CHAPTER 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pellagra was connected with a dietary defect, chiefly as regarded some factor in a preponderating diet of maize, had been replaced by one assigning as cause some infectious process, probably protozoal, possibly bacterial.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.

[Illustration: FIG. 84.—Marked symmetry of all lesions. Illinois case. (From Lavinder and Babcock.)]

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).

[Illustration: FIG. 85.—Dry dermatitis on face, hand, neck and upper chest. Egyptian case. (From Lavinder and Babcock.)]

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.

[Illustration: FIG. 86.—“Butterfly” eruption on face of child two years old. (Deaderick and Thompson.)]

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.

[Illustration: FIG. 87.—Wet dermatitis. Localization usual. Hands oedematous. Cachectic state. South Carolina case. (From Lavinder and Babcock.)]

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.

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