epilepsy and disorders of neuronal migration

1035

16. Deapen DM, Henderson BE. A case-control study of amyotrophic lateralsclerosis. Am J Epidemiol 1986; 123: 790-99.

17. Haynal A, Regli F. Zusammenhang der amyotrophischen Lateralsklerosemit 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 infamilial amyotrophic lateral sclerosis. Neurology 1989; 39: 919-25.

20. Editorial. Loading the lods. Lancet 1990; 336: 778-79.

EPILEPSY AND DISORDERS OF NEURONALMIGRATION

Gross disorders of neuronal migration are almost invariablyassociated with the early onset of epileptic seizures.12 Newnon-invasive techniques for investigation of the brain3-6 andmore detailed neuropathological examination of specimensobtained at necropsy7 or operation8 have led to theidentification of localised or lesser degrees of migrationaldisorder.

In the normal human brain, between 7 and 16 weeks ofgestational age, young neurons, guided by radial glial fibres,migrate to the cortical plate.9 The layers of the neocortex areformed from within outwards, so waves of later migrationpass through layers that are already established. Neuronsthat do not migrate normally are at increased risk of stuntingor early death. Among the underlying biochemical

mechanisms, there is some evidence that fatty acid oxidationin peroxisomes and mitochondria is relevant, and that celladhesion molecules and polyamines are important.9 9

Migrational disorders can be classified into

morphological types.9 In agyria/pachygyria there isextensive disorganisation, whereas microgyria, verrucousdysplasias, and neuronal heterotopias may vary in severityand thus in clinical expression. Even diffuse subcorticalheterotopias, giving the appearance of a double cortex, maycause only mild epilepsy and behaviour and learningdifficulties.5 Severe migration disorders can also result inschizencephaly and related disorders. Agyria/pachygyria, orlissencephaly type I, can be a feature of the Miller-Diekersyndrome, or an isolated anomaly in which theabnormalities of gross brain morphology tend to be lesssevere In the Miller-Dieker syndrome seizures, ofteninfantile spasms, almost invariably start in the first 6 monthsof life.1,10-12 In the isolated lissencephaly syndrome, whenagyria is prominent, seizures including infantile spasmsalways start in the first half year; if pachygyria is the moreobvious feature, seizures, although commonly present, donot necessarily begin early.1OThere are several subgroups of lissencephaly type II, all of

which are autosomal recessive. In addition to smoothness ofthe hemispheric surfaces, features include hydrocephalus,retinal dysplasia, and disorders of muscle. Seizures are lessprominent in lissencephaly type II than in type 1.

Microgyria are found in several genetically determinedconditions in which early seizures are common—eg,Fukuyama cerebromuscular dystrophy, 13 Bloch-Sulzbergersyndrome,14 and the disorders of peroxisomes, Zellwegersyndrome and neonatal adrenoleucodystrophy.9 Inverrucous dysplasias of the neocortex tiny "herniations" ofthe second into the first neocortical layer present on thecortical surface. These abnormalities are commonest in thefrontal and Rolandic areas and have been particularlyassociated with multiple acyl-CoA dehydrogenasedeficiency 9 Neuronal heterotopias also occur in manysyndromes--eg, tuberous sclerosis and hypomelanosis of

Ito-with which seizures are very frequently, if not

invariably, associated. 9

Neuropathological studies in infantile spasms with15 orwithout’ 16 other features of Aicardi syndrome; severe

myoclonic epilepsy of infancy; ’ Lennox-Gastaut

syndrome;18 partial epilepsy of temporal lobe origin ;8 andprimary generalised epilepsies7 have revealed areas ofdisordered neuronal migration, often referred to as

microdysgenesis.Gross disorders of neuronal migration can be identified

on ultrasoundl9 or computed tomography (CT)34 scans, butmagnetic resonance imaging (MRI) gives better delineation4and may show lesions that are invisible on CT scans.5 In

addition, positron emission tomography has shown areas ofdysgenesis undetected by CT or MRL6 6

Thus, disorders of neuronal migration may be thecommon denominator for seizures symptomatic ofotherwise apparently diverse clinical pictures. Further

investigation of the mechanisms involved in migration maybe important in the greater understanding of the aetiology ofepilepsy.

1. 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 cerebro-oculo-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 andpachygyria. Pediatr Radiol 1989; 19: 151-56.

4. Byrd SE, Osborn RE, Bohan TP, Naidich TP. The CT and MRevaluation 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 subcorticalheterotopia or "double cortex" in two children. J Neurol NeurosurgPsychiatr 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.New York: Raven, 1987: 1-8.

8. Hardiman O, Burke T, Phillips J, et al. Microdysgenesis in resectedtemporal 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. DevMed 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 MedChild Neurol 1987; 29: 167-80.

13. Fukuyama Y, Osawa M, Suzuki H. Congenital progressive musculardystrophy of the Fukuyama type—clinical, genetic and pathologicalconsiderations. Brain Dev 1981; 3: 1-29.

14. O’Doherty NJ, Norman RM. Incontinentia pigmenti (Bloch-Sulzbergersyndrome) with cerebral malformations. Dev Med Child Neurol 1968;10: 168-74.

15. Donnenfield AE, Packer RJ, Zackai EH, et al. Clinical, cytogenic andpedigree findings in 18 cases of Aicardi syndrome. Am J Med Genet1989; 32: 461-67.

16. Meencke HJ, Gerhard C. Morphological aspects of etiology and thecourse of infantile spasms (West-syndrome). Neuropediatrics 1985; 16:59-66.

17. Renier WO, Renkawek K. Clinical and neuropathologic findings in a caseof 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. TheLennox-Gastaut syndrome. New York: Alan R Liss, 1988.

19. Trounce JQ, Fagan DG, Young ID, Levene MI. Disorders of neuronalmigration: sonographic appearances. Dev Med Child Neurol 1986; 28:467-71.