VOLUME 41 NUMBER 4

PUBLISHED TWICE A MONTH

EDITOR I I . K. ROY, M.D. (CAL.)

AUGUST 16, 1963 CALCUTTA

} ORIGINAL

ARTICLES

LATHYRISM* : A CLINICAL AND EPIDEMIOLOGICAL STUDY

R. N. CHAUDHURI, T. K. SAHA,
F.R.C.P.E., F.N.I.,

Director and Professor of Tropical Medicine

AND

M. K. CHHETRI, M.D., M.R.C.P.**, Reader

M.D., D.PHIL'.,

Assistant Professor

P. P. MITRA,

M.B.B.S.,

Lecturer

Sdiool of Tropical Medicine, Calcutta I;., Lathyrism is a disease of which the most fti prominent clinical feature is muscular weakness of i*legs and later spastic paraplegia ; it occurs amongst ippeople whose staple diet is a vetch, Lathyrus. In |v India, Lathyrus sativus, locally known as Khesari is incriminated. We here describe an outbreak I that occurred in a remote rural area, about 250 'kilometres from Calcutta, which we investigated I both locally as well as by admitting several patients Hto hospital.
EPIDEMIOLOGY

It first came to the notice of the authorities j; early in 1960 when some apparently healthy |: persons were seen limping about with or without the aid of sticks. The affected locality consisted of ^several small hamlets scattered about on either ;side of a river over an area of about 12 square p'/miles. Rice was the staple diet of the inhabitants fwith very little khesari (Lathyrus) but 6 years jago there was a heavy flood which left a thick of. silt and sand in the fields, making them limfit for paddy "cultivation. So they started ^growing khesari instead, and as these plants grew ^luxuriantly and cost very little, they made it an Jannual event and had been using these grains iliberally in recent years. After harvesting in

February the seeds were stored in earthen pots* and consumed daily after removal of the husks as flour (simply.mixed with water), hand-made bread or as dal (cooked in water like soup). This was supplemented sometimes by a little rice or wheat. After 3 or 4 months when the stock of khesari was exhausted, they would take to fice again. Some vegetables were taken, but rarely fish, meat or milk. The people were mostly cultivators and possessed no land of their own and served as labourers for which they were paid either in khesari or money which they in turn spent on this article of food, it being much cheaper than rice.. It was after this heavy consumption of khesari that cases of lathyrism began to appear, reaching the peak period in June-July and then declining with the change to rice. This sequence of events had been occurring every year over a period of 4 or 5 years. No reliable information could be obtained as regards the extent of its incidence, but we were able to trace 82 victims in various stages of the disease amongst 54 families. 18 such families had each more than one person affected up to a maximum of 4, the members falling ill in about the same season within a period of 2 to 6 weeks. The remaining families had no more than

P p ' * The earlier part of the work was carried out by the Clinical Research Unit (I.C.M.R.) at the School of Tropical Ipledicine, Calcutta. ,, ** Now at the Institute of Postgraduate Medical Education & Research, Calcutta. 169

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J. INDIAN M. A.,'VOL. 41, NO. 4, AUGUST 16, 1963 changes were generally absent except areas of hyperaesthesia in one patient and loss of vibration sense in another. Abdominal and cremasteric reflexes. were absent in 8 and 13 cases respectively and plantar reflex was bilateral extensor in all. Knee and ankle jerks were exaggerated in all, associated with ankle and patellar clonus in about half. The gait was spastic with varying flexor spasms of the muscles of lower limbs. Report from School of Physical Medicine on the neurological findings in 14 cases of the present series was as follows : There was upper motor neurone type of lesion in all cases and the nerve conduction was positive in all. There was no evidence of denervation except in one case (the severely disabled one) with diffuse atrophy of the muscles of the lower limbs. Examination of the individual muscles revealed some selective distribution of weakness or spasm : (a) Gluteus medius and maximusmarked weakness in all cases, (b) Invertors and evertors coordination testsinvertor spasm in all cases, (c) Tibialis anteriornot contracting properly due to weakness and also due to gastrosoleus spasm, (d) Spasm and in some cases contracture of hamstrings. These factors are responsible for the characteristic gait. The spasm of the muscles cannot be due to peripheral mechanism because injection of 2 per cent lignocaine hydrochloride in the muscles did not relieve the same.
INVESTIGATIONS

one victim in each. There were, of course, many people in and outside these families who escaped, though consuming similar food. Persons of all ages were affected, but only 8 females were encountered.
CLINICAL FEATURES

These are based on the history and examination of 22 patients who were brought to Calcutta and admitted to the Carmichael Hospital for Tropical Diseases for investigation. Except 2 girls and 1 boy aged between 7 and 8 they were all adult males. The duration of their illness varied from 5 months to 5 years. All possessed fairly good health except 3 who had moderate anaemia. There were no obvious vitamin or other nutritional deficiencies. Prodromal symptoms had been present in 16 patients. They were: (1) Painful spasms and cramps of calf muscles and tingling sensation in the legs in 13 cases. These occurred especially at night and continued for varying period of 3-15 days before the onset of paralysis. (2) Precipitancy of micturition in one case for as long as 90 months, and then he found his legs stiff. (3) Heaviness of the lower limbs in one case. (4) Fever in one case. The onset of actual paralysis of -lower limbs Was sudden in 12 cases following some exertion, e.g., ploughing, walking a long distance or carrying a heavy load. In others, the onset" was slow and indefinite with gradual development of jveakness and spasticity of legs. Other symptoms fsresent with it were: (1) Cramps and tingling which persisted to a variable degree in those who had them in the prodromal stage, but developed in 5 others after the onset of paralysis. (2) Pain at the back in the lumbodorsal region, persistent in nature, in 16 cases. (3) Precipitancy of micturition in 13 cases . (4) Faecal incontinence in .4 cases. (5) Sexual impotence in 2 cases. The motor functions gradually worsened, walking being particularly affected. In the majority the maximum disability was reached in 2-7 months, after which the condition usually remained stationary, but in a few there was further deterioration over a longer period, one of them being severely disabled. 7 patients, while at hospital, were using one or two sticks for walking. The upper limbs were entirely unaffected. Examination of the nervous systemHigher functions, speech and cranial nerves were normal. In both the lower extremities, the muscle tone was increased, more of the flexors than extensors. Power was diminished in all. Diffuse atrophy of muscles was noticed in one patient and atrophy of quadriceps on one side in 2 others. Sensory-

(a) HaematologicalThe average haemoglobin was about 11 g. per cent. Three patients were moderately anaemic. Eosinophilia of 10 to 21 per cent was noticed in 14 cases. Erythrocyte sedimentation rate (Westergren) was elevated in all except 2, the average value being 33 mm./lir., but in some it was over 80. Total serum B1= level was within normal range. (b) BiochemicalThe most significant finding was hyperglobulinaemia in all (Table 1). Electrophoresis showed a significant rise in gamma-globulin. The average findings, were as follows : serum albumin 3'7 g. per cent, serum globulin 3'7 g. per cent, gamma-globulin fraction 38 per cent. Thymol turbidity was above the normal range in most of the cases. (c) Other examinationsStool had hookworm ova in 20 cases and ascaris ova in 11 cases. X-rays showed no abnormalities in chest or bones (vertebrae and long, bones). The cerebrospinal fluid showed no significant.abnormality. Thus the most significant abnormalities were the increase of serum globulin and gamma-globulin, elevated ESR, increased thymol turbidity and moderate, rise of eosinophils.

' " LATHYRISMCHAUbHURr"Bf^Lr~^':';WFfc^^

I ' ' TABLE I S H O W I N G PLASMA PROTEIN'S AND S S R IN THE 22 PATIENTS UNDER OBSERVATION

- Serum protein
Total - (g- %)
Albumin Globulin

Gamma-. globulin

ESR (mm. / hr.)

(g. %) 4-5 3-6 3-4 4-0

(g- %)39 3-5 . 4-6 4-2 3-7 4-4 40

incontinence of faeces also'disappeared "-111"-nearly '""" half the cases. The' improvement appeared more ;-.' striking in those with .shorter-duration. Symptoms .''.'. like backache, cramps and the tingling sensa- .-. .. tion in legs however remained uninfluenced. It. should be mentioned that placebo injections "to'' 'some patients made no difference until substituted^
by prostigmin. . " . ' " . Nine months after. discharge from-the hospital, ;:,O the patients were followed up in their villages.- H .:.'.was found that those who had given up eating". -.. khesari maintained the improvement, attained:.in.. the hospital, - but the condition of others deterio : . rated to the old state. -. ' ..'"-'
CONTROL AND PREVENTION . . - : " - .

8-4 7-1 7-0

"8-2 G-7 7-8 7-5 7-5 6-7 6-9 8-0 70 7-8 8-0 6-4 7-1 7-3 6-9 7-6 6-5 7-6 8-2

31-4 34-0
36-9 27-6 22-0 32-i 23 27-5 31-2

34
45

85 15 48 28 _ 24 78 14. 58 35 28 17
25
' 4

Many. theories have been' put forward to-.ex-^jSa 3-6 22 plain the aetiology of lathyrism, but the- actual' vp|i 3-0 28 cause is still in doubt: Briefly., they assume-the ;,v;.^ ' 19 3-2 ..presence of a toxin in lathyrus ..or-.in some _,con-^J 1 1 31 29-4 taminant of the lathyrus.crop*'which'acts" -'-'^-'**' . 34 3-2 36-1 .nervous system, most probably in the 18 4-0 38-3 some unknown food factor-. Poisoning'by:'metals such as selenium (Rudra,-1952) and.mang'a-%^ nese (Gutierrez, 1950, 1954 ; Sadasivan .etSialZ'V-'i For comparison, a series df\27 'normal' indivi1960) said to be. present in the-seeds has also: been .vS from the affected families having similar postulated. On the other.-, hand,.'. Minchin, (1940) ,'r i dietetic history was investigated. Surprisingly, 13 and Gopalan (1950) have described sporadic occur : " v |?'of them had hyperglobulin'aemia (about 3'5 g. per rence of the syndrome in non-lathyrus-eating ;--. .S cent) along with a rise of gamma-globulin (above population in South India. . 'f 34 per cent). These figures were normal in the Lathyrism cases rarely originate in - West , remaining 14 subjects. Bengal. Incidentally, in the year- 1949-50 a few ' Further, 10 normal subjects of the locality families were affected in a rural- area of Howrah .. tj reported to have never consumed khesari preparaDistrict and 3 patients were . admitted to this \ tions were also similarly investigated and the hospital. They were ..early cases ' and improved,"y, findings were all normal. considerably after a course of prostigmin injections '.' " (Chaudhuri, . 1961). '' In .the affected' area under"" -: I . TREATMENT report, there was no known lathyrism.prior to^the^present outbreak. Flood and reasons of economy" "' L With hospital diet all the patients gained in drove the villagers to grow' lathyrus and consume :"% weight with improvement in blood picture, but it as their main diet for about 3 months in a year;=rV^ * there was no apparent effect on the neurological' when the disease began to. occur. By this time the - . Muscle relaxant like mephenesin v manifestations. stock of lathyrus at their homes was exhausted and '-" k (tolseram) also had no effect whatsoever. But they had changed their diet to rice. Then it I prostigmin injections 0'5 mg. daily for 10 days gradually began fo decline! This had been going | Were distinctly beneficial. Stiffness gradually dimion for some years until steps were taken to disfnished, power of legs was regained to a certain courage the cultivation of lathyrus, and this | extent and most of those using sticks could .do. reduced the incidence of fresh cases to ml. Two , -without them. Precipitancy.. of . micturition. and -

3-6' 3-4 3-5 3-6 3-5 -2-3 .3-9 3-3 4-1 3-4 3-4 3-7 3-7 3-9 4-4 3-4 4-4 4-2

3-9'

32 4-6 4-1* 3-7 3-7

4-6
30 3-"4

35-330-9 32-5 . 27-5

29-7

The Director of Health Services,. West Bengal". . " " , -, was apprised of the findings. The villagers were '-''. discouraged by means of propaganda to cultivate . ' khesari and the stock was replaced by'paddy as .". -"-f much as possible, and in this way the incidence . . . . ' of fresh cases went down from. 29 in 1-959. to 6. in :>". 1960, 5 in 1961 and'none in 1962!- ". " ". " '" ".':... : ^ '..-. 'DISCUSSION;.-.--.--. ... ;< .-l^:kM

36-6 34-2 33-6 30-5 37-5

19

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j . INDIAN M. A., VOL, 41, NO. 4, AUGUST 16, 1963

i m p o r t a n t factors w o r t h n o t i n g in this outbreak are ingestion of large quantities of the seeds a n d almost entire absence of food of animal origin. I n c i d e n t a l l y t h e seeds were examined and identi-

fied as those of Lathyrus sativus. Lathyrism is essentially a disease of the nervous system. Experimental studies and autopsy reports are scanty. Buzzard and Greenfield (1921) found on postmortem in a patient, the margins of the spinal cord presenting a honey-combed appearance as is seen in subacute combined degeneration. Filimonoff (1926) observed sclerosis of the lateral region of the cord, not strictly confined to the pyramidal tract, with the small blood vessels sclerosed and obliterated in places. Acton and Chopra (1922) demonstrated constriction of the spinal vessels supplying the anterolateral column in rats after feeding them with extract of Lalhyrus sativus. It was postulated by Acton (1922) that the lesion in the spinal cord in clinical cases of lathyrism was due to thrombosis of blood vessels supplying the anterior and anterolateral tracts ; this caused degenerative changes which only partially affect the crossed pyramidal tract and partially or wholly the extrapyramidal tract. The fully developed clinical picture in our casesparalysis, increased knee jerks, loss of abdominal reflexes and of sphincteric control, pain in the lumbodorsal region and increase in muscle tone also indicates that the lesion whatever its nature, is highly selective and localised in the posterolateral region of the cord, predominantly affecting the pyramidal and extrapyramidal tracts at the upper lumbar and dorsal segments. The epidemiological data clearly point to the action of some toxin but the manner of its action is unknown. Detailed investigation in the present series of 22 patients revealed hyperglobulinaemia, and a rise of gamma-globulin with raised ESR, eosinophilia and the increased thymol turbidity in the majority. We suggest that lathyrism is the result of antigen-antibody reaction and that the above changes are but manifestations of the same process.' It may be that the antigen-antibody reaction has injurious effect on the central nervous system in its most vulnerable part (upper lumbar and lower dorsal segment) which results in the clinical syndrome. The history that there was an interval of a few months between the commencement of lathurus intake and the onset of the illness suggests thaWhe body was being sensitised during this period with the formation of antibodies against the -toxin. ___The severity of the__r.eaction must depend on, among other possible, factors, the amount of lathyrus ingested, individual susceptibility and repeated sensitisation by the toxin. Identical biochemical and haematological abnor-

malities were also present in half the number of 'normal' individuals in the affected families living on similar diets. Presumably these were the persons in whom the reactions were mild and who were still in what may be called the biochemical phase, whilst others in whom this mechanism was very active and periodically stimulated, progressed to manifest clinical disease. In lathyrism, apart from finding the nature of the supposed toxin, there still remain obscure points which require elucidation. For instance, Mackenzie (1927) opined that people suffered only when Lathyrus sativus is grown in virgin soil or newly cultivated land and that it loses its lathyrogenic property after a few years' cultivation. In the outbreak under report the seeds were originally brought from a neighbouring State (Bihar) where lathyrism is common. These seeds were distinctly of larger size than the local variety though they belonged to the same species. No contaminant was detected such as seeds of Vicia saliva which, has been incriminated by some workers as the cause of the disease (Anderson et al., 1925).
SUMMARY

An outbreak of lathyrism in a hitherto unaffected rural area due to heavy consumption of Lathyrus sativus peas, the plants having been widely cultivated with seeds imported from a neighbouring endemic state, is reported. The clinical features are described. The haematological and, biochemical findings suggest that the neurological manifestations are the result of antigen-antibody reactions injuring the spinal cord. Prostigmin injections definitely ameliorated the condition specially in caaft with shorter duration. By means of propaganda the lathyrus cultivation in the area was reduced considerably and with it the disease came under control.
ACKNOWLEDGMENT

The authors thank Dr. R. h. Nath, Professor of Biochemistry, Dr. J. B. Chatterjea, Professor of Haematology, Dr. S. P. Basu, Radiologist, and Professor S. RBose, Botanist, for help in the investigations. Thanks are also due to Dr. S. Sarkar, Physiothe'rapeutist, School of Physical Medicine, Calcutta, for the special neurological reports of 14 patients of the present series.
REFERENCES

ACTON, H. W.Indian Med. Gas., 57 : 241, 1922. ACTON, H. W. AND CHOPRA, R. N.Ibid., 57 : 412, 1922.
ANDERSON, L:. A. P., HOWARD, A. AND SIMONSEN, J. L. Indian J.'fried. Res., 1 2 : 613, 1925.

BUZZARD, E. :F.. AND . GREENFIELD, J. G.The Pathology

of the Nervous System, -1921, Constable & Co.,. London, p. 232.

I
* CHAUDHURI, R. N.Annual Rep. Calcutta School Trop. *- Aled. 195-9-60, 1961, Supdt. Govt. Printing, West * Bengal, Aiipore, p. 34.
X FiuUONOFF, L . N . Z . Ces. Neurol. 1926. Psychiat., 1 0 5 : 76,

BASAL CELL CARCINOMAAHMAD ET AL.

METHODS AND MATERIAL ""'

173

GonLAN, CTrans. Roy, Soc. Trop. Mcd. Hyg., 4 4 : * * 33, 1950. ^GUTIERREZ, F. H,Ann. Bromatol (Madrid), 2 : 261, 1950. ijdo10 Congress Internat. Ind. Agri. Y. Aliment T, (Mandit), 1954, p. 560.
MACKENZIE, L- H. h.Indian
t

The material for the study comprised of suitable sized pieces obtained from the lesions which were serially cut wherever necessary. The sections were stained with Harris' haematoxylin and eosin, Van Gieson's stain for collagen and Verhoeff's stain for elastic fibres.
RESULTS

Mcd. Gaz., 62 : 201, 1927.

*MiNCHix, R. L. K.Brit. Mcd. ]., \ : 253, 1940.

RUDRA, M. IS.Nature, 170 : 124, 1952. " > SAD Si VAN, T. S., SULOCHANA, C. B., JOHN, V. T., SUEBARAM, M. R. AND GOPALAN, C.Curr. Sci., 29 :

,.

86, 1960.

Age and sex incidenceOf the 120 cases, 86 were males and 34 females. The maximum age incidence was in the fourth and fifth decades (Table 1). 23 out of 118 tumours were in patients under the age of 30 years. The youngest patient was aged 8 years and the oldest 84 years.
TABLE 1SHOWING AGE DISTRIBUTION OF 118 CASES (AGE NOT STATED it$* CASES)

.
<* f

BASAL CELL CARCINOMA : A CLLNICOPATHOLOGIC STUDY OF 120 CASES

K. N . AHMAD, M.D. Demonstrator in Pathology

Age in years
61 & above 6

0-10 11-20 21-30 31-40 41-50 51-60

K. M. W A H A L , M.D., D.SC, F.C.A.P. Total cases 1 2 20 35 34 20

"
^

Reader in Pathology
AND

? %. 3r T

R. M. L. MEHROTRA, M.D., PH.D. Professor of Pathology Department of Pathology & Bacteriology K.G.'s. Medical College, Lucknow

Basal cell carcinoma is seemingly a biologic g enigma as it arises from the more primitive ^epidermal basal cells and yet is biologically less ^.active or malignant than squamous cell carcinoma jfwhich arises from prickle cells, a maturer cell than basal cell. The other interesting feature about this ptumour is its histogenesis. Ewing (1940) and 'Willis (1960) believe that basal cells, of the 41 epidermis or of the skin appendages, are the ^source of this tumour. Other workers, have criticised this view and they derive these tumours from specialised basal cells destined to form skin lands (Krainz, 1921), hair matrix (Haythorn, 11931 ; Wallace and Halpert, 1950 ; Swerdlow, Jl.958). I^ever (1954) and other dermatologists ^consider that these tumours arise from the primary [epithelial germ cells. 1" During the period 1949 to 1961, we came |cross 120 cases of basal cell carcinoma which iWere thoroughly studied keeping in mind their JSstogenesis, histological appearances and clinical ||eatures. The present communication describes findings on this material.

LocationThough the tumours were located in all the regions of the body, over 75 per cent of the tumours were on' the head and face, the eyelids (30), face (31), scalp (19) and nose (6) being the sites of predilection (Table 2). The incidence of lesions on the face was over six times more in males than in females except in the case of tumours arising from the eyelids where the incidence was equal (15 males and 15 females). The distribution in other sites of the body did not reveal any sex bias or any particular area of predilection except for the tumours of the hand (5 cases) and back (3 cases) all of which were observed in males. Clinical featuresIn every instance the lesion was a solitary one and no case of multiple tumours was recorded in this series. The tumours manifested in the majority (86 cases) as a solitary, slow growing nodule or as an irregular growth which was pigmented in 10 cases. The remaining 34 cases presented with an indolent ulcer which bled on touch. The duration of the lesions was variable, the average being 1'8 years. In one instance the lesion had been there for 45 years, in 3 cases the tumour had existed for over 20 years and in 48 cases over 2 years. The shortest period recorded was 2 months in a 25-year old male. Regional lymph nodes were enlarged in 6 cases but unfortunately none was submitted for histological examination.