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pellagra was connected with a dietary defect, chiefly as regarded some factor in a preponderating diet of maize, had been replaced by one assigning as cause some infectious process, probably protozoal, possibly bacterial.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

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.