Eur J Pediatr (2000) 159: 555±562

Ó Springer-Verlag 2000

REVIEW

Lieven Lagae

Cortical malformations: a frequent cause of epilepsy in children

Received: 25 November 1999 and in revised form 10 January 2000 / Accepted: 10 January 2000

Abstract In this review, a simpli®ed scheme for classi®cation of cortical malformations is introduced and illustrated based on the work of Barkovich et al. [8]. Detailed MRI studies identify cortical malformations as a major cause of epilepsy in children. Two aspects that are becoming increasingly important for the paediatrician are emphasised. First, knowledge of the genetic background of cortical malformations is necessary for appropriate genetic counselling. Although the majority of cortical malformations occur sporadically, recent studies have shown a familial pattern in speci®c epilepsy syndromes associated with cortical malformations. Second, the epilepsy becomes refractory to the common anti-epileptic drugs in many patients with cortical malformations so that epilepsy surgery should be considered. In this respect, the paediatrician can play a pivotal role in referring candidate patients for further specialised assessment. Conclusion The input of the paediatrician will become crucial to link clinical, genetic and neuro-imaging data in children with the great variety of possible cortical malformations. Key words Epilepsy á Cortical malformations á Migration disorders á Magnetic resonance imaging á Brain development Abbreviations MRI magnetic resonance imaging á EEG electro-encephalogram á PET positron emission tomography á CT computed tomography á FISH ¯uorescence in situ hybridisation Introduction

The introduction of MRI techniques in paediatric neurology has substantially increased our knowledge about possible abnormalities during cortical development. An increasing number of cortical malformations has been reported in recent years [7, 8, 9, 10, 22, 34, 35]. Almost all of these developmental abnormalities can present with epilepsy, behavioural, psychiatric or cognitive problems. In many children with epilepsy, cortical abnormalities are identi®ed if studied with detailed MRI protocols [46]. Two clinically relevant aspects of cortical malforL. Lagae (&)1 Department of Paediatric Neurology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium

mations are emphasised in this review. First, the genetic background of several cortical malformations is now better understood so that genetic counselling becomes a mandatory part in the overall assistance of a family with an epileptic child. Second, the epilepsy becomes refractory to the common anti-epileptic drugs in many epileptic children with cortical malformations. Therefore, at some point during their illness, epilepsy surgery should be considered. A thorough understanding of the nature and the location of the cortical malformation serves as a guideline for deciding on eligibility for epilepsy surgery and also for predicting the possible outcome thereafter [70]. e-mail: [email protected], Tel.: +32-16-343834; Fax: +32-16-343842 1

Holder of UCB-Chair in Cognitive Dysfunctions in Children

556

In this review, we will describe the most common types of cortical malformations, following the classi®cation scheme developed by Barkovich et al. [7, 8]. For the practising paediatrician, it is important to become familiar with this classi®cation and with the terminology used. As will be pointed out, this classi®cation scheme will help in outlining the work-up in a child with a cortical malformation. Stages in cortical development: the basis for classi®cation of cortical malformations

At any stage during prenatal development, intrinsic genetic or extrinsic environmental factors may disturb normal cortical development. It is still believed that especially the timing and to a lesser degree the nature of the `insult' will determine the extent and the severity of the cortical malformation. Abnormalities during the earliest stages of brain development, namely the dorsal and ventral induction periods, are beyond the scope of this review. Malformations originating from this early period are incompatible with life or cause severe neurological syndromes in which epilepsy usually is only a `minor' symptom. The best known abnormalities in this category are anencephaly and holoprosencephaly. Di€erent genes for holoprosencephaly have been identi®ed. They play an important role in normal forebrain development [68]. In the ®rst weeks of pregnancy, neuronal proliferation and di€erentiation of the neuroblasts in the periventricular region starts. At this early vulnerable stage, interruption of normal development or abnormal proliferation can cause abnormalities involving extensive parts of the brain as seen in tuberous sclerosis (TS) and hemimegalencephaly. However, also very focal cortical dysplasia can originate from this prenatal period. The neuroblasts start to migrate around the post-menstrual age of 6±7 weeks, leaving the periventricular region and ®nding their way to the cortex, guided by radial glial ®bres [53]. Abnormalities can occur at any of the migration stages: failure to migrate (e.g. subependymal heterotopia), arrest during migration (e.g. band heterotopia, subcortical heterotopia) or formation of an abnormal cortex (e.g. lissencephaly). Once the young neurons reach the cortex, a long period of further differentiation and synapse formation begins. Polymicrogyria following an intrauterine cytomegalovirus infection is a notable example of a post-migrational cortical malformation. Barkovich et al. [8] proposed a classi®cation scheme based on these three major developmental stages: the neuronal and glial proliferation period, the migration period and the post-migration period. The other relevant parameter used in this scheme is the distinction between generalised and focal abnormalities. A simpli®ed overview of their classi®cation is given in Table 1. The most common disorders will be discussed in the next sections, with emphasis on genetic background and epilepsy. Table 2 gives an overview of

the known genetic abnormalities in the cortical malformations that are discussed in this review text. Abnormal neuronal and glial proliferation

Distinction should be made between neoplastic and nonneoplastic lesions. In the latter category, TS and hemimegalencephaly are classical examples. TS is well known in paediatric practice because of its multi-organ involvement. TS, an autosomal dominant disorder with variable expression, can be considered as the result of a fundamental abnormality in suppressor gene regulation. This syndrome is linked to chromosome 9q34.3 (TSC1 gene, MIM 191100) or 16p13.3 (TSC2 gene, MIM 191092) [28, 39, 66]. These genes code for hamartin and tuberin respectively and are both involved in cellular di€erentiation, tumour suppression and intracellular signalling [16]. The key intracranial lesions are cortical tubers, characterised by a disorganised cortex with a mixture of atypical neuron-like cells, neuroepithelial cells and other bizarre glial cells. The adjacent white matter is also abnormal. Other possible malformations in TS patients are subependymal nodules, giant-cell astrocytomas and white matter lesions. The incidence of epilepsy is very high in children with TS. Infantile spasms are very frequent in infancy, inasmuch that TS should be considered in the di€erential diagnosis in any infant presenting with infantile spasms. Until recently, TS was a relative contra-indication for epilepsy surgery. However, if seizure symptomatology is concordant with ictal EEG monitoring and MRI data, these children can be considered for surgery [33]. In this respect, Chugani et al. [15] recently showed that positron emission tomography is a sensitive tool to di€erentiate active epileptogenic tubers from non-epileptic ones. Hemimegalencephaly is a rather infrequent abnormality with a great variety in clinical presentation. In the a€ected enlarged hemisphere, di€erent cortical malformations can be found in di€erent areas, illustrating the severe disruption of hemispheric organisation: pachygyria, focal cortical dysplasia, nodular heterotopia etc. The white matter is usually involved and the ventricular system is enlarged. Clinically, the child presents with a hemiparesis, which is often surprisingly mild. Further examination can show a hemi-anopsia. Mental retardation is also very variable. The hemimegalencephaly can be an isolated ®nding or part of a neurocutaneous syndrome: e.g. epidermal naevus syndrome (MIM 601359) [67], hypomelanosis of Ito (MIM 146150) [11], or neuro®bromatosis. Partial epilepsy is very common and epilepsy surgery can be of great bene®t in refractory cases. In children with a severe hemiplegia, a functional hemispherectomy is proposed [2]. In others, more limited tailored cortical resections can be considered, if seizures and functional neuro-imaging indicate a very focal onset of the seizures. Figure 1 illustrates the MRI of a 16-year-old boy with partial hemimegalencephaly. He presented with psychomotor retardation, hemipare-

557 Table 1 Simpli®ed classi®cation of cortical malformations [8] Cortical malformations Abnormal neuronal/glial proliferation

Abnormal neuronal migration

Abnormal cortical organisation

Generalised

Focal/multifocal

Generalised

Focal/multifocal

Generalised

Focal/multifocal

Microlissencephaly

Non-neoplastic TS Hemimegalencephaly Focal cortical dysplasia with balloon cells Neoplastic Dysembryoplastic neuroepithelial tumour Ganglioglioma, gang liocytoma

Lissencephaly type 1, Agyriapachygyria spectrum Lissencephaly type 2 Heterotopia Subependymal Subcortical Subpial

Focal agyriapachygyria Unlayered polymicrogyria Focal heterotopia

Layered polymicrogyria

Polymicrogryia Schizencephaly Focal cortical dysplasia without balloon cells Microdysgenesis

Table 2 Genetic background in selected cortical malformation syndromes Early abnormalities Holoprosencephaly Abnormal neuronal and glial proliferation TS Abnormal neuronal migration Lissencephaly type 1 Isolated lissencephaly, Miller Dieker X linked lissencephaly X linked subcortical band heterotopia Lissencephaly type 2 Muscle-eye-brain disease Fukuyama congenital muscular dystrophy Heterotopia Bilateral periventricular nodular heterotopia Abnormal cortical organisation Familial bilateral schizencephaly

Chr 7:SHH Chr 13:ZIC2 Chr 2:SIX3

Homeobox genes

Chr 9q34.3:TSC1 Chr 16p13.3:TSC2

Hamartin Tuberin

Chr 17p13.3:LIS1 Chr Xq22.3:XLIS Chr Xq22.3:XLIS-SBHX

Platelet activating factor acetylhydrolase Doublecortin Doublecortin

Chr 1p32±34 Chr 9q31±33

Fukutin

Chr Xq28

Filamin 1

Chr 10q26.1:EMX2

Homeobox gene

sis and refractory partial epilepsy. The right hemisphere is enlarged, especially in the posterior parts with irregular cortex (pachygyria), white matter changes and hyperintense spots lining the occipital pole of the ventricle (heterotopia). Low-grade neoplastic lesions can also present with epilepsy. The distinction with focal cortical dysplasia is sometimes dicult on standard MRI. Two entities are frequent: the ganglioglioma/gangliocytoma and the dysembryoplastic neuroepithelial tumours [17, 23]. On MRI, they show up as an ill-de®ned lesion, involving grey and white matter. Their predilection location is the (anterior) temporal pole which makes this lesion very epileptogenic. Many patients therefore present with complex partial seizures with typical temporal lobe characteristics. Anterior temporal lobectomy is proposed when epilepsy becomes refractory or when tumour growth causes other neurological symptoms. It should be emphasised that tumour resection alone not always suces to stop the seizures [40, 42].

Abnormal neuronal migration

The majority of the abnormalities in this category belong to two major entities: the agyria-pachygyria spectrum or the heterotopia spectrum. The best known abnormality is the classical lissencephaly type 1 picture with a broad (>10 mm) smooth cortex with only the central sulcus visible. Pathologically, the cortex has four cortical layers instead of six. In the white matter, heterotopic clusters of neurons can be found; the corpus callosum is hypoplastic and the ventricles are dysmorphic. This is the extreme of the wide agyria-pachygyria spectrum [1]. Agyria refers to a thick cortex with no visible sulci, while pachygyria indicates a thick cortex but with some discernible sulci. Six grades are de®ned. Grade 1 indicates di€use agyria as seen in classical lissencephaly. In grade 2, some sulci are seen in the frontal and temporal lobes. Grade 3 shows better developed but still abnormal gyri in the frontal lobes.

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Fig. 1 MRI of a 16-year-old boy with partial hemimegalencephaly of the right hemisphere. Di€erent cortical malformations are recognised; see text for further explanation

Typically, agyria is found in the posterior parts of the brain. Grade 4 is characterised by di€use pachygyria. Grade 5 is characterised by a combination of pachygyria and subcortical band heterotopia (see below). Grade 6 refers to subcortical band heterotopia. Two subtypes are de®ned for all grades: the A subtype indicates more severe abnormalities (agyria) in the posterior parts; the B subtype indicates more severe abnormalities in the anterior parts of the brain. Figure 2 is an example of a grade 3A abnormality. This 14-year-old boy has the Lennox-Gastaut syndrome. Both sporadic [38] and genetically determined cases have been described. In classical lissencephaly (grades 1 to 3), a deletion can be found on chromosome 17p13.3 in many patients [14, 44, 55]. The LIS-1 gene codes for a brain platelet activating factor acetylhydrolase isoform Ib [37]. In a study of Fogli et al. [26], a ®rst correlation between the amount of intracellular LIS-1 protein and the severity of the clinical picture was illustrated. In the Miller Dieker syndrome (MIM 247200), classical lissencephaly is associated with (sometimes subtle) facial dysmorphic features: long thin upper lip, micrognathia, malformed ears, upturned nares, broad nasal bridge with epicanthal folds, bitemporal hollowing, abnormal irides and tortuous fundal vessels [20, 47]. Fluorescence in situ hybridisation testing shows 17p13.3 deletions in more than 90%. If a deletion is found, parental studies should be performed to ®nd balanced translocations. Lissencephaly always presents with a severe clinical picture: hypotonia at birth, feeding problems, overall delay in psychomotor development and epilepsy. Epilepsy starts early on and usually evolves into a catastrophic epileptic syndrome characterised by refractory myoclonic seizures, infantile spasms or other seizure types. In these cases, epilepsy surgery is of little bene®t because of the widespread involvement. In selected cases, palliative corpus calloso-

Fig. 2 Grade 3A lissencephaly in a 14-year-old boy. Some rudimentary sulci are seen in the frontal lobes and agyria in the posterior parts

tomy can be proposed [43]. Children ultimately develop spastic quadriplegia, blindness and inability to communicate. The mortality rate is still very high at a young age. The clinical picture in the other forms of agyria-pachygyria depends on the extent and the location of the abnormal cortical regions. The incidence of epilepsy is very high in all cases with pachygyria and is usually dicult to control. Unless the pachygyria are very focal, there is little indication for epilepsy surgery. Subcortical band heterotopia should be considered as the result of an arrested migration leaving a band of neurons in the white matter (MIM 300067) [3, 48]. Subcortical band heterotopia, also called double cortex syndrome, is almost exclusively seen in females and is caused by an X linked abnormality (Xq22.3). Females with subcortical band heterotopia are thus heterozygotes for the disease. Surviving males present with classical lissencephaly [19, 45, 51, 57]. The gene product is called doublecortin, a protein with an unknown function [31]. In any male child with lissencephaly, one should therefore look for the 17p13.3 deletion and also perform MRI in the mother to exclude subcortical band heterotopia. In subcortical band heterotopia, symptoms are usually less severe with, e.g. only mild mental retardation. Even asymptomatic cases have been described. In one study, the degree of mental retardation was correlated with the band thickness illustrating that a thicker band is the result of a more severe insult during migration with more repercussion on brain functioning [6]. If seizures occur in subcortical band heterotopia, they commonly start beyond infancy. Figure 3 is an illustrative example of a double cortex syndrome in a 9-year-old girl with severe mental retardation. She was admitted for aggressive outbursts. There were no clinical seizures, although long-term video-EEG monitoring showed epileptic spikes over the frontal regions.

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Fig. 3 Double cortex syndrome in a 9-year-old girl. A thick grey matter band is seen in between the ventricles and the cortex. See text for clinical details

Less known is the lissencephaly type 2, also called cobblestone lissencephaly because of the irregular cortex abnormalities. The cortex is thick with irregular grouping of neurons and gliovascular scars with areas of heterotopia. A typical feature is also the involvement of the cerebellum showing cortical dysplasia and other cortical abnormalities [18]. A key feature of type 2 lissencephaly is the possible association with neuromuscular diseases. Type 2 lissencephaly can be part of the WalkerWarburg syndrome (MIM 236670), muscle-eye-brain disease (MIM 253280) and Fukuyama congenital muscular dystrophy (MIM 253800) [21, 29, 36, 58, 65, 70]. Heterotopia refers to a never started or arrested migration of groups of neurons. Heterotopia can be widely distributed throughout the brain or very focal. Depending on the location of the abnormal neuronal groups, one can distinguish subependymal, subcortical or subglial heterotopia [5, 27]. Recent studies have illustrated the intrinsic epileptogenic characteristics of heterotopic tissue explaining the high incidence of epilepsy in children with heterotopia [30, 50, 59]. Periventricular nodular heterotopia is a rather well de®ned syndrome, with heterotopic nodules lining the lateral ventricles (MIM 300049). It can occur sporadically, but X linked transmission has been described (Xq28, coding for ®lamin 1 [27]). It has also been described in association with other syndromes such as the Aicardi syndrome (MIM 304050) [22, 34, 60]. Focal or multifocal heterotopia can be seen in some metabolic diseases such as Zellweger syndrome (MIM 214100) [24].

derdiagnosed. Three di€erent abnormalities will be discussed in this section: focal cortical dysplasia, polymicrogyria and schizencephaly. Actually, these abnormalities can also be seen as a result of an earlier insult, thus belonging to the abnormal neural and glial proliferation group. Especially schizencephaly remains dicult to classify. MRI and neuropathology can di€erentiate between an earlier insult and a later insult. This is an important issue because insults occurring later in pregnancy are more likely to be due to extrinsic insults such as prenatal infections. Focal cortical dysplasia is a localised abnormality with changes in the normal architecture of the cortex [61, 63]. Sometimes underlying white matter changes accompany the cortical abnormality. Type 1 cortical dysplasia refers to a post-migration disorder without abnormal balloon cells. Type 2 cortical dysplasia is a true abnormality in proliferation of the neuronal and glial cells. In this type, large abnormal cells can be recognised (balloon cells) [13]. White matter changes are much more frequent in type 2 than in type 1 cortical dysplasia. The delineation of type 2 lesions from the lesions seen in TS is sometimes dicult. The incidence of epilepsy is very high in children with cortical dysplasia and usually starts later in the ®rst or early second decade [54]. In refractory cases with perfect concordance between ictal symptomatology, anatomical and functional neuro-imaging, resection surgery can reduce or stop the epilepsy [49, 52]. Success rate of epilepsy surgery however is determined by the possible presence of other dysplastic regions in the brain that are not recognised at the MRI level (`microdysgenesis'). Figure 4 shows a focal cortical dysplasia in the right parietal region in a 10-year-old boy. He presented with complex partial seizures at the age of 6 years. Secondary generalisation

Abnormal cortical organisation

Malformations due to an abnormal cortical organisation in late pregnancy have long been unrecognised and un-

Fig. 4 Focal cortical dysplasia in the right parietal area in a 10year-old boy. See text for clinical details

560

could be treated successfully with anti-epileptic drugs but the `auras' still occur at a frequency of about ®ve per week. Polymicrogyria is a complex malformation with an excess of sulci and cortical foldings in parts of the brain. CT scan of the brain can completely overlook the abnormality. With MRI, the abnormality is seen as a thick cortex. In other cases, the excess of sulci can be recognised [35]. Here also, two types are distinguished referring to the origin of the abnormality. In the postmigration type, individual layers of the cortex can still be recognised: layered polymicrogyria. In the type that originates from the migration period, individual layers can no longer be recognised: unlayered polymicrogyria [25]. Layered polymicrogyria can be di€use or follow arterial boundaries [56]. Therefore, it is believed that perfusion failure and/or hypoxia can cause this abnormality in pregnancy due to infection, carbon monoxide intoxication or severe trauma etc. Cytomegalovirus infection is a notable example in this respect [62]. A syndrome of bilateral perisylvian polymicrogyria is increasingly recognised, clinically characterised by bulbar signs, speech problems, mental retardation and epilepsy (MIM 260980) [41, 64]. In schizencephaly, there is a unilateral or bilateral cleft between the cortex and the ventricle. The cleft can be `open' with cerebrospinal ¯uid between the two lips of the cleft, or `closed' with adjacent cleft lips. The cleft is usually bordered by abnormal polymicrogyric or heterotopic cortex. One hypothesis is that the cleft is the result of a circulatory failure interrupting the cortical mantle. The cortical abnormalities in the cleft lips can then be considered as a sort of late and inadequate repair mechanism. In some cases with bilateral clefts, a de®cit in the homeobox gene EMX2 has been described (MIM 600035) [12, 32]. With the introduction of MRI, it became clear that schizencephaly has a very variable clinical presentation. Most children with schizencepaly nevertheless present with a central motor de®cit (hemiplegia), mental retardation and epilepsy [4]. Symptomatology is usually much more severe in bilateral cases. Conclusions

This review paper illustrates that the growing variety of cortical malformations can be adequately classi®ed into one of the three categories described by Barkovich et al. [8]. High quality MRI is necessary for a detailed analysis of the cortical abnormalities and has become the gold standard in the assessment of (partial) epilepsy in children [46]. Nevertheless, the input of the clinician remains necessary to couple these neuro-anatomical data with e.g. family history, seizure characteristics, dysmorphic features, metabolic data and genetic ®ndings. Only then, well-delineated syndromes can be described and adequate counselling of the patients becomes possible, both in terms of outcome and genetics.

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