J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.40.3.268 on 1 March 1977. Downloaded from Journal ofNeurology, Neurosurgery, andPsychiatry, 1977, 40, 268-275

Some observations on SMON from Bombay

N. H. WADIA From the Department ofNeurology, J. J. Group ofHospitals, Byculla, Bombay, India

SUMMARY Nine patients in whom subacute myelo-opticoneuropathy (SMON) was diagnosed with varying degrees of confidence are discussed. The cases were discovered after a retrospective examina- tion of our records for the period 1967-71, and a prospective search from March 1972 to date. Sub- acute myelopathy with predominant dysaesthesiae and greater involvement ofthe pyramidal tracts was seen more often than fully developed SMON. Subacute myelopathy was seen in six instances, optico- myelopathy in two and myeloneuropathy only once. Clioquinol could not be excluded as an aetio- logical agent. The difference in the reported prevalence of SMON between Japan and India is noted, and factors which may account for this difference are discussed. Problems related to the diagnosis of SMON outside Japan, and particularly in India, are stressed. guest. Protected by copyright. Subacute myelo-opticoneuropathy (SMON) as a preliminary report was published concerning the clinical entity has only recently found its place in possible occurrence of SMON in Bombay (Wadia, Western monographs and books on neurology 1973). (Pallis and Lewis, 1974; Ashworth, 1975; Le Quesne, This paper reports the cumulative data of two 1975) although it is known to have afflicted the Japan- searches for cases of SMON, the first retrospective ese since 1956 (Sobue et al., 1971). A voluminous (based on clinical records and covering a five year literature onall aspects ofthe disease has accumulated period), the second prospective (covering a four and in Japan but there have been only occasional reports a half year period). These efforts resulted in the (often of single cases and at times of dubious authen- finding of nine patients considered, on clinical ticity) from Australia (Selby, 1972, 1973), India grounds, to be suffering from SMON. The main aim (Wadia, 1973), Switzerland (Kaeser and Wuthrich, of the surveys was to identify such patients, and to 1970), Sweden (Osterman, 1971), Singapore (Tay, study them in depth with a view to excluding alterna- 1973), Great Britain (Terry, 1971; Spillane, 1971, tive diagnoses. 1972), United States (Kean, 1972), France (Grenier et al., 1972; Castaigne, et al., 1973), and Holland Criteria for patient selection (Van Beeck and Scholten, 1972). The disproportion- ately high prevalence ofthis disease in Japan has been The criteria used to make a diagnosis of SMON were on the themselves from the commented by Japanese (Kono, gathered Japanese literature and from the http://jnnp.bmj.com/ 1971; Tsubaki et al., 1971; Shiraki, 1973). Tsubaki experience of examining such patients in Japan. et al., (1971) were the first to point out that most of Kono's (1971) diagnostic 'guideline' was liberally their patients had taken clioquinol before the onset of interpreted. Patients with neurological disorders of this disease. It soon became accepted, more so in acute or subacute onset, characterised by persistent Japan than elsewhere, that SMON was a clinically distal dysaesthesiae, myelopathy, peripheral neuro- identifiable entity that could occur as a result of the pathy and optic atrophy, occurring in various com- ingestion of clioquinol. binations were considered possible cases of SMON. An to first hand of As in the Japanese cases, presence ofall the symptoms opportunity acquire knowledge on September 25, 2021 by SMON was afforded by a visit to Japan in January and signs was not deemed necessary to make a 1972. It was later felt that a search for SMON in diagnosis. Bombay, a city in which clioquinol is ingested in vast Kono (1971) stressed two cardinal symptoms, amounts, might provide additional information. A present in the overwhelming majority of the Japanese patients: (1) abdominal complaints preceding the neurological disorder, (2) acute or subacute dysaes- Accepted 28 October 1976 thesiae, starting and predominating in the lower 268 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.40.3.268 on 1 March 1977. Downloaded from

Some observations on SMONfrom Bombay 269 limbs. He also mentioned 'deep sensory disturbances' Results and weakness of the lower limbs. We therefore evaluated as possible cases of SMON all patients with The retrospective scrutiny was based on the in- persistent distal dysaesthesiae, especially if of patient records of the Department of Neurology at ascending pattern and associated with evidence of the J. J. Hospital, Bombay (covering the period myelopathy. Physical signs of associated peripheral 1967-71), and on the records for 1970-71 from my or optic neuropathy were not considered essential. private practice; 5,168 records were examined with Although ankle jerks were absent in the majority of special attention to cases with a diagnosis of peri- Japanese patients, this was not always the case. Their pheral neuropathy, myelopathy, sensory ataxia, preservation, in our cases, was not held to invalidate optic atrophy, and myeloneuropathy of known or a diagnosis of SMON. The first cardinal feature of the unknown aetiology, or combinations of these. From Japanese guidelines (namely abdominal disturbances this material, 83 records were thought to merit further or pain immediately preceding the onset of neuro- study, and an attempt was made to trace and recall logical symptoms) was not considered mandatory for these patients. A satisfactory follow-up was possible diagnosis. We realised that if we accepted this in only 41 instances. The retrospective study yielded criterion strictly, no case of SMON would be two cases (R1 and R2) suffering from conditions con- diagnosed. sidered 'compatible with SMON'. Clioquinol could After an overall assessment of the natural history, not be excluded as the cause in the disorder. In nine symptoms, and signs, a diagnosis of SMON was further patients a somewhat similar neurological made on a descending scale of likelihood, the cate- syndrome was seen: eight had not taken clioquinol gories adopted being 'definite SMON', 'probable and one had taken the drug only in very small

SMON', and 'compatible with SMON'. Several amounts. guest. Protected by copyright. patients reviewed were deemed not to have SMON, Prospectively, we kept a sharp look-out for SMON. though perhaps affected by a condition resembling it Our interest in the condition was made known in in some respects. The initial appraisal was made on professional or personal meetings with general purely clinical grounds, without reference to the physicians, gastroenterologists, and neurologists. question of clioquinol intake. On obtaining a history Between March 1972 and August 1976 we saw seven of clioquinol consumption its relation to the disease patients (P1 to P7) deemed to have SMON. All were was assessed, taking into consideration the amount questioned carefully for details of drug intake, with of drug ingested, the period over which it was taken, special reference to clioquinol. and the relationship of this period to the time of onset The Table summarises the clinical manifestations, of symptoms. If the clioquinol intake had exceeded the electrophysiological findings, the clioquinol in- 10 grams and if the temporal relationship was close, take, and our overall conclusion regarding the nine it was felt that a diagnosis of clioquinol-induced patients accepted, with varying degrees of confidence, SMON could not be excluded. as suffering from SMON.

Table Clinical and electrophysiological data in SMON

Patients P1 P2 P3 P5 P6 P,R7 R2 P4 http://jnnp.bmj.com/ AF AB DF BK PP MB VD DJ GD Sex/age (yr) F/60 F/60 F/53 M/55 F/40 F/65 M/21 M/42 F/9 Preneurological abdominal disorder + - - - - Pyramidal tractsign + ++ ++ + - + ++ ++ + Posterior column disorder + + + + + + + + + + + Ankle jerks - ++ ++ + + ++ ++ ++ ++ Cutaneous sensory loss (level) L - - L3 - _ D1o Visual disturbance - + - + Bladder symptoms + - - + - - + + EMG-NC Normal Normal - Normal Normal Normal - Normal on September 25, 2021 by Clioquinol intake Amount in grams (approximate) 25.2 1000 125 80 45 420 500 1000 21 Period 32 d 3 yr 2 yr 60 d 4 mo 14 yr 4 yr 18 yr 42 d Improvement Drugcontinuing/drugstopped -1+ -/+- /+-/-/++ -1 + +/+ +/+ -/ + Clinical pattern MN OM M OM M M M M M Final conclusion D p p P P P C C C

EMG=electromyography. NC=nerve conduction study. 4. =denervation and delayed nerve conduction. + =present. - =absent. O=optic neuropathy. M=myelopathy. N=peripheral neuropathy. D=definite SMON. P=probable SMON. C=compatible with SMON. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.40.3.268 on 1 March 1977. Downloaded from

270 N. H. Wadia

We considered one patient (Pi) as definitely suffer- PROBABLE SMON ing from SMON, and five (P2, P3, P5, P6, P7) as The patients (P2, P3, P5, P6, P7) with a diagnosis of probably suffering from SMON. In three other 'probable SMON' were given a lower rating because, patients (R1, R2, P4) the natural history of the disease though all of them had prolonged diarrhoea, none and the physical signs led us to consider the myelo- had preneurological abdominal disturbance or a pathy as 'compatible with SMON'. Clioquinol definite peripheral neuropathy on clinical or electro- could not be excluded as the cause of the disorder in physiological assessment. Visual disturbances were these nine patients. Investigations (including myelo- complained of by two patients (P2 and P5). Thorough graphy, CSF examination, and studies to exclude investigations were carried out in three cases (P3, P6, vitamin B12 deficiency) were carried out as required. P7) to exclude an alternative diagnosis. The other two No reasonable alternative diagnosis was forth- patients (P2, P5) did not permit a lumbar puncture or coming. myelogram but, in the presence of visual symptoms and a subacute ascent of severe dysaesthesiae up to DEFINITE SMON groin level, no alternative diagnosis seemed likely, AF (Pi), a 60 year old female, was admitted for surgery although demyelinating disorders were considered. with constipation due to anal stenosis. She was at All patients had taken sufficient clioquinol, in an first prescribed clioquinol (Mexaform) 1.2 g daily and appropriate temporal relationship, to suggest that diloxanide furoate (Furamide) 0.5 g three times a day, clioquinol might be a possible causative agent. With- for six days. Eleven days later both drugs were again drawal ofclioquinol arrested or reversed the progress prescribed, along with oxytetracycline for two weeks. of the disease. On the ninth day ofthe second course she complained The case history of P2 illustrates some of the differ-

of abdominal discomfort. Three days later she ex- ential diagnostic difficulties. guest. Protected by copyright. perienced disturbing tingling, numbness, and weak- AB (P2), a 60 year old female with hypertension ness of the lower limbs with hesitancy of micturition. and osteoarthritis, had received many antibiotics and Severe paralysis ofthe lower limbs with dense sensory other drugs for undiagnosed pyrexia of a month's loss below T7 dermatome was noted. The drug was duration. Towards the end of this period distressing withdrawn and she gradually began to improve. paraesthesiae ascended within a few days to her Two weeks later there was minimal residual weak- knees and thighs. The legs felt weak and she could ness of the dorsiflexors and evertors of the feet, with only take a few steps with support. slight hypertonia at the knees. The tendon reflexes Neurological examination carried out two and four were exaggerated except for the ankle jerks, which months later showed grade 2 hypertensive retinopathy were absent. Both plantar responses were extensor. but no optic atrophy. There was moderate spastic The patient complained of distal dysaesthesiae. Pain paraparesis with exaggerated deep reflexes and ex- and tactile sense were impaired below the groins. tensor plantar responses. Vibration and postural Vibration and postural sense were diminished dis- sense were impaired in the feet. tally. Romberg's sign was positive and she could only Five months later she complained of bilateral pro- walk with support. gressive dimness of vision. She could only count Routine blood and CSF examinations were normal. fingers at a distance of 1 metre and the visual fields The VDRL was negative. Electrodiagnostic examina- were constricted. The fundi were unchanged. tion revealed chronic partial denervation and slight Examination after a further three months revealed slowing ofmotor and sensory nerve conduction in the optic atrophy. Thereafter a slight lessening of the http://jnnp.bmj.com/ lower limbs. Myelography showed no abnormality. paraesthesiae and some improvement in walking She refused further investigation. were noticed. Examination still showed mild spastic Seen again 18 months later, she had improved weakness of the legs with only slight impairment in somewhat in that she walked without support. The vibration and postural sense in the toes. Only now did ataxia and dysaesthesiae were still present. The re- she admit, on direct questioning, to having taken flexes were unchanged. She had no abdominal clioquinol (Mexaform) at a dose of 1200 mg per day, symptoms and had not taken further clioquinol. for two and a half years before the onset of the In the face of other features of the condition, the neurological symptoms, for recurrent abdominal on September 25, 2021 by absence of optic nerve involvement was not con- 'upsets' without diarrhoea. She had continued to take sidered strong enough evidence, in this patient, to the tablets during the first four months of the illness, downgrade the rating from 'definite' to 'probable' the drug only being withdrawn when visual dis- SMON. There had been no diarrhoea or other ab- turbance appeared. Visual deterioration had then dominal disorder at any stage of the illness, except ceased and a slight improvement in walking and in the immediately before the onset of neurological paraesthesiae was observed. symptoms. Electromyographic examination showed no evi- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.40.3.268 on 1 March 1977. Downloaded from

Some observations on SMONfrom Bombay 271 dence of a lower motor neurone lesion. Radiographs boldened us to accept her condition as 'compatible of the spine, blood and other routine examinations with SMON'. She continues to remain well and takes including VDRL were normal. CSF examination was neither metronidazole nor clioquinol. Her diarrhoea not allowed. and other abdominal symptoms persist. The initial diagnosis had been of a subacute trans- Accepting these nine patients as cases of SMON, verse myelitis. When optic atrophy appeared a analysis (Table) showed that females predominated demyelinating disorder of unknown aetiology was (6:3), and that five of the nine patients were above considered. Large doses of vitamin B12 had not the age of 50 years when first seen. All except P1 were arrested the condition. The massive dose of clio- suffering from chronic, distressing, recurrent diar- quinol ingested and the slight improvement following rhoea, flatulence, and abdominal discomfort or pain, withdrawal of the drug led us to consider the case as often of many years standing. These symptoms were 'probable SMON' due to clioquinol. controlled or made tolerable by the frequent con- The case history of P3 is recorded in an earlier sumption of clioquinol and, in some instances, of paper (Case 3, Wadia, 1973). other drugs. In only one or perhaps two patients were we convinced that there was a specific abdominal NEUROLOGICAL DISORDER COMPATIBLE WITH SMON disturbance immediately preceding the neurological In three patients (R1, R2, and P4), a diagnosis of illness. Dysaesthesiae, usually up to the lower ab- neurological disorder 'compatible with SMON' was domen, were intense and distressing. They persisted made. The lower grading was given because these distally, in all cases, despite withdrawal of clioquinol patients had neither immediate prodromal abdominal (except in patient P4 whose disease was fleeting). disturbance, nor peripheral or optic neuropathy. Clinical evidence of posterior and/or lateral

Clioquinol had been taken in large doses by R1 and column involvement at a thoracolumbar level was guest. Protected by copyright. R2, though intermittently over a period of years. The present in all cases. Case P6 had only sensory ataxia. condition had not worsened and had even improved One patient (P7) had predominant sensory ataxia of slightly while the patients continued to take small but spinal origin. Three patients (Pi, P4,. and P5) had equal repeated doses of clioquinol. They were advised to involvement of lateral and posterior columns. Four stop the drug. The detailed case histories are recorded patients (P2, P3, R1, and R2) had greater pyramidal elsewhere (Case 1 and 2, Wadia, 1973). The history of tract involvement. The pyramidal tract disorder was P4 illustrates the difficulty in diagnosing SMON. usually evidenced as spasticity, weakness, and GD (P4), a girl aged nine years, had suffered from exaggerated deep reflexes; the plantar responses recurrent abdominal pain, sometimes associated with were extensor in only four of the seven patients with loose stools, for three years. She had taken several other evidence of lateral column involvement. Only courses of metronidazole (Flagyl) and clioquinol one patient (P1) was bedridden at the onset. The (Mexaform) for Giardia lamblia infestation. From others were all ambulant. Even patient P1 began December 1974, she took metronidazole and clio- walking after clioquinol withdrawal. quinol in two separate courses (12 g ofthe former and Surprisingly, peripheral neuropathy (as evidenced 21 g of clioquinol, over a period of six weeks). To- by absent ankle jerks, predominantly or restrictedly wards the end of the last course she began falling. distal dysaesthesiae, and reduced nerve conduction Over the next few days she noticed increasing diffi- velocities or distal denervation) was only seen un- culty in walking and experienced bilateral paraes- equivocally on one occasion (P1). thesiae up to groin level. Clioquinol was stopped. Clioquinol had been taken in varying amounts by http://jnnp.bmj.com/ Within 24 hours her gait began to improve. Two days all patients. The maximum ingested was 1000 g, later she was walking with a mild spastic ataxic gait. taken continuously over a period of three years Postural sense was impaired in the toes and Rom- (P2). Most other patients had taken the drug re- berg's sign was positive. There was slight weakness of peatedly, over months or years. Clioquinol was dorsiflexion and eversion of the feet. The deep re- actually being taken by all patients at the time ofonset flexes were present, including the ankle jerks which of their neurological complaints. No 'latent period' were, in fact, brisk. The plantar responses were between stopping the drug and the onset of neuro- flexor. Electromyography and nerve conduction logical symptoms was seen in any of our patients. on September 25, 2021 by velocity were within normal limits. Seven patients were deteriorating when we asked Had there been no history ofclioquinol intake, this them to stop the drug: withdrawal of the drug girl with dysaesthesiae and a fleeting spastic-ataxic was followed by arrest or improvement in their myelopathy might have been diagnosed as suffering neurological condition. In two patients (R1 and from transverse myelitis, possibly of viral origin. The R2) the inadvertent resumption ofdrug intake, admit- story of clioquinol ingestion, in sufficient dose, tedly in small doses, had not obviously resulted in before the onset of neurological symptoms em- deterioration. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.40.3.268 on 1 March 1977. Downloaded from

272 N. H. Wadia In summary, subacute myelopathy was seen in six pathies to be labelled SMON, merely on the basis of patients (P3, P4, P6, P7, R1, and R2), opticomyelo- the patient having taken clioquinol. Kono (1971) pathy in two patients (P2 and P5), and myeloneuro- quotes a figure of 2808 cases of 'suspected SMON' pathy once (P1). No case of the full syndrome (as opposed to 5048 cases of 'confirmed SMON') in a (myelo-opticoneuropathy) was encountered. These national survey ending in October 1970. This nine cases are, in our opinion, acceptable as cases of suggests that it is not so easy to distinguish SMON SMON (of varying grades of certainty). No clear from other diseases as is usually maintained. In a alternative diagnosis was evident. Clioquinol could discussion of the differential diagnosis of SMON, not be excluded as the cause. Pallis (1976) stresses the difficulties, and maintains that large series tend to be 'contaminated' with Discussion patients suffering from other neurological disorders. Spillane (1971), Pallis and Lewis (1974), and Meade It must be stressed at the outset that no attempt to (1975) have expressed similar views. carry out an epidemiological survey on the preva- If we accept our nine patients as cases of SMON, lence of SMON was made. the following overall picture emerges. Females, The points of interest centre around three main specially elderly females, predominated. Abdominal questions. symptoms (pain, diarrhoea, flatulence, and mucous 1. Are the cases described here those of SMON due discharge) are troublesome. This abdominal condi- to clioquinol, especially as no other published tion is nonspecific and was unrelated to amoebiasis. report has appeared from India, even after the The gastroenterological symptomatology was re- common knowledge of SMON since 1971 ? lieved, often rapidly, by short or long courses of

2. Why is SMON not more evident in India where so clioquinol and at times by other drugs. Abdominalguest. Protected by copyright. much clioquinol is consumed? pain or other abdominal symptoms, immediately 3. What are the problems encountered in diagnosing preceding the nervous symptoms, were only seen SMON? once. Dysaesthesiae, often ascending up to the When all the manifestations are present, including groins or umbilicus (with signs of myelopathy) were the preneurological abdominal disorder, SMON is an complained of in all cases. Pyramidal tract signs were identifiable nosological entity with a narrow differ- more obvious than ataxia, but both were often seen. ential diagnosis. This is so even if there is no history Surprisingly, definite peripheral neuropathy was only of clioquinol intake. When the incidence of such confirmed once. Optic neuropathy was seen twice. cases assumes epidemic proportions, as reported Clioquinol was being ingested in appropriate from Japan, the diagnosis may become easier. amounts right up to the day of onset of the neuro- In our anxiety not to miss possible cases of SMON logical condition, unlike what was seen in some of the our criteria may have erred on the side of not being Japanese cases. sufficiently strict. For instance, we included cases in The widely held view, shared by Japanese authors whom some of the allegedly important components (Kono, 1971; Tsubaki et al., 1971; Shiraki, 1973), of SMON (such as preneurological abdominal that SMON is rare outside Japan appears to be disturbances and peripheral neuropathy) were confirmed by this study. Whereas some 10,000 cases absent. Hence it would not be difficult to challenge of SMON were reported from Japan over a 15 year the diagnoses of 'probable SMON' or of 'compatible period, we have only been able to find nine cases in with SMON' in some of our cases. But for the same Bombay, in a little over nine years. If we consider the http://jnnp.bmj.com/ reasons we feel we have not underestimated the prospective study alone, we have seen only seven prevalence of SMON. cases of SMON in four and a half years. It would be We felt emboldened to include for analysis cases incorrect to compare the total Japanese experience, which did not satisfy all the criteria of SMON, collated through a Commission of Inquiry, with the because despite the claim of the Japanese authors personal experience of an individual observer. that this condition has distinctive features, a number Against this it might be mentioned: (a) that a nation- of their own cases clearly did not fulfil all their own wide scrutiny of retrospective data, carried out by a criteria. Sobue et al. (1971), while maintaining that host of physicians, leads to a greater amount of on September 25, 2021 by myeloneuropathy with abdominal symptoms in observer bias, perhaps inflating the figures; (b) that Japan differs from any other neurological diseases no report of a series of cases, or even of single cases reported in the literature, mention that the disease of SMON has appeared from India to date, despite 'may be myelopathy or peripheral neuropathy or common knowledge of the disorder through books both, the combination varying according to the and manufacturers' warnings on packages and cases'. This leaves the door wide open for many leaflets. No reports of SMON have appeared from unidentified peripheral neuropathies and myelo- Brazil, Africa, Pakistan, Bangladesh, Thailand, J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.40.3.268 on 1 March 1977. Downloaded from

Some observations on SMONfrom Bombay 273 Malaysia, and Indonesia, which between them must diseases, especially renal or hepatic, contributed to contain the bulk of the world's clioquinol-consuming SMON by impeding the excretion of clioquinol? population; (c) that the Japanese literature mentioned It is also possible, however, that no specific outbreaks and endemic pockets of SMON, even 'Japanese' factor exists. The difference in the reported before clioquinol had been incriminated as a possible prevalence of the disease would then reflect differ- cause. We doubt that obvious clusters ofcases, in and ences in the methods of gathering and interpreting around big neurological centres in India, would have data. SMON may still be misdiagnosed (or under- been missed, especially after the Japanese experience diagnosed) in India, but as Spillane (1971), Pallis and had been widely publicised. (d) Individual experi- Lewis (1974), Meade (1975) and Pallis (1976) have ences in the two countries, may be worth comparing. pointed out it may also have been misdiagnosed J. J. Hospital and Bombay City can be roughly (or overdiagnosed) in Japan. compared to Nagoya University Hospital and How does one diagnose SMON, especially in its Nagoya City. Between 1956 and 1969 Sobue et al. incomplete form, in the absence of any specific (1971) were able to collect 752 cases of SMON laboratory tests and without using the fact of clio- (an average of 54 cases a year). In the subsequent quinol consumption as a diagnostic criterion? two years, after Tsubaki et al. (1971) had pro- Today, the diagnosis of SMON outside Japan is pounded the clioquinol hypothesis, Sobue et al. largely, if not totally, based on an acceptance of the (1973) added 349 further cases (an average of 175 Japanese experience (Osterman, 1971; Selby, 1972). cases per year). If such an epidemic had occurred in This results, at times, in the acceptance of patients as Bombay, especially during the four and a halfyears of cases of SMON (or of their acceptance as cases of our prospective study, they would have been de- clioquinol neurotoxicity), when the neurological

tected. With a constant watch in a sizeable neuro- picture is far from typical. In such cases, the very guest. Protected by copyright. logical practice, the contrast (seven cases in four and a fact of clioquinol intake tends to become-probably half years versus 349 cases in two years) is too unconsciously-a diagnostic criterion. This is illus- obvious to need further comment. It suggests that trated in the cases mentioned by Spillane (1971, there is some factor in addition to clioquinol intake 1972). Clioquinol is so widely consumed in India, which operates in Japan. Many persons in India that a history ofclioquinol ingestion by patients with (Wadia, 1973) take more than '10 to 40 g of clio- diseases of the CNS, including myelopathies of quinol', the dose deemed sufficient to cause SMON known and unknown aetiology, is not beyond the in Japan (Kono, 1971). realm of mere coincidence. During the course of this The factor determining this difference in pre- study, and in the day-to-day practice of neurology, valence has not yet been identified. Various con- we have come across patients who resembled those jectures have been made. Shiraki (1973) discusses diagnosed as SMON in this paper. They differed fully the endogenous and exogenous factors, other only in that most of them have not suffered preceding than clioquinol, which could have contributed to the diarrhoea or other gastrointestinal disorder, and had, aetiology of SMON in Japan. therefore, not taken clioquinol. Had they taken The possibility of racial or genetic predisposition clioquinol, the diagnosis of SMON would have been (based on a presumed specific enzymatic defect in the seriously considered. Japanese leading to greater clioquinol neuro- The difficulties in diagnosis are exemplified by the toxicity), has never been supported by any evidence. following examples. No definite case reports of Japanese overseas 1. We saw patients with slowly progressive spastic http://jnnp.bmj.com/ developing SMON have yet appeared (Meade, myelopathy who had taken clioquinol. SMON could 1975). The greater chemical pollution of the Japanese not be diagnosed because of the insidiousness of the environment may be a contributory factor, yet hard onset, the slowness of progression, and the rather proof is lacking. The role of associated diseases, or of indefinite nature of the paraesthesiae. No other cause other drugs taken to treat them, needs evaluation. for the chronic myelopathy could, however, be Many of the Japanese patients had tuberculosis, established. diabetes, malignancy, renal failure, etc. and must 2. We encountered patients with subacute myelo- have taken drugs for them as did some of our pathy resembling SMON who had taken clioquinol, on September 25, 2021 by patients. Drugs like metronidazole (Holdstock, 1975; but for short times and in small doses. The temporal Coxon and Pallis, 1976) and isonicotinic acid data made it unlikely that there was a cause and hydrazide are known to be neurotoxic, and on effect relationship. occasion to cause peripheral neuropathy. Could drug 3. There were patients with fleeting transverse mye- interaction have precipitated SMON in some litis of uncertain aetiology who had casually taken patients, when each drug individually may have had small doses ofclioquinol, within a short period of the no neurotoxic effect? Is it possible that associated onset of the symptoms. The clinical picture ruled out J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.40.3.268 on 1 March 1977. Downloaded from

274 N. H. Wadia SMON and the dose ruled out a clioquinol-induced Advances in Clinical Neurology, p. 101. Edited by W. B. disorder. The association seemed coincidental. Our Matthews. Churchill Livingstone: London. case P4 has been accepted as 'compatible with Castaigne, P., Rondot, P., Lenoel, Y., Duman, J.-L. R., SMON' because she took sufficient clioquinol, but and Autret, A. (1973). My6lopathie severe, neuropathie the periph6rique et nevrite optique survenues au cours same objections could be levelled against the data d'un traitement par la chloroiodoquine (clioquinol). presented as against the cases of Spillane (1971, Therapie, 28, 393-400. 1972). Coxon, A., and Pallis, C. A. (1976). Metronidazole 4. We have come across a patient the cause of whose neuropathy. Journal of Neurology, Neurosurgery, and myelopathy could not be found at the initial examina- Psychiatry, 39, 403405. tion. He had taken clioquinol and SMON was Grenier, B., Rolland, J. C., Casenave, C., and Desbuquois, considered. Later investigation established the G. (1972). Myeloradiculo-nevrite subaigue et traite- correct diagnosis as myelopathy due to cervical ment parlachloroiodoxyquinoleine. ArchivesFran!paises spondylosis. If this patient had not been followed up de Pediatrie, 29, 1015. or Holdstock, D. J. (1975). Drug treatment in Crohn's investigated carefully, a wrong diagnosis of disease. Lancet, 2, 1260. clioquinol-induced SMON would have been made. Kaeser, H. E., and Wiuthrich, R. (1970). Zur Frage der 5. Finally, we have seen a patient with myeloneuro- Neurotoxizitat der Oxychinolone. Deutsche Medizin- pathy 'compatible with SMON' who had taken a fair ische Wochenschrift, 95, 1685-1688. amount of clioquinol, apparently in proper temporal Kean, B. H. (1972). Subacute myelo-optic neuropathy. relationship to the onset of disease. Yet on careful Journal of the American Medical Association, 220, questioning it became apparent that one or two 243-244. neurological symptoms had preceded the intake of Kono, R. (1971). Subacute myelo-optico-neuropathy, a new neurological disease prevailing in Japan. Japanese clioquinol. Should this case have been included as an guest. Protected by copyright. of SMON? Journal ofMedical Science and Biology, 24, 195-216. example Even if the rest of the picture Le Quesne, P. M. (1975). Neurotoxic substances. In resembled SMON, can we justifiably attribute the Modern Trends in Neurology-6, pp. 91-93. Edited by condition to clioquinol? D. Williams. Butterworths: London. These and other questions have arisen during the Meade, T. W. (1975). Subacute myelo-optic neuropathy course of our observations, making us wonder about and clioquinol. An epidemiological case history for the validity of a diagnosis of neurotoxicity based diagnosis. British Journal of Preventive and Social merely on a history ofpreceding intake ofa particular Medicine, 29, 157-169. drug. In 1977, it would be imprudent totally to ignore Osterman, P. 0. (1971). Myelopathy after clioquinol the Japanese experience. If the factor which makes treatment. Lancet, 2, 544. for the difference in SMON is Pallis, C. A. (1976). Proceedings Honolulu Symposium on reported prevalence 'Epidemiological issues in reporteddrug-induced illnesses: genetic, SMON may never appear in India on an SMON and other examples'. McMaster University epidemic scale. But if the factor is environmental or Press: Hamilton (Ontario). infective, then a change in the Indian environment Pallis, C. A., and Lewis, P. D. (1974). Neurological may result in the appearance of SMON. Meanwhile complications of clioquinol therapy. In The Neurology clioquinol has been recommended for production in of Gastrointestinal Disease, pp. 179-188. 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Some observations on SMONfromn Bombay 275 Spillane, J. D. (1971). SMON. Lancet, 2, 1371-1372. Van Beeck, J. A., and Scholten, J. B. (1972). Polyneuro- Spillane, J. D. (1972). SMON. Lancet, 1, 154. pathie na langdurig gebruik van clioquinol (Enterovio- Tay, C. H. (1973). SMON in Singapore. Lancet, 1, 1519. form). Nederlands Tijdschrift voor Geneeskunde, 116 Terry, S. 1. (1971). Transient dysaesthesiae and persistent 1621-1622. leucocytosis after clioquinol therapy. British Medical Wadia, N. H. (1973). Is there SMON in India? Neurology Journal, 3, 745. India, 21, 95-103. Tsubaki, T., Honma, Y., and Hoshi, M. (1971). Neurological syndrome associated with clioquinol. Lancet, 1, 696-697. guest. Protected by copyright. http://jnnp.bmj.com/ on September 25, 2021 by