Toxic polyneuritis in Bombay due to ortho-cresyl-phosphate ...

J. Neurol. Neurosurg. Psychiat., 1962, 25, 234

Toxic polyneuritis in Bombay due toortho-cresyl-phosphate poisoning

D. D. VORA, DARAB K. DASTUR, BEATRIZ M. BRAGANCA, L. M. PARIHAR,C. G. S. IYER, R. B. FONDEKAR, AND K. PRABHAKARAN

From Lokmanya Tilak Municipal General Hospital, Sion, Neurology Unit, Indian Council of MedicalResearch, and Department ofEnzyme Chemistry, Indian Cancer Research Centre, Bombay

Since 1930 poisoning with ortho-cresyl-phosphatehas been recognized as a cause of peripheral poly-neuritis (Smith, Elvove, and Frazier, 1930). Ortho-cresyl-phosphate (O.C.P.) is widely used as aplasticiser and in the production of heat-stablelubricating oils. Many cases of industrial poisoningwith O.C.P. have been reported since then but as aresult of strict precautionary measures it has nowbecome a rarity. However, the occasional contamina-tion of food with O.C.P. is not uncommon.

Poisoning with O.C.P. was first reported inpatients with pulmonary tuberculosis who under-went treatment with phospho-creosote (Hunter,1956), and physicians became well versed in theclinical picture of poisoning with O.C.P. after theoutbreak of polyneuritis, described as 'Jamaicaginger paralysis' which occurred in the U.S.A. in1930 (Burley, 1932). A similar picture appeared inHolland in women who used Apiol (containingO.C.P.) as an abortifacient (Guttmann, 1932). In1937, there was an outbreak of sudden peripheralpolyneuritis in Durban, produced by the use ofBestol superfine cooking oil. This was subsequentlytraced to the original oil which had been sent fromEngland in large drums previously used for storinglubricating oil containing O.C.P. (Sampson, 1942).Humpe (1942) reported five cases of peripheralpolyneuritis caused by the accidental consumptionof fat contaminated with O.C.P. An outbreak of thecharacteristic polyneuritis due to O.C.P. occurredin Morocco, when about 10,000 persons wereaffected, and the source was traced to a lubricantwhich had been used to adulterate the cooking oil(Smith and Spalding, 1959).

EPIDEMIOLOGY

On 12 January 1960 a man living in the Mahim areaof Bombay city was admitted to Lokmanya TilakMunicipal General Hospital with characteristicperipheral polyneuritis. He mentioned that severalof his room-mates were similarly affected. They

purchased food from the same grocer in their neigh-bourhood. He also mentioned that others staying inthe same locality and consuming mustard oil, butpurchasing their food from other grocers, were notaffected. The examination of the other affected per-sons revealed identical histories and clinical pictures.In this group there was no history of gastro-enteritisor of febrile illness preceding the paralysis. Thesepatients also asserted that all those who were buyingtheir food from the same grocer but who were notconsuming mustard oil were unaffected and led oneof us (D.D.V.) to suspect strongly some toxic factorin mustard oil as the responsible agent. Thereuponan epidemiological investigation was begun. A notewas issued to the local press on 19 January 1960advising consumers of mustard oil to be cautious,as illness was suspected to arise from its consump-tion. A week later, another similar outbreak wasreported from another part of Bombay (Dharaviarea), where more than 30 persons were affected.Twenty of them were subsequently admitted toLokmanya Tilak Municipal General Hospital.

Further investigation of the patients and residentsof the localities in which these patients resided ledto the inference that only those who consumedmustard oil (all from the state of Uttar Pradesh) andbelonging to a very low income group (hawkers,washermen, and textile weavers) suffered from thedisease. Individuals belonging to different com-munities and having different food habits, thoughresiding with the patients in adjoining rooms,remained unaffected. This ruled out the possibility ofinfection as the aetiological factor.

Samples of food (including a large number ofedible oils) were taken for analysis from shops in thelocalities where the two outbreaks occurred, as wellas from the wholesale dealers who supplied edibleoils to retail grocers in the affected areas. Allpatients belonged to low income groups and wereknown to buy their food in daily rations so it wasnot possible to obtain samples of oils consumed bythe patients. Neither O.C.P. nor any toxic factor

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Toxic polyneuritis in Bombay due to ortho-cresyl-phosphate poisoning

could be detected on analysis of samples of oilobtained from shops in these areas. A few of thesamples of oil collected some time after the outbreakof the epidemic were found to contain very smallconcentrations of phenol and phosphates, presum-ably derived from O.C.P.On 9 May 1960 (four months after the previous

outbreaks), two patients with a similar peripheralpolyneuritis and with identical histories, comingfrom the Mahim area of Bombay, were admitted toLokmanya Tilak Hospital. It was observed that allthe cases from the Mahim area admitted in Januaryand in May 1960 had purchased their mustard oilfrom the same grocer. Three hundred and forty-foursamples of oil were collected and examined betweenMay and July 1960. Ortho-cresyl-phosphate wasdetected in 49 of these samples, the concentrationvarying from 0 65 mg. to 32-5 mg. per 100 g. of oil.It is interesting to note that four samples of oilcollected from one wholesale dealer in Bombay werefound adulterated with 2 to 12% of mineral oilcontaining ortho-cresyl-phosphate.The total number of cases recorded in the city

was 58 (53 men and five women). Thirty-two patientswere studied in hospital (29 men and three women),and of these, 29 were admitted in January 1960, onein February, and two in May.

It is worth noting that the patients in this serieswere individuals whose families were not residing inBombay. The majority (27) were males in the age-group 11 to 40 years. This explains the higherincidence of males in the present series as contrastedwith the age and sex distribution in the Moroccoepidemic (Smith and Spalding, 1959). Thirty-one ofthe patients used mustard oil for cooking and formassaging the body. One patient denied emphaticallyhaving used mustard oil for cooking and insistedthat he used it only for massaging the body. None ofthe patients came in contact with O.C.P. as a resultof his occupation.

CLINICAL FEATURES

HISTORY All the patients had been using mustardoil for cooking and massaging their bodies for years.They did not observe any significant change in theappearance, taste, or smell of the oil at any time.It was therefore not possible to establish the intervalbetween the consumption of the toxic factor in theoil and the onset of paraesthesiae. Nine personsreported the history of diarrhoea with or withoutgriping abdominal pain a few days before the onsetof illness. None of them had fever preceding theillness, except one case of extensive bilateral pul-monary tuberculosis.

Twenty-three patients reported either a continuous

cramp-like pain or heaviness in the calves beforethe onset of paralysis. Of these, 17 also complainedof paraesthesiae. The same symptoms were referredto the upper extremities in nine of the 23 patients.Commonly, paresis of the legs developed within 12hours of onset of pain or paraesthesiae, followedwithin 12 to 36 hours by paresis of the hands. Thepain subsequently disappeared within four days inthe majority of patients. Patients who were emaciatedor in poor health were the worst affected. Thepatient with pulmonary tuberculosis was moreseverely paralysed than others.On examination the abnormal findings were con-

fined to the nervous system. The motor system wasmost affected. The muscles of legs were more severelyaffected than those of the hands and forearms. In20 patients power was severely reduced, six of thesebeing completely paralysed at the wrists also. Thirtypatients were paralysed at the toes and ankles. Thedorsiflexors and everters of the feet were maximallyinvolved, causing foot drop. There was only a mildto moderate degree of weakness of muscles actingon the knee and elbow joints. Tone was diminishedin varying degree in all except two cases. Thisdiminution was symmetrical in distribution and wasmore in the distal segments of the limbs. In manypatients, the biceps and knee reflexes were exag-gerated in spite of diminished tone, wasting, and aplantar flexor response.

Sensations of touch, pain, and temperature in 27patients were impaired, this being of 'glove andstocking' distribution. The lower limbs were usuallymore affected than the upper. There was anaesthesiaof palms and feet in five patients. Joint sense wasnormal in all except one patient, in whom it wasunilaterally affected. The vibration sense wasdiminished in four patients in the lower limbs only.

All patients had a high-stepping gait associatedwith tilting of the pelvis on alternate sides. This gaitwas so characteristic that in the Medical Out-patient Department even the orderlies diagnosed theentering patients as those having telwali bimari(illness of oil). None of the patients could standsteadily on one spot without support. When requiredto stand without support, they alternately lifted thelegs as if marching. It was curious that even thoughthey could not stand, they were able to run fast witha high-stepping gait and jump well enough to playvolley-ball unaided. None of these patients couldeat properly with their hands and fingers (in theIndian style) nor could they hold the spoon. Initiallythey had to be fed by others. When asked to eat bythemselves, they held the morsel in the palm, withthe fingers and thumb flexed at the interphalangealjoints and ate directly from the palm. This findingwas seen in all the cases.

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D. D. Vora and others

At a subsequent neurological examination threeto four weeks later, an increase in the weakness ofthe limbs, persistence of the sensory impairment,and tenderness of the calves were observed in mostof the patients.Attempts were made to rehabilitate them by

physiotherapy and occupational therapy. Eachpatient was given daily injections of thiaminehydrochloride (100 mg.) and cyanocobalamine (100,ug.) intramuscularly. Improvement was very slow.Except for four patients who remained in thehospital for about six months, all sought dischargeagainst medical advice within two weeks of admis-sion. They showed progressively a fair degree of gainin power of the affected muscles, sufficient to enablethem to return to their respective occupations. Oneof them was a weaver requiring dextrous finger move-ments to work on automatic looms. These patientsappeared to have benefited from physiotherapy andoccupational therapy.

CLINICAL INVESTIGATIONS The routine investiga-tions at the time of admission revealed the followingsalient features. Eighteen cases showed a mild degreeof anaemia. The white cell count was more than10,000/c.mm. in four cases, was less than 5,000/c.mm. in two cases, and in the rest it was between5,000/c.mm. and 9,000/c.mm. Examination of thestool samples revealed cysts of Entomoeba histolyticain three, ova of Ankylostoma duodenale in two, ovaof Ascaris lumbricoides in two, and ova of Hymeno-lepis nana in one. Urine analysis (all cases), cerebro-spinal fluid examination (15 cases), and gastricanalysis (seven cases) revealed nothing abnormal.The blood Kahn test was negative in all cases.An E.C.G. was recorded in 12 cases. Eight casesshowed findings within normal limits, and fourshowed minor abnormalities. Virological investi-gations on stool samples, throat washings, and bloodsera were negative.

DISCUSSION All patients investigated in this studyshowed clearly the symptoms of acute peripheralpolyneuritis from the onset, with overwhelmingaffection of distal segments of the limbs. The clinicalpicture in the present study was clearly suggestive ofO.C.P. poisoning.

Epidemiological data indicated that O.C.P. presentas a contaminant in mustard oil used for cookingwas the responsible toxic material. A third of thepatients had consumed the oil purcbased from oneshop only, and it is significant that those who con-sumed food other than mustard oil bought in thatparticular shop remained unaffected. The patientsstudied all belonged to the lower economic strataknown to purchase their articles of food in daily

rations. This could account for the failure todemonstrate O.C.P. by analysis in samples of oilcollected a few days after the outbreak from thepatients' houses. It is important that 49 out of 344samples of mustard oil collected during one periodfrom various dealers in the city were found to con-tain ortho-cresyl-phosphate.

According to the literature (Hunter, 1955; Jordi,1952; Burley, 1932) symptoms of O.C.P. toxicityappear between five and 21 days after absorption ofthe toxic material. For the first day or two persistentgastrointestinal symptoms are known to occur inthe form of abdominal pain, nausea, vomiting, anddiarrhoea (Hotston, 1946) but the diarrhoea andgriping abdominal pain experienced by some of thepatients of this series could not be attributed to thetoxic effects as many of them showed ova and/orcysts of several pathogenic organisms in the stools.

Reports of the Morecco epidemic (Smith andSpalding) include bradycardia and fever among themanifestations. In the present series, none of thepatients had fever but five of the 32 manifestedbradycardia. During the first two or three weeksafter the onset of paralysis in the lower limbs, hyper-hidrosis, cyanosis, mottling, or coldness of the legswere noted by Burley. None of the cases of thepresent series showed these signs.The pain and paraesthesiae of calf muscles at the

onset of the disease are, after about two days,generally followed by weakness of muscles of thefeet and hands. In a small number of cases aninterval of 10 days has been reported betweeninvolvement of the feet and hands (Hunter, 1956).In the present study the interval between the onsetof pain and weakness was much shorter (less than12 hours) and the maximum interval betweenaffection of the feet and hands was 36 hours. Thesensory involvement was more significant in thepresent series compared with the reports fromMorocco. On the other hand, signs suggestive ofinvolvement of pyramidal and spinocerebellar tractsreported from Morocco were not detected in thepresent study.

HISTOPATHOLOGICAL FINDINGS

MATERIAL AND METHODS These findings are based on astudy of specimens of skin of the calf and of the gastro-cnemius muscle, removed at operation from 14 of the 32patients admitted to hospital. (Adequate muscle tissuewas available for examination in only 11 of these.)Formalin-fixed samples of both skin and muscle wereblocked in paraffin and lO/L thick sections were examinedafter staining with haematoxylin and eosin and, in themajority of cases, with Holmes' silver method for thedemonstration of nerve fibres. In all cases, the skinsections were also stained by the Picro-Mallory technique

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TABLE I

HISTOPATHOLOGICAL CHANGES IN AFFECTED MUSCLES

Necrosis and InflammatoryPhagocytosis Changes

Regeneration Degenerative InflammatoryChanges in Changes inNerves Vessels

Degree of change

No. of cases showingchange

Severe Mod- Milderate

2 7 2

11

for connective tissues. Wherever possible, both transverseand longitudinal sections of the muscle tissue and sectionsof the skin from different areas of the specimen suppliedwere examined.

CHANGES IN MUSCLE The main pathological altera-tions in muscle, the degree of their severity, and theincidence of their occurrence are presented inTable I. The most constant and noticeable changewas muscular atrophy. This generally took the form

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FIG. 1 (NP/A-888). Cross section of muscle fasciclesshowing generalized atrophy and muscle necrosis ofa singlefibre with replacement by phagocytes (haematoxylin andeosin x 175).

of a more or less uniform reduction in the size offibres and also of groups of fibres, e.g., the musclefasciculi. The extent of atrophy varied from case tocase, and in two of the 11 it had involved all thefibre groups within the specimen. The atrophy was

accompanied by a variable generalized increase inmuscle nuclei, which were generally restricted to theperiphery of the muscle fibres.The second frequent change encountered was

necrosis of single or parts of single muscle fibreswhich showed the disintegration or actual dis-appearance of muscle substance and its replacementby groups of mononuclear histiocytes (Fig. 1).Entire muscle fasciculi were never found to benecrosed.Accompanying the muscular atrophy and necrosis

there was, in the majority of specimens, a mild tomoderate degree of perivascular or interstitialinflammation, small mononuclear cells predominat-ing. In only two instances was there an indication ofthe perivascular infiltrate affecting the vessel wall,and even here there was no indication of a frankmural necrosis.

Regeneration of muscle fibres when encounteredwas evidenced by the presence of coarse basophilicfibres with prominent muscle fibrils and sarcolemmalnuclei. The latter appeared more swollen andvesicular than the other nuclei and occasionallyrevealed clear nucleoli also.The inter- and intra-fascicular nerve twigs at

times showed degenerative changes which generallytook the form of an overall increase in the nerve

sheath nuclei, and, occasionally, of a pallor and fray-ing of the nerve twig (Fig. 2a) or a collagenoushyalinization (Figs. 2b and 2c). Inflammatorychanges were not seen in any intramuscular nerves.The few muscle spindles that were noticed appearedunremarkable.

There was no appreciable increase in adipose or

connective tissue within or around the musclefascicles in any specimen. In one case a number ofmuscle fibres showed large 'sarcocysts', but withoutany reaction and, as shown before (Dastur andIyer, 1955), of no pathogenic significance.

MuscularAtrophy

Mod- Mild Nilerate3 6 2

11

Mod- Mild Nilerate2 6 3

11

De- Sug- Nilfinite gestive3 4 4

11

De- Sug- Nilfinite gestive3 4 4

11

Sug- Nilgestive2 9

11

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CHANGES IN SKIN Small foci of inflammatory cells,around dermal blood vessels (Fig. 3a) or alongneurovascular bundles, were more than normallyprominent in all the specimens examined. In half ofthese cases infiltration of the vessel wall by thesecells was also encountered (Fig. 3a). The pre-dominant reactive cell was again the small mono-nuclear, but larger mononuclear cells appearinglike histiocytes and suggesting focal necrosis werealso not infrequent (Fig. 3b).The changes (Table II) in the intradermal nerve

twigs resembled those observed in the intramuscularnerves but were milder. Early nerve degenerationwas again suggested by an irregular increase in thenuclei of the nerve sheaths, indicating internal dis-organization (Fig. 3c). In addition there were in afew cases small chronic inflammatory infiltrates, inthe form of small mononuclear cell aggregates,within such nerve twigs.

In many of the cases, there were areas of swellingand hyalinization or of diffuse pallor and fragmenta-tion (Fig. 3b) of the dermal collagen. In Picro-Mallory preparations central pink-staining bands,suggesting fibrinoid degeneration, were observedwithin the thickened blue collagen bundles. Theepidermal keratin was prominent in the majority ofthe specimens, but this might be related to the siteof skin biopsied (the calf) which was an exposedsurface in these patients.

There were no alterations in the dermal appen-dages. In a few specimens prominent clusters ofwhat looked like small, newly formed vascularchannels, of the size of arterioles, were seen by theside of the sweat glands.

DISCUSSION The salient histopathological changesobserved in these biopsied specimens comprisedpatchy degeneration of intramuscular and intra-dermal nerve twigs, early neurogenic muscularatrophy, moderate perivascular inflammation inskin and muscle, especially the former, and occa-sional collagen degeneration. Of these, the neuralchanges do not appear inconsistent with thosedescribed in the nerve trunks in cases of O.C.P.poisoning and in experimental animals given thiscompound.

Thus in early cases from the American epidemic,Smith and Lillie (1931) and Burley (1932) hadobserved non-inflammatory changes in the peripheralnerves. Aring (1942), in an extensive study of thelate changes encountered at necropsy in these cases,described neurogenic muscular atrophy, nervedegeneration with heavy overgrowth of endo- andperineural connective tissue, and degeneration ofcertain long tracts of the spinal cord. The histo-pathological effects of O.C.P. on nervous tissues ofthe hen have been studied by Barnes and Denz(1953) and in greater detail by Cavanagh (1954).The latter has stressed the Wallerian nature of thechanges observed in the nerves, the varying grades ofdegeneration in adjacent fibres, and the greaterinvolvement of fibres of larger diameter going intomuscular branches. Changes in both axons andmyelin progressed from the beginning of the secondweek to the end of the third, while Schwann cellproliferation became noticeable only towards theend of the second week.The similarities between the few changes observed

in our limited biopsy material and those describedabove are apparent. Thus, there was more severeevidence of nerve fibre degeneration in relation tothe muscle than to the skin; in the same specimendegenerating and normal nerve twigs were fre-quently found; and biopsy having been performedon our cases between four to six weeks after theonset of the neurological disorder, proliferation ofsheath nuclei and of sheath fibres was clearly inevidence (Figs. 2 and 3). Besides the neurogenic typeof muscular atrophy, our findings have one otherfeature in common with those of Aring, namely, aproliferation in clusters of capillaries and smallblood vessels, with the difference that we noted thisinfrequently and only in skin and not in muscle. Wedo not consider it justifiable, therefore, to assignany significant pathogenetic role to this phenomenon.A feature of note regarding the histological

changes was the evidence of mild collagen degenera-tion and perivascular inflammation with occasionalmural infiltration in the skin, and the necrosis andoccasional regeneration of muscle fibres. These areobviously not neurogenic changes, and they point toan 'allergic or hypersensitivity' phenomenon leading

TABLE IIHISTOPATHOLOGICAL CHANGES IN SKIN

Degeneration orHyalinization of Collagen

Definite Sug- Nilgestive

5 5 4

14

Degeneration orInflammation of VesselWalls

Moderate Mild Nil

4 3 7

14

Perivascular Inflammation Degenerative orInflammatory Changes inCutaneous Nerves

Severe Moderate Mild Definite Sug- Nilgestive

0 10 4 3 9 2

14 14

Degree of change

No. of cases showingchange

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FIG. 2a FIG. 2b FIG. 2c

FIG. 2. (NP/A-892, 896). lnterfascicular nerve twigs showing (a) rarefaction and vacuolation, (b) hiyalinization of nervesheath elements, and (c) loss of nerve fibres (a and b, haematoxylin and eosin, c, Holmes's silver stain; each x 385).

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FIG. 3a (NP/A-892). Dermal blood vessel showing perivascular and intramural infiltration with small mononuclear cells.FIG. 3b. (NP/A-884). Subepidermalfocus of small and round, and irregularly shaped mononuclear cells, together withcollagen fragmentation.FIG. 3c (NP/A-888). Neurovascular bundle in dermis showing proliferation ofsheath nuclei of the nerve twig and of thevessel wall nuclei.(Fig. 3a-3c haematoxylin and eosin x 175)

239

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to a chronic polymyositis or dermatomyositis typeof picture (Walton and Adams, 1958). The recentinteresting observation of Glees (1960) that adminis-tration of cortisone, together with or after anapplication of O.C.P. to the comb of the hen,prevented the onset of paralysis or, if paralysis hadalready set in, reduced the bird to a mild state ofpostural imbalance, appears to point in the samedirection.

CHANGES IN BLOOD CHOLINESTERASE

Determinations of cholinesterase were made onblood samples obtained from seven of the patientsadmitted to hospital in late January 1960. Twoamong this group of patients (1369 and 1371, batch I)as well as two others admitted late in May 1960(7718 and 7811, batch II) were followed up forseveral months. For the four cases where serialdeterminations were possible, the cholinesterase ofplasma and of erythrocytes was determined periodic-ally in blood samples collected once a month.

METHOD Determinations of cholinesterase were carriedout by the manometric method using the Warburgapparatus (Ammon, 1933). The values obtained give ameasure of the relative level of cholinesterase in thesamples compared with the standards under identicalconditions. The standard controls consisted of freshlydrawn blood from normal healthy individuals.

RESULTS AND DISCUSSION As is well known theplasma cholinesterase is the non-specific or pseudo-cholinesterase, whereas the cholinesterase of erythro-cytes, according to most evidence, is identical withthe enzyme hydrolysing acetylcholine in brain tissue.The average results of determinations of plasmacholinesterase and the erythrocyte cholinesterase inthe initial blood samples from nine cases are givenin Table III. It is evident that there is a considerablediminution in the erythrocyte (true) cholinesterasewhereas the values for the plasma enzyme show arise in the patients compared with that in controls.The result of serial determinations carried out on

two batches of patients admitted to the hospitalat different times is illustrated in Fig. 4. It is apparent

that the erythrocyte cholinesterase was reduced to agreater extent in the second group. It is also to benoted that the reduction is considerable and occursquite soon after the onset of clinical symptoms. Therise in the plasma cholinesterase in the initial samplesof blood from the first batch of patients is found tobe higher than the corresponding values of the secondbatch. Considering the fact that in the first batch ofpatients the samples of blood were withdrawn afterthey had been in hospital for about a month, whereasin the second batch blood was taken after only 10days, it appears that the increase in the plasmaenzyme occurs after a period in the course of thedisease. In conformity with this view, it is seen thatthe plasma cholinesterase values of the second batchare found to be higher in the subsequent deter-minations.

It is clear from the pattern of results of serialdeterminations carried out on four patients that thetwo enzymes studied tend to converge to withinnormal limits after about three months. Thus, theerythrocyte cholinesterase, which is reduced bymore than 50% shortly after the onset of clinicalsymptoms, rises gradually and reaches the normalrange of values after three months. The plasmacholinesterase shows a transient increase reaching amaximum in about a month and then graduallydecreases, reaching the normal limits after a periodof three to six months.Although there are numerous studies pertaining to

changes in blood cholinesterase in O.C.P. toxicityand other conditions producing similar clinicalsymptoms, the correlation of cholinesterase changeswith neuromuscular lesions is not at all clear. Intwo cases of poisoning by an organic phosphorusinsecticide (bismonoisopropyl amine fluorophos-phine oxide, Mipafox) Bidstrup, Bonnel, andBeckett (1953) found that the plasma and erythrocytecholinesterases were considerably decreased. Addi-tion of O.C.P. in vitro to human nerve tissue orserum has been found to inhibit pseudocholinesterase75 to 99%, causing only 7 to 10% inhibition of truecholinesterase (Earl and Thompson, 1952). Theeffect on tissues of experimental animals was foundto be less. Mendel and Rudney (1944) have, however,

LE III

ACETYLCHOLINESTERASE ACTIVITY OF INITIAL SAMPLES OF BLOOD

Total No. Plasma (ju. C02120 min.)

Average

872

54-58164

Range

41-6972-8860-68

R.B.C. (,ul. COJ20 min.)

Average

178-511984

Subject

NormalPatients of batch IPatients of batch II

Range

156-193103-13977-91

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.

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0 5 10 15 20 25 30

FIG. 4. Acetylcholinesteraseactivity of blood.O red blood cells,x -x plasma.1, Case 1369; 2, Case 1371;3, Case 7811; 4, Case 7718.

WEEKS AFTER ADMISSION

reported that oral administration of O.C.P. to ratsproduced an 80% decrease in the pseudocholine-sterase and had no effect on the true cholinesterase.According to the meagre data on blood choline-

sterase reported from Morocco (Geoffroy, Pascal,Slomic, and Benebadji, 1960), the pseudocholin-esterase was found to be lowered during the first threemonths. Actual values given for three cases beforeand after treatment with pilocarpine, which isreported to have produced clinical improvement,show, however, that erythrocyte cholinesterase isincreased on treatment and pseudocholinesterase isdiminished. These results are qualitatively in thedirection observed in the present studies. During theacute phase of the disease the plasma cholinesterasewas high and erythrocyte cholinesterase was verysignificantly decreased. With progress of treatmentand amelioration of the clinical condition thecholinesterase values tended to converge towardsthe normal.The physiological significance of the non-specific

cholinesterase is not established. Experiments onnerve degeneration with chickens (Cavanagh,Thompson, and Webster, 1954) indicate that thepseudocholinesterase is a component of the Schwanncells of the nerve. On nerve section, the true choline-sterase was reduced to zero, whereas the pseudo-cholinesterase showed a striking increase after a

6

pericd, and then returned to normal limits. Thesuggestion has been made that this transient increasemay be associated with the active multiplication ofSchwann cells in the degenerating nerve. It is possiblethat the increase in pseudocholinesterase observedin the present study may also be associated with asimilar phenomenon. It is of interest in this con-nexion that the histopathological findings reportedin the present study show that in some of the cases inwhich the pseudocholinesterase level was raised,there was also evidence of nerve fibre degenerationand regeneration with proliferation of sheath nuclei.The data on human material are, however, yet toomeagre to correlate the changes in blood cholines-terase with the neurological lesions in O.C.P.poisoning.

SUMMARY

This paper reports a detailed investigation on 32 of58 cases of toxic polyneuritis encountered in Bombaycity in 1960. Evidence has been presented to showthat toxicity was due to ortho-cresyl-phosphatepresent as a contaminant of mustard oil used forcooking.The clinical features were similar to those re-

ported in previous epidemics of O.C.P. poisoning.All cases showed that the distal groups of muscles

2 10

180

150

N0U

120

90

60

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were mainly affected, causingunsteadiness onstandingand a high-stepping, lurching gait. There was also aglove and stocking type of sensory impairment in themajority of cases, a finding not encountered fre-quently in previous outbreaks elsewhere.

Histological examination of skin and musclesamples removed at biopsy in 14 of the 32 casesshowed moderate neurogenic muscular atrophy,with degenerative changes in the intramuscular andintradermal nerve twigs, findings corroboratingearlier observations on nerve trunks. However, con-current changes of muscle fibre necrosis and occa-sional regeneration, together with frequent altera-tions in the dermal collagen and mild chronic peri-vascular inflammation in the skin and the muscle,suggested a 'hypersensitivity' type of reaction also.

Determination of blood cholinesterase levelscarried out on nine of the patients admitted tohospital has demonstrated that the plasma choline-sterase was increased after a month in the course ofthe disease. The erythrocyte cholinesterase level wasconsiderably diminished (50%) quite early after theonset of the clinical symptoms. Both the plasma anderythrocyte cholinesterase activities returned tonormal levels after about three months.

Our thanks are due to Dr. V. S. Shevade, officiatingsuperintendent, Lokmanya Tilak Municipal GeneralHospital, and to Dr. V. R. Khanolkar, Director, IndianCancer Research Centre. We are grateful to ProfessorP. V. Gharpure, Officer-in-Charge, I.C.M.R. PolioResearch Unit, Bombay, for the virological studies; toDr. V. Sadashivan, analyst, Bombay Municipality, foranalysis of samples of oil; to Dr. A. R. Shirodkar,

assistant health officer, Bombay Municipality, forepidemiological investigations; to Drs. K. N. Desai andV. M. Mandlekar of the Lokmanya Tilak MunicipalGeneral Hospital, for clinical assistance; and to Mr. P.B. Nath, of I.C.M.R. Neurology Unit, for assistance withhistopathological techniques.

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