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LATHYRISMB Y B R E V E T - C O L O N E L R A M N A T H C H O P R A , C .I .E . ,

S c . D . , M . D . , M . R . C . P . , K . H . P . , I . M . S .P R O F E S SO R O F P H A R M A C O L O G Y , S C H O O L O F T R O P I C A L M E D I C I N E

A N D M E D I C A L C O L L E G E , C A L C U T T A ; S E N I O R P H Y S I C I A N ,C A R M I C H A E L H O S P I T A L F O R T R O P I C A L DIS E A SE S

1. D E F I N I T I O N - - - - - - P 6 5 12 . H I S T O R Y - - - - - - 6513 . A E T I O L O G Y - - - r - - 6 5 24 . M O R B I D A N A T O M Y - - - - - 6545. C L I N I C A L P I C T U R E - - - - - 6546. C O U R S E A N D P R O G N O S I S - - - - 6567 . D I A G N O S I S A N D D I F F E R E N T I A L D I A G N O S I S - 6568. T R E A T M E N T - - - - - - 656

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652of the C entral Provinces

L A T H Y R I S M

Geographic!incidence

Species ofLathyr us

Lathyruspeas as food

Susceptibilityof animals

Responsiblefactor

( V O L . V I I18 33-4. I r v in g co n tr ib u ted a series ofvaluable papers (1859-68) on o u tb r eak s in the United Provinces. Anextensive epidemic was recorded by A n d r ew B u ch an an ( 19 0 4) in theC entral Provinces when about 7 ,600 persons were affected. Acton (1922 )estimated that in N orth Rewa there were 60,000 victims or 6 per centof the in h ab itan ts . M cC o mb ie Y o u n g (19 27 ) rep o r ted th at in somear eas as man y as 13 per cent of the ad u lt male p o p u latio n and 3 percent of the adult female population were affected.

3.-AETIOLOGYit Lathyn'sm occurs in those districts in which vetches, Lathyrus saiivusand allied species, form the main article of d iet. In India the disease ismo st p r ev alen t and is co mmo n ly met with in the C en tr al P r o v in ces,N o r t h B i h a r, and some districts in the United Provinces, althougho u tb r eak s are not u n k n o w n in Sind and C h o t a N a g p u r . It also occursto a lesser extent in France, Italy, Algeria, Abyssinia, and Persia.Th e th r ee imp o r tan t sp ecies of Lathyrus which are regarded as causingthe poisoning in man and an imals are:

(i) Lathyrus sativus Linn., generally known in India as khesari dal,teora, or butiorah-ka-dal. The p eas are of two sizes; the larger, knownas lakh, is grown on dry w h eat- lan d , and the smaller, iakhari, is culti-vated on wet rice-fields.(ii) Lathyrus cicera Linn. This dwarf chick-pea is grown in F r an ce,Italy, and Algeria and is used as fodder for cattle. W h en w h eat is d ear ,

it is used instead of flour to mak e b r ead .(iii) Lathyrus clymenum Lin n . The Spanish vetch is g r o w n in Spain,N o r th A f r ica, and the Lev an t.L. tuberosus an d L:aphaca have also been regarded as possible causes.Th e Lathyrus peas yield a cheap food, the co n su mp tio n of which isliable to p r o d u ce the disease. The plants are h ar d y and grow well evenduring famine years. They therefore constitute the bulk, ifnot the whole,of the diet at such times, and it is then that lathyrism becomes prevalent.Apart from famines, large agricultural populations in so me p ar ts ofIndia subsist to a great extent on Lathyrus peas, such as khesari, teora,an d matra. These peas are used in several ways; they may be groundinto flour and eaten r aw ; the flour may bem a d e up in h an d -mad e b r eador chappaties. The vetch is also boiled in water with salt, and the thickp ea-so u p , k n o w n as dal, is eaten with rice or b r ead . Du r in g times of

f amin e and d r o u g h t it almost completely supersedes all other articlesof food, including even rice and vegetables.Lathyrus is also used as food for domestic cattle which, like humanbeings, are liable to lathyrism. Horses are peculiarly susceptible andoften have died after eating khesari dal. Elep h an ts and mo n k ey s arealso k n o w n to be affected.Th er e is little doubt that there is an in timate r elatio n b etw een theingestion of L. sativus as food and the o ccu r r en ce of lathyrism in

I

- f e

S.KEV 930] AETIOLOGY 65$m a n . Theexact factor responsible for its p r o d u ctio n is not yet under-s to o d . S to ck man ( 19 17) and Dilling (1920) extracted from the seedsof L. sativus min u te q u an tit ies of an alkaloid al substance , with whichthey inoculated animals and p r o d u ced sy mp to ms r esemb lin g th o se oflathyrism. Acton and C h o p r a ( 19 22) f o u nd in the seeds a toxin of thenature of a w ater -so lu b le amin e, and p r o d u ced sy mp to ms r esemb lin gthose of lathyrism in d u ck s and mo n k ey s by injection of the solubleamine. Acton suggested that this toxic amine was produced inL. sativusd u r in g g er min atio n , and that this accounted for the high incidence ofthe disease during the rainy season of the year, July, August, andSeptember. The results of an imal ex p er imen ts r eco r d ed by differentobservers have been conflicting. The d iscr ep an cy is main ly due to thefact that there is v er y co mmo n ly a co n tamin atio n by the seeds ofvarious weeds in the samp les of Lathyrus.

H o w ar d , S imo n sen , and A n d er so n elab o r ately s tu d ied the subject.They showed that samples of khesari, collected from many parts ofIndia where lathyrism was prevale nt, contained,, apart from Lathyrussativus, v ar io u s w eed s w h ich co n tamin ated the true khesari. F eed in gexperiments on animals showed that the pure grain formed a h ar mlessand nourishing food, and chemical investigation of n u mer o u s samp lesof botanically pure khesari failed to d e m o n s t r a t e the presence in theseed of bases of an alk alo id al n atu r e. Th ey sh o w ed th at a vetch knownas akta, V icia saliva Lin n . var. angustifolia, was present in all thesamples of L. saliva. C h emical in v estig atio n of akta d emo n str ated thepresence of b ases h av in g alk aio id al p r o p er ties . Two such bases, vicineand divicine, and a cyanogenetic glucoside, vicianin, were isolated.The glucoside breaks up on hydrolysis into a sugar and the base divicine.Definite signs of poisoning with involvement of the cen tr al n er v o u ssystem could be obtained with divicine in lab o r ato r y an imals , su chas guinea-pigs. Vicine is ap p ar en tly n o n - to x ic but by hydrolysis maybecome the toxic divicine; this can readily occur during gastric digestion.A lth o u g h so me of the s y m p t o m s in mo n k ey s fed on d iets co n tain in gakta are suggestive, there is still insufficient evidence to connect lathyrismin man with the ingestion of akta. M cC o mb ie Y o u n g p o in ted outthat some other factor was responsible besides the mer e p r esen ce ofL. sativus in the diet, and he was inclined to believe that lathyrismmight be to some extent a deficiency disease. Degenerative changesoccur in the spinal cord of d o g s fed on diets deficient in v itamin A.It is possible that the ab sen ce of v itamin A from the diet allows theneurotoxin in the peas to exert its harmful effects on the central nervoussy stem. S to ck man ( 19 34) r ep o r ted th at a watery extract of Lalhyruspeas contained salts of phytic acid, which exerted a mar k ed actio n onthe brain and sp in al co r d . M o d er ate d o ses p r o d u ced to r p o r and de-pression and larger doses clonic and tonic spasms. Feeding with largequantities of Lathyrus p eas and the injection of the salts isolatedfrom them caused degeneration of nerve-cells and nerve-fibres of thecerebrospinal and sy mp ath etic sy stems. S to tt , on the other hand, could

Vicine anddivicine

Relation tovitamins

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Racialincidence

Ageincidence

Sexincidence

Prodrome

654 LATHYRISM ( VOL. VI Inot produce toxic symptoms in horses by prolonged feeding of purecultures of either L. salivas or Vicia saliva.It will thus be seen that there is divergence of opinion, and furtherinvestigation into the problem is necessary.Race, age, and sex are factors in its causation. The Hindus are particu-

larly susceptible to the disease. The comparatively low incidence amongthe Mohammedans may be due to their mixed diet and also possiblyto lower Mohammedan population in the affected areas. In the majorityof the cases in Acton's series the age was between fifteen and thirtyyears, i.e. the most active period of life, but children are not exemptfrom the disease. It is curious to observe that women rarely suffer fromlathyrism. It has been suggested that they eat less in order to save foodfor their husbands and children and are less exposed to inclemenciesof the weather and hardship. Lathyrism usually affects poor people,the patients being generally peasants or casual labourers.

4.-MORBID ANATOMYThe patient rarely dies during the acute stages, and necropsies arealmost impossible owing to religious prejudices. Probably the firsthistological study was carried out by Buzzard and Greenfield (1921),who reported a well marked degeneration in the crossed and directpyramidal tracts and to a lesser extent in the column of Goll. Somemarginal degeneration was also noticed. Filimonoff (1926) observed asclerosis of the lateral region of the cord, not strictly confined to thepyramidal tract, throughout the lower cervical, dorsal, and upperlumbar cord. The small blood-vessels were sclerosed and obliteratedin places.

In horses well marked degenerative changes have been described inthe cells of the grey matter of the cord, in the vagal and accessory nucleiof the medulla, in the lateral columns and motor nerve-roots of thespinal cord, and in the recurrent laryngeal nerves, with thickening ofthe walls of the arterioles and capillaries in the spinal cord. Fattydegeneration of the heart and of the laryngeal muscles supplied bythe degenerated recurrent laryngeal nerve has also been found.No clinical evidence of lateral sclerosis in the cervical and dorsalregion of the spinal cord is ordinarily seen, although Filimonofffound sclerosis in these regions.

5.-CLINICAL PICTUREThe symptoms vary according to the quantity of khesari consumeddaily and the period of time during which it was eaten. The onset isusually dramatically sudden. It occurs abruptly after the individualhas been living on Lathyrus for two to five months. In a few casesthe onset is insidious, and prodromal symptoms, such as fever, chills,backache, burning pains, cramps, and tingling or pins and needles in

S.KEY 93 0] CLIN ICAL PICTURE 655the legs, may have been noticed. Such cases, however, are few. Veryoften the disease follows over-exertion or exposure to cold or rain, the Historyvictim finding the legs and loins weak and heavy. A typical history isthat a patient has had a heavy day's ploughing and has taken shelterunder a tree, and then finds that he is unable to walk and has to becarried home. Or he is at work in the field when he is seized with arigor and fever; he goes home to bed for a few days, and on getting up

L ^ j s i g ? 1 S*'^!? 1 ' S& ***& .n "fe"t w

F I G . 1 5 9 . C h a r a c t e r of gait in different s tages of lathyris m(From Indian Medical Gazette, 1922)he finds he cannot walk properly. The muscles become tremulous when Symptomsweight is put on them; there is dragging of the legs with inability towalk. Weakness and stiffness of the legs rapidly become more severe,reaching a maximum in a few days. After this there may be some symp-tomatic improvement, but the paresis persists indefinitely. Generally thesphincters are not affected, but occasionally there may be incontinenceof urine and faeces. The sexual power is said to be enfeebled, butthe mind, speech, and pupils escape. The affected muscles are in mostcases not wasted, and sensation is generally normal. In a few cases the

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656 LATHYRISM [VOL. VI Iarms have been affected in the same way as the legs. Convulsive m ove-ments of the extremities and muscular wasting have been observed.Signs The physical signs are those of typical spastic paraplegia. The knee-and ankle-jerks are exaggerated, with ankle and patellar clonus andGait extensor plantar response. The characteristic gait depends on the degreeof involvement of the spinal tracts; at first the attitude of the legsis one of extension with adduction, the patient walking on tiptoe;the body is raised high before the toes leave the ground, giving riseto up and down movement of the shoulders, and progression is effectedby tilting the pelvis and circumducting the legs. The legs are crossedscissors-wise. The more feeble patients use one or two long sticks forsupport in walking. Later paraplegia in flexion develops, and in thefinal stages walking is impossible. Progression is made by crawling onthe balls of the toes and on the hands, which are often supportedon wooden sandals (see Fig. 159). In most cases the trunk and upperlimbs are unaffected, and the chest and arm muscles are usually welldeveloped owing to the extra work put upon them. The cerebrospinalfluid was found by Trabaud and others to contain an excess of proteinwith a normal cell count.

6.-COURSE A N D PROGNOSISThe disease runs a very chronic course. Degeneration limited to themotor tract is not a direct danger to life. The degeneration may bearrested, but there is not any possibility of cure in the sense of restorationto the previous condition of health. The degree of paralysis producedby the original attack remains permanent for the rest of life.7 .-DIAGNOSIS AN D DIFFERENTIAL DIAGNOSIS

Diagnosis is made by the history of prevalence of other cases in thelocality, inquiry into the diet, especially with regard to khesari dal, andthe clinical manifestations of spastic parap legia. Differential diagnosismust be made from other causes of spastic paraplegia, e.g. syphiliticmyelitis, spinal caries and tumours, injury to the spine, disseminatedsclerosis, subacute combined degeneration, amyotrophic lateral sclerosis,and syringomyelia.

8.-TREATMENTProphylaxis Prevention of the disease depends on the improvement of the economiccondition of the poor agricultural population of India. Howard andhis associates suggested that khesari dal should be planted in drillsand the contaminating Vicia sativa removed by weeding. This shouldbe done not only in places where lathyrism is rife but also in areasfrom which grain is sent to the famine- stricken areas. In view of thedivergent views on the part played by Vicia in the spread of the diseasesuccessful measures cannot yet be devised.Curative N o specific remedy for l a t h y r i s m is k n o w n . Th e c o n s u m p t i o n of

4

S.KEY930] T R E A T M E N T 657khesari dal must be discontinued, and exposure to chills and wetshould be avoided. Massage and electrical treatment are sometimeshelpful. The patient should be properly nourished. Mellanby (1934)has suggested the use of vitamin A. It is always desirable to see that thediet is generous and rich in available proteins and vitamins.

REFERENCESAct on, H. W. ( 1 9 2 2 ) Indian med. Gat., 5 7 , 2 4 1 . a n d C h o p r a , R . N . (1922) Indian med. Gaz., 5 7 . 4 1 2 . ( 1 9 2 7 ) Trans. Far-East. Ass. trap. Med., 7 th Congre ss, 3 . 4 4 4 .B u c h a n a n , A. (1904) Report on Lathyrism in the Central Provinces in 1896-1902, N a g p u r.B u c h a n a n , W. J. (1899) J. trop. Med. (Hyg), 1 , 2 6 1 .B uzzard, E. F . , an d Greenfield, J. G. (1921) The Pathology of the Nervous

System, L o n d o n .Dilling, W. 1. (1920) J. Pharmacol.. 1 4 . 3 5 9 .Do n , G . ( 1 8 3 2 - 8 ) A General System of Gardening and Botany founded uponMiller's 'Gardeners Dictionary', L o n d o n , 4 vols.Filimonoff, I . N . (1926) Z. gas. Neurol. Psychiat., 10 5 , 76 .H o w a r d , A. , Simonsen, J. L-, and Anders on, L. A. P. (1922) Indian J. med.Res., 10 , 8 5 7.Irving, J. (1859) Indian Ann. med. Sci., 6 , 424. (1861) ibid., 7 , 1 2 7 , 5 0 1 . (1868) ibid., 12, 9 0 .McC arris on, R. (1928) Indian J. mjd. Res., l j , 7 3 7 .Mellanby, E . (1934) Nutrition and Disease. The Interaction of Clinical andExperimental Work, E d i n b u r g h , p . 136 .Sleeman, W . H . (1844) Rambles and Recollections of an Indian Official,L o n d o n , 1 , 1 3 4 .Stockman, R. (1917) Etlinb. med. J., N . S . 1 9 , 2 7 7 , 2 9 7 . (1929) J. Pharmacol, 3 7 , 4 3 . (1931) J. Hyg., Camb., 31, 5 5 0 . (1934) ibid., 3 4 , 1 4 5 .Stott, H. (1930) Indian J. med. Res., 1 8 , 5 1 .T r a b a u d , J. (1929) Me'decine, 10 , 9 10 .Y o u n g , T . C . M c C . (1927) Indian J. med. Res., 1 5 , 4 5 3 .

LAURENCE-MOON-BIEDLSYNDROMESee B L I N D N E S S , V o l. I I , p . 43 6 ; C E R E B R O - R E T I N A L S Y N D R O M E S

O F TH E H E R E D O - D E G E N E R A T I V E T Y P E , V o l . I l l , p . 3 7 ; andPIT U IT A R Y G L A N D D ISE A SE S

E . M. V O L . V II