in tryptophane and lysine, two important amino-acids necessary for proper nutrition. Chick apparently produced pellagra in a monkey fed on a low protein diet (Total protein 8.2 grams, of which all but 2.7 grams was from zein.). The monkey was given an abundance of accessory food substances in butter, marmite and orange juice.
Amino-acid Deficiency.—In a recent paper Goldberger and Tanner note that a low biological protein value is not necessarily indicative of a pellagra-producing diet. In a series of experiments the deficiency of vitamines did not seem to be related to pellagra production and the same was true of the mineral elements. In studying the nature of low protein biological values they were of the opinion that this rested in certain amino-acid deficiencies in the proteins consumed by the pellagrins. Benefit seemed to result from administering cystine to two cases of pellagra and in a third case there was steady improvement following the giving of both cystine and tryptophane.
It is a question whether zein, the principal protein of maize, contains any cystine.
Goldberger and his colleagues, after a careful investigation of pellagra epidemiology, decided that such facts as the complete absence of the disease among the nurses and attendants of the pellagrous insane, or among the prison guards of institutions where pellagra prevailed extensively, as well as among those caring for pellagrous orphans, indicated that a dietary factor rather than an infectious one was operative in the disease. Even where it was stated that attendants and inmates of institutions had the same dietary investigation indicated that as a matter of fact the insane and the prisoners were not as well fed as the other group. Then too the insane frequently fail to avail themselves of the food provided.
A study of the records of the Army and Navy of the United States failed to show that a single case of pellagra had ever developed among the personnel, although large numbers of the men came from pellagrous districts of the South. This exemption they thought due to the generous service ration.
In an investigation of the diet of the workingman’s family in the North and South it was found that the southern one consumed much larger quantities of starches and fats than the northern one, but less fresh meat. In the family of the cotton mill operative, a class showing a great incidence of pellagra, corn bread, flour biscuits, and fat pork were the chief articles of diet. There is a great deal of ancylostomiasis among these cotton mill people and the debilitating effect of this disease may predispose to pellagra. The general rise in the cost of food and, in particular, the disproportionate increase in price of meats over cereals, since 1907, may explain the greater incidence of the disease since that time. The wages of southern mill operators have also suffered on account of frequent periods of financial depression during the last ten years, thus causing them to buy cereals rather than meats.
Goldberger’s Experiment.—In February, 1915, Goldberger started a “pellagra squad,” consisting of 11 prisoners on a diet of wheat flour (patent), corn meal, corn grits, corn starch, polished rice, granulated sugar, cane syrup, sweet potatoes, fat fried out of salt pork, cabbage, collards, turnip greens and coffee. Baking powder was used for making biscuits and corn bread. The food value of each man’s diet averaged 2952 calories.
A control was carried out with prisoners on a normal diet. The experiment was continued until Oct. 31, 1915. Of the 11 volunteers on the excessive carbohydrate diet six developed symptoms. Loss of weight and strength and mild neurasthenia were early symptoms. Definite cutaneous manifestations appeared only after five months. The skin lesions were first noted on the scrotum, later appearing on backs of hands in two cases and back of neck in one case.
There are those who believe that the methods of preserving foods, cereal or proteid, by sterilizing at high temperatures, destroy the vitamines so essential to proper metabolism so that people who subsist extensively on canned vegetables and preserved meats, instead of fresh meats and vegetables, may develop pellagra. Evidence of this sort is obtainable in the mill villages of the Southern States of the United States where pellagra is so very prevalent.
We are now beginning to recognize that slight and vague digestive trouble may be pellagrous in nature although never going on to the development of the cutaneous, neurological and alimentary tract diagnostic triad of symptoms.
Again there would appear to be efficient resistance to pellagra in those who are in good physical condition, but when reduced by illness, or the effects of poor diet and defective hygienic surroundings, they may develop it. There are those who think that hookworm disease is an important factor in predisposing to pellagra.
Not only does alcoholism, when coexistent with pellagra, make for a bad prognosis but there are many who think that any abuse of alcohol predisposes to pellagra. Against this however is the fact that pellagra in the United States is about five times as common among women as among men. It is generally recognized that pregnancy and lactation predispose to pellagra.
Pellagra in Turkish and German Prisoners.—There were (up to the close of 1919) 9257 cases of pellagra among 105,668 Turkish prisoners (1 in 11) and 79 cases among 7606 German prisoners (1 in 96). The Turkish prisoners had been on a deficient diet before capture and the diet after capture had a B. P. V. of 33.5. The labour group of the prisoners had a B. P. V. of 36.8 and the disease was much more prevalent among them than in those not working. Hammond-Searle notes that the diet of the nonworking European prisoners was probably insufficient to prevent pellagra. On the average the disease appeared among the German prisoners 4½ months after capture. They stated that while in Turkey their diet had been excellent but almost all had suffered from dysentery or malaria. In the Turkish prisoners diarrhoea was a prominent feature and Bigland suggests a possible toxin action resulting from a damaged intestinal mucosa. Stools from pellagrous Turkish prisoners showed organisms similar to B. perfringens in 90% of cases while such organisms were not found in the stools of healthy prisoners.
The Zeistic Views.—The idea which was at one time entertained that maize, whether good or bad, brought on pellagra has now been generally abandoned, owing to investigations, which proved that corn possessed a fair nutritive value and was easily assimilable, together with evidence to show that where care was taken in the maturing of the grain and the prevention of decomposition by moulds or bacteria, pellagra was either nonexistent or diminished in a district where such measures were instituted.
The statement is frequently seen that pellagra did not make its appearance in Europe until after the introduction of maize, subsequent to the discovery of the New World. There are authors who think Casal was suspicious of a maize dietary.
The zeistic views now incorporate some additional factor with the basic one of a rather exclusive maize dietary.
1. The verderame theory of Ballardini. From noting on the corn grains a covering with a greenish mould, Ballardini in 1845 advanced the view that pellagra was due to this mould and from this time on we have the so-called zeitoxic views, which hold that pellagra is caused by spoiled corn. Ceni and Fossati regard a toxin elaborated by various moulds as causative. The fungi toward which attention has been chiefly directed are Aspergillus fumigatus and A. flavescens as well as certain species of Penicillium and Mucor.
2. The Lombroso view that as a result of the action of moulds or bacteria, toxins are elaborated which, when ingested, give rise to the disease.
3. That the toxins have origin in the action of various organisms, especially B. coli, on the ingested corn, while in the intestines.
4. Recently views have been brought forward that pellagra is an anaphylactic phenomenon connected with sensitization to the maize proteins.
5. Rabitschek has brought forward a photodynamic theory which is that pellagra is due to a preponderating maize or possibly other cereal dietary which results in certain photodynamic substances being introduced into the circulation. These substances become toxic under the influence of sunlight. Hirschfelder has failed to find any fluorescent body in the serum of five patients suffering with severe pellagra.
Among arguments in favor of the maize etiology of pellagra may be mentioned the following:
(a) Among the natives of Upper Egypt, where millet instead of maize is the staple cereal, pellagra is rare, while in Lower Egypt where much maize is eaten the disease is far more prevalent.
(b) While the natives of Corfu, prior to 1857, grew their own maize and ate only sound grains there was no pellagra but later, when the corn crop was less profitable, and the grain was imported from Roumania, much spoiled maize was brought in and pellagra made its appearance.
(c) Alsberg has shown that in recent years new methods of harvesting corn have become common in the Southern States of the United States. Instead of topping the corn it is cut and shocked with the result that conditions are more favorable for the spoiling of the corn. He also notes that varieties of corn are now planted which have a greater oil content, which means a larger embryo, and that it is this embryo which most easily spoils. Again he notes that much corn is now raised in Northern States where the season is shorter, so that there is a greater probability of immature corn being marketed. All of these facts might explain the recent appearance of pellagra in the U. S. and its previous nonexistence. Thomas has shown that where 30 grams of a superior protein, such as that of meat, would suffice, it would require 102 grams of corn protein, an inferior protein. This inferiority is due to a lack of assimilability of the amino-acids of corn protein. Protein deficiency is the outstanding feature of a pellagra-producing diet and in the corn protein we have one of inferior value.
The Antizeistic Views.—As a rule the advocates of nonimportance of maize in the production of pellagra hold that we are dealing with an infectious disease and that it can only come into existence by transmission from some other case.
1. The Thompson-McFadden Commission, while holding a very conservative attitude, feel that certain faecal bacteria may be the etiological factors.
2. Alessandrini believes that the causative factor may be present in certain waters.
These views are that colloidal silica in water is responsible for the disease. Voegtlin noted the great amount of aluminium in certain vegetables and suggested this as the toxic causative substance. A mixture of colloidal alumina and silica in water is supposed to be operative as well as silica alone. Against the colloidal silica hypothesis is the statement of Sandwith that the water of the Nile, the drinking water of Egypt, is low in colloidal silica content.
3. Long has suggested that amoebae may be the cause.
4. Tizzoni has incriminated a streptobacillus which he stated he found in the blood and organs of pellagrins as well as growing on maize.
=Epidemiology.=—As the result of very careful epidemiological studies the Thompson-McFadden Pellagra Commission came to the conclusion that there was evidence against the transmission of pellagra by ticks, lice, bedbugs, cockroaches, fleas, mosquitoes and buffalo gnats (Simulium).
They were rather disposed to consider that the disease showed a greater prevalence where the disposal of faeces was unhygienic, as in unsanitary privies, and that the existence of an efficient water sewerage system prevented pellagra. If faecal bacteria should act as infectious agents then the house fly would possibly be worthy of suspicion.
Many of the peculiarities of sex and place distribution could be explained by the stable fly, Stomoxys calcitrans, a fly which bites viciously in the district in which they worked. This fly bites only by day and is intimately associated with human dwellings so that the greater incidence of the disease in the women, who stay at home, as against an incidence five times less in the men who work in the mill during the day might be explained by Stomoxys bites.
At the same time their failure to transmit pellagra to monkeys by injections of defibrinated pellagra blood would militate against any infectious agent existing in the blood. It may be stated that Harris has claimed to have produced a disease resembling pellagra in two monkeys by injecting filtrates from emulsions of brain, skin and intestinal tract of cases dying of pellagra.
Lavinder and Francis injected 79 monkeys and 3 baboons with varying material from pellagra autopsies. Some of the animals were injected with emulsions or Berkefeld filtrates of such emulsions made from brain and cord. Other monkeys were inoculated with material from skin similarly prepared, others with stomach and mouth mucosal emulsions, and still others with intestine and faeces emulsions. Blood, urine and cerebro-spinal fluid were also injected. Feeding experiments were also carried out. With one exception, and that one only suggestive of pellagra, the experiments were negative.
Sixteen volunteers, working under Goldberger, tried to infect themselves with blood, nasopharyngeal secretions, epidermal scales, feces and urine from pellagrins. Various atria of infection were tried according to material; blood by intramuscular injection, excreta by mouth. After a period of six months all the subjects of the experiments remained well. This evidence is certainly against the infectious nature of the disease.
Greater Prevalence in Women.—Now that we attach no weight to insect transmission of pellagra we have only the debilitating effects of menstruation, pregnancy and lactation to explain the marked susceptibility shown by women of from seventeen to forty years of age. Before and beyond these ages the incidence in males and females is about the same.
Before Goldberger began his experiments he was struck by the relation poverty had to pellagra epidemiology, and as diet is the chief element differentiating poverty and affluence, he chose this line of research with the results recorded under etiology. His explanation of the greater incidence in adult females, especially wives and mothers, was their act of denying themselves the more desirable parts of the food.
Sandwith has noted the great frequency of pellagra in hookworm patients, thus of 300 such cases in Egypt, 46% had pellagra.
The Thompson-McFadden Commission was unable to note any evidence that would distinctly point to corn, good or bad, as giving rise to pellagra outbreaks. They did note, however, a very limited use of fresh meats.
PATHOLOGY AND MORBID ANATOMY
There is nothing very constant or characteristic in the pathological changes of pellagra. In the second stage the urine shows an indicanuria and the faeces an abundance of skatol. The examination of the gastric contents gives findings of anacidity and deficiency in pepsin. The HCl deficiency probably causes disturbance of pancreatic efficiency leading to mal-assimilation of fats and proteins.
The blood shows a moderate lymphocytosis but not an increase in the percentage of the large mononuclears as has been claimed by the adherents of the protozoon theory.
At autopsy we find rather marked emaciation. The wasting of all organs seems to be greater than in any other wasting disease. The skin lesions show degenerative changes in the corium with slight cellular infiltration. In the epidermis there is superficial atrophy but still some thickening in the stratum granulosum.
Warthin states that the lesions are those of a chronic intoxication. The spleen shows atrophy and in the follicles there is necrosis of germ cells as well as hyaline changes. The liver and kidneys often show fatty change. In general the changes are those of a senile character. There is atrophy of the mucosa of the small intestines and there may be small ulcers present.
The mesenteric glands are enlarged. Roaf has noted the presence of involvement of the adrenals and the Committee investigating pellagra in Turkish prisoners found a marked supra-renal inadequacy.
Macroscopically no changes are seen in the central nervous system but histologically we often note chromatolysis with bulging of borders, eccentric nucleus and disappearance of tigroid substance in various nerve cells, especially those of the anterior horn, posterior ganglia, Clark’s column and Betz cells of cortex. There is an absence of chronic meningo-encephalitis and meningo-myelitis which should be present in the general type of protozoal infective lesions.
Degenerations in the posterior columns and crossed pyramidal tracts have been reported from certain autopsies.
The cell count of the cerebro-spinal fluid is normal and there is usually an absence of globulin increase with a negative Wassermann. The blood chemistry findings in pellagra appear solely to be low nonprotein nitrogen and urea values.
SYMPTOMATOLOGY
There is probably no other disease which shows such a multiplicity of symptoms and such variations in these symptoms.
Upon questioning a patient who has developed a pellagra eruption in the spring months there is often obtained a history of more or less prolonged neurasthenic manifestations during the preceding winter, chiefly dizziness, insomnia, apprehension, occipital heaviness and muscular fatigue. There may also have been previous sensitiveness of the mouth and slight epigastric discomfort. Along with the appearance of the eruption we may have more marked alimentary tract disorders consisting of stomatitis, gastric disturbances, especially pyrosis, with a recurring diarrhoea. Upon examining the eruption we note localized, sharply delimited, strikingly symmetrical skin lesions of those parts of the body which are chiefly exposed to the sun’s rays.
This erythema is very similar to sunburn but often follows inadequate exposure to the sun and the erythema persists instead of fading. Desquamation continues for weeks or months instead of healing. The dry scaling area usually shows a striking pigmentation at the borders even after the central portions of the erythema have cleared up. The skin lesions instead of being dry and atrophic as is usual may more rarely be moist and oedematous.
From a vague neurasthenia we have now more distinct neurological manifestations such as variations in the reflexes, tremors, especially of tongue, head and upper extremities and a depressed mental state with lack of mental concentration or lapses of memory. Later on we may have a toxic psychosis in which mutism is often noted in a mental state characteristically melancholic.
A final cachexia, with dementia, loss of control of the vesical sphincter and a terminal diarrhoea, marks the end. Recurrences of clinical manifestations each spring, or possibly skipping a year, are striking features of the disease. While the skin and alimentary tract disturbances are usually in abeyance in the winter, this holds to less degree with the nervous symptoms.
THE DIAGNOSTIC TRIAD
We may then state that in a typical case we have the diagnostic triad or pellagrous symptom-complex of (1) symmetrical sharply delimited erythemas of certain portions of the skin surface exposed to the sun with (2) alimentary tract disturbances of stomatitis, epigastric and substernal soreness and burning, with pyrosis and a recurring diarrhoea and (3) neurological manifestations in which a prodromal neurasthenia is followed by paraesthesias, in which burning sensations are prominent, at times leading to suicide by drowning, with alterations of deep reflexes, tremors and, in more advanced stages, a confusional insanity.
Burning sensations are noted in mouth, gullet and stomach as well as of the skin. Then too a burning sensation may be complained of in the area formerly the seat of a pellagrous eruption. The palms of the hands and soles of the feet often give a burning sensation.
One of the characteristic features of pellagra is the periodic recurrences in spring, with almost complete cessation of skin and alimentary tract symptoms in the winter and, again, the tendency in many cases for one group of symptoms to overshadow the symptoms which usually accompany them. These periodic recurrences may well be associated with seasonal variation in diet.
=Stages in Pellagra.=—For many reasons it is peculiarly difficult to recognize stages but for convenience many authors describe the disease under a prodromal, 1st, 2d and 3d stage.
These stages have reference solely to the degree of severity of the manifestations and a case may never progress beyond the 1st stage, although recurring for a number of years. Again a case may rapidly progress to the 2d stage and even run through the 3d or cachectic stage in a few months. We must not consider these stages as tending to follow in sequence as we do in connection with the stages of syphilis.
The prodromal manifestations of neurasthenia, malaise, loss of weight, loss of strength, vertigo and digestive disturbances would be suited to many other diseases, especially tuberculosis, and they are rarely recognized as belonging to pellagra until the appearance of typical skin or other symptoms brings about their association with pellagra. There is little definite information as to the period of incubation although Sandwith places it at from nine to twelve months.
In Goldberger’s cases the eruption did not appear until after five months on the experimental diet. In the study of cases of pellagra occurring among Armenian refugees, and in Turkish prisoners of war, oedema was not infrequently noted and its occurrence usually preceded the eruption.
=First Stage.=—In the first stage we note the alimentary tract disturbances of sodden fissured conditions at the angles of the mouth, a large indented tongue with central coating and bare glistening sides and tips, often with a shiny mucus coating these red borders and a red buccal mucosa. The fungiform papillae appear as pinhead red elevations. Later on the tongue becomes bare, red and fissured. There is often an increased flow of saliva. Aphthous ulcers are less common than in sprue. The gums are often quite tender and in cases where they are somewhat spongy and swollen, with a tendency to bleed, we note the appropriateness of “Alpine scurvy” as a synonym for pellagra.
In cases with very severe stomatitis there may be enlargement of the salivary glands. The pharynx is congested and a similar condition of the oesophagus gives rise to a burning sensation which is often described by the patient as going up the gullet from the stomach.
Gastric disturbances, especially gastralgia, pyrosis and eructations, may be pronounced. Anacidity and deficiency of pepsin are noted in gastric juice examinations. The intestinal symptoms are those of recurring diarrhoea or occasionally of a mild dysentery but in many cases there is a normal functioning of the bowels. Although the skin manifestations usually follow those of the alimentary tract they may precede them or occur simultaneously.
The Eruption.—It is usual to designate the skin lesions of the first stage as erythematous, in that they resemble a sunburn. These pellagrous eruptions may follow some source of skin irritation as well as that from exposure to the sun; thus the perianal, perineal, vulvar, and even scrotal regions may show a marked erythema from the slight irritation of the rubbing of clothes or opposite parts. Chemical irritants may also be operative.
The pellagrous erythema shows itself most commonly during the late spring or early summer. It may appear in the early spring or late summer or early fall, but only exceptionally does it occur in the winter. There are, however, alterations in the skin previously involved which can at times be noted during the winter.
The typical eruption, however, is that which shows itself on the backs of the hands or running up beyond the wrist to the lower third of the forearm. The phalanges and especially the knuckles may also show the eruption. On the face the eruption is most common over the bridge of the nose, on the cheeks and forehead. There may be spots back of the ears or on the nape of the neck. Occasionally the butterfly outline of lupus erythematosus is seen. The face may show the so-called pellagrous mask. On the neck we may have a band-like eruption extending to the upper part of the sternum (Casal’s necklace) or the erythema may extend down the sternum (cravat).
Very important were the observations of Goldberger that in his six experimental cases the eruption first showed itself as a symmetrical involvement of the sides of the scrotum.
On the feet the dorsal eruption does not usually go above the malleoli and rarely involves the dorsal surfaces of the external toes although rather commonly affecting the great toe. In the U. S. the eruption may extend up the front and back of the leg (boot). The soles of the feet and palms of the hands are not infrequently involved in American cases as is also true of the tip of the elbow.
The eruption on the elbows rarely occurs until the patient takes to his bed and is probably incident to irritation over olecranon. Sandwith states that the skin lesions in Egypt are more widespread than those seen in Italy.
These skin eruptions show striking symmetry, marked delimitation from unaffected skin, with often more intense pigmentation at the border line, and they burn rather than itch.
In 1679 cases of pellagra Merk found 77% with eruption solely on backs of hands, 13% on backs of hands and neck, 8% on neck alone. The eruptions on dorsal surfaces of feet and calves of legs are chiefly seen in barefooted children. In the pellagra cases among Turkish prisoners Bigland noted an eruption on the hands in all but one of 232 cases. Rashes on the feet were noted in 111 cases and rashes on the face with bilateral symmetry were observed in 47 cases. One case showed a scrotal eruption.
The more advanced skin lesions are those of a dermatitis rather than an erythema. The affected skin is at first of a dull red color like a sunburn and later becomes reddish-brown or livid or chocolate-colored. Fox has likened the eruption to that of a carbolic acid burn.
The normal elasticity is lost and the area appears as a dry, scaly, atrophic patch—it is the skin of a very old man. The moist oedematous skin lesions are far more common in the U. S. than elsewhere and may show bullae and even gangrene. Such cases may show the gauntlet desquamation.
The nervous symptoms of this stage are chiefly vertigo, headaches, which are usually occipital, and depression of spirits. Insomnia may be a marked feature. Lack of mental concentration is often noted.
=Second Stage.=—In the second stage we have a continuation and aggravation of the skin and alimentary tract symptoms with pronounced neurological manifestations. Tremors of the tongue and hands appear. There is great muscular weakness of the legs. Paraesthesias in great variety are common. Pain on pressure in the dorsal and lumbar regions of the back is common. The gait is more that of marked muscular weakness.
Attacks of giddiness with tendency to fall forward or backward are often reported. The deep reflexes may show variations from normal and there may be variations in the reflexes of the two sides, thus the patellar reflex on one side may be exaggerated and that on the other normal or diminished. Ankle clonus is rare. Neurological manifestations are slight in pellagrous children, the main symptoms being the cutaneous ones.
The mental state is confused and the patient shows depression and is often morose. The most common psychosis is that of simple retardation. The patient answers questions in monosyllables and in a low tone of voice after a more or less prolonged delay. Goldberger states that mental disturbances sufficient to require institutional care do not occur in more than 2 or 3% of cases.
In the second stage the urine shows rather marked indicanuria and the faeces contain an excess of skatol. Loss of weight is as marked a feature of pellagra as of tuberculosis. Well nourished pellagrins are the exceptions.
=Third Stage.=—With the setting in of a confusional insanity and a terminal cachexia we have the third and last stage of the disease. On account of so many of the victims of pellagra becoming inmates of insane asylums the disease is peculiarly dreaded.
Pellagra often runs a rather acute course in the U. S., the patient dying within two or three months. The usual course in Europe is one prolonged over years, with at times intermissions covering one or more years.
A form of pellagra known as typhoid pellagra often shows a high fever with symptoms more or less resembling a very toxic case of typhoid.
A mental state resembling the acute delirium of paresis may be present. Such states are often terminal. The usual course of pellagra is afebrile. Such terms as pellagra sine pellagra are given to cases which may not show the skin lesions and the designation pseudopellagra has usually been used by those who insist upon limiting the name pellagra to those cases which fit in with their special etiological views so that cases clinically pellagra but in which the special etiological factor does not obtain are called pseudopellagra.
Symptoms in Detail
The cutaneous neurological and alimentary tract disturbances have each already been separately described in detail.
The Blood.—Hillman has made very careful blood examinations of a series of cases and found a variable degree of chloranaemia which however, was not a prominent feature. He notes the occasional occurrence of a leucocytosis in the course of the disease. As a rule there is a definite lymphocytosis, the average percentage of lymphocytes being 33.99. The average percentage for the large mononuclears was 2.59. The average percentage of eosinophiles was 2.73. The determinations of the coagulation time of the blood gave normal figures.
In Ridlon’s series the average red count was 4,720,000, the white count varied from 14,200 to 4200, average 8027. The polymorphonuclear percentage averaged 68.2, that of lymphocytes 21, of large mononuclears 8 and of eosinophiles 2.
Hb percentage averaged 77 and color index 0.81. The blood serum failed to give positive Wassermann reactions.
The Urine.—There is rarely any increase in albumin. The most important urinary finding is in connection with indicanuria, 96.4% of Ridlon’s cases showing this finding. As convalescence comes on indicanuria tends to lessen.
The Temperature Chart.—We expect a normal temperature in an uncomplicated case of pellagra but in typhoid pellagra and in the terminal stages of the disease a fever of from 101° to 103°F. is generally noted. Fever makes for a bad prognosis. There is nothing special about the circulatory system other than low blood pressure and a tendency to vasomotor disturbances. With the genito-urinary system other than the rather marked indicanuria, there is nothing of note.
DIAGNOSIS
In the presence of the diagnostic triad of cutaneous, nervous and alimentary tract manifestations there is little difficulty in diagnosis but when the skin lesions are absent or only slightly developed the difficulty is great. One of the most important points in diagnosis is a history of preceding attacks.
There is no reliable laboratory test and the reports as to positive reactions following injections of maize extracts seem unreliable. Again there do not seem to be any antibodies in the serum of pellagrins which can be utilized in serological diagnosis. A primary requirement would be a suitable antigen. Competent workers have been unable to find any bacterial organism in the blood of pellagrins.
Erythema multiforme and dermatitis venenata seem to be the skin diseases most liable to cause confusion.
In old people with arterio-sclerotic changes and consequent mental symptoms there may be lesions of the hands or feet of more or less gangrenous type, which may be a real source of confusion. The lack of sharp delimitation of such lesions and the absence of the pellagrous stomatitis should differentiate.
Poison ivy dermatitis, if bilateral, may be confusing, as may also chapping of the hands.
In Italy a disease due to eating ergot-diseased rye meal and called ergotism may be a source of confusion as this disease shows gangrenous manifestations. The gangrene of ergotism is a dry one.
Sprue does not show the dermatitis, and the nervous manifestations are solely those of irritability or possibly slight neurasthenia. The sprue stool is not found in pellagra. See Diagnosis under Sprue.
Typhoid pellagra may be confused with severe typhoid fever or other acute infectious diseases or with conditions associated with coma, as diabetes or uraemia.
PROGNOSIS
It is a risk to venture a prognosis in pellagra because cases that seem mild may suddenly become severe. The extent of the skin lesions does not parallel the severity of the case although moist or gangrenous dermatitis is usually seen only in severe cases.
When fever comes on the prognosis of the case is unfavorable and when the mental manifestations are prominent the prognosis is bad.
The Italian physicians give a more hopeful prognosis than the American ones, which is easily understood when it is considered that American mortality from pellagra is given as from 25 to 39.10%. That of Italy is certainly below 10% and recent statistics have shown a mortality of only 3%. In the U. S. the mortality is now below 10%.
Of particular importance is the question of the liability to mental trouble. Singer states that about 40% of all cases of pellagra develop mental disturbances and that this incidence is much higher in cases presenting recurrences. In Italy it is estimated that from 5 to 10% of pellagrins become permanently insane.
The earlier a case of pellagra comes under treatment the more favorable the prognosis.
In the first stage the prognosis is very good but in the second, when there is more or less involvement of the central nervous system, it is much less favorable. In the third stage, or that of the terminal cachexia with marked mental deterioration, the prognosis is extremely bad. Each recurring attack makes the condition more serious. The older the patient the more serious the prognosis.
PROPHYLAXIS AND TREATMENT
=Prophylaxis.=—There does not seem to be any satisfactory evidence as to the contagiousness of pellagra, so that any method involving isolation is not indicated.
Even if the use of spoiled corn is not productive of pellagra it is certainly advisable to prevent its sale by state regulation.
As a proper, well-balanced dietary is an important curative measure it is therefore prophylactic.
=Treatment.=—In a disease which characteristically shows a marked amelioration in the winter or a disappearance of symptoms for one or more years we should be very conservative in attributing improvement to any drug.
At the New York Post Graduate hospital, 17 cases were apparently cured on rest in bed and full nutritious diet. Hospital treatment, thereby removing the patients from the environment in which the disease developed, is generally conceded of the greatest benefit.
It is always recommended by the advocates of some special drug treatment that the patient be kept on a nutritious diet. Roussel in 1866 stated: “Without dietetic measures all remedies fail.”
Many authorities speak highly of arsenic in various forms as Fowler’s solution, atoxyl, salvarsan, etc. Others are equally pessimistic as to the value of arsenic in any form.
Niles is a strong advocate of hydrotherapeutic measures. He recommends the drinking of two to six glasses of tepid water daily as well as colon irrigations, cold abdominal compresses, hot packs and saline baths.
Deeks prefers to eliminate sugar and starchy food from the dietary of pellagrins for a few days at a time and to give fresh fruit juices, with broths and milk. He highly recommends dilute nitric acid, well diluted, before meals. As there is almost constantly anacidity and pepsin deficiency in the gastric juice it would seem that this condition should be treated.
It is advisable to keep the patient out of the sun and require him to take his exercise after sunset.
Dyer recommends ½ to 1 ounce gelatin daily together with the juice of two or more oranges or lemons. He prefers a diet of eggs, milk and well-cooked vegetables. He also gives quinine hydrobromate in 3 grain doses 3 times daily.
Psychotherapy seems to be of importance in the treatment of pellagra.
Lavinder says that many people have pellagra because they have some other condition and when this is cured the pellagra is also cured.
In truth, pellagra is very rarely a primary condition. We must then give careful attention to the predisposing causes which may not only be ancylostomiasis, alcoholism, or malaria, but, as well, various gynaecological or alimentary tract disorders.
With the colloidal silica etiology in view Allesandrino has recommended sodium citrate in treatment.
Goldberger has cited the following as showing the influence of diet:
In an orphan asylum with 211 orphans, 68, or 32%, had pellagra. These children were divided into 3 groups and given different rations, those under six years of age receiving milk and eggs, while those over twelve years were given meat, as they assisted in the work of the institution. The children between six and twelve lived practically on a vegetarian diet in which corn products and syrup preponderated with deficiency of legumes. Of 25 young children only 2 showed pellagra, and there was but 1 case in the 66 children over twelve years of age while the 120 between six and twelve gave 65 cases or 52%.
As the result of increasing the milk supply, so that every child under twelve years got a pint daily, also at least one egg daily, together with an increase in the use of beans and peas, as well as fresh meat, the disease was entirely eradicated. The corn elements of the diet were reduced but not excluded. There was increase in proteins and a decrease of carbohydrates.
As to the diet in pellagra Niles recommends the exclusion of all maize articles of diet. He recommends meat, eggs, milk or buttermilk with peas and beans. When intestinal symptoms are severe he gives barley gruel, rice-water, thick broths and dry meat powders. As a drug treatment for diarrhoea he uses bismuth beta-naphthol.
Babcock, recognizing the importance of the treatment of the pellagrous neurasthenia, recommends the Weir-Mitchell plan of prolonged rest in bed, nutrition, hydrotherapy and hygienic measures. “Fat and blood” should be our aims and he notes the value of cacodylate of soda in increasing fat. He also refers to the susceptibility to suggestion of pellagrins and is an advocate of psychotherapy.
Having in mind the vitamine deficiency view Voegtlin has treated cases of pellagra with extracts of substances rich in vitamines. Extracts prepared from fresh ox liver and fresh hog thymus caused definite improvement in pellagrins so treated while extracts of yeast and rice polishings seemed to be without value. It will be remembered that the glands of animals are rich in fat soluble A. For the burning of the erythema Niles recommends a lotion of calamine (4 drams), powdered zinc oxide (3 drams), in 1 pint of lime water. As regards climatic treatment the same authority believes that a colder climate is indicated and that a patient with pellagra should avoid hot weather for a year after all symptoms have disappeared.
XX. SPRUE
DEFINITION AND SYNONYMS
=Definition.=—Under the designation sprue we have a form of chronic diarrhoea characterized by periods of improvement alternating with a return to the previous condition. The disease is afebrile, of insidious onset and first manifests itself by soreness of the buccal mucosa and vague digestive disturbances.
The soreness of mouth and gullet is soon followed by erosions, especially at the site of the posterior molars, and a bare raw tongue. Exceedingly characteristic are the voluminous, frothy stools which are evacuated chiefly in the morning hours. The patient becomes weak, emaciated, irritable and of an earthy pallor.
The disease chiefly affects Europeans who have lived in Southern China, Cochin China and Java, and unless treated early tends to progress to a fatal termination.
=Synonyms.=—The word sprue is a corruption of the Dutch term “spruw” used to designate this tropical aphtha or aphthous stomatitis. The name psilosis, meaning bare, was suggested by Thin and is the term employed in many books instead of the better recognized designation, sprue.
Other designations are: Chronic diarrhoea of the tropics, Ceylon sore mouth and Cochin China diarrhoea.
HISTORY AND GEOGRAPHICAL DISTRIBUTION
=History.=—The French (1868-1872) described this disease under the name of chronic or endemic diarrhoea of Cochin China and noted its resemblance to Moore’s “Hill Diarrhoea.” In 1876 Normand incorrectly associated Strongyloides with the disease.
The physicians of the Dutch East Indies described the disease under the designation “spruw” and Manson in a very complete description of the disease called it “sprue,” a corruption of the Dutch name.
It is interesting to note that Hillary in 1766, described a similar disease of Barbadoes, W. I., which he called aphthoides chronica.
=Geographical Distribution.=—It is particularly prevalent in South China and the East Indies. India and Ceylon are also regions of the disease. In the West Indies it has been carefully studied, in Porto Rico by Ashford, and of particular interest is the fact that Wood has recently insisted on the presence of sprue in the Southern States of the U. S. The Philippines and tropical Africa are also sections from which the disease is reported.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—The cause is unknown. The disease makes its appearance chiefly in Europeans who have lived many years in the tropics and may not show itself until the patient has returned home. (In one case reported by Thin seventeen years after the return home.)
It seems to select those who are weakened by dysentery or other debilitating diseases, or who are compelled to subsist on indigestible food or to lead a life of exposure to hardships. Women in whom the menstrual flow is excessive or who are in the period of lactation seem to be especially susceptible. Some think alcoholics more susceptible. The idea has been advanced that the abuse of calomel has been a factor and this view is one to be given weight because it is well recognized that at the present there is much less sprue than formerly and with this there has been a more rational use of calomel. The excessive use of highly seasoned food, so common with Europeans in the tropics, may have an influence.
Some have thought that sprue was the manifestation of a tropical pancreas; at first congestion and later exhaustion of its function. The character of the stools lends support to this view.
At one time it was thought that Strongyloides stercoralis was the cause; this idea had its origin in the finding of these larvae in the stools of a patient with Cochin China diarrhoea.
Certain authors have considered bacteria giving a granulose staining reaction as the cause while others have thought cocci to be concerned.
Kohlbrugge found organisms resembling Oidium albicans in the intestines, oesophagus and tongue. He found similar organisms in the stools and tongue scrapings of cases of sprue. Beneke found bacilli in the tongue, oesophagus and intestines and considered these as causative, regarding the thrush-like membranous deposit as connected with the cachectic state and not causative.
Bahr is inclined to believe that Monilia albicans (Oidium albicans) is the cause, as he found these saccharomycetes in the deep layers of the tongue, in the mucoid coating of the intestines and in the deposit in the oesophagus. He thinks it the ordinary thrush species which may take on greater virulence in the tropics. Ashford states that he has found a species of Monilia, different from that of thrush, almost constantly in tongue scrapings and stools of sprue cases and he regards this species as the cause of sprue. He states that this organism is common in Porto Rico bread and thinks it possible that the disease is transmitted in this way. It has been called Parasaccharomyces ashfordi. It is a round yeast, 4 to 7 microns in diameter. Wood has recently expressed the view that sprue is not infrequently mistaken for pellagra in the Southern United States.
Castellani, in a study of moulds of the genus Monilia in sprue stools, holds them responsible for the excessive gas production, although not the cause of the disease. Various protozoa, as amoebae and spirochaetes, have been considered as possible causes.
While there does not seem to be any vitamine deficiency implicated yet there is disordered assimilation, which may be due to alimentary tract infection or to insufficiency of pancreatic functioning. It has been suggested that secretin deficiency is the essential disturbance.
=Epidemiology.=—The disease is rare in natives and is entirely endemic. Some authorities have suggested a greater frequency of the disease in those intimately exposed to a case, as in husband and wife or the members of a family.
Sprue is usually a disease of mature life and affects women more frequently than men. While climate cannot be considered as causing sprue yet the effects of hot climates in producing exhaustion states in Europeans must be borne in mind. The sprue patient should always leave a tropical climate.
PATHOLOGY AND MORBID ANATOMY
The changes in the alimentary tract apparently originate in the structures lying beneath the epithelial coverings, thus indicating that the toxic material acts through the blood rather than as a surface irritant to the mucosa. At first there is congestion of the underlying connective tissue with a round cell infiltration. Later on the epithelial covering of the alimentary tract suffers and auto-intoxication, as evidenced by indicanuria, becomes operative.
At autopsy the subcutaneous fat is found to have almost disappeared. The intestines, especially the ileum, show marked thinning, this atrophy especially affecting the mucosa, the surface of which is covered by a layer of dirty gray mucus. The submucosa generally shows connective-tissue increase. The gut is pale and diaphanous. The solitary follicles may show as small cysts filled with a gelatinous material or as ulcers.
The liver is markedly atrophied. The mesenteric glands are usually enlarged. The pancreas may show cirrhotic changes.
SYMPTOMATOLOGY
=A Typical Case.=—It is very difficult to obtain definite information as to the onset which is characteristically insidious.
There is usually first noted a sensitiveness of the buccal mucosa so that alcoholic drinks and acid or highly seasoned food cannot be taken without marked discomfort. A sense of fulness or distention in the epigastric region is often an early symptom. Frequently there is a history of a rather intractable morning diarrhoea which may alternate with periods of constipation.
The diarrhoeal movements are remarkably copious and soon change from bile-colored, liquid evacuations to the characteristic putty-colored, pultaceous, gas bubble permeated, offensive stool of sprue. While the patient experiences a sense of relief from the evacuation of the fermenting mass yet there is at times an excoriation about the anus which may cause pain when at stool. Neuralgic pains of the region of the anus may be present late in the disease.
When examined microscopically the stools are found to show much fat, yeasts and undigested food. The fats are chiefly in the form of neutral fats and fatty acids rather than as soaps. The reaction is acid. Nausea and vomiting, especially about noon, may be complained of.
While the characteristic stools best show the full development of the disease there are also changes noted in tongue and buccal mucosa. Following the marked sensitiveness of the mouth above noted there soon appears a redness of the sides and tip of the tongue with a glistening coating of the surface. Small vesicles later becoming superficial erosions develop along the tongue borders, frenum and buccal mucosa.
There is also congestion and swelling of the fungiform papillae.
Very characteristic are ulcers at the site of the rear molars (Crombie’s ulcers). Later on the tongue becomes bare, fissured and even glazed, as if varnished.
The gullet may be raw and very sensitive. The appetite is apt to be capricious and the patient may be very intractable, insisting upon dietary indiscretions which he knows will aggravate his condition. There is a progressive loss of strength, weight and energy. The liver progressively diminishes in size but is difficult to map out owing to the bulging, dough-like abdominal contents. The urine is usually free of albumen but shows marked indicanuria. Sprue is characteristically afebrile.
Anaemia becomes marked, the red cells going as low at times as under 2,000,000, per cmm. and the Hb. percentage less markedly reduced (color index above 1). The polymorphonuclears are reduced in percentage.
There is a tendency to depression and irritability.
The period during which sprue runs its course is very variable. Some cases drag on for ten or twelve years while others may be subacute in type, death ensuing within a year or two.
In addition to the typical or complete sprue described above Bahr would add: (1) Incomplete sprue, in which with typical stools there is no abnormal appearance of the tongue, and (2) Tongue sprue, in which with characteristic mouth involvement there is absence of the sprue stool.
Symptoms in Detail
The Stomatitis.—At first we have a disagreeable bitter taste in an unusually sensitive mouth. Later there develop superficial ulcers along the sides and frenum of the tongue, which subsequently involve the buccal mucosa. The gums may be quite tender and saliva dribble from the mouth.
In the later stages the tongue becomes bare, red, fissured and glazed.
The Stools.—Commencing as early morning diarrhoea, with at times alternating constipation, there gradually sets in that which makes for a diagnosis of sprue—putty-colored, fermenting, offensive stools which are extraordinarily copious.
They are also very fatty and of acid reaction. They show a proteid loss as well as lack of fat absorption.
The Blood Findings.—There is a marked secondary anaemia with great reduction in red cells and Hb. percentage.
The color index averages higher than normal and with the poikilocytosis resembles the blood picture of an atypical pernicious anaemia. Nucleated reds are rarely found. The eosinophiles are reduced in percentage. The polymorphonuclears often show a great number of nodes, as 7 or 8 instead of the ordinary three.
There is a mononuclear increase with polymorphonuclear reduction. The white count is somewhat below normal—4000 to 6000.
Other Features of the Disease.—The liver is notably diminished in size. The urine shows indicanuria. The patient has a dry earthy skin and may show oedema about ankles.
Mentally there is lack of concentration with marked irritability and moroseness. Tetany has been reported as occurring rarely in very severe cases. The abdomen is doughy and the temperature in the later stages tends to become subnormal.
DIAGNOSIS
Thrush is characterized by the membranous coating which microscopically shows the fungus. It also is chiefly a disease of children and those who live under wretched hygienic conditions and with insufficient food. The characteristic stools are absent.
Pellagra.—The stomatitis, diarrhoea and mental irritability are very similar in the two diseases. There is, however, absence of the sprue stools in pellagra and the periodical recurrence and skin manifestations of pellagra are absent in sprue.
Wood thinks that in the absence of any evidences of organic nervous disease in sprue we have an important differentiation as he finds that pellagra has as great a tendency to invade the nervous system as has syphilis. Salivation is marked in pellagra, not in sprue. The two diseases, however, are best differentiated by the darker, more fluid, less copious stool of pellagra as contrasted with the copious, light colored stool of sprue. Stools containing great amounts of undigested fat are most characteristic of sprue; fat absorption in pellagra is about normal (95%) while in sprue it is only about 75%.
Syphilis with its buccal mucous patches or geographical tongue may be mistaken for tongue sprue.
=Hill Diarrhoea.=—Many authorities do not consider this as a disease distinct from sprue. The English, however, note the features of its occurrence only at high altitudes; thus persons going to Simla suffer from hill diarrhoea but upon their return to the sea level the disease disappears. The characteristic features of hill diarrhoea or Simla trot, as it is often called, are the passage of from 2 to 6 watery, whitish stools in the early morning hours. The patient is usually free from diarrhoea in the afternoon. The color may resemble that of freshly made whitewash, hence diarrhoea alba.
At first it is only the annoyance that is complained of but later on the appetite is lost and the patient becomes weak.
There is an absence of the sprue mouth. The laboratory diagnosis, other than the finding of excess of fatty acids, soaps, undigested food remnants and yeasts is unimportant.
PROGNOSIS
While the disease responds to treatment in those who are not too far advanced yet it always should be considered a serious affection. The chances of a complete restoration to health are better for those who can leave the tropics and reside permanently elsewhere.
TREATMENT
It is essential that the patient possess the will power to carry out the course of treatment; the clothing should be of wool to prevent chilling and the patient should remain in bed until his condition has decidedly improved.
The Milk Treatment.—A preliminary dose of castor oil is given and when this acts the patient should begin taking milk as the sole food. At first about 4 pints of skimmed milk are given daily. The milk should be given in two-hour feedings, well warmed and taken through a glass tube or with a teaspoon—it should not be drunk. As the stools become less frothy the amount of milk is increased so that the patient takes from 6 to 7 pints daily. Milk should be the sole food for six weeks from the time the stools become solid and the mouth symptoms disappear. Rele prefers buttermilk to skimmed milk. Eggs are usually well borne after the milk course. Stale bread or toast is cautiously added and then some fish or chicken.
At times the patient seems benefited by giving a meat treatment day once or twice a week during the course of the milk treatment.
Meat Treatment.—If the patient is very ill it may be advisable, after the preliminary dose of castor oil, to give meat juice obtained by expressing the juice from slightly broiled meat, about 2 teaspoonfuls every half hour. If possible however one starts in with the meat cure, which is about 4 ounces of a lightly broiled chopped-up beefsteak, every four hours. Raw meat is usually given in this treatment but there is danger of T. saginata infection.
At least 4 pints of warm water should be taken daily but not at the same time the patient eats the meat. Rest in bed and the avoidance of chilling are important measures. In all food treatments we should avoid forcing the patient to eat—it is better to give food only when the patient desires it.
Some prefer to alternate the milk treatment with the meat one.
Fruit Treatment.—The patient is allowed fruit in great abundance. Strawberries, peaches, grapes, ripe gooseberries and fully ripe bananas are usually recommended. Papayas are particularly well suited. Pomegranates are also highly recommended. Sour or fibrous fruits should be avoided. Strawberries and milk are highly advocated. Cooked strawberries or other cooked fruits do not benefit the patient, the curative principle being apparently destroyed by heating. At all times alcoholic drinks and highly spiced foods should be avoided.
The only drug that has been advocated to any extent is yellow santonin, in doses of 5 grains, night and morning. It is very doubtful if any drug treatment is of the least value.
LeDantec, with the elimination of the granulose bacteria in mind, has recommended the cutting off of carbohydrates and the giving of a strictly albuminous diet. Subsequently he gives lactic acid producers as contained in Bacillus bulgaricus preparations.
Schmitter has recommended emetine in the treatment of sprue, but Ashford has found this drug, as well as santonin, of negative value. Brown has had success in treating a case of sprue with pancreatin, 30 grains daily. Since then he has had marked success in three other cases. He now combines the pancreatic extract with calcium carbonate.
In connection with Ashford’s work with a specific Monilia, M. psilosis, cases of sprue have been treated with vaccines made from this organism.
An autolysate of the cultures is sterilized at 56°C. for an hour and then centrifugalized. A one per cent. suspension of the sediment is used for injection increasing from about 0.1 cc. to 1 cc. at weekly intervals. Five or six injections are given.
It is stated that the symptoms at the start of the treatment are aggravated.
SECTION IV
HELMINTHIC INFECTIONS
XXI. ANCYLOSTOMIASIS
HISTORY AND GEOGRAPHICAL DISTRIBUTION
=History.=—It is very probable that hookworm disease existed in Egypt in the remote past and it has been claimed that a disease mentioned in the Ebers Papyrus was of that nature.
Goeze found a hookworm in a badger in 1782. He named the parasite Ascaris criniformis. Froelich, in 1789, found hookworms in the fox and named them hookworms from the hook-like ribs of the copulatory bursa. He proposed the generic name Uncinaria. Therefore Uncinaria belongs to the hookworms of the fox and is not valid for any human species.
In 1838, Dubini noted that these worms were generally found in very anaemic cases and that the mucosa of the duodenum or jejunum frequently showed punctate haemorrhages. On account of the four ventral teeth projecting from the mouth he gave it the name Agchylostoma or correctly Ancylostoma.
In 1854 Griesinger, as a result of frequently noting the lesions produced by the worms, stated that they were the cause of Egyptian chlorosis. In 1866, Wucherer connected hookworms with a disease of Brazil called opilacao. In 1878 Grassi noted that the disease could be diagnosed by the finding of the characteristic eggs in the stools of patients.
It was the prevalence of a severe anaemia among the workmen employed in the construction of the St. Gothard tunnel, which Perroncito proved to be due to hookworm infection, that established the great importance of this parasitic disease as the cause of a severe and fatal anaemia (1879). About the same time it became generally considered that the anaemias which affected workmen in mines were of a similar nature.
That the disease was very prevalent in the Southern States of the U. S., as long ago as 1849, is shown by the writings of Duncan, who noted the frequency of anaemia, often associated with dirt eating, among the slaves. He described the oedematous legs, the protuberant belly and cardiac palpitation. There were several cases reported in the U. S. from 1893-1897 but they were mainly in foreigners.
From 1895 to 1901, Stiles kept insisting that hookworm disease should be of frequent occurrence in the U. S.
A. J. Smith found several cases in persons living in Texas and recognized the fact that these hookworms were different from those of Europe. It was from a study of material from Smith and Claytor in the U. S. and, later on, from Ashford in Porto Rico, that Stiles, in 1902, reported a new genus of hookworm as existing in man. It was first named Uncinaria americana but Uncinaria, belonging to the hookworm of the fox, was not valid, so he changed the name to Necator americanus.
=Geographical Distribution.=—The disease is rare outside the tropical and subtropical countries except in mines or tunnels where suitable conditions of warmth and moisture exist.
It is extremely prevalent in India and Egypt as well as in China and other parts of the East. It is a very important infection in Porto Rico and the Philippine Islands. It is extensively distributed in South America, especially Brazil, as well as in Central America, Mexico and the Southern States of the U. S. The inhabitants of many of the islands of the Pacific are heavily infested. Hookworm disease is common in southern Europe.
ETIOLOGY AND EPIDEMIOLOGY
=Etiology.=—The hookworm infections of man come almost entirely from two parasites, Ancylostoma duodenale, the Old World species, and Necator americanus, which is generally called the New World species from its having first been reported from the U. S. by Stiles. Hookworms belong to the class Nematoda and family Strongylidae.
Quite recently Lane has reported a new species, A. ceylanicum, as having been obtained from 3 men in Bengal, after treatment. This species is the one that infects the civet cat in Ceylon. So far as we know the other human species belong solely to man.
The male hookworms are a little more than ⅓ of an inch (9 mm.) long and the females a little more than ½ inch (13 mm.) in length. The males can readily be distinguished by their posterior, umbrella-like expansion or copulatory bursa. The tail of the female is pointed. The vulva of A. duodenale is located in lower half of the ventral surface; that of N. americanus in upper half. The large, oval mouth of the Old World hookworm has four claw-like teeth on the ventral side of the buccal cavity and two knob-like teeth on the dorsal aspect. It also has a pair of ventral lancets below the four ventral teeth. One cannot make out a dorso-median tooth. In N. americanus the buccal capsule is round, smaller and the ventral teeth are replaced by chitinous plates. Dorsally there are two similar but only slightly developed lips or plates. A very prominent, conical dorso-median tooth projects into the buccal cavity. Through it passes the duct of the dorsal oesophageal gland. There are also 4 buccal lancets. The copulatory bursa of the Necator americanus is also different, being terminally bipartite and deeply cleft in the division of the dorsal ray, rather than tripartite and shallow, as with A. duodenale.
The anterior extremity of Ancylostoma bends in the same direction as the general body curve while that of Necator hooks back in an opposite direction to the body curve.
By dropping the worms, while still alive, into hot 70% alcohol they readily assume the attitudes noted above.
In general, Ancylostoma is larger and thicker than Necator.
The name hookworm was given to these nematodes from the hook-like processes of the ribs of the rays of the copulatory bursa. Dubini called the Old World parasite Agchylostoma, properly Ancylostoma, on account of the 4 formidable hook- or claw-like ventral teeth of the buccal capsule. (αγχὶλος, hook, and στομα, mouth.)
A. ceylanicum is somewhat smaller than A. duodenale and in the copulatory bursa of the male we have a deeper cleft in the dorsal ray and 2 rather long tips to each branch instead of the shallow cleft and 3 stumpy processes of the 2 branches as in A. duodenale.
=Life History.=—The delicate-shelled eggs pass out in the faeces, and in one or two days a rhabditiform embryo (200 × 14 microns) is produced. The mouth cavity of the embryo is about as deep as the diameter of the embryo at the posterior end of the mouth cavity; that of Strongyloides is only about one-half as deep as the diameter.
As a practical point, the anaerobic conditions in the intestines seem to prevent development of the hookworm ova or at any rate the absence of the oxygen, so necessary for the segmentations preliminary to the formation of the embryo, prevents it. Therefore hookworm ova in freshly passed faeces never show other than commencing segmentation while development of the larvae of Strongyloides takes place in the intestines, so that in freshly passed faeces we find, generally, actively moving larvae or at least eggs containing fully developed embryos. Hookworm ova very rarely show more than 4 segments or exceptionally 8 segments in the freshly passed egg.
In the presence of oxygen these ova rapidly develop into larvae, particularly at a temperature of about 27°C. Beyond 37°C. and below 14°C. development does not seem to take place.
The rhabditiform larvae grow rapidly and by the 3rd day are about 300 microns long and undergo a primary moulting. By the 5th day the bulb-like swellings disappear and the larva becomes possessed of a straight oesophagus, thereby becoming a strongyloid larva. It then undergoes a 2nd ecdysis or moulting, but instead of casting off this old covering, it retains it as a protecting sheath. The full grown larva is about 550 by 24 microns. At this time it ceases to take food but can move actively in its sheath so that it can crawl up blades of grass or vertical sides of mines. They can live in this state for months, when moisture and shade are present, but are rapidly killed by drying. Before becoming encysted hookworm larvae are readily destroyed by the action of the sun or chemicals or even by dilution of the faeces, especially with urine. Cort and others have found it a common occurrence for mature larvae to lose their sheaths while living in the soil, and to continue their lives in the unsheathed state. The proportion losing their sheaths varies from 52 to 98%.
This is the infecting stage in which the larvae bore their way into the skin, which is the usual method of infection, or, occasionally, by entering the mouth on vegetables or otherwise.
Looss thought that they entered the skin by way of the hair follicles but the idea now is that they can bore into any part of the skin. It only requires a few minutes for the larvae to enter the skin. From the subcutaneous tissues they effect an entrance into lymphatics or veins, go to the right heart, thence to lungs. From the alveolar capillaries they pass into the pulmonary alveoli, thence up the bronchi and trachea, to pass out of the larynx and then down the oesophagus to the stomach. The larva loses its protecting sheath in the stomach and in a few days develops a provisional buccal capsule.
By the end of the 2nd week, after another ecdysis, the larvae have grown to be about 2 mm. long and 130 microns broad and in about 4 weeks become adults, usually in the jejunum, where, after fertilization of the females by the males, the giving off of eggs begins. The adults attach themselves to the mucosa of the intestine, feeding on the deeper structures of the mucosa, or on the tissues of the submucosa. Sambon believes that the larvae can work their way into the jejunum without going there by way of the trachea and oesophagus.
By providing an exit to the trachea, Fülleborn demonstrated that in dogs, infected with the dog hookworm, great numbers of larvae poured out of the trachea. In other dogs he stitched the oesophagus to the skin and noted larvae coming out of these openings. In these dogs, with the ordinary channel obstructed, infection did occur with, however, only a few worms, thus showing the truth of Sambon’s views but at the same time demonstrating the unimportance of such a route of infection.
The mouth cavity of the embryo is about as deep as the diameter of the embryo at the posterior end of the mouth cavity, that of Strongyloides is only about one-half as deep as the diameter. The genital anlage of Strongyloides is much larger than that of Ancylostoma.
=Epidemiology.=—When faeces containing hookworm eggs are deposited where conditions of moisture, warmth and shade exist, they develop into the infecting stage, which is the nonfeeding but motile larva inside the cuticle formed by the second moulting. While eggs and younger larvae are killed rapidly, the encysted larvae withstand drying for considerable periods.
Stiles notes that the more favorable conditions for development are in a porous, sandy soil rather than in a clay one. Where a sewerage system exists there is very little danger of the spread of hookworm disease and the same is true where there is proper disposal of the faeces by burning, boiling or treatment in a septic tank. In rural districts, however, where the stool is often deposited in the shade and retirement of a clump of trees, the soil becomes infested with myriads of larvae, so that one standing with bare feet on such a spot easily becomes infected. It is for this reason that shoes are of protective value. In infected mines with temperatures below 22°C. infection is rare (6%); from 22°C. to 25°C. more common (16.6%), and above 25°C., it may reach high figures (61%).
Those of the negro race do not suffer from the infection as do the whites. They appear to have an immunity but serve as carriers of the disease. There is difference of opinion as to the length of time the parasites may live in man in the absence of reinfection. Some consider this period one of a few months, others of two or three years. We can certainly consider that a case leaving an infested region will get rid of his parasites within seven years.
PATHOLOGY
The site of entrance of the larvae is characterized by a dermatitis which is often called “ground itch” or “foot itch” by reason of its frequent location in the foot which has come in contact with the faeces-polluted soil. The dermatitis disappears in about two weeks unless some secondary infection occurs. There are reports of pulmonary irritation which may be explained by the wandering of the larvae through the lungs.
Pronounced anaemia with yellow, wax-like skin is a feature of severe cases but emaciation is rare, the subcutaneous fat still remaining. There is frequently oedema about the ankles. In the jejunum we find small haemorrhagic spots from the size of a pea to that of a half dollar. A worm may be found in the center of this spot. In sections from the tissues injured by the bite we note an infiltration of eosinophiles. The heart often shows fatty degeneration with dilatation. The liver and kidneys usually show fatty change while the spleen is generally shrunken. Sandwith noted splenic enlargement in many of his autopsies but such enlargement must have been due to other causes.
There are many views as to the manner in which the damage due to the hookworm is brought about. Some think it by bacterial infections occurring through the wounds made by the worms, others that it is due to a haemolytic toxic material excreted by the worms, while Stiles considers the ingestion of the patient’s blood important. Looss thinks it due to the gradual destruction of the intestinal mucosa from the feeding on this, and especially of the submucosa, by the worms. In their feeding the worms move from site to site. When they leave a point bleeding continues and this may account for much of the anaemia.
On the side of the blood we have at first a moderate leucocytosis which disappears with the anaemia. Eosinophilia and Hb. percentage reduction are often observed. In 3 cases I have known a fatal pernicious anaemia to develop.
SYMPTOMATOLOGY
In a secondary anaemia, with early and marked cardiac palpitation together with epigastric tenderness and a tendency to mental retardation and physical deterioration, one should always examine the stools for hookworm eggs.
The course of the disease is decidedly insidious and indefinite and the clinical diagnosis notoriously uncertain, as shown by many reports where physicians of experience, after examining a number of persons in a mill or school and only diagnosing 2 or 3% as infected, have been astonished, upon examination of the faeces of the group, to obtain positive evidence of infection in 70 to 80% of the number examined.
For convenience, it is well to divide hookworm cases into 3 groups; 1. Where the person infected fails to show any special evidence of abnormality, the diagnosis resting almost entirely on the finding of ova in the faeces.
Such cases may show very slight reduction in haemoglobin and only admit of a certain lack of energy. The best indication that hookworm infection is doing the host injury is that after treatment they gain in weight and energy and show improvement in mental concentration.
2. Mild cases with moderate degrees of anaemia, the Hb. percentage ranging from 55 to 75. In these cases there is rather marked epigastric tenderness with frequent attacks of acid eructations. Cardiac palpitation and a tendency to shortness of breath may be quite noticeable. Headache and vertigo may be present.
3. Severe cases. In such cases we may find extreme anaemia with Hb. percentages around 35 or even as low as 15. I have always felt that one was only approximating when recording percentages of 10 or lower.
These cases are very weak and show marked cardiac palpitation and dyspnoea upon the slightest exertion. There is often dilatation of the stomach and a protuberant abdomen. The red cells may fall below 1,000,000. There is also oedema, especially about the feet and ankles. Tinnitus aurium is rather frequent.
Such cases often show depravity of appetite, the best-known craving being that for earth. Other patients crave chalk, wood, cotton, etc.
It is in children that we have the most serious effects of the disease, there being marked stunting of the growth with a corresponding mental backwardness. Such children show marked retardation and delay in answering the question asked them and often repeat it in a drawling manner. Tested by the Binet-Simon method we may find a sixteen year old child to have the mental development of a ten year old one, but at the same time we would note that from a standpoint of physical development the child only seemed ten years old.
As the child approaches adult age we note a striking lack of sexual development and the lack of pubic hair. In girls there is delay in the onset of the menstrual periods or these may never appear.
In from 80 to 90% of cases there is a history of dermatitis, particularly of toes or feet, which is commonly called “ground itch,” “foot itch,” or “dew itch.” This is most frequent between the toes or on the inner side of the sole of the foot. The irritation is due to the penetration into the cutaneous tissues of the hookworm larvae. The itching is intense and secondary infections often occur as the result of scratching. Vesicles appear about the second day and are often ruptured by the scratching with a resulting pustular or impetiginous conditions. The skin and hair generally are dry.
As a rule the temperature is normal throughout the course of an uncomplicated case of hookworm disease. During the first week or so following a heavy infection there may be pulmonary manifestations when the larvae are migrating by way of the lungs.
In the diagnosis of a case Stiles attaches much importance to a tallow-yellow color of the alae of the nose and the forehead, as well as to the eye characteristics which are like those seen in the eye of a fish or that of an intoxicated person.
He also notes that the pupil tends to dilate instead of to contract when the patient looks at a bright light. It has seemed to me that the condition is rather one of hippus. In severe cases retinal haemorrhages may occur. There may be night blindness. Ascites may be present in advanced cases.
Symptoms in Detail
Skin Manifestations.—The dermatitis following the penetration of the larvae is most often about the toes or inner side of the sole of the foot. The skin is very dry and often a pale earthy color. A tallow-yellow tinting of the alae of the nose may be observed. The hair is dry and scanty or absent in pubic and beard regions. Oedema, especially of ankles or feet, is common.
Circulatory and Respiratory Systems.—Palpitation of the heart is early and marked. Functional murmurs are frequent in the advanced stages. Pulsation of the neck veins is also common. The pulse rate averages about 110 and the blood pressure is low. There is frequently some right side dilatation of the heart. A high pulse pressure is common in severe cases. Shortness of breath on slight exertion is the most common respiratory symptom. There are at times cough and bronchitis, probably induced by the irritation of the larvae in the pulmonary alveoli.
Digestive System.—Epigastric tenderness going to the right is very characteristic. The stomach is often dilated and the gastric juice hyperacid. As the anaemia increases the acidity diminishes. It has been suggested that the desire to neutralize this acidity with an alkali is the explanation of the desire for alkali-containing earth on the part of “dirt eaters.”
Patients often are pot-bellied. Constipation is rather a common feature and the stools very rarely show macroscopic blood.
Nervous System.—Hookworm patients are not only physically tired but, as well, mentally tired. The infection in children leads to a backward mental state. Patients have very little energy or initiative and are often considered stupid and lazy. Hypochondriasis is at times noted and some severe cases become melancholic.
The Blood.—The red cell count averages in marked cases 2,500,000 to 3,000,000 red cells per cu. mm. The Hb. percentage is down in such cases to between 30 and 50. The color index is well below 1, except in certain rare cases, when the color index is that of pernicious anaemia, being above 1. These latter cases are very resistant to treatment and often show very few infecting worms notwithstanding the severity of the symptoms.
There is at times a moderate leucocytosis but as a rule the white count is approximately normal.
Eosinophilia is quite characteristic and usually ranges from 15 to 35% of the leucocytes. Eosinophilia tends to disappear as the cases become advanced.
The spleen and liver very rarely give rise to any symptoms and while albuminuria is rather common in advanced cases with oedema about the feet, yet casts are but rarely found.
DIAGNOSIS
=Clinical Diagnosis.=—The diseases with which it is most likely to be confused are beriberi, chronic nephritis and malarial cachexia. Stiles notes that heavy Ascaris infections may give rather similar symptoms.
The signs of a multiple neuritis should differentiate beriberi, and the presence of casts or high blood pressure, chronic nephritis. Recently, there has been a great deal written about the danger of confusing hookworm disease and malarial cachexia, the statement being often made that splenic enlargement is a feature of ancylostomiasis. Most authorities, however, state that the spleen of ancylostomiasis is not enlarged, this point being of diagnostic value in differentiating it from malaria and kala-azar.
=Laboratory Diagnosis.=—As a matter of fact the diagnosis is almost invariably made by finding hookworm ova in the faeces. The eggs are oval and thin-shelled with a wide, clear, glassy zone separating the more or less segmented, granular central portion from the shell.
Formed stools are more satisfactory for examination than the liquid ones resulting from a dose of salts. Put about 2 drops of water or 1% trikresol solution in the centre of a glass slide and emulsify in it as much of the faeces as is held by the spatulate end of a wooden toothpick. A small piece of wood or a match stick will answer. These preparations can be readily examined without a cover-glass, using a ⅔ inch objective, with a 1-inch ocular.
Cultural methods give a higher percentage of success than looking for ova in the stools. Put a pile of 2 inch filter papers in the center of a Petri dish. Fill the dish with water to the level of the paper island. Smear a thick layer of faeces on the paper. The larvae hatch out and can be found by centrifuging the water.
It is usually stated that about 500 worms must be present for several months to produce symptoms. Grassi has thought that the presence of 150 eggs in 0.01 gm. faeces indicates the presence of 1,000 worms, of which 25% would be males.
There may be as many as 4,000,000 eggs in a stool. Bass has proposed the following method for the examination of faeces for ova: The faeces, which have been made fluid, should be centrifuged and the supernatant fluid containing vegetable débris poured off. The sediment contains hookworm eggs. Then pour on sediment a calcium chloride solution of sp. gr. 1.050. Again centrifuge and decant. Next add calcium chloride solution of a sp. gr. of 1.250 and centrifuge. This brings to the surface the hookworm eggs which may be pipetted off. As a rule, the finding of hookworm eggs is very easy without such a technique.
Recently we have been using Barber’s technique. Emulsify the faeces in equal parts of glycerine and saturated salt solution on a slide. The eggs rise to the surface and are easily discovered with the ⅔-inch objective. As a centrifuge method, Barber emulsifies faeces in this same mixture which brings the eggs to the surface. A wisp of cotton is placed on the surface and 3 or 4 drops of melted agar dropped on the cotton. The disc of agar is removed with the cotton, deposited on a slide and examined for entangled eggs. With operculated eggs this method does not seem to be satisfactory as the salt solution loosens the operculum and floods the contents of the shell,—thus altering the specific gravity of the egg and preventing flotation.
Lane Levitation Method.—Clayton Lane recommends a technique which he designates as the levitation method. In this procedure the concentrated sediment of a centrifuged specimen is transferred to a glass slide, where it is mixed with one cc. of water. The slide is allowed to stand for five minutes and is then immersed in water and manipulated until all coarse matter has floated free. The hookworm ova stick firmly to the slide and are not washed away. Lane reports that on an average this method results in a ten-fold concentration of ova.
In certain cases, where a microscope is not available, the diagnosis may be made by finding the worms in the stool following a thymol treatment.
Whyte has recommended the phenolphthalein test for occult blood as of value in determining the cure of ancylostomiasis. This test is so delicate that the least trace of blood from the mucosal lesion will be detected.
The presence of eosinophilia is of great assistance in diagnosis but it should be remembered that not rarely severe cases of the disease fail to show any excess of eosinophiles.
Charcot-Leyden crystals are often present in hookworm stools.
PROGNOSIS
The disease is more serious in children than in adults, on account of its interfering with physical and mental development. The dark races do not seem to suffer as much as the white ones. Treatment is usually most successful, but in those who are debilitated by other diseases or, in those in whom the disease has assumed a pernicious anaemia tendency, the outlook is not good.
The presence of eosinophilia is of good prognostic significance as the absence of eosinophiles indicates an exhaustion of the haemopoietic system.
The disease shortens the life of the people in an infected district and makes them readily fall victims to intercurrent diseases. Various statistics give the mortality as from less than one-half of 1% to figures approximating 7%.
PROPHYLAXIS AND TREATMENT
=Prophylaxis.=—The first measure is to diagnose infections in carriers and to insist upon the treatment of such persons. The proper disposal of the fecal material from hookworm patients is the objective point in prophylaxis.
The use of some type of properly constructed privy is essential as there is nothing more favorable to the development of the hookworm larvae from eggs to infecting stage than the practice of defecating on the ground where conditions of porous, sandy soil, shade and moisture exist. Later on, such a spot teems with infecting larvae and the person stepping there with bare feet is almost sure to become infected. For this reason the wearing of shoes is an important prophylactic measure. At the same time shoes are not a sure protection, as Ashford has noted infections in soldiers who wore good shoes. The fecal material, collected in a pail or tub, should preferably be burned or boiled. Otherwise it should be buried not less than 300 feet from the water supply and down hill from the same.
The best method is to use some septic tank process as the anaerobic processes of fermentation destroy the eggs.
The use of an amount of compound cresol solution equaling the fecal mass, plus urine, is of value.
Hookworm disease tends to disappear in towns or cities where there is an efficient sewerage system.
Hookworm disease is one of the most conspicuous examples of soil pollution disease.
Some authors think Ancylostoma more difficult to expel than Necator.
=Treatment.=—The drugs best known in treatment are thymol and chenopodium but carbon tetrachloride offers the greatest promise.
The Thymol Treatment.—Bozzolo introduced this drug in the treatment of hookworm disease in 1879. Thymol has an aromatic, thyme-like odor and a pungent taste and, while soluble in about an equal amount of alcohol, is only soluble in water in the proportion of 1 to 1100.
It is usual to prescribe the drug in 5-grain capsules or preferably in cachets, one part of thymol being triturated with an equal amount of sugar of milk. If the cachet is moistened with a little water it may be swallowed like a raw oyster.
Stiles prefers giving the treatment on Sunday so that the working days of the patient may not be lessened. By giving the patient bicarbonate of soda for a few days before the treatment it is thought that the mucus lining of the jejunum is cleared away so that the worms are more readily affected by the drug. At any rate one should give about 1 or 2 ounces of a 50% solution of Epsom salts on Saturday evening. Sodium sulphate is preferred by some.
The following morning at 6 A.M. the patient takes one-half the dose of thymol proper for his age and at 8 A.M. he takes the remaining half of the dose. At 10 A.M. he takes another dose of Epsom salts. The reason for dividing the dose of thymol is that should untoward symptoms occur after the first portion of the dose we do not give the second. Stiles now prefers to divide his dose into three portions, one to be given at 6 A.M., one at 7 A.M. and the remaining third portion at 8 A.M., followed by salts at 10 A.M. The patient should lie on the right side while taking the treatment to facilitate the passage of the drug from the often dilated stomach.
The patient should remain in bed until 12 o’clock when he may take some coffee, without milk, and crackers.
Patients must be warned to avoid anything containing fats or alcohol while undergoing treatment as fats and alcohol dissolve the thymol and tend to cause poisoning. Under no circumstances should castor oil be used. People are apt to forget that butter, milk, etc., contain the dangerous fats.
Seidell has shown that about one-third of the thymol dosage is excreted in the urine and very little by faeces. This shows absorption of the drug. It is thought some of the drug may be excreted by the lungs. Congestion of the lungs has been reported in fatal cases of thymol poisoning.
Mild symptoms of poisoning are burning in the pit of the stomach and tingling sensations of the body. More severe symptoms are those associated with cardiac weakness and respiratory distress. Coffee and strychnine are the usual remedies for thymol poisoning. Inhalation, but not swallowing, of aromatic spirits of ammonia is often of value.
The thymol dosage recommended according to the age, or rather the apparent age of the patient, is:
Under 5 years old 7½ grains. From 5 to 9 years old 15 grains. From 10 to 14 years old 30 grains. From 15 to 19 years old 45 grains. From 20 to 59 years old 60 grains. Above 60 years old 30 to 45 grains.
Total dose to be divided into 2 or 3 portions. The patient is allowed to eat only a light luncheon and supper the day of the treatment but the next day he may resume his regular meals.
As a rule most of the worms expelled by the treatment will have been passed by night of the day of treatment, although an occasional one may be passed for four or five days.
In from 25 to 50% of cases all the worms may be expelled in one treatment but it is usually necessary to give as many as 3 treatments, one on each of three Sundays.
Thymol and Beta-naphthol.—Nicol in a comparison of the efficacy of various drugs, noted that thymol in 90-grain doses, taken in 3 portions of 30 grains each, at 6, 8, and 10 A.M. expelled 98% of the worms at the first treatment and the remaining worms at the second treatment a week later. With this rather large dose he frequently observed a tendency to syncope. He used Epsom salts as a purgative.
On the other hand, while using 60 grains of beta-naphthol, given in two portions at 6 and 8 A.M., followed by salts, 86% of the worms were expelled at the first treatment and 14% with the second one. He did not observe any bad effects from beta-naphthol.
The great objection to beta-naphthol is that it is a renal irritant and may damage a kidney already diseased.
Nicol found the treatment with eucalyptus oil, 2 cc., chloroform, 3 cc. and castor oil, 30 cc. vastly inferior in anthelminthic effect to the other two treatments and liable to cause severe manifestations of nausea and syncope.
It is better to divide the dose as just stated into two portions, the second half to be given about one-half hour after the first portion. This reduces the danger from the chloroform.
Schüffner tried male fern and only obtained 7 hookworms while the next day, using thymol, 1253 hookworms were expelled. He notes that thymol is dangerous when administered to patients with acute or subacute dysentery.
In Brazil a tabloid of 5 grains beta-naphthol combined with 1 grain of phenolphthalein has been generally employed. Using phenolphthalein in this way enables them to dispense with purgation.
Oil of Chenopodium Treatment.—As the result of comparing the relative efficiency of thymol and oil of chenopodium the International Health Board Commission reported in favor of oil of chenopodium. In only 7.6% of the cases treated with chenopodium was there failure to eradicate the parasites while there was noted 23.6% of failures with thymol. The dose of oil of chenopodium recommended was 1.5 cc. given in three divided doses of O.5 cc. at 7, 8, and 9 o’clock in the morning. Two such treatments will remove 99% of worms present in a case. The Commission found the oil more efficient than an emulsion of the oil.
The low diet and preliminary dose of salts, as noted under thymol treatment, are to be recommended although the commission found various purges to have little effect on the results of treatment. At 11 o’clock give a purgative dose of magnesium sulphate.
The maximum dose of oil of chenopodium is usually given as 3 cc. but a number of deaths have followed the administration of doses of from 2 to 3 cc., so that it is better to keep within 1.5 cc.
After effects of treatment, such as dizziness, depression, unsteady gait, partial loss of consciousness, tingling of hands and feet, burning sensation in the epigastric region and nausea are more frequent with chenopodium than following thymol. The toxic symptoms may be greatly delayed and even be postponed for a day or so. A large dose of castor oil seems to be the most important measure in treating a case of chenopodium poisoning. The same methods of stimulation as noted under thymol poisoning are also indicated.
Kantor has treated a large number of cases with oil of chenopodium administered through the duodenal tube. After the bucket had passed the pylorus he introduced into the duodenum about 2 cc. of oil of chenopodium and followed this in six minutes with two (2) ounces of a warm saturated solution of magnesium sulphate. The tube is withdrawn after introducing the salts. Several copious watery stools follow in a short time.
Carbon tetrachloride in a dose of 3 cc. administered in hard gelatine capsules, is recommended by Hall for the removal of hookworms and ascarids. The drug is cheaper, more effective, and, when chemically pure, safer than thymol or chenopodium. It does not depress unstriated musculature or lessen peristalsis, thus eliminating the use of purgatives, which is an item of expense in extensive hookworm campaigns. The drug is of no value in treatment of tapeworms and is as unreliable as other anthelminthics for the removal of whip-worms.
There is a rapidly growing mass of reports concerning the clinical use of carbon tetrachloride, all of which agree in confirming experimental observations regarding its effectiveness, and indicate that a standard dosage as high as 10 to 12 cc. may be safely employed.
After expelling the worms it is advisable to give the patient a tonic containing iron or arsenic. In those cases with a tendency to pernicious anaemia the arsenic treatment is better than that with iron.
In the treatment of ground itch the usual application is a zinc oxide ointment containing 10 grains of salicylic acid to the ounce.
Barlow recommends a 3% salicylic acid solution in alcohol.