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Journal of , Neurosurgery, and Psychiatry 1992;55:997-1001 997 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.11.997 on 1 November 1992. Downloaded from The environment in childhood and risk of motor disease

C N Martyn, C Osmond

Abstract motor , such individuals would be To investigate a possible link between especially vulnerable to further neuronal loss, subclinical with in perhaps through or because of a second childhood and increased risk of motor insult to the . neuron disease in adult life, environmen- A prediction from this hypothesis is that risk tal determinants of infection in early life of disease will be related to were compared in 98 cases of motor factors that determine likelihood of poliovirus neuron disease and 335 age and sex mat- infection in childhood and the age at which it ched controls. A weak but consistent rela- occurs. The prevalence of seropositivity to tion was found between motor neuron poliovirus in the middle aged and elderly is disease and factors in the childhood envi- high9 partly because exposure to wild type ronment known to increase likelihood of during the first half of the century was enteric infection. Relative risks associated common and partly as a result of programmes with spending the first 10 years of life in a of active immunisation against the virus. without domestic amenities such as Unfortunately, serological techniques do not a bathroom, running hot water or flushing distinguish between those who acquired anti- lavatory, living in overcrowded condi- bodies as a result of infection with wild type tions, frequent changes of address or virus and those who are seropositive because having a sibling with paralytic poliomye- they have been immunised; they cannot there- litis were all greater than unity, although fore be used to estimate childhood exposure to only those for absence of running hot poliovirus retrospectively. Population-based water and frequent changes of address surveys carried out in the , 102 however, were statistically significant. before mass immunisation programmes were instituted, identified the important environ- (X Neurol Neurosurg Psychiatry 1992;55:997-1001) mental determinants of poliovirus infection as the presence or absence of domestic amenities such as running hot water, flushing lavatories In England and Wales the current geographical and bathrooms, degree of domestic over- distribution of mortality from motor neuron crowding and social class. disease correlates closely with the pattern of We present the results ofa case control study notifications ofpoliomyelitis in the past. ' There designed to investigate whether these variables http://jnnp.bmj.com/ are also similarities in the time trends of the were associated with risk of motor neuron two diseases. The steady rise in mortality from disease. seen in , Scandi- navia and North America over the past 25 years" has paralleled the increase in incidence Patients and methods of poliomyelitis that occurred in the same We attempted to recruit all prevalent cases of

countries during the first half of the century. motor neuron disease resident in the area on September 23, 2021 by guest. Protected copyright. These epidemiological data suggest that there served by the Wessex Regional Health Author- might be a causal relationship between the two ity. To achieve as complete ascertainment of conditions. Although evidence from case series cases as possible, several different methods suggests that a history ofparalytic poliomyelitis were used to identify individuals with the can be obtained from patients with motor disease. Principal sources of information were neuron disease more often than could be the case records of the Wessex Neurological chance 6 is clear that General a MRC Environmental expected by alone,5 it Centre, Southampton Hospital, Epidemiology Unit, most patients cannot recall ever having had diagnostic register maintained by the clinical Southampton General poliomyelitis. Any link therefore, must be with department of the Wessex Hospital, with poliovirus rather Neurological Centre and a list of members of Southampton C N Martyn than with poliomyelitis itself. the Motor Neuron Disease Association whose C Osmond It is possible that subclinical forms of - addresses corresponded to the geographical " Correspondence to: virus infection exist in humans,' as have been area of the study. All patients included in the Dr C N Martyn, MRC shown in in which the infection as cases seen a Envirornmental Epidemiology primates,8 study had been by consultant Unit, Southampton General involves the but is not neurologist and all diagnoses were checked by Hospital, Southampton S09 severe to cause . the case records for the 4XY, UK. enough reviewing original or, these subclinical cases would never few cases where this was not Received 10 September Although possible, by 1991 and in revised form have been diagnosed as having poliomyelitis, writing to the neurologist whose care the 20 January 1992 and motor neurons cri- 16 March 1992. considerable loss of could have patient was under. Minimum diagnostic Accepted 23 March 1992 occurred. Left with a depleted population of teria were clinical or electrophysiological signs 998 Martyn, Osmond J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.11.997 on 1 November 1992. Downloaded from of both upper and disease the recorded address was no longer current or and that both and at least one region because they had died. Of the 502 who were of the were affected. In addition, sent a letter explaining the study and request- evidence was required ofprogression of disease ing permission for an interviewer to visit, 167 over time. Cases who showed atypical clinical declined to take part. Interviews were obtained features or in whom the diagnosis was doubtful from 335 subjects-a response rate of 67%. were not entered into the study. To avoid any For three cases we did not succeed in inter- confusion with cases of late degeneration after viewing three or more matched controls; each poliomyelitis, any subject whose medical of these cases was matched with two controls. records indicated that they had suffered from Three controls from whom interviews had poliomyelitis in the past or who, when inter- been obtained were excluded from the analysis viewed, gave a history of acute paralytic polio- because they were matched to the case who, was excluded. during the interview, gave a - In the later stages of the study, when it myelitis. became clear that insufficient numbers of cases Demographic characteristics of the cases in could be identified within the area defined this study were fairly typical of patients with above, we recruited patients from contiguous motor neuron disease in the UK: 61% were district health authorities outside the Wessex men; median age at the time of interview was health region who were under the care of 62 years (range 32-84); and all were white. No neurologists in Bristol, Gloucester and Oxford. case gave a family history of motor neuron The same criteria for diagnosis were applied. disease. For each case, six potential controls, mat- The method used for matching controls by ched for sex and within the same five year age age proved satisfactory; 86% of controls were band as the case (40-44, 45-49, 50-54 etc), within two years of age of the case and there were selected from the list of the general was no systematic tendency for controls to be practitioner. who had originally referred the older or younger than cases. case for investigation. The list of patients Analysis of the data was carried out using registered with the general practitioner was conditional logistic regression techniques to searched forward from the entry for the case take account of the matching of cases and and the first six eligible controls were identi- controls.'3 Results have generally been pre- fied. sented as an odds ratio as an estimate of After obtaining permission from the general relative risk. practitioner, patients and the first four controls selected for each case, were sent a letter requesting permission for an interviewer to Results call. Those who failed to respond were con- There was a consistent relation between both tacted by a personal visit. Where fewer than the absence of domestic amenities and over- three controls agreed to be interviewed, the crowding within the home during the first 10 remaining two controls were approached in the years of life and risk of motor neuron disease. same way. The interviewer administered a Odds ratios associated with the lack of a room questionnaire enquiring about the subject's with a fixed bath, lack of a running hot water domestic, social and family circumstances system, lack of an indoor flushing lavatory and during the first 10 years of their life. All domestic crowding of 1 5 persons per bedroom http://jnnp.bmj.com/ interviews, both of patients and controls, were or more were all greater than unity when carried out by the same person. compared with the presence of these amenities From the various sources described above, or a lesser degree of crowding. None of these 223 possible cases of motor neuron disease odds ratios was large and only that for lack of a were identified. Of these, 77 had died by the hot water system was statistically significa'nt. time we made contact with the general practi- These results are shown in table 1. tioner. In 21 cases the was either not No relation was between social diagnosis found class on September 23, 2021 by guest. Protected copyright. confirmed as motor neuron disease or there at birth (assessed by father's occupation), size was an indication in the case records that the of family, educational level (assessed by age at patient had previously suffered an attack of which the subject ceased full time education), acute paralytic poliomyelitis. Eleven patients or the size of the town lived in and risk of had moved from the area of the study and no motor neuron disease (table 2). attempt was made to trace them further. Six Subjects who changed address more than proved to be duplicates. There were thus 108 three times in the first 10 years of life had a cases eligible for recruitment into the study: in higher relative risk of motor neuron disease three cases we were refused permission to (table 2) than subjects who moved less often or approach the patient by the general practi- remained in the house in which they were tioner; six declined to take part after receiving born. This increased risk persisted after adjust- a letter explaining the study and one case was ment in a multiple regression model for later excluded because she gave a history of absence of domestic amenities and crowding. paralytic poliomyelitis during the interview. Subjects with a sibling who had suffered The results presented here were therefore from paralytic poliomyelitis had an increased obtained from 98 cases who were successfully relative risk of motor neuron disease. The risk interviewed. was higher in those who recalled that the In total, 610 subjects were selected as affected sibling was living in the same house at controls from general practice lists. Of these, the time of infection (table 3). No association 108 proved to be untraceable, either because was found with other infectious diseases of The environment in childhood and risk of motor neuron disease 999 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.11.997 on 1 November 1992. Downloaded from Table I Relative risk of motor neuron disease according to domestic conditions in the first of motor neuron disease, although of these, home. (Each variable analysed individually) only the increased risk associated with lack of Numbers of Odds running hot water was statistically significant. cases exposed ratio 95% CI There were also increases in relative risk with a No room with fixed bath 59 1-2 0-8 to 2-0 measure of overcrowding within the home and No running hot water 69 1-8 1-1 to 3-0 with frequent changes of address during the No indoorWC 59 1-4 0 9 to 2-2 Crowding - 2 1-5/bedroom 60 1-4 0-9 to 2-2 first 10 years of life. These two factors are known to be linked to higher rates of infection in childhood.'4 '5There was also a suggestion, though numbers were very small, that risk of motor neuron disease was higher in those who Table 2 Relative risk ofmotor neuron disease associated with indicators ofliving conditions recalled having a sibling with poliomyelitis- in childhood. (Each variable analysed individually) especially if he or she had been living in the Numbers of Odds same house at the time of the infection. cases exposed ratio 95% CI We were forced to use indirect indicators of Social class of father past exposure to poliovirus because serological (III, IV, V compared with I and II) 69 0 7 0 4 to 1-4 are unable to between Number of siblings techniques distinguish (0 or 1 compared with 2 or more) 30 1 1 0-7 to 1-9 those who have acquired to polio- Age at leaving school virus because of previous infection with wild (< 14 years compared with > 14 years) 47 1-3 0-8 to 2-2 Size of town type virus and those who have been actively (Large town compared with small town or village) 46 1 0 0-6 to 1-5 immunised. The results ofthe on the More than 3 changes of house before study rely age of IO years 12 2-6 1-2 to 5-6 su6ject's recall of the conditions under which he or she was brought up and it is inevitable that lapses in memory will have led to inaccu- racies in the information that was obtained. Since the subjects were unaware of the hypoth- Table 3 Relative risk of motor neuron disease associated with recall of infection in esis being tested, we do not think it likely that childhood. (Each variable analysed individually) there would have been systematic differences Numbers of Odds in the quality of recall between cases and cases exposed ratio 95% CI controls. This source of error could therefore Sibling with paralytic poliomyelitis 5 1 9 0 6 to 5-8 be expected to obscure, rather than enhance, Sibling with paralytic poliomyelitis any relationship between the variables meas- living in the same household 2 4-4 1-2 to 16-6 75 0-6 0-3 to 1-3 ured and risk of motor neuron disease and to Scarlet fever 12 1-2 0-6 to 2-3 bias the odds ratio towards unity. Diphtheria 4 0-6 0-2 to 1-7 Chicken pox 62 0-8 0-7 to 1-3 The response rate in controls was lower than Rheumatic fever 5 2-3 0-8 to 7-3 that for cases; only 67% of the control subjects approached agreed to be interviewed whereas we were able to obtain completed question- naires from 92% of eligible cases. The factors that led subjects to decide not to take part in childhood. the study are unknown but it seems unlikely Because of the range of ages of the subjects that they were closely related to the conditions

in the study, the time during which they were in which they spent their childhood. The http://jnnp.bmj.com/ children spanned most of the first half of this possibility that a bias was introduced by century. During this period considerable chan- differences in response rates cannot be exclu- ges both in domestic conditions and rates of ded. infection occurred. We investigated whether The likelihood of the central nervous system the strength of the observed associations being affected by poliovirus is highly depend- between risk of motor neuron disease and ent on the age at which infection occurs. possession of domestic amenities, domestic Infection in childhood, adolescence or adult overcrowding, frequency of moving house and life leads to neurological disease very much on September 23, 2021 by guest. Protected copyright. experience of childhood varied with more frequently than infection during infancy. the age of the subjects. No such effect was If poliovirus is involved in the aetiology of seen. Attempts to examine the effect of these motor neuron disease, cases of motor neuron factors in combination, using multiple regres- disease should have spent their childhood in an sion analysis, were unsuccessful because many environment in which first exposure to polio- of the variables were highly correlated. virus would have been delayed beyond the relatively safe period of infancy. We have previously suggested that such an environment Discussion would have been characterised by good social The results of this case-control study show a and domestic circumstances.' In fact, the weak but consistent association between risk of results of this study showed quite the opposite; motor neuron disease and factors in the cases of motor neuron disease were more likely childhood domestic environment that are to have spent their childhood in poor circum- known to increase rates of infection with stances. poliovirus. Absence of a room with a fixed Although we stand by the prediction that bath, lack of running hot water and lack of an cases of motor neuron disease would have inside flushing lavatory in the house lived in spent their childhood in conditions associated during the first 10 years of childhood were all with delayed exposure to poliovirus, we now individually associated with an increase in risk believe that our former suggestions about the 1 000 Martyn, Osmond J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.11.997 on 1 November 1992. Downloaded from sort of conditions that led to delayed exposure variation in severity.8 were wrong. Population studies in Scotland, What pathogenetic mechanism could link Northern Ireland and the USA in the 1950s subclinical infection with poliovirus to the later showed that most children, regardless of social development of motor neuron disease? There class or the domestic conditions in which they was no evidence of continuing poliovirus infec- lived, first became seropositive to poliovirus tion in a case of motor neuron disease with some time after the first year of life.`0-12 So, antecedent poliomyelitis"9 and attempts to even those children living in poor conditions demonstrate poliovirus-related RNA or DNA first encountered poliovirus at an age when sequences in the central nervous system or an they would have been vulnerable to its neuro- increase in cell-mediated to polio- tropic effects. virus in patients with motor neuron disease The prevalence of seropositivity, however, have produced conflicting results.2023 But lack was lower at all ages in those living in good of evidence of persistence or latency does not social conditions and it is probable that preclude an aetiological role for poliovirus. As between 10 and 20% of children escaped was pointed out in the introduction, infection infection altogether. If the hypothesis linking with the virus, even if subclinical, might lead to poliovirus with motor neuron disease is right, loss of motor neurons and increased suscepti- these individuals who never encountered bility to the attrition of these neurons that is poliovirus will be at lower risk of motor neuron known to occur with increasing age.24 disease. A good domestic environment in Previous epidemiological investigations of childhood should therefore be associated with motor neuron disease have largely been a reduced risk of the disease. focused on events in adult life. They have not The environmental factors associated with consistently identified any strong risk factors increased likelihood of poliovirus infection at a for the disease. 16-1825-27 The results of this vulnerable age are not unique to that micro- study suggest that cases of motor neuron organism. They also indicate an increased risk disease spent their childhood in conditions of other infections transmitted by the faecal- associated with an increased risk of enteric oral route. By themselves, the results presented infection. They are compatible with, although here cannot be interpreted as implicating they do not provide strong direct support for, poliovirus in the causation of motor neuron the hypothesis that poliovirus, or a micro- disease. But we suggest that the results of this organism that is transmitted in a similar way, is study should be considered in combination involved in the aetiology of motor neuron with what is already known about the relation disease. They also suggest that the initial events between motor neuron disease and poliovirus in the chain of causation that leads to motor infection. The geographical correlation neuron disease occur in early life. between mortality from motor neuron disease We are grateful to Drs M Campbell, G M Cochrane, R Langton and past poliomyelitis is remarkable for its Hewer, L S Illis, C Ellis, P Kennedy, N Lawton, D Stephens, A specificity. No other notifiable infectious dis- Turner and G Wakefield for allowing us to study patients under their care, to Dr M Sedgewick who made the diagnostic index ease correlates as strongly.' There is also of the neurophysiology department of the Wessex Neurological evidence from case series that a history of Centre available to us, to the many general practitioners without whose cooperation the study would not have been possible, to paralytic poliomyelitis can be obtained from Mrs M Mitchell, who carried out all the interviews for this patients with motor neuron disease more often study, and to the Motor Neuron Disease Association for allowing us access to their records and for a grant towards the

than could be expected from a chance associa- interviewer's travelling expenses. We thank Professor D J P http://jnnp.bmj.com/ tion of the two diseases.5 6 No significant Barker and Dr A Hall for their advice and encouragement. association between the two diseases has ever been found in case-control studies'6-8 but the very small numbers of subjects reporting polio- 1 Martyn CN, Barker DJP, Osmond C. Motoneuron disease myelitis in these studies limit the interpretation and past poliomyelitis in England and Wales. Lancet 1988;i: 1319-22. of these negative findings. 2 Lilienfeld DE, Chan E, Ehland J, et al. Rising mortality The types ofneurons that are predominantly from motoneuron disease in the USA, 1962-1984. Lancet motor 1989;i:710-3. on September 23, 2021 by guest. Protected copyright. affected-the first and second order 3 Flaten TP. Rising mortality from motoneuron disease. neurons-are the same in both diseases. The Lancet 1989;i:1018-9. 4 Durrleman S, Alperovitch A. Increasing trend of ALS in clinical picture of acute paralytic poliomyelitis France and elsewhere: are the changes real? Neurology is, of course, dominated by lower motor 1989;39:768-73. 5 Zilka KJ. Discussion on motor neurone disease. Proc R Soc neuron signs, whereas patients with motor Med 1962;55:1028-31. neuron disease typically show signs of upper 6 Poskanzer DC, Cantor HM, Kaplan GS. The frequency of preceding poliomyelitis in amyotrophic lateral sclerosis. In: motor neuron involvement. But pathological Norris FH, Kurland LT, eds. Motor neuron disease. New studies, both of fatal cases in humans and of York: Grune and Stratton, 1969. 7 Martyn CN. Poliovirus and motor neuron disease. J Neurol experimental poliomyelitis in primates, show 1990;237:336-8. that the distribution of extends beyond 8 Bodian D. Poliomyelitis. In: Minckler J, ed. Pathology of the nervous system, vol III. New York: McGraw-Hill, 1977; the of the anterior horn of the 2323-43. spinal cord. The posterior and intermediate 9 Roebuck M, Chamberlain R. Prevalence of antibodies to poliovirus in 1978 in subjects aged 0-88 years. Br Med J columns of grey matter, the substantia gelat- 1982;284:697-700. inosa, the brainstem-including the 10 Backett EM. Social patterns of to poliovirus. Lancet 1957;i:778-83. and , the nuclei of the cere- 11 MacLeod RC, MacGregor LG, Larminie HE, Grist NR. bellum and the motor areas of the cerebral Serological epidemiology of poliomyelitis in central Scot- land. Scot Med J 1958;3:76-81. cortex are also affected. Further, the distribu- 12 Fox JP, Hall CE. in families. Littleton, MA: PSG tion of lesions in the brain is essentially the 1980. 13 Breslow NE, Day NE. Statistical methods in cancer same in nonparalytic cases as it is in sympto- research. Volume 1-The analysis of case-control studies. matic cases, although there is great individual IARC Scientific Publication No. 32. Lyon: International The environment in childhood and risk of motor neuron disease 1001 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.11.997 on 1 November 1992. Downloaded from Agency for Research in Cancer, 1980. nervous tissue of amyotrophic lateral sclerosis and control 14 Brimblecombe FSW, Cruickshank R, Masters PL, Reid patients. Ann Neurol 1985;18:337-43. DD, Stewart GT, Sanderson D. Family studies of 22 Behan PO. Cell mediated immunity in motor neurone respiratory infections. Br Med J 1958;1:1 19-28. disease and poliomyelitis. In: Rose FC, ed. Clinical 15 Visscher BR, Bunnell DH, Detels R. and neuroimmunology, Oxford: Blackwell Scientific Publica- multiple moves: an etiologic hypothesis. Am J Epidemiol tions, 1979. 1981;113:140-3. 23 Bartfeld H, Dham C, Donnenfeld H, et al. Immunological 16 Felmus MT, Patten BM, Swanke L. Antecedent events in profile of amyotrophic lateral sclerosis patients and their amyotrophic lateral sclerosis. Neurology 1976;26:167-72. cell-mediated immune responses to viral and CNS 17 Gawel M, Zaiwalla Z, Rose FC. Antecedent events in motor antigens. Clin Exp Immunol 1982;48:137-47. neuron disease. J Neurol Neurosurg Psychiatry 1983;46: 24 Tomlinson BE, Irving D. The numbers of motor 1041-3. neurones in the human lumbosacral cord throughout life. 18 Deapen DM, Henderson BE. A case-control study of Y Neurol Sci 1977;34:213-9. amyotrophic lateral sclerosis. Am J Epidemiol 1986;123: 25 Bharucha NE, Schoenberg BS, Raven RH, Pickle LW, Byar 790-9. DP, Mason T. Geographic distribution of motor neuron 19 Roos RP, Viola MV, Wollmann R, Hatch MH, Antel JP. disease and correlation with possible etiologic factors. Amyotrophic lateral sclerosis with antecedent poliomye- Neurology 1983;33:911-5. litis. Arch Neurol 1980;37:312-3. 26 Kurtzke JF, Beebe GW. Epidemiology of amyotrophic 20 Kott E, UIvni E, Zamir R, Kuritzky A. Cell mediated lateral sclerosis: 1. A case-control comparison based on immunity to polio and HLA antigens in amyotrophic ALS deaths. Neurology 1980;30:453-62. lateral sclerosis. Neurology 1979;29: 1040-44. 27 Armon C, Kurland LT, Daube JR, O'Brien PC. Epidemio- 21 Brahic M, Smith RA, Gibbs CJ, Garruto RM, Tourtellotte logical correlates ofsporadic amyotrophic lateral sclerosis. WW, Cash E. Detection of sequences in Neurology 1991 ;41: 1077-84.

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The Anatomy Lesson of Dr Tulp by Rembrandt 9 4 (1606-69) Rembrandt's anatomy lesson paintings of Drs Tulp and Deyman hung on either side ofthe fireplace in the anatomy theatre of the Neiuwe Waag in Amsterdam. Tulp demon- b strates the anatomy of the arm muscles to a group of seven-he alone wears a hat to mark the official nature of his demonstration. Some of the listeners are looking at the open page of an anatomical atlas at the feet of the corpse, some at the exposed arm muscles and others at the lecturer. It was Nicholas Tulp, with other Dutch , who Indies. 4 http://jnnp.bmj.com/ first described cases of beriberi in the Dutch East 4 The Anatomy Lesson of Dr Tulp is reproduced on the 4 same set of stamps issued by the Republic of in 1968 which also showed The Anatomy Lesson of Dr Joan Deyman (Stanley Gibbons 597, Scott 647). L F HAAS I AL on September 23, 2021 by guest. Protected copyright.