"Pellagra." Transactions of the Medical Association of the State of Alabama (April 1910): 336-349.

              PELLAGRA. E. MARVIN MASON, M. D., MONTGOMERY. Member of the Medical Association of the State of Alabama. In a posthumous publication that appeared in 1762, Gaspar Casal, of Oviedo, Spain, gave the first description of the disease that we know as pellagra. His observations on the malady began in 1735, and he gave it the name Mal de la Rosa, from the characteristic color of the skin eruption. The name pellagra (Italian, pelle, skin, agra, rough,) was introduced by Frapolli, in 1771, though it appears that this appellation was in common use before that time. These two publications establish the first scientific recognition of the disease, but it is very doubtful if they bear any true chronologic relation to its origin. Frapolli himself believed that the pellarella of the 16th century was nothing more than pellagra. Soon after its recognition in Spain, pellagra was reported in Italy, its stronghold ever since, and in a few years it became disseminated over southern Europe. At the present time it is known to exist in all the countries bordering on the Mediterranean, and it has appeared in India, Africa, the West Indies and South America. Although one or two cases of pellagra were reported in the United States during the civil war, and other sporadic cases were heard of from time to time, these observations were viewed with suspicion and were generally supposed to be either mistakes in diagnosis or imported cases. Medical authorities agreed that the disease did not exist in the United States. In 1907, Searcy reported 88 cases from the Colored Insane Asylum at Mt. Vernon, Alabama, and a few months later a number of cases were discovered by Dr. Babcock and his assistants in the State Asylum, at Columbia, S. C. These reports at once aroused much interest in the disease and, in a short time, the medical journals began to publish frequent reports of cases in widely separated localities. In this connection it is interesting to note that many of the older practitioners are now able to make retrospective diagnoses of pellagra in puzzling cases that were seen by them as long ago as 25 years or more. At present pellagra is known to exist in a third of the states of the Union, including chiefly the Southern States. Climatologic and geographic studies have established the fact that pellagra thrives best in countries of low altitude and a warm, moist climate. In these respects our southern states bear a close resemblance to southern Europe, hence the explanation of the prevalence of the disease in the South. As to the number of cases in this country, Dr. Kerr, Assistant Surgeon General of the United States Public Health and Marine-Hospital Service, estimates that in 1909 there were at least 5,000 pellagrins in the United States. We believe that in the neighborhood of 300 cases occurred in Alabama. That pellagra is a definite disease entity is no longer questioned, but its etiology remains obscure. A full discussion of the theories that have been advanced and the arguments that have been offered in support of them would lead too far afield for the limits of this paper. The two chief views of today are; first, that of the Zeists, who follow Ballardini and Lombroso in the belief that pellagra is a chronic intoxication due to poisons elaborated in decomposing maize; and second, that of the Anti-Zeists, who hold with Manson and Sambon that the malady is probably caused by a specific organism. Many recent articles give full presentations of the rival claims of these two groups of authors. Sambon's paper in the British Medical Journal and the article of Babes and Sion in Nothnagel's Pathologie will prove valuable to students of this phase of the subject. An enormous amount of work has been done by the Zeists in the effort to establish their claims. The distinguished Italian criminologist, Cesare Lombroso, devoted many years of his life to the study of pellagra and arrived at the conclusion that the disease is an intoxication rather than an infection. He showed that the common saprophytes of corn, harmless in themselves, produce certain toxins by their action on decomposing maize. From extracts made from fermenting corn he obtained two toxins, one of which resembled coniine in its action, the other, strychnine. Their combined action was held to be necessary to produce pellagrous intoxication. Experimenting with these toxins, Lombroso caused certain symptoms in fowls, animals and men that he thought characteristic of pellagra. As Sambon has pointed out, none of the lesions produced by these toxins bore any definite relation to pellagra, and similar symptoms have been caused by inoculation of analogous substances obtained from wheat and other harmless foods. Very many other workers have investigated various toxins, fungi and bacteria obtained from spoiled corn and its products. Ceni has done much work on the fungi, chiefly hypomycetes. He first thought pellagra due to certain aspergilla, but now thinks, in common with the majority of the adherents of the mycotic theory, that it is due to the toxic products caused by the growth of penicillium glaucum, the common blue mould, on corn. Of those who have reported the discovery of bacteria that they considered specific, Tizzoni has been most persistent in his claims. His strepto bacillus pellagrae has, in his hands, produced symptoms in animals which he thinks are truly pellagrous. Other workers have failed to verify his claims and, indeed, to isolate the organism. In our own work, all blood cultures have been sterile, the ordinary media being employed. The arguments of the more recent school of those who favor the probability of a protozoon infection have been well presented by Sambon in the article referred to. In a paper read before the National Conference on Pellagra at Columbia, Taylor viewed these claims and offered further striking arguments, chiefly by comparison with the better known protozoon infections such as syphilis, malaria and trypanosomiasis. When all is said, however, the question of etiology still remains an open one. Until we have proved or disproved the relation of corn to it would be wise to recognize the common belief, at least to the extent of taking precautions to prevent the consumption of unripe and damaged corn. The prevalent belief that pellagra is contagious seems based on the erroneous idea that any disease with skin manifestations of such severity must of necessity be capable of direct transmission from one person to another. This belief is without foundation in fact. In Italy, where pellagra has been known for two centuries, direct transmission of the disease from one person to another has never been reported and the authorities consider isolation and quarantine of patients unjustifiable. Once the disease has appeared in this country particular attention has been paid to this question, and the consensus of opinion among authorities is that pellagra is not contagious. The morbid anatomy in pellagra is varied, but in no sense characteristic. Many of the changes described are due rather to intercurrent disease than to pellagra itself. The most striking lesions are those found in the central nervous system. The cord shows degeneration of the posterior columns, especially the columns of Goll, in the dorsal and cervical regions. The lumbar region, in contradistinction to tabes, usually shows no changes. In some cases there is involvement of the lateral columns, chiefly in the dorsal region. Dr. Batten, working with Sandwith, in a case with well marked degeneration of the posterior columns found one pair of roots normal from the dorsal to the cervical region. He considered this as proof that the posterior sclerosis is of root origin. Nothing of special interest is found in the peripheral nerves. The central nervous system may show further degenerative changes resembling those found in general paresis. There is usually much emaciation, with pigmentation and fatty degeneration of the viscera. Liver and spleen are small and the intestines show more or less atrophy and pigmentation. Babes reports many cases of thickening and amyloid degeneration of the musculature of the large bowel, often associates with diphtheroid inflammation. The kidneys may show cirrhotic changes and the bones are usually fragile. The skin is hypertrophied and pigmented or atrophied and parchment-like, according to the stage of the disease. The symptoms of pellagra are best considered under three headings, corresponding to the portions of the body most prominently affected by the disease: first, cutaneous; second gastrointestinal and third, nervous. The course of the disease may also be divided into three stages, but it is well to emphasize the fact that the lines of demarcation are not sharply drawn in the grouping and that the symptoms are extremely variable both in sequence and severity. Frequently one or more of the characteristic symptoms may be absent. The condition of pellagra sine pellagra, in which the skin lesions entirely fail, is not unusual. Dr. Babcock states that at the London School of Tropical Medicine students are required to make the diagnosis without depending on the skin lesions. The prodromal stage is variable. According to some authors, patients show premonitory symptoms in the winter preceding the spring attack. None of our patients have given this history. As a rule, the first symptoms are noticed in the early spring. The patient complains of weakness, loss of appetite, indigestion pyrosis, headache, vertigo and vague pains in the extremities and back. There is apt to be unusual nervousness and irritability. Soon the characteristic eruption appears, often so suddenly that it is attributed by the patient to sunburn, hot water, or exposure to lye, fertilizer or other irritants with which he came in contact. The erythema appears first on the backs of the hands as irregularly outlined, moderately swollen, reddish-brown areas that may be the seat of burning, tingling or itching sensations. The itching is not so intense as in eczema, nor is the pain so intense as that of a burn. Similar areas of eruption may appear on the feet and legs and on the face, back of neck, forearms, elbows, chest and back as well as on other portions of the body that may be exposed to the sun. An occasional patient shows a peculiar semilunar crescent under each eye. The extent and distribution of the lesions may often be varied at will, as has been shown by Gheradini and Hameau, by arranging the clothing so as to allow the sun's rays to strike certain parts of the body while excluding them from other parts. That the distribution of the lesions is not altogether due to the effects of the sun, however, is well illustrated by the observation of Neusser who noticed that Roumanian gypsy children, who habitually go naked, frequently developed the erythema only on the backs of the hands and feet. We have repeatedly seen the lesions on the feet of patients who always wore shoes when out-of-doors. The lesions, wherever they appear, are bilaterally symmetrical. On the hands the erythema usually stops at the wrists, but it may extend to the elbows or even to the shoulders. When limited to the hands, one usually finds a patch on each elbow as well. The eruption may extend to the thenar and hypothenar eminences, but, beyond a slight freckling occasionally, the palms of the hands and the soles of the feet are never involved. The inflamed areas are hyperaemic, the color disappearing momentarily on pressure. At time bullae and even petechiae may form; severe cases, from confluence of bullae and secondary infection of ruptured blisters, presenting an appearance not unlike that seen in wet eczema. In these cases practically the entire "boot" or "glove" may come away from the foot or hand, leaving a raw, tender surface. In the wet, infected cases deep ulcers and sloughs may form and the flesh itself may come away in patches. The uncomplicated eruptive stage ordinarily lasts from two to three weeks and is followed by foliaceous and furfuraceous desquamation. The affected skin is left roughened and pigmented from the first attack; subsequent outbreaks intensify the picture and may produce a hard, rough scaly condition of the skin. In patients who have had many attacks the skin becomes atrophied, sclerotic and parchment-like. Coincident with the skin eruption, and preceded by more or less digestive disturbance and gastric distress, a condition of sore mouth develops. The tongue and mucous membrane take on a fiery red color, the mouth is sore and there may be profuse salivation. Frequently the papillae toward the tip of the tongue are elevated, prominent and of a brilliant red color: occasionally they may be bluish-black instead of red. As the disease progresses the mucosa may show ulcerated spots and may finally slough off in patches. The rectum, and in women the vagina, shows a condition similar to that just described for the mouth. There is every reason to believe that the process is continuous throughout the entire alimentary tract. There is profuse diarrhoea [diarrhea] with characteristically foul smelling stools. Bloody diarrhoea [diarrhea] is not infrequent. Occasionally a patient may be constipated throughout the disease. In this stage patients are usually nervous and tremulous, with exaggeration of the deep reflexes. There may be melancholia, mental confusion and disorientation with obstinate sleepiness or insomnia. Pellagra is described as a feverless disease, but we have frequently found a temperature of from 99 to 101, with a disproportionately high pulse rate. The urine may show a small amount of albumen, with a few hyaline and granular casts. The blood picture is not characteristic. There is secondary anemia, with the count ranging from two to four million cells. The leucocytes are normal or slightly diminished except as influenced by intercurrent infection. Some authors report a relative increase in the large mononuclear lymphocytes, an observation that we have been unable to confirm. Eosinophilia is sometimes reported, but we do not consider it a feature of the disease. The well known frequency of intestinal parasites in pellagrins should warn one against attributing and ordinary eosinophilia to pellagra, and the frequent co-existence of malarial infection should offer a similar warning in case a lymphocytosis of the large mononuclear variety is found. As the intensification of the infection during the second stage progresses the patient becomes profoundly depressed both physically and mentally. Usually he is melancholic and tends to mutism, though there may be periods of acute mania which may take the form of self destruction. It has been said that the pellagrin usually attempts suicide by drowning, but our observations do not bear out this statement. Various complications of interest may occur, good accounts of which may be found in any of the more lengthy treatises on pellagra. From the condition which we have attempted to describe three transitions are possible: 1. Absolute recovery without recurrence. 2. Increase in severity of the disease, with fatal termination. 3. Gradual improvement in the course of two or three months, with fairly good health during the following winter and a recurrence of the disease in the following spring, or after the lapse of a year or more. The chronic cases show annual vernal recurrence with some improvement in winter, but with a gradual downward course terminating fatally in from 2 or 3 to 15 or 20 years or more. A rare but very interesting variation from the usual mode of termination is seen in typhus pellagrosus in which there is a condition clinically somewhat like typhoid, though the typhoid bacillus is not a factor in its production. The patient, usually greatly emaciated, is profoundly prostrated. There is severe diarrhoea [diarrhea], high fever, delirium or stupor and a peculiar rigidity of the entire body, with stiffness of the neck and extremities and sometimes opisthotones. Having once seen a typical case, diagnosis is easy, especially when the characteristic triad of cutaneous, gastro-intestinal and nervous symptoms is present. These symptoms in a person from a pellagrous district at once establish the diagnosis. It frequently happens, however, that one or more of the cardinal symptoms is lacking. In such cases diagnosis is often exceedingly difficult and calls for careful study of the patient with the elimination of other possible infections. Writers on pellagra usually mention many diseases that might be confusing in arriving at a diagnosis in a difficult case, but, for us in Alabama at least, the majority of these are of little importance. It is well to bear in mind the more common skin eruptions, such as those of syphilis, eczema and other similar skin diseases, arsenical and mercurial poisoning, and the irritation dermatitis such as poison ivy infection. On the gastro-intestinal side drug and food intoxications should be remembered, as well as sprue, which undoubtedly occurs in the South. The terminal infections of alcoholics and chronic dements may occasionally be confusing. Finally, pellagrophobia has appeared and is very prevalent among neurotics, both men and women. As a rule the prognosis in pellagra is unfavorable, but many patients recover even after several years of the disease. In asylum cases the death rate has averaged around 60 per cent. For patients in the early stages of the malady, and particularly those who can be given the advantages of good food and improved hygienic conditions, the outlook is more helpful. As the disease progresses from year to year the prospect of recovery becomes more and more gloomy, and the chronic cases are usually incurable. Fortunately, the downward course is not always progressive. A patient may suffer severely one year and escape with a light attack the next, or he may go two or three years without a recurrence. The mortality promises to be much lower in private practice than in asylum cases. European records show that about 10 per cent. of the patients become insane. The treatment of pellagra is unsatisfactory in that we have no specific medication for the disease. From our present knowledge, drug treatment is secondary to other forms of therapy. The patient should, if possible, be given the benefit of an absolute change of climate and environment, preferably going to a cold, dry climate. The majority of our patients, however, will be unable to leave their homes. These should be placed under improved hygienic conditions and should be given a liberal diet of good, well cooked food with, for the present at least, the elimination of corn and its products from the dietary. The diarrhoea [diarrhea] is, as a rule, trophic rather than inflammatory and it should be no bar to the administration of the sufficient quantity of wholesome food to overcome the anemia and debility of the patient. Absolute rest in bed should be prescribed for debilitated patients. Cold baths or cold packs will be found of benefit in many cases, especially when there is nervousness and insomnia. Hypnotics and other symptomatic drugs may be used as indicated. For the severer types of diarrhoea [diarrhea] opium in some form is preferred. It may be advantageously combined with bismuth or lead acetate. Mercury is of value only if the patient be syphilitic. Of other drugs, iron, strychnine, quinine and arsenic have been recommended. Of these, arsenic has proved most valuable. Babes, in particular, reports very favorable results from its use in the form of atoxyl. More recent he has added to this an arsenic pill internally and arsenic ointment for the skin lesions. Others prefer Fowler's solution to atoxyl. The latter is certainly much less toxic than Fowler's solution and a larger total quantity can be borne without discomfort. Atoxyl should always be given hypodermatically. With proper care no pain or danger need be anticipated. If given by mouth it is decomposed by the gastric juice and may produce toxic symptoms. Local treatment for the skin lesions is best confined to the application of a mildly antiseptic, soothing lotion in order to allay the irritation and to prevent infections. For this purpose a saturated solution of boric acid or a 1 to 5,000 solution of bichloride of mercury will prove of value. The results of serum therapy either by injections of serum from healed pellagrins or by direct transfusion have been disappointing. Cole and Winthrop have reported one recovery and several cases of marked improvement following direct transfusion after the method of Crile, but it is doubtful if the benefits derived from this procedure were due to anything more than the quantity of good blood supplied to the anemic and debilitated patients. The technique is difficult, and there are contraindications that make it seem probable that transfusion will not become a usual therapeutic procedure in the treatment of pellagra. Finally, one should not neglect the psychic side. The popular dread of pellagra may do much toward lessening the chances of patient's recovery by causing a condition of hopelessness and despondency that can only be counteracted by cheerfulness and optimism on the part of the physician. DISCUSSION. Dr. Herbert P. Cole, Mobile: I have seen probably as many cases of pellagra as any man in Alabama, and I am very glad to have heard Dr. Mason's paper, especially the statement about pellagrophobia. It must be a new word. I have never heard it before. As an illustration of the term pellagraphobia, I will say that I have a young man at one of the infirmaries today with a burn on the back of his neck. It is a dermatitis, and he came a hundred and fifty miles to be treated for pellagra. Another case from Tifton, George, was treated two months for pellagra, before coming to Mobile; he was markedly anemic, and insisted on transfusion; he went home and died in three weeks from tubercular peritonitis. His case was included as a death from pellagra. The public is alarmed very much over this disease, and especially as regards the treatment. I have had six cases of pellagra that were treated with eggnogs, cold baths, strychnia, and gastric tonics, and in these the hemoglobin came up, and in four of them there was no recurrence up to this spring. Two of them had pellagraphobia, came to Mobile, thinking they possibly had pellagra. They had been seen by Dr. Bondurant and others, but had no signs or symptoms of pellagra. Dr. Harper told me of a patient who had committed suicide because of pellagraphobia. He was waiting for pellagra to appear. As far as the treatment is concerned, I fully agree with Dr. Mason in what he has said. I had some interesting correspondence with Lombroso before he died, and was encouraged by the fact that I had been antedated in the theory of the serum treatment of pellagra in a different way by two of his workers, who took serum from the severe cases and injected it hypodermically in large doses with beneficial results. It is similar to the transfusion treatment. Lombroso seems to consider that in certain cases it would be a valuable procedure. With reference to transfusion being applied to all cases of pellagra, I should say that in most cases it is unnecessary, and in a great many it is impractical both from the standpoint of the place where the operation is to be performed and from the standpoint of performing the operation in moribund cases. We have transfused twelve cases to date. And of this number six are dead, and six living. In no case was transfusion ferformed except after all local treatment was given up, and the patients were losing ground. In one of the first cases the woman had taken no nourishment for several days and was practically dead. She rapidly recovered and has remained well for two years, but is now undergoing a second attack of pellagra. I can offer no explanation as to why these transfused patients should not have a second attack, yet this is the only one of the six cases that has had a recurrence that we know of. We do not claim that any one has been cured by the transfusion, but most likely, the six patients who are now living would probably not be living under other circumstances. Whether any specific in the blood itself had anything to do with the results in these cases, or not, is uncertain. Of the six cases that died, three should not be included in the list. One had a pulse of 160 when operated on, and died two hours later. Of the two other cases, one was sent in from Mississippi in a moribund condition. We could not obtain blood at the first transfusion on account of the arteriosclerotic condition of the donor, and at the second transfusion the patient was in a moribund condition, so that only two cases should be included. The type of cases brought in for transfusion can be illustrated by referring to the chart in which one case died in twenty minutes before she got the second transfusion. A case at Mount Vernon, Alabama, a woman, was transfused, although it was thought she could not recover and would soon die. Of two cases picked out for transfusion, one died before being operated on. The other was walking around the ward within a week or ten days after operation. There are a few cases in which transfusion is applicable. In extreme cases it is not applicable. In certain cases that are apparently dying under medical treatment transfusion certainly can do no harm. There is not enough danger from the operation to offset the possibilities of benefit which may be derived from it, and in certain cases of that type it is a valuable procedure. One case of Dr. Bondurant's, that of a woman who was brought in from Tuscaloosa; she had a low muttering delirium, and delusions of grandeur; she gained eleven pounds in the first ten days after the first transfusion, and is in normal health today, which is about a year after the operation. Strangely enough, she has no recollection of her stay in Mobile, during which time transfusion was performed. Certain patients who gain immediately after operation go on and get well. The patients that die never at any time after operation show any sign of improvement. If we were able to find out the cases which will be benefited by transfusion, we might be able to avoid doing the operation in certain hopeless cases. On behalf of the association, I want to thank Dr. Mason for his paper and for the amount of work he has done in connection with pellagra. He has traveled all over the State seeing these cases and has seen, with the possible exception of Dr. McCafferty, as many cases of pellagra as any man in the South. I should like to take this occasion to state something probably which is not known to all members of the Association. The cases reported from the Mount Vernon Insane Asylum were worked up by Dr. McCafferty, who studied them for a year or more, but did not publish them. They were published by Dr. Searcy's son, who is now in the West, and Dr. McCafferty should be credited with doing the first work on pellagra, and has had more experience in treating these cases than any man in the State, and possibly more than any man in the South. Dr. Stephen F. Hale, Mobile: I have listened with a great deal of pleasure to the paper of Dr. Mason and to the interest discussion of Dr. Cole. I think this discussion on pellagra is very timely because I regard pellagra as a menace to the South. I believe pellagra, like appendicitis and hookworm disease, is a disease that has always been with us, but which hitherto has not been recognized, due largely to the fact that only recently has it appeared sporadically. I think the existence and prevalence of the disease are due to the fact that corn is now handled differently from what it was in former times, and the people of this country are eating now more of spoiled corn than they did heretofore. I am glad Dr. Cole has mentioned and called our attention to the fact that Dr. McCafferty, of Mount Vernon, is the one to whom due credit must be given for having worked up so many cases and having recognized the first case of pellagra seen here. The Medical Society of Mobile County has gone on record to the effect that Dr. McCafferty was the first one to recognize cases of pellagra in Alabama, but for some reason or other Dr. McCafferty has not been given credit for this fact before. By the mistakes of the past people should profit, and I may say that I have had two grand opportunities in my life that I allowed to slip by. One was this: The first case of hookworm disease seen in Mobile County I saw, and I am willing to acknowledge to this Association that I did not know what the disease was. I passed it by without knowing what it was. This case went through the hands of several doctors until Dr. Siddenfield, of Mobile, suspicioned it might be the new disease (hookworm disease) of which he had read some years ago in an article published in some journal by Dr. Stiles, and he called the attention of Dr. Anderson and Dr. Bondurant to the importance of investigating these cases. These cases were examined and hookworms were demonstrated. This perhaps was the worst case of hookworm disease I ever saw or ever will see. Returning to the subject of pellagra, in 1901, I saw a case of this disease, but did not recognize it. Had this discussion occurred before I saw it, I would have immediately recognized the case as one of pellagra. But it was a strange and mysterious malady, and I failed to recognize it, and let a grand opportunity slip through my hands. My object in calling attention to these mistakes is this: no doubt, there are many cases other than pellagra that exist in this State that are unrecognized, and that doctors discover diseases upon which they can place no diagnosis, and they should call upon their brother practitioners to aid them in making a diagnosis, and if a diagnosis cannot be made they should publish the symptoms of the disease and see if doctors in other states cannot help them make a diagnosis. Another thing: corn is one of the most nutritious food we have, and all this agitation about corn and pellagra may cause a number of people, and especially the poorer class, whose main support is cornbread, to avoid eating corn and corn products for fear of contracting this disease. This would be bad for the South because one of the mainstays of the South is corn. We can tell whether corn contains the aspergillus fumigates or not. Only spoiled corn contains this fungus growth, and corn which sours and smells in from five to twenty-four hours may be considered unsafe. Therefore, if we wait a little while, and place the meal aside as a sample for from five to twenty-four hours, and if at the end of that time the meal is not spoilt, we may safely use the rest of it as food. We use corn because it contains about six times more fat than the average cereal we use, and fat, especially in the poorer classes, is needed a great deal, and with it we are able to maintain the proper amount of calories necessary to keep the economy in proper working condition. Dr. Mason (closing): I have been asked about the treatment of hookworm disease in cases of pellagra. By all means, treat the patient for hookworm infection. Of course, that will have no direct bearing on his pellagra, but when he is relieved of hookworm infection, the improvement in the patient's condition from that will necessarily increase his chances in recovering from pellagra. A large percentage of pellagrins in certain parts of the State, I think, have hookworm disease as well as pellagra.