34ournal of Neurology, Neurosurgery, and Psychiatry 1993;56:314-316

SHORT REPORT

Localised neuronal migration disorder andintractable epilepsy: a prenatal vascular aetiology

David C Reutens, Samuel F Berkovic, Renate M Kalnins, Penny McKelvie,Michael M Saling, Gavin C A Fabinyi

Austin Hospital,Heidelberg, Australia,Department ofNeurologyD C Reutens*S F Berkovic*Department ofAnatomical PathologyR M KalninsP McKelvieDepartment ofNeuropsychologyM M SalingtDepartment ofNeurosurgeryG C A FabinyiThe University ofMelbourne,Melbourne, AustraliaDepartments ofMedicine* andPsychologytCorrespondence to:Dr Reutens, Department ofNeurology, Austin Hospital,Heidelberg 3084, Australia.Received 2 January 1992and in revised form14 April 1992Accepted 24 April 1992

AbstractLocalised neuronal heterotopias are anincreasingly recognised cause of intract-able focal epilepsies. The aetiology ofthesecircumscribed disorders of neuronalmigration is often unknown although insome instances proximity to areas of pre-natal infarction suggests that severeischaemia was responsible. A patient isdescribed with intractable complex par-tial seizures associated with heterotopicgrey matter and cerebral hypoplasia con-fined to the territory of the left posteriorcerebral artery; the left hippocampus wasspared. Angiography showed a normal leftanterior choroidal artery but a hypo-plastic left posterior cerebral artery,implicating prenatal ischaemia withoutfrank infarction as the aetiology of themalformation.

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Although circumscribed disturbances of neu-ronal migration have long been recognised innecropsy or surgical specimens, MRI hasincreased awareness of their importance as acause of intractable focal epilepsies. ' 2 In manycases the cause of the malformation isunknown. However, a vascular aetiology hasbeen implicated when the disruption of histo-genesis, most commonly polymicrogyria, lies

adjacent to an area of putative infarction.'' Wepresent evidence that nodular heterotopiasmay also result from ischaemia without frankinfarction occurring early in gestation.

Case reportA 25 year old woman was referred for evalu-ation of intractable complex partial seizures.The perinatal period had been uneventful butbetween the ages of 18 and 24 months thepatient had 7 brief febrile convulsions withoutfocal features. Early development was normal.There was no family history of epilepsy.At the age of 15, typical complex partial

seizures started. They were characterised by aninitial motionless stare, an unusual epigastricsensation, gustatory hallucinations, dystonicposturing of the right arm and automatisms.Secondarily generalised tonic-clonic seizureswere infrequent. The seizures occurred at leastweekly despite treatment with several anti-convulsants including carbamazepine, pheny-toin and primidone.

Neurological examination revealed anincongruous, homonymous, peripheral rightsided field defect. She was left handed, ofaverage intellectual capacity and detailed neu-ropsychological assessment ofvisuoperceptual,language and material specific recent memoryfunction was normal.MRI showed that the left occipital lobe was

considerably smaller than the right (fig lA).

Figure 1 A) Axialcranial MRI scan showingmarked hypoplasia of theleft occipital lobe; B)Coronal Tl-weightedcranial MRI scan showingareas of ectopic grey matterin the subcortical whitematter of the left posteriortemporal lobe (arrow).

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Localised neuronal migration disorder and intractable epilepsy: a prenatal vascular aetiology

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Figure 2 Right vertebral angiogram showing a hypoplastic left posterior cerebral artery(arrow) arising from the left superior cerebellar artery.

Areas of ectopic grey matter were present inthe white matter of the left occipital andposterior left temporal lobes (fig iB); theanterior quarter of the temporal lobe appearedunaffected. The left hippocampus appearednormal in size.

Figure 3 Section of thetemporal lobe specimen.Normal inferomedialtemporal neocortex is seen(A). A large mass ofectopic grey matter (-*)and several smaller greymatter nodules (-k) arepresent in the subcorticalwhite matter. Luxol FastBlue. Magnification x 5.

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Interictal surface EEG recordings revealedan active epileptiform abnormality at T3 withnormal background activity. Five ictal surfacerecordings and a recording employing sphenoi-dal electrodes showed rapid spike activitybeginning at T3. An interictal blood flow studywith 99mTc-HMPAO single photon emissioncomputed tomography6 showed reduced leftoccipital perfusion in the region of the struc-tural abnormality. Marked hyperperfusion inthe left temporal region was present in the ictalstudy.At angiography, a hypoplastic left posterior

cerebral artery was seen after vertebral and leftinternal carotid artery injections. It arose fromthe ipsilateral superior cerebellar artery (fig 2).The left anterior choroidal artery was normal.A left internal carotid artery amytal test pro-duced a brief period of anarthria followed bynormal naming, reading, sentence repetitionand preserved verbal specific memory.

Left temporal lobectomy was performed; theneocortical margin of resection was 6-5 cmfrom the temporal tip. The mesial temporalstructures were also removed. Microscopicexamination of the neocortex of the temporalpole and lateral temporal lobe revealed normalvertical and horizontal lamination. In the whitematter of the temporal lobe, ectopic masses ofgrey matter composed of randomly organisedlarge and medium sized neurons with asso-ciated oligodendrocytes and astrocytes werepresent (fig 3). The histology of the anteriorhippocampus was normal with no evidence ofpyramidal cell loss, gliosis or neuronal het-erotopia.

In the eighteen months following temporallobectomy, she has experienced no complexpartial seizures and only rare auras.

DiscussionDuring fetal development, radial glial fibresspan the telencephalon, guiding the migrationof neurons from the ventricular and sub-ventricular areas to their destinations in thecerebral cortex. Destruction of these fibresplays an important role in the pathogenesis ofneuronal migration disorders. The majority ofneurons migrate between 7 and 16 weeksgestational age making it likely that the devel-opmental insult occurred in the early fetalperiod in this patient.79 Absence of glialscarring is further evidence for an early gesta-tional lesion; during this period the cell bodiesof astrocytes are restricted to the periven-tricular region.'0We propose that the aetiology of the neu-

ronal migration abnormality in this patient wasintrauterine ischaemia in the territory of theleft posterior cerebral artery. The artery washypoplastic with an anomalous origin. Thesalient abnormalities in our patient, left occipi-tal hypoplasia and occipitotemporal grey mat-ter heterotopia, were limited to the artery'szone of perfusion. In keeping with the fetalpattern of arterial supply, hippocampal histol-ogy and thalamic morphology on MRI wereunaffected. The developing hippocampus anddiencephalon are supplied by the anterior and

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Reutens, Berkovic, Kalnins, McKelvie, Saling, Fabinyi

posterior choroidal arteries, prominent bran-ches of the primitive internal carotid artery."The peculiar distribution of abnormalitiesmakes a primary vascular event far moreplausible than a patchy, multifocal pathoge-netic process affecting both neuronal andvascular structures. Furthermore, the presenceof normal major cerebral vessels in other caseswith substantial abnormalities of neuronalmigration and peroxisomal disorders supportsthe case for a primary vascular event in thispatient. 2

Intrauterine cerebral ischaemia is a recog-nised cause of disordered neuronal migration.In most previously described cases, the ischae-mia has been severe. For example, Dekaban,3Levine et al4 and Ferrer' described areas ofpolymicrogyria located at the borders of exten-sive porencephalic defects and Norman'3 des-cribed heterotopic clusters of neuroblasts andbilateral encephaloclastic lesions in a fetalbrain following a putative hyproxic-ischaemicinsult at about the third gestational month.Can abnormal histogenesis occur with

ischaemia insufficient to produce frank infarc-tion? Our case supports this possibility. Barthand van der Harten'4 describe the product ofparabiotic twin pregnancy with focal cerebralhypoplasia, microgyria and nodular hetero-topias in the territories of bilateral hypoplasticposterior cerebral arteries. Richman et al'5 andMcBride and Kemper'6 have also describedcases of microgyria restricted to a vascularterritory and unassociated with cavitation;however, the description of arterial supply wasincomplete in both cases.Our case provides clear evidence of an

arterial abnormality in association with neu-

ronal heterotopia and focal cerebral hypo-plasia. It gives further support for a vascularaetiology in at least some instances of dis-ordered neuronal migration. The spectrum ofpathogenetic mechanisms responsible for thesemalformations has been extended to includereduced perfusion without frank infarction.

1 Osborn RE, Byrd SE, Naidich TP, et al. MR imaging ofneuronal migrational disorders. AJNR 1988;9: 1101-6.2 Kuzniecky R, Berkovic S, Andermann F, et al. Focal corticalmyoclonus and rolandic dysplasia: clarification by mag-netic resonance imaging. Ann Neurol 1988;23:317-25.

3 Dekaban A. Large defects in cerebral hemispheres asso-ciated with cortical dysgenesis. J Neuropath Exp Neurol1965;24:512-30.

4 Levine DN, Fisher MA, Caviness VS. Porencephaly withmicrogyria: a pathologic study. Acta Neuropathol (Berl)1974:29:99-113.

5 Ferrer I. A Golgi analysis of unlayered polymicrogyria. ActaNeuropathol (Berl) 1984;65:68-76.

6 Rowe CC, Berkovic SF, Sia STB, et aL Localisation ofepileptic foci with postictal single photon emissioncomputed tomography. Ann Neurol 1989;26:660-8.

7 Barth PG. Disorders of neuronal migration. Can J NeurolSci 1987;14:1-16.

8 Sidman RI, Rakic P. Neuronal migration, with specialreference to developing human brain: a review. Brain Res1973;62: 1-35.

9 Rakic P. Specification of cerebral cortical areas. Science1988:241:170-6.

10 Fujita S. Cytogenesis and pathology of neuroglia andmicroglia. Path Res Pract 1980;168:271- 8.

11 Padget DH. The development of the cranial arteries in thehuman embryo. Carnegie Inst of Wash Contrib Embryol1948;22:205-6 1.

12 Evrard P, Caviness VS, Prats-Vinas J, Lyon G. Themechanism of arrest of neuronal migration in the Zellwe-ger malformation: an hypothesis based upon cytoarchitec-tonic analysis. Acta Neuropathol (Berl) 1978;41: 109-17.

13 Norman MG. Bilateral encephaloclastic lesions in a 26 weekgestation fetus: effect on neuroblast migration. Can JNeurol Sci 1980;7:191-4.

14 Barth PG, van der Harten JJ. Parabiotic twin syndrome withtopical isocortical disruption and gastroschisis. ActaNeuropathol (Berl) 1985;67:345-9.

15 Richman DP, Stewart RM, Caviness VS. Cerebral micro-gyria in a 27 week fetus: an architectonic and topographicanalysis. J Neuropath Exp Neurol 1974;33:374-84.

16 McBride MC, Kemper TL. Pathogenesis of four-layeredmicrogyric cortex in man. Acta Neuropathol (Berl)1 982;57:93-8.

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