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What causes motoneuron disease?
1033
EDITORIALS
What causes motoneuron disease? Variation in the pattern of occurrence of a disease between different places and over time can often be a Thus it is source of ideas about its cause. disappointing to find that, with the exception of foci in the western Pacific, the frequency of motoneuron disease is thought to be similar world wide.1 Virtually universal acceptance of this notion has encouraged epidemiologists to use the local rate of motoneuron disease as a yardstick against which to measure the frequency of other neurological disorders when there is no reliable population denominator. 2,3 However, if one pauses to consider the variety of conditions in which people live (and therefore the range of environmental agents to which they are exposed) and the diversity of their genetic inheritance, the idea that any disease, whatever its aetiology, could be evenly distributed throughout the world seems scarcely credible. With the possible exception of schizophrenia (and even here the unsatisfactory nature of the evidence has now been exposed4), no other disease has a homogeneous global pattern. A fresh look at the facts justifies this scepticism. It is true that most of the population-based surveys published in the past twenty years have estimated the annual incidence to be about 1 per 100 000 population, but these estimates were derived from populations in North America, Western Europe, and whose current Scandinavia-countries living standards and recent social histories are similar. If environmental factors are important in the aetiology of motoneuron disease, it is scarcely surprising that these surveys have shown little variation in the frequency of the condition. In Eastern Europe and Central America the incidence seems to be considerably lower. The usual rather glib explanation for the discrepancy is that ascertainment of cases was less complete in the surveys that produced low estimates of incidence. This argument is least convincing when it is applied to a survey carried out in Mexico, where the disease was found to be strikingly rare,since the methods adopted were similar to those used in studies that have produced higher estimates elsewhere. Moreover, geographical differences in mortality from motoneuron disease have lately been found within the same country. Thus, in the USA mortality is higher in
counties to the west of the Mississippi than it is to the east,and in England and Wales mortality is higher in the south and east of the country than it is in the north and west7 There is also evidence that mortality from the disease is changing rapidly over time. Death rates from motoneuron disease have increased at all ages over the past two decades in the USA, the UK, and Scandinavia.’-1° Since mortality data are ultimately derived from what is written on death certificates, could this increase merely reflect the increasing ability of medical practitioners to recognise the disease? Whilst improved diagnosis may have contributed to the rising mortality in the USA, where there has been a large increase in the number of neurologists, it is unlikely to be the complete explanation. In nationwide analyses of deaths from motoneuron disease in the USA and in England and Wales, rates were not much affected by the ratio of physicians to population or by the local density of neurologists. 6,8 There has been no comparable expansion in neurological services in the UK or Norway over the same period that could account for the rising mortality in these countries. Nor have time trends in other neurodegenerative diseases in the USA followed the same pattern, as might have been expected if access to neurologists had had a major effect on how neurological diseases were recorded. 11 Although there is still some uncertainty about the true magnitude of the increase, there can be little doubt that motoneuron disease is becoming commoner in the countries of the western world. If we accept the reality of these geographical variations and time trends, what can they tell us about aetiology? At the very least, they refute the argument that, because of the uniform pattern of occurrence, environmental factors are unimportant. More positively, they suggest that some factor associated with "westernisation" influences the risk of getting the disease. An old idea that has lately been given a new twist is that motoneuron disease might be causally linked to past infection with poliovirus. The hypothesis has its origins in the similarities of the neuropathological features of the two diseases: the same populations of nerve cells-first and second order motor neuronsare mainly affected. (Physicians who point out that the clinical features of poliomyelitis are characterised by
1034
and symptoms of lower motor neuron involvement should remember that the distribution of lesions, as shown by histopathological techniques, extends far beyond the anterior horns of the spinal cord. There is loss of neurons in the motor areas of the cerebral cortex, the cerebellum, and the brainstem.12) It has now been shown that the current geographical distribution of motoneuron disease in England and Wales mirrors the pattern of incidence of poliomyelitis forty years ago.Most patients with motoneuron disease have never had acute paralytic poliomyelitis, but Martyn and colleagues suggest that motoneuron disease may be a late consequence of subclinical poliovirus infection. More evidence is needed, but one reason for taking the suggestion seriously is that a link with poliovirus infection could account for both the geography and the secular trends of motoneuron disease. What about other clues? There is some indication that certain occupational groups are at increased risk. Two studies have reported a small excess of deaths from motoneuron disease in workers in the leather industry.8,13 One theory to explain this observation is that exposure to solvents, which is high in some jobs in the industry, is directly or indirectly neurotoxic.14 Other investigators have failed to confirm this finding: there was no increased mortality from motoneuron disease in a cohort of more than 5000 men employed in the boot and shoe industry, 15 nor was there any increased risk for leather workers in a large casecontrol study from the USA.16 Electrical workers have also been reported to be at increased risk, 17 and some case-control studies have shown an association between electric shock and motoneuron disease.16 The biological significance of these findings and the miscellany of other risk factors revealed by casecontrol studies is harder to assess than their statistical significance. Apart from the technical drawbacks of some of these studies-small size, multiple comparisons between cases and controls, and possible biases introduced by poor choice of control groups and the way in which information was obtainedthere are at least two reasons for doubting whether any of the putative risk factors is more than a red herring. The first is lack of corroboration-no single factor has consistently been found to be strongly associated with the disease. The second is that, when extrapolated to the generality of patients with the disease, the proportion of cases that could be attributed to any of these factors is rather small. Unless one is prepared to believe that the syndrome of motoneuron disease is the end result of a variety of different insults to the nervous system, no risk factor yet identified is likely to be a powerful aetiological explanation.
signs
Some patients with motoneuron disease seem to have a defect in the hepatic metabolism of sulphurcontaining compounds,18 although the number of cases studied is small and there are doubts about whether the control groups were representative of the
general population. We also need to be sure that this apparent metabolic defect is not merely a result of loss of lean body mass. Despite these reservations, this finding raises the possibility that a proportion of the population might be especially vulnerable to environmental or endogenous toxins that are normally metabolised by sulphoxidation. Unfortunately, there have not yet been any suggestions about what these toxins might be. It is hardly surprising that the success of the new genetics in localising the genes responsible for some of the inherited diseases of the nervous system has encouraged the idea that sporadically occurring neurodegenerative diseases might also have an important genetic component in their causation. Several groups are now applying the techniques of molecular genetics to motoneuron disease. The task here is likely to be many times harder than in diseases with a demonstrable mendelian pattern of inheritance; familial cases of motoneuron disease are rare and it will be difficult to collect kinships that are potentially informative. No genetic linkage has yet been established for motoneuron disease.,19 perhaps because so few families with the disease are available for the investigation and because only a small part of the genome has been examined. However, the disappointing results of attempts to establish genetic linkage in psychiatric disease,20 where the prima facie case for an important genetic contribution to the aetiology is much stronger, should serve as a warning against over-enthusiasm for this approach. Environmental rather than genetic factors may yet prove to be decisive in determining who gets the disease. 1. Kurtzke JF. Epidemiology of amyotrophic lateral sclerosis. In: Rowland LP, ed. Human motor neuron diseases. New York: Raven, 1982. 2. Kurtzke JF. A reassessment of the distribution of multiple sclerosis. Part one. Acta Neurol Scand 1975; 51: 110-36. 3. Kurtzke JF. A reassessment of the distribution of multiple sclerosis. Part two. Acta Neurol Scand 1975; 51: 137-57. 4. Der G, Gupta S, Murray RM. Is schizophrenia disappearing? Lancet 1990; i: 513-16. 5. Olivares L, San Esteban E, Alter M. Mexican "resistance" to
amyotrophic lateral sclerosis. Arch Neurol 1972; 27: 397-402. Schoenberg BS, Raven RH, Pickle LW, Byar DP, Geographic distribution of motor neurone disease and correlation with possible etiologic factors. Neurology 1983; 33: 911-15. 7. Martyn CN, Barker DJP, Osmond C. Motoneuron disease and past poliomyelitis in England and Wales. Lancet 1988; i: 1319-22. 8. Buckley J, Warlow C, Smith P, Hilton-Jones D, Irvine S, Tew JR. Motor neurone disease in England and Wales 1959-1979.J Neurol Neurosurg Psychiatry 1983; 46: 197-205. 9. Lilienfeld DE, Chan E, Ehland J, et al. Rising mortality from motoneuron disease in the USA, 1962-84. Lancet 1989; i: 810-13. 10. Flaten TP. Rising mortality from motoneuron disease. Lancet 1989; i: 6. Bharucha NE, Manson TJ.
1018-19. 11. Lilienfeld
DE, Chan E, Ehland J, et al. Two decades of increasing mortality from Parkinson’s disease among the US elderly. Arch Neurol
1990; 47: 731-34. 12. Bodian D. Poliomyelitis. In: Minckler
J, ed. Pathology of the nervous system, vol III. New York: McGraw-Hill, 1977: 2323-43. 13. Hawkes CH, Fox AJ. Motor neurone disease in leather workers. Lancet 1981; i: 507. 14. Hawkes CH, Cavanagh JB, Fox AJ. Motoneuron disease: a disorder secondary to solvent exposure? Lancet 1989; i: 73-76. 15. Martyn CN. Motoneuron disease and exposure to solvents. Lancet 1989; i: 394.
1035
16. Deapen DM, Henderson BE. A case-control study of amyotrophic lateral sclerosis. Am J Epidemiol 1986; 123: 790-99. 17. Haynal A, Regli F. Zusammenhang der amyotrophischen Lateralsklerose mit gehauften Elektrotraumata. Confin Neurol 1964; 24: 189-98. 18. Steventon GB, Williams AC, Waring RH, Pall HS, Adams D. Xenobiotic metabolism in motoneuron disease. Lancet 1989; ii: 644-47. 19. Siddique T, Pericak-Vance MA, Brooks BR, et al. Linkage analysis in familial amyotrophic lateral sclerosis. Neurology 1989; 39: 919-25. 20. Editorial. Loading the lods. Lancet 1990; 336: 778-79.
Ito-with which seizures
are
very
frequently,
if
not
invariably, associated.9 Neuropathological studies
in infantile spasms with15 or without’ 16 other features of Aicardi syndrome; severe myoclonic epilepsy of infancy; ’ Lennox-Gastaut syndrome;18 partial epilepsy of temporal lobe origin ;8 and primary generalised epilepsies7 have revealed areas of disordered neuronal migration, often referred to as
microdysgenesis. EPILEPSY AND DISORDERS OF NEURONAL MIGRATION Gross disorders of neuronal migration are almost invariably associated with the early onset of epileptic seizures.12 New non-invasive techniques for investigation of the brain3-6 and more detailed neuropathological examination of specimens obtained at necropsy7 or operation8 have led to the identification of localised or lesser degrees of migrational disorder. In the normal human brain, between 7 and 16 weeks of gestational age, young neurons, guided by radial glial fibres, migrate to the cortical plate.9 The layers of the neocortex are formed from within outwards, so waves of later migration pass through layers that are already established. Neurons that do not migrate normally are at increased risk of stunting or early death. Among the underlying biochemical mechanisms, there is some evidence that fatty acid oxidation in peroxisomes and mitochondria is relevant, and that cell adhesion molecules and polyamines are important.99 Migrational disorders can be classified into morphological types.9 In agyria/pachygyria there is extensive disorganisation, whereas microgyria, verrucous dysplasias, and neuronal heterotopias may vary in severity and thus in clinical expression. Even diffuse subcortical heterotopias, giving the appearance of a double cortex, may cause only mild epilepsy and behaviour and learning difficulties.5 Severe migration disorders can also result in schizencephaly and related disorders. Agyria/pachygyria, or lissencephaly type I, can be a feature of the Miller-Dieker syndrome, or an isolated anomaly in which the abnormalities of gross brain morphology tend to be less severe In the Miller-Dieker syndrome seizures, often infantile spasms, almost invariably start in the first 6 months of life.1,10-12 In the isolated lissencephaly syndrome, when agyria is prominent, seizures including infantile spasms always start in the first half year; if pachygyria is the more obvious feature, seizures, although commonly present, do not
necessarily begin early.1O
There are several subgroups of lissencephaly type II, all of which are autosomal recessive. In addition to smoothness of the hemispheric surfaces, features include hydrocephalus, retinal dysplasia, and disorders of muscle. Seizures are less prominent in lissencephaly type II than in type 1. Microgyria are found in several genetically determined conditions in which early seizures are common—eg, Fukuyama cerebromuscular dystrophy, 13 Bloch-Sulzberger syndrome,14 and the disorders of peroxisomes, Zellweger syndrome and neonatal adrenoleucodystrophy.9 In verrucous dysplasias of the neocortex tiny "herniations" of the second into the first neocortical layer present on the cortical surface. These abnormalities are commonest in the frontal and Rolandic areas and have been particularly associated with multiple acyl-CoA dehydrogenase deficiency 9 Neuronal heterotopias also occur in many syndromes--eg, tuberous sclerosis and hypomelanosis of
Gross disorders of neuronal migration can be identified ultrasoundl9 or computed tomography (CT)34 scans, but magnetic resonance imaging (MRI) gives better delineation4 and may show lesions that are invisible on CT scans.5 In addition, positron emission tomography has shown areas of dysgenesis undetected by CT or MRL66 Thus, disorders of neuronal migration may be the common denominator for seizures symptomatic of otherwise apparently diverse clinical pictures. Further investigation of the mechanisms involved in migration may be important in the greater understanding of the aetiology of on
epilepsy. Dobyns WB, Stratton RF, Greenberg F. Syndromes with lissencephaly. I: Miller-Dieker and Norman-Roberts syndromes and related lissencephaly. Am J Med Genet 1984; 18: 509-26. 2. Dobyns WB, Kirkpatrick JB, Hittner HM, Roberts RM, Kretzer FL. Syndromes with lissencephaly. II: Walker-Warburg and cerebrooculo-muscular syndromes with a new syndrome with type II lissencephaly. Am J Med Genet 1985; 22: 157-95. 3. Byrd SE, Osborn RE, Bohan TP, Naidich TP. The CT and MR evaluation of migrational disorders of the brain. 1. Lissencephaly and pachygyria. Pediatr Radiol 1989; 19: 151-56. 4. Byrd SE, Osborn RE, Bohan TP, Naidich TP. The CT and MR evaluation of migrational disorders of the brain. 2. Schizencephaly, heterotopia and polymicrogyria. Pediatr Radiol 1989; 19: 219-22. 5. Livingston JH, Aicardi J. Unusual MRI appearance of diffuse subcortical heterotopia or "double cortex" in two children. J Neurol Neurosurg Psychiatr 1990; 53: 617-20. 6. Chugani HT, Shields WD, Shewmon DA, Olson DM, Phelps ME. Infantile spasms. I: PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Ann Neurol 1990; 27: 406-13. 7. Meencke HJ. Neuropathology of generalized primary epilepsy. In: Wolf P, Dam M, Janz D, Dreifuss FE, eds. Advances in epileptology, vol 16. 1.
New York: Raven, 1987: 1-8. 8. Hardiman O, Burke T, Phillips J, et al. Microdysgenesis in resected temporal neocortex: Incidence and clinical significance of focal epilepsy. Neurology 1988; 38: 1041-47. 9. Barth PG. Disorders of neuronal migration. Can J Neurol Sci 1987; 14: 1-16. 10. de Rijk-van Andel JF, Arts WFM, Barth PG, Loonen MCB. Diagnostic features and clinical signs of 21 patients with lissencephaly type I. Dev Med Child Neurol 1990; 30: 707-17. 11. van Allen N, Clarren S. A spectrum of gyral anomalies in Miller-Dieker (lissenencephaly) syndrome. J Pediatr 1983; 102: 559-64. 12. Gastaut H, Pinsard N, Raybaud Ch, Aicardi J, Zifkin B. Lissencephaly (agyria-pachygyria): clinical findings and serial EEG studies. Dev Med Child Neurol 1987; 29: 167-80. 13. Fukuyama Y, Osawa M, Suzuki H. Congenital progressive muscular dystrophy of the Fukuyama type—clinical, genetic and pathological considerations. Brain Dev 1981; 3: 1-29. 14. O’Doherty NJ, Norman RM. Incontinentia pigmenti (Bloch-Sulzberger syndrome) with cerebral malformations. Dev Med Child Neurol 1968; 10: 168-74. 15. Donnenfield AE, Packer RJ, Zackai EH, et al. Clinical, cytogenic and pedigree findings in 18 cases of Aicardi syndrome. Am J Med Genet
1989; 32: 461-67. 16. Meencke course
HJ, Gerhard C. Morphological aspects of etiology and the of infantile spasms (West-syndrome). Neuropediatrics 1985; 16:
59-66. 17.
Renier WO, Renkawek K. Clinical and neuropathologic findings in a case of severe myoclonic epilepsy of infancy. Epilepsia 1990; 31: 287-91. 18. Roger J, Gambarelli-Dubois D. Neuropathological studies of the Lennox-Gastaut syndrome. In: Niedermeyer E, Degen R, eds. The Lennox-Gastaut syndrome. New York: Alan R Liss, 1988. 19. Trounce JQ, Fagan DG, Young ID, Levene MI. Disorders of neuronal migration: sonographic appearances. Dev Med Child Neurol 1986; 28: 467-71.
EDITORIALS
What causes motoneuron disease? Variation in the pattern of occurrence of a disease between different places and over time can often be a Thus it is source of ideas about its cause. disappointing to find that, with the exception of foci in the western Pacific, the frequency of motoneuron disease is thought to be similar world wide.1 Virtually universal acceptance of this notion has encouraged epidemiologists to use the local rate of motoneuron disease as a yardstick against which to measure the frequency of other neurological disorders when there is no reliable population denominator. 2,3 However, if one pauses to consider the variety of conditions in which people live (and therefore the range of environmental agents to which they are exposed) and the diversity of their genetic inheritance, the idea that any disease, whatever its aetiology, could be evenly distributed throughout the world seems scarcely credible. With the possible exception of schizophrenia (and even here the unsatisfactory nature of the evidence has now been exposed4), no other disease has a homogeneous global pattern. A fresh look at the facts justifies this scepticism. It is true that most of the population-based surveys published in the past twenty years have estimated the annual incidence to be about 1 per 100 000 population, but these estimates were derived from populations in North America, Western Europe, and whose current Scandinavia-countries living standards and recent social histories are similar. If environmental factors are important in the aetiology of motoneuron disease, it is scarcely surprising that these surveys have shown little variation in the frequency of the condition. In Eastern Europe and Central America the incidence seems to be considerably lower. The usual rather glib explanation for the discrepancy is that ascertainment of cases was less complete in the surveys that produced low estimates of incidence. This argument is least convincing when it is applied to a survey carried out in Mexico, where the disease was found to be strikingly rare,since the methods adopted were similar to those used in studies that have produced higher estimates elsewhere. Moreover, geographical differences in mortality from motoneuron disease have lately been found within the same country. Thus, in the USA mortality is higher in
counties to the west of the Mississippi than it is to the east,and in England and Wales mortality is higher in the south and east of the country than it is in the north and west7 There is also evidence that mortality from the disease is changing rapidly over time. Death rates from motoneuron disease have increased at all ages over the past two decades in the USA, the UK, and Scandinavia.’-1° Since mortality data are ultimately derived from what is written on death certificates, could this increase merely reflect the increasing ability of medical practitioners to recognise the disease? Whilst improved diagnosis may have contributed to the rising mortality in the USA, where there has been a large increase in the number of neurologists, it is unlikely to be the complete explanation. In nationwide analyses of deaths from motoneuron disease in the USA and in England and Wales, rates were not much affected by the ratio of physicians to population or by the local density of neurologists. 6,8 There has been no comparable expansion in neurological services in the UK or Norway over the same period that could account for the rising mortality in these countries. Nor have time trends in other neurodegenerative diseases in the USA followed the same pattern, as might have been expected if access to neurologists had had a major effect on how neurological diseases were recorded. 11 Although there is still some uncertainty about the true magnitude of the increase, there can be little doubt that motoneuron disease is becoming commoner in the countries of the western world. If we accept the reality of these geographical variations and time trends, what can they tell us about aetiology? At the very least, they refute the argument that, because of the uniform pattern of occurrence, environmental factors are unimportant. More positively, they suggest that some factor associated with "westernisation" influences the risk of getting the disease. An old idea that has lately been given a new twist is that motoneuron disease might be causally linked to past infection with poliovirus. The hypothesis has its origins in the similarities of the neuropathological features of the two diseases: the same populations of nerve cells-first and second order motor neuronsare mainly affected. (Physicians who point out that the clinical features of poliomyelitis are characterised by
1034
and symptoms of lower motor neuron involvement should remember that the distribution of lesions, as shown by histopathological techniques, extends far beyond the anterior horns of the spinal cord. There is loss of neurons in the motor areas of the cerebral cortex, the cerebellum, and the brainstem.12) It has now been shown that the current geographical distribution of motoneuron disease in England and Wales mirrors the pattern of incidence of poliomyelitis forty years ago.Most patients with motoneuron disease have never had acute paralytic poliomyelitis, but Martyn and colleagues suggest that motoneuron disease may be a late consequence of subclinical poliovirus infection. More evidence is needed, but one reason for taking the suggestion seriously is that a link with poliovirus infection could account for both the geography and the secular trends of motoneuron disease. What about other clues? There is some indication that certain occupational groups are at increased risk. Two studies have reported a small excess of deaths from motoneuron disease in workers in the leather industry.8,13 One theory to explain this observation is that exposure to solvents, which is high in some jobs in the industry, is directly or indirectly neurotoxic.14 Other investigators have failed to confirm this finding: there was no increased mortality from motoneuron disease in a cohort of more than 5000 men employed in the boot and shoe industry, 15 nor was there any increased risk for leather workers in a large casecontrol study from the USA.16 Electrical workers have also been reported to be at increased risk, 17 and some case-control studies have shown an association between electric shock and motoneuron disease.16 The biological significance of these findings and the miscellany of other risk factors revealed by casecontrol studies is harder to assess than their statistical significance. Apart from the technical drawbacks of some of these studies-small size, multiple comparisons between cases and controls, and possible biases introduced by poor choice of control groups and the way in which information was obtainedthere are at least two reasons for doubting whether any of the putative risk factors is more than a red herring. The first is lack of corroboration-no single factor has consistently been found to be strongly associated with the disease. The second is that, when extrapolated to the generality of patients with the disease, the proportion of cases that could be attributed to any of these factors is rather small. Unless one is prepared to believe that the syndrome of motoneuron disease is the end result of a variety of different insults to the nervous system, no risk factor yet identified is likely to be a powerful aetiological explanation.
signs
Some patients with motoneuron disease seem to have a defect in the hepatic metabolism of sulphurcontaining compounds,18 although the number of cases studied is small and there are doubts about whether the control groups were representative of the
general population. We also need to be sure that this apparent metabolic defect is not merely a result of loss of lean body mass. Despite these reservations, this finding raises the possibility that a proportion of the population might be especially vulnerable to environmental or endogenous toxins that are normally metabolised by sulphoxidation. Unfortunately, there have not yet been any suggestions about what these toxins might be. It is hardly surprising that the success of the new genetics in localising the genes responsible for some of the inherited diseases of the nervous system has encouraged the idea that sporadically occurring neurodegenerative diseases might also have an important genetic component in their causation. Several groups are now applying the techniques of molecular genetics to motoneuron disease. The task here is likely to be many times harder than in diseases with a demonstrable mendelian pattern of inheritance; familial cases of motoneuron disease are rare and it will be difficult to collect kinships that are potentially informative. No genetic linkage has yet been established for motoneuron disease.,19 perhaps because so few families with the disease are available for the investigation and because only a small part of the genome has been examined. However, the disappointing results of attempts to establish genetic linkage in psychiatric disease,20 where the prima facie case for an important genetic contribution to the aetiology is much stronger, should serve as a warning against over-enthusiasm for this approach. Environmental rather than genetic factors may yet prove to be decisive in determining who gets the disease. 1. Kurtzke JF. Epidemiology of amyotrophic lateral sclerosis. In: Rowland LP, ed. Human motor neuron diseases. New York: Raven, 1982. 2. Kurtzke JF. A reassessment of the distribution of multiple sclerosis. Part one. Acta Neurol Scand 1975; 51: 110-36. 3. Kurtzke JF. A reassessment of the distribution of multiple sclerosis. Part two. Acta Neurol Scand 1975; 51: 137-57. 4. Der G, Gupta S, Murray RM. Is schizophrenia disappearing? Lancet 1990; i: 513-16. 5. Olivares L, San Esteban E, Alter M. Mexican "resistance" to
amyotrophic lateral sclerosis. Arch Neurol 1972; 27: 397-402. Schoenberg BS, Raven RH, Pickle LW, Byar DP, Geographic distribution of motor neurone disease and correlation with possible etiologic factors. Neurology 1983; 33: 911-15. 7. Martyn CN, Barker DJP, Osmond C. Motoneuron disease and past poliomyelitis in England and Wales. Lancet 1988; i: 1319-22. 8. Buckley J, Warlow C, Smith P, Hilton-Jones D, Irvine S, Tew JR. Motor neurone disease in England and Wales 1959-1979.J Neurol Neurosurg Psychiatry 1983; 46: 197-205. 9. Lilienfeld DE, Chan E, Ehland J, et al. Rising mortality from motoneuron disease in the USA, 1962-84. Lancet 1989; i: 810-13. 10. Flaten TP. Rising mortality from motoneuron disease. Lancet 1989; i: 6. Bharucha NE, Manson TJ.
1018-19. 11. Lilienfeld
DE, Chan E, Ehland J, et al. Two decades of increasing mortality from Parkinson’s disease among the US elderly. Arch Neurol
1990; 47: 731-34. 12. Bodian D. Poliomyelitis. In: Minckler
J, ed. Pathology of the nervous system, vol III. New York: McGraw-Hill, 1977: 2323-43. 13. Hawkes CH, Fox AJ. Motor neurone disease in leather workers. Lancet 1981; i: 507. 14. Hawkes CH, Cavanagh JB, Fox AJ. Motoneuron disease: a disorder secondary to solvent exposure? Lancet 1989; i: 73-76. 15. Martyn CN. Motoneuron disease and exposure to solvents. Lancet 1989; i: 394.
1035
16. Deapen DM, Henderson BE. A case-control study of amyotrophic lateral sclerosis. Am J Epidemiol 1986; 123: 790-99. 17. Haynal A, Regli F. Zusammenhang der amyotrophischen Lateralsklerose mit gehauften Elektrotraumata. Confin Neurol 1964; 24: 189-98. 18. Steventon GB, Williams AC, Waring RH, Pall HS, Adams D. Xenobiotic metabolism in motoneuron disease. Lancet 1989; ii: 644-47. 19. Siddique T, Pericak-Vance MA, Brooks BR, et al. Linkage analysis in familial amyotrophic lateral sclerosis. Neurology 1989; 39: 919-25. 20. Editorial. Loading the lods. Lancet 1990; 336: 778-79.
Ito-with which seizures
are
very
frequently,
if
not
invariably, associated.9 Neuropathological studies
in infantile spasms with15 or without’ 16 other features of Aicardi syndrome; severe myoclonic epilepsy of infancy; ’ Lennox-Gastaut syndrome;18 partial epilepsy of temporal lobe origin ;8 and primary generalised epilepsies7 have revealed areas of disordered neuronal migration, often referred to as
microdysgenesis. EPILEPSY AND DISORDERS OF NEURONAL MIGRATION Gross disorders of neuronal migration are almost invariably associated with the early onset of epileptic seizures.12 New non-invasive techniques for investigation of the brain3-6 and more detailed neuropathological examination of specimens obtained at necropsy7 or operation8 have led to the identification of localised or lesser degrees of migrational disorder. In the normal human brain, between 7 and 16 weeks of gestational age, young neurons, guided by radial glial fibres, migrate to the cortical plate.9 The layers of the neocortex are formed from within outwards, so waves of later migration pass through layers that are already established. Neurons that do not migrate normally are at increased risk of stunting or early death. Among the underlying biochemical mechanisms, there is some evidence that fatty acid oxidation in peroxisomes and mitochondria is relevant, and that cell adhesion molecules and polyamines are important.99 Migrational disorders can be classified into morphological types.9 In agyria/pachygyria there is extensive disorganisation, whereas microgyria, verrucous dysplasias, and neuronal heterotopias may vary in severity and thus in clinical expression. Even diffuse subcortical heterotopias, giving the appearance of a double cortex, may cause only mild epilepsy and behaviour and learning difficulties.5 Severe migration disorders can also result in schizencephaly and related disorders. Agyria/pachygyria, or lissencephaly type I, can be a feature of the Miller-Dieker syndrome, or an isolated anomaly in which the abnormalities of gross brain morphology tend to be less severe In the Miller-Dieker syndrome seizures, often infantile spasms, almost invariably start in the first 6 months of life.1,10-12 In the isolated lissencephaly syndrome, when agyria is prominent, seizures including infantile spasms always start in the first half year; if pachygyria is the more obvious feature, seizures, although commonly present, do not
necessarily begin early.1O
There are several subgroups of lissencephaly type II, all of which are autosomal recessive. In addition to smoothness of the hemispheric surfaces, features include hydrocephalus, retinal dysplasia, and disorders of muscle. Seizures are less prominent in lissencephaly type II than in type 1. Microgyria are found in several genetically determined conditions in which early seizures are common—eg, Fukuyama cerebromuscular dystrophy, 13 Bloch-Sulzberger syndrome,14 and the disorders of peroxisomes, Zellweger syndrome and neonatal adrenoleucodystrophy.9 In verrucous dysplasias of the neocortex tiny "herniations" of the second into the first neocortical layer present on the cortical surface. These abnormalities are commonest in the frontal and Rolandic areas and have been particularly associated with multiple acyl-CoA dehydrogenase deficiency 9 Neuronal heterotopias also occur in many syndromes--eg, tuberous sclerosis and hypomelanosis of
Gross disorders of neuronal migration can be identified ultrasoundl9 or computed tomography (CT)34 scans, but magnetic resonance imaging (MRI) gives better delineation4 and may show lesions that are invisible on CT scans.5 In addition, positron emission tomography has shown areas of dysgenesis undetected by CT or MRL66 Thus, disorders of neuronal migration may be the common denominator for seizures symptomatic of otherwise apparently diverse clinical pictures. Further investigation of the mechanisms involved in migration may be important in the greater understanding of the aetiology of on
epilepsy. Dobyns WB, Stratton RF, Greenberg F. Syndromes with lissencephaly. I: Miller-Dieker and Norman-Roberts syndromes and related lissencephaly. Am J Med Genet 1984; 18: 509-26. 2. Dobyns WB, Kirkpatrick JB, Hittner HM, Roberts RM, Kretzer FL. Syndromes with lissencephaly. II: Walker-Warburg and cerebrooculo-muscular syndromes with a new syndrome with type II lissencephaly. Am J Med Genet 1985; 22: 157-95. 3. Byrd SE, Osborn RE, Bohan TP, Naidich TP. The CT and MR evaluation of migrational disorders of the brain. 1. Lissencephaly and pachygyria. Pediatr Radiol 1989; 19: 151-56. 4. Byrd SE, Osborn RE, Bohan TP, Naidich TP. The CT and MR evaluation of migrational disorders of the brain. 2. Schizencephaly, heterotopia and polymicrogyria. Pediatr Radiol 1989; 19: 219-22. 5. Livingston JH, Aicardi J. Unusual MRI appearance of diffuse subcortical heterotopia or "double cortex" in two children. J Neurol Neurosurg Psychiatr 1990; 53: 617-20. 6. Chugani HT, Shields WD, Shewmon DA, Olson DM, Phelps ME. Infantile spasms. I: PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Ann Neurol 1990; 27: 406-13. 7. Meencke HJ. Neuropathology of generalized primary epilepsy. In: Wolf P, Dam M, Janz D, Dreifuss FE, eds. Advances in epileptology, vol 16. 1.
New York: Raven, 1987: 1-8. 8. Hardiman O, Burke T, Phillips J, et al. Microdysgenesis in resected temporal neocortex: Incidence and clinical significance of focal epilepsy. Neurology 1988; 38: 1041-47. 9. Barth PG. Disorders of neuronal migration. Can J Neurol Sci 1987; 14: 1-16. 10. de Rijk-van Andel JF, Arts WFM, Barth PG, Loonen MCB. Diagnostic features and clinical signs of 21 patients with lissencephaly type I. Dev Med Child Neurol 1990; 30: 707-17. 11. van Allen N, Clarren S. A spectrum of gyral anomalies in Miller-Dieker (lissenencephaly) syndrome. J Pediatr 1983; 102: 559-64. 12. Gastaut H, Pinsard N, Raybaud Ch, Aicardi J, Zifkin B. Lissencephaly (agyria-pachygyria): clinical findings and serial EEG studies. Dev Med Child Neurol 1987; 29: 167-80. 13. Fukuyama Y, Osawa M, Suzuki H. Congenital progressive muscular dystrophy of the Fukuyama type—clinical, genetic and pathological considerations. Brain Dev 1981; 3: 1-29. 14. O’Doherty NJ, Norman RM. Incontinentia pigmenti (Bloch-Sulzberger syndrome) with cerebral malformations. Dev Med Child Neurol 1968; 10: 168-74. 15. Donnenfield AE, Packer RJ, Zackai EH, et al. Clinical, cytogenic and pedigree findings in 18 cases of Aicardi syndrome. Am J Med Genet
1989; 32: 461-67. 16. Meencke course
HJ, Gerhard C. Morphological aspects of etiology and the of infantile spasms (West-syndrome). Neuropediatrics 1985; 16:
59-66. 17.
Renier WO, Renkawek K. Clinical and neuropathologic findings in a case of severe myoclonic epilepsy of infancy. Epilepsia 1990; 31: 287-91. 18. Roger J, Gambarelli-Dubois D. Neuropathological studies of the Lennox-Gastaut syndrome. In: Niedermeyer E, Degen R, eds. The Lennox-Gastaut syndrome. New York: Alan R Liss, 1988. 19. Trounce JQ, Fagan DG, Young ID, Levene MI. Disorders of neuronal migration: sonographic appearances. Dev Med Child Neurol 1986; 28: 467-71.