Abnormalities of brain development and epilepsy

Introduction

The cerebral cortex derives from telencephalic vescicles of the forebrain and starts to develop soon after the hemispheric vesicles form as diverticula of the primitive prosencephalon, in postovulatory week 4 of gestation. Earlv specification of the forebrain is related to the expression of several homeobox-containing and winged helix containing genes. In animal models, loss of func tion of these genes produces abnormalities in forebrain specification and development.[1, 2, 3, 4, 5, 6, 7]

At the early stages, the cerebral hemispheres consist of a single layer of pseudo-stratified columnar epithelium with frequent mitotic activity. The nuclei of these cells move up and down within the cytoplasm of the cell, undergoing mitotic division only at the ventricular surface. As the cerebral hemispheres grow in size, the initial columnar epithelium persists adjacent to the ependyma as the ven tricular zone. Rapidly proliferating precursor cells in the ventricular zone generate many postmitotic but still immature neurons. The second or marginal layer is a sparsely cellular zone which forms superficial to the ventricular zone by week 5.

The next major phase of cortical development begins at this time, when immature neurons start to migrate away from the proliferative zone, primarily by climbing radial glia fibers. The first wave of migrat ing cells forms the preplate during weeks 6 and 7, and begins formation of the cortical plate before slowing down by week 10. The second and larger wave begins gen erating neurons in week 10, peaks during weeks 12-14 and ends by week 16 when the ventricular zone is mostly depleted of cells. [8, 9] These cells form the major portion of layers 2-6 of the mature cortex.

Classical studies have shown that the cerebral cortex is formed by an 'inside-out' migration of ventricular zone cells, so neurons that are generated early during cortical development and migrate to the cortical plate first will occupy deeper layers, whereas later migrating neurons pass the established cells to occupy progressively more superficial positions.[10] By about week 22, the first distinctive layers begin to appear in the cortex. Further maturation consists of additional synaptogenesis, retraction of early axons which did not establish appropriate connections, neurotransmitter biosynthesis, and other processes. By week 27 of gestation, all six layers of the mature cortex are visible.[9]

Genes responsible for malformation of cortical development (modified from Barkovich et al[11]
Syndrome	Locus	Gene	Protein
ILSDCX	Xq22.3-q23	DCX = XLIS	DCX or doublecortin
SBHDCX	Xq22.3-q23	DCX = XLIS	DCX or doublecortin
MDS	17p13.3	Several contiguous	PAFAH1B1 and others
ILSLISI	17p13.3	LIS1	PAFAH1B1
SBHLIS1	17p13.3	LIS1	PAFAH1B1
LCHRELN	7q22	RELN	Reelin
FCMDFCMD	9q31	FCMD	FCMD fukutin
MEB	1p32	Unknown	Unknown
BPNH	Xq28	FLM1	Filamin-1
TSC1	9q32	TSCl	Hamartin
TSC2	16p13.3	TSC2	Tuberin
ILS, isolated lissencephaly sequence; SBH, subcortical band heterotopia; MDS, Miller-Dieker syndrome; LCH, lissencephaly with cerebellar hypoplasia; FCMD, Fukuyama congenital muscular dystrophy; MEB, muscle-eye-brain disease; BPNH, bilateral periventricular nodular heterotopia; TSC, tubrous sclerosis.

Classification and nomenclature of cortical malformations

Three distinct but overlapping processes are involved in development of the cerebral cortex, neuronal and glial proliferation, neuronal migration and cortical organization. Any or all of these processes can be altered, resulting in cortical malformations.[12, 13] A classification system of cortical malformations, based on fundamental embryologic and genetic principles and a combination of neuroimaging, gross pathologic and histologic criteria, has been developed and subsequently updated .[13, 14, 15] The framework of this classification system is based on the three major embryological processes of cellular proliferation, neuronal migration and cortical organization. When more than one process was involved, classification was based on the earliest embryologic abnormality.

The abnormalities that primarily affect proliferation are usually associated with an alteration in both neuronal and glial cell differentiation, producing abnormal cell size and morphology.[13] Disorders affecting neuronal migration are characterized by abnormal neuronal positioning.[13] When arrest of migration occurs early, heterotopic collections of immature neurons are found beneath the cortex, as in isolated subcortical nodular heterotopia and the agyria-pachygyria-band spectrum. When migration is arrested during later cortical development, abnormal cell position is more likely to be restricted to the cortex, as in unlayered polymicrogyria. In both of these malformations, horizontal neuronal lamination is severely disrupted, but radial (vertical) organization is still recognizable.

The best-known cortical malformation originating after neuronal migration is completed, during the stage of later cortical organization, is four-layered polymicrogyria, in which horizontal neuronal lamination usually persists.[13] This pattern of abnormality may result from damage to intermediate cortical layers which produces a difference in growth rate between outer and inner cortical layers, with consequent excessive folding of the cortical surface.[16]

Classification of cortical malformations(modified from Barkovich et al.[11])

1. Malformations due to abnormal neuronal and glial proliferation or apoptosis
   1. Decreased proliferation/increased apoptosis: microcephalies
      1. Microcephaly with normal to thin cortex
      2. Microlissencephaly (extreme microcephaly with thick cortex)
      3. Microcephaly with polymicrogyria/cortical dysplasia
   2. Increased proliferation/decreased apoptosis (normal cell types): megalencephalies
   3. Abnormal proliferation (abnormal cell types)
      1. Non-neoplastic
         1. Cortical hamartomas of tuberous sclerosis
         2. Cortical dysplasia with balloon cells
         3. Hemimegalencephaly (HME)
      2. Neoplastic (associated with disordered cortex)
         1. DNET (dysembryoplastic neuroepithelial tumor)
         2. Ganglioglioma
         3. Ganglioeytoma
2. Malformations due to abnormal neuronal migration
   1. Lissencephaly/subcortieal band heterotopia spectrum
   2. Cobblestone complex
      1. Congenital muscular dystrophy syndromes
      2. Syndromes with no involvement of muscle
      3. Heterotopia
         1. Subependymal (periventricular)
         2. Subcortical (other than band heterotopia)
         3. Marginal glioneuronal
3. Malformations due to abnormal cortical organization (including late neuronal migration)
   1. Polymicrogyria and schizencephaly
      1. Bilateral polymicrogyria syndromes
      2. Schizencephaly (polymicrogyria with clefts)
      3. Polymicrogyria with other brain malformations or abnormalities
      4. Polymicrogyria or schizencephaly as part of multiple congenital anomaly/mental retardation syndromes
   2. Cortical dysplasia without balloon cells C Microdysgenesis
4. Malformations of cortical development, not otherwise classified
   1. Malformations secondary to inborn errors of metabolism
      1. Mitochondrial and pyruvate metabolic disorders
      2. Peroxisomal disorders
   2. Other unclassified malformations
      1. Sublobar dysplasia
      2. Others

Malformations related to abnormal prolifertion of neurons and glia

Hemimegalencephaly (HME)

In HME one cerebral hemisphere is enlarged and presents with thick. cortex, wide convolutions and reduced sulci. Although the abnormality is strictly unilateral in most cases[17] postmortem examination showed minor abnormalities of the apparently unaffected hemi sphere in two cases and mild cortical dysplastic abnormal ities in another.[18, 19] Laminar organization of the cortex is absent and gray-white matter demarcation is poor. There are giant neurons (up to 80 µm in diameter) throughout the cortex and the underlying white matter. In about 50 per cent of cases large, bizarre cells are observed, also called balloon cells.[17, 18] HME is probably a heterogeneous condition. Localization of the abnormality to one cerebral hemisphere may indicate somatic mosaicism.21 It has also been suggested that HME may result from a fault in pro grammed cell death (apoptosis).[20]

HME has been associated with many different disor ders but can occur in isolation. There is a broad clinical spectrum, ranging from severe epileptic encephalopathy beginning in the neonatal period[18] to patients with normal cognitive function.[21, 22] Indeed, the milder end of the clinical spectrum in HME includes patients with well-controlled seizures or no seizures at all. However, most patients have a severe structural abnormality and almost continuous seizures. The most common presentation is with asymmetric macrocrania, hemiparesis, hemianopia, mental retardation and seizures. The electroclinical features usually include partial motor seizures beginning in the neonatal period, infantile spasms and often a suppression burst pattern on sleep HG[23, 24, 25]. Patients with early onset, severe epilepsy almost always develop major cognitive and motor impairment[26] In addition, there is a high mortality rate in the first months or years of life with status epilepticus being the most important cause of death.[17, 26, 27, 28] Seizure intract ability in these patients can usually be established within the first year of life.[23, 24] This is important because hemi-spherectomy may prevent both life-threatening seizures and permanent loss of functioning of the healthy hemi sphere.[24, 29] There are indications that the operation should he performed early.[30] Transfer of functions to the normal hemisphere is greater in younger children and a better neuropsychological outcome is achieved in subjects operated on at an early age.

Focal cortical dysplasia (FCD)

ECD was originally described in 10 patients who were treated surgically for drug-resistant epilepsy.[31] The histo logic abnormalities are restricted to one lobe or a small segment. Careful examination of brains with FCD may, however, show widespread minor dysplastic changes.[32] Histological abnormalities include local disorganization of laminar structure, large aberrant neurons, isolated neuronal heterotopia in subcortical white matter, balloon cells sharing histochemical characteristics of both neuronal and glial cells, giant and odd macroglia, and foci of demyelination and gliosis of adjacent white matter.[33] The abnormal area is not usually sharply delimited from adjacent tissue.[33, 34] One or more of the above components may not be present and three main subtypes of FCD are recognized, which may correspond to the different times of embryologic origin. Type 1 is characterized by abnormal cortical lamination and ectopic neurons in white matter; type 2 presents with giant neurofilament-enriched neurons in addition to altered cortical lamination; and type 3 corresponds to Taylor-type FCD with giant dysmorphic neurons and balloon cells associated with cortical laminar disruption.[35] MR images show focal areas of cortical thickening, with simplified gyration, and rectilinear or blurred boundaries between gray and white matter .[36] Some cases present the involvement of an entire lobe (so-called partial HME). Normal brain MRI has been reported.[37, 38]

FCD usually presents with intractable partial epilepsy, which may start at any age but generally before the end of adolescence. The focal features of the seizure depend on the location of the lesion and focal status epilepticus has frequently been reported.[37, 38, 39] Location in the precen-tral gyrus is often complicated by epilepsia partialis con tinua.[40] Unless the dysplastic area is large, patients do not suffer from severe neurological deficits. Interictal EEC shows focal, rhythmic epileptiform discharges in about half of the patients.[41] The ictal EEC abnormalities are highly specific for FCD, are located over the epileptogenic area and correlate with the continuous epileptiform discharges recorded during electrocorticography (EcoC).[39, 42] ECoC seizure activity shows spatial co-localization with the lesion. At follow-up, most patients with complete resection of the tissue producing ictal ECoC discharges were seizure free or had over 90 per cent reduction in major seizures. None of the patients with persistence of discharging tissue had a favorable outcome.

Dysplastic tissue seems to have a peculiar tendency to produce epileptiform activity[43, 44]. The mechanisms under lying the epileptiform activity generated by dysplastic neocortex remain to be elucidated. In the abnormal cor-tical multilaminar organization typical of FCD, neurons arc prevented from establishing normal synaptic connec tions with their neighbors and are dysfunctional. Intra cellular recordings from neurons of dysplastic human neocortex have revealed no abnormalities in the mem brane properties of single neurons[45] However, a dys function of synaptic circuits seems to be responsible for the abnormal synchronization of neuronal populations under-lying the genesis of epileptiform activity. Abnormalities in the morphology and distribution of local-circuit GABAemic inhibitorv neurons have been observed using immunocytochemistrv.[46, 47] Such abnormal circuitry may play an important role in originating and maintaining the epileptiform activity.

Conditions associated with hemimegalencephaly
Epidermal nevus syndrome Klippel-Trenaunay-Weber syndrome Proteus syndrome Neurofibromatosis Ito hypomelanosis Focal alopecia Tuberous sclerosis Dysembryoplastie neuroepithelial tumor

Most descriptions of FCD and HMF are based on studies from epilepsy surgery centers, where histological diagnosis can be made during life. Thus, the clinical and electrophysiological features described are likely to be typical only of the most severe cases. Our experience indicates that there are some patients with well controlled seizures in whom MRI shows focal dysplastic lesions identical to those present in patients with histologically proven FCD.[48]

Tuberous sclerosis

Tuberous sclerosis or tuberous sclerosis complex (TSC) is a multisystem disorder involving primarily the central nervous system, the skin and the kidney.[49] The charac teristic neuropathologic features are cortical tubers, subependymal nodules and giant cell tumors. The corti cal tubers are characterized by their nodular appearance, firm texture, and variability in site, number and size and are the lesions that are most directly related to epilepto genesis.

Microscopically, the tubers consist of subpial glial proliferation and an irregular neuronal lamination with giant multinucleated cells that are not clearly neuronal or astrocytic. These pathologic changes are similar to those seen in focal cortical dysplasia. The junction between gray and white matter is indistinct and may be partly demyelinated. Cortical tubers are usually well visualized by MRI scan as enlarged gyri with atypical shape and an abnormal signal intensity, involving mainly the subcortical white matter [50] Tubers have a tendency to calcify, which increases with age.

TSC is transmitted as an autosomal dominant trait, with variable expression. Recurrence in sibship of nonaffected parents has rarely been reported and is thought to be related to low expressivity or gonadal mosaicism. There is no clear evidence of nonpenetrance for TSC, so careful clinical and diagnostic evaluation of apparently unaffected parents is indicated before counseling the families. Between 50 and 75 per cent of all cases are sporadic. Linkage studies have allowed the identification of two loci for TSC, mapping to chromosome 9q34 {TSCl) and 16p 13.3 (TSC2).[51] About 50 per cent of the families are linked to TSCl.[52]

The TSCl gene consists of 23 exons and encodes for a predicted protein of 1164 amino acids called hamartin.[53] A mutation in this gene has been identified in about 80 per cent of the families linked to chromosome 9q34.[54] The identification of the gene mapping to 16pl3.3 has been facilitated by the identification of interstitial deletions in five unrelated TSC patients.[55] A gene (TSC2) was found to be disrupted by all the deletions and was demonstrated to harbor intragenic mutations in other nondeleted TSC patients.[55] Both germline and somatic mutations in the TSC2 genes have been demonstrated in tumors derived from patients with TS.

Epileptic seizures are frequent in TS, but it is not clear whether the epilepsy phenotype and long term seizure outcome of patients with TSCl and TSC2 are different. However, sporadic patients with TSCl mutations usually have a milder disease than patients with TSC2 mutations. They have a lower frequency of seizures and moderate to severe mental retardation, fewer subependymal nodules and cortical tubers, less severe kidney involvement, no retinal hamartomas, and less severe facial angiofibroma.[56] The seizures usually begin before the age of 15, with 70 per cent presenting before 2 years[49]

Infantile spasms are the most common manifestation of epilepsy in the first year of life, sometimes preceded by partial seizures.[57] In their study of 126 patients, Roger et al[58] found 63 (50 per cent) with infantile spasms and 63 (50 per cent) with other types of epilepsy (35 partial, 11 Lennox-Gastaut syndrome, 4 symptomatic generalized, 6 occasional seizures and 7 unclassifiable). Two thirds of those patients without infantile spasms had their first seizure before the age of 2 years, and a poor prognosis was strongly related to early onset. Almost all patients were cognitively impaired, and the course of epilepsy was severe in about one third. The number and size of tubers seems to be correlated with the severity of epilepsy and of mental disturbances.[59] In children with partial epilepsy or with infantile spasms, the largest tuber was found in the area corresponding to the main EEC focus.[60]

However, MRI may fail to show all the tubers in infants if myelina-tion is not complete.[50] Patients with TS must be carefully investigated in order to determine whether there is a single epileptogenic area in that its surgical removal can yield good control of seizures.[1, 61]

Gangliogliomas and dysembrioplastic neuroepithelial tumors (DNET)

These highly heterogeneous lesions are supratentorial tumours resembling gliomas, but characterized by a benign evolution and a distinct cortical topography. Ganglio gliomas are histologically characterized by a glioma com ponent intermixed with an atypical neuronal or ganglion cell component Atypical neuronal or ganglion cells are frequently binucleate. Cell proliferation studies show that the tumor growth rate is slow.[62] DNET are similar to gangliogliomas, but cytological atypia are rarer. The observation that dysplastic neurons are frequently adjacent to the neoplastic lesions[62, 63] has suggested a malde velopmental basis for the tumor origin. [63, 64]

In large series of patients with chronic drug-resistant epilepsy due to neoplastic lesions, gangliogliomas and DNET represent the majority (50-75 per cent) of histopathologically diagnosed lesions after surgery. [63, 65, 66, 67] Any lobe can he affected, but the temporal lobe is the most frequent for both gangliogliomas and DNET [63]

Neuroradiological studies typically show an hypodense lesion on CT scan, with possible associated hyperdense calcified lesions. The overlying skull can be deformed in superficially located lesions. [63] A cystic component is fre quently observed. MR1 scan hows an hypcrintense T1 lesion, with peripheral enhancement after gadolinium administration. Gray and white matter are both involved.[63] A well-demarcated, multilocular appear ance is typically seen.

The typical clinical presentation is with a drug-resistant partial epilepsy with onset before age 20.[63] In a population of 89 patients presenting with DNET, par tial seizures were the first clinical signs in 75 per cent of patients; only 9 per cent had neurological deficits con sisting of quadrantanopia[63] Epilepsy started at a mean age of 9 years (range 1-20 years) and proved resistant to different antiepileptic medications. Complete surgical removal of the lesion is associated to remission of epi lepsy in all patients.[63]

Malformations due to abnormal neuronal migration

Scattered and rare heterotopic neurons are occasionally found in subcortical white matter of normal subjects, but a density exceeding 8 neurons/2 mm is considered neu ronal heterotopia[68] and a density visible to the naked eye is considered gray matter heterotopia[69] Histologically, these neurons have a normal morphology but lack nor mal synaptic connections[70] The most common type of heterotopia is nodular heterotopia located in either a subependymal or subcortical location. Other minor forms of heterotopia include leptomeningeal neuronal heterotopia,[20] subpial neuronal heterotopia, and ectopic neurons scattered throughout the molecular layer. Gray matter heterotopia has the same signal characteristics as normal cortex on MRI and the same metabolic activity as normal gray matter on FDG-PET imaging[71] Gray matter heterotopia can occur diffusely or be localized. Diffuse involvement occurs as subcortical band (or laminar) het erotopia[72] and as bilateral periventricular nodular het erotopia. Localized forms can be unilateral or bilateral subependymal, unilateral subcortical (nodular, laminar), or may extend from the subependymal region to the sub cortex unilaterally.

Bilateral periventricular nodular heterotopia (BPNH)

BPNH consists of confluent and symmetric subependy mal nodules of gray matter located along the lateral ven tricles particularly along the ventricular body . The extent of the heterotopia and associated clin ical symptoms are heterogeneous. BPNH occurs much more frequently in females, as part of the syndrome of X-linked BPNH, which is associated with prenatal lethality in almost all males[73] and a 50 per cent recurrence risk in the female offspring of affected women. X-linked BPNH and BPNH occurring sporadically have been associated with mutations of the filamin A gene (FLNA).[74, 75] BPNH is an X-linked dominant disorder and heterozy gous females have epilepsy and coagulopathy. The dis ease has been mapped to Xq28 by linkage analysis, and mutations in FLNA have been demonstrated in both familial and sporadic patients with BPNH.[74, 76] Other unidentified genes may cause bilateral periventricular heterotopia in both sexes, with slightly different anatomic characteristics. FLNA promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins.

Approximately 88 per cent of patients with BPNH have epilepsy,88 which can begin at any age. Seizure intractability is common. Female patients with BPNH usually have nor mal to borderline intelligence and epilepsy of variable severity. The only two living male patients reported both have features similar to those described in females.[76] Several other syndromes characterized by BPNH and men tal retardation have also been described. These always occur sporadically and almost exclusively in boys.[77]

Classical lissencephaly and subcortical band heterotopia (the agyria-pachygyria-band spectrum)

Lissencephaly (smooth brain) is a severe abnormality of neuronal migration characterized by absent (agyria) or decreased (pachygyria) convolutions, producing a smooth cerebral surface.[78] Although there are several types of lissencephaly,[12] the most frequent and best-characterized forms are caused by mutations of the LIS1 gene[79] and of the XLIS (or OCX) gene.[80, 81]

Subcortical band heterotopia (SBH) is at the mild end of the agyria-pachygyria-band spectrum of malformations.[73] In SBH, the gyral pattern is usually simplified with broad convolutions and increased cortical thickness. Just beneath the cortical ribbon, a thin band of white matter separates the cortex from a heterotopic band of gray matter of variable thickness and extension .[82] In general, the thicker the heterotopic band, the higher the chances of finding a pachygyric cortical surface.[72] XLIS lissencephaly and SBH have been observed in different indi viduals within the same family.[83, 84]

Pathological studies of both lissencephaly and SBH demonstrate incomplete neuronal migration. In classical lissencephaly, the cere bral cortex is abnormally thick. The cytoarchitecture consists of four primitive layers including an outer marginal layer, a superficial cellular layer which corresponds to the true cortex, a variable cell sparse layer and a deep cellular layer composed of heterotopic neurons.89 As neuropathological studies were carried out before the distinction between LIS1 and XLIS lissencephaly was made, it is not known whether these two forms have distinctive histologic findings.

SBH con sists of symmetric and circumferential bands of gray mat ter, which may extend from the frontal to occipital regions but show regional predominance in many patients. The cortex overlying the bands appears either normal or pachygyria Pathologic study of the brains of three women with SBH[70] revealed that the cerebral cortex had normal cell density and laminar organization. Neurons in the het erotopic band were either arranged haphazardly or organ ized in a pattern suggestive of columnar organization. Several malformation syndromes associated with classical lissencephaly have been described. The best known of these is Miller-Dieker syndrome, which is caused by large deletions of LIS1 gene and contiguous genes.96 The most frequent form, X-linked dominant lissencephaly and SBH, is characterized by classical lissencephaly in hemizy-gous males and SBH in heterozygous females.

The DCX gene is located on chromosome Xq22.3-c</cite>24.[81, 85, 86] Mutations of the coding region of DCX were found in all reported pedigrees[84] and in 38-91 per cent of sporadic female patients.[87, 88, 89] Whereas all women with DCX mutations have anteriorly predominant band/ pachygyria, about one fourth of those with anterior band and all those with posteriorly predominant band or with unilateral band have not shown DCX mutations, suggesting that other loci or mosaicism may be responsible for these variable phenotypes.[89, 90] Maternal germline or mosaic DCX mutations may occur in about 10 per cent of cases of either SBH or XLIS[90] The rare cases of SBH reported in boys have been associated with missense mutations of DCX or LISI.[91]

The genetics and function of DCX are discussed extensively by Gleeson in a recent review.[82] LIS I (approved gene symbol PAFAH1B1) is the gene responsible for Miller-Dieker lissencephaly and maps to chromosome 17pl3.3.90 In addition, approximately 65 per cent of patients with classic lissencephaly who lack the facial changes of Miller-Dieker syndrome, isolated lissencephaly (ILS), show a mutation involving the LISI gene. Among all the patients with ILS, 40 per cent exhibit a deletion involving the entire gene,104 and 25 per cent show an intragenic mutation (4 per cent gross rearrangement, 17 per cent deletion/truncating mutations, 4 per cent missense mutations).[92] Patients with missense mutations generally have milder malformations than those with truncating/deletion mutations.[91, 93]

Classical lissencephaly appears to be quite rare, with a prevalence of 11.7 per million births (1 in 85470).[94] Affected children have early developmental delay and eventual profound mental retardation and spastic quad-riparesis. Some children with lissencephaly have lived more than 20 years, but life span is often much shorter.

Seizures occur in over 90 per cent of children, with onset before 6 months in about 75 per cent. About 80 per cent of children have infantile spasms, although the EEC may not show typical hypsarrhythmia. Most children subsequently have multiple seizure types including persisting spasms, focal motor and generalized tonic seizures,[21, 95, 96] complex partial seizures, atypical absences, atonic and myoclonic seizures.

In this severe malformation the physiological processes of postnatal cortical maturation are lacking as shown by the absence of any age- or localization-related changes in regional cerebral blood flow using SPECT.[97]The EEG in many children with lissencephaly demonstrates diffuse high-amplitude fast rhythms[98] and this pattern is considered to be highly specific for this malformation.[99]

The main clinical manifestations of SBH are mental retardation and epilepsy. Cognitive function ranges from normal to severe retardation and correlates with the width of the band and degree of pachygyria.[72] Epilepsy is common, although very early seizure onset is uncommon. About 85 per cent of patients have epilepsy[21, 72],[100, 101, 102, 103, 104] and 65 per cent have an intractable form. Among patients with epilepsy, about 50 per cent have partial epilepsy and 50 per cent have a generalized form, often Lennox-Gastaut syndrome. Those with more severe MRI abnormalities have significantly earlier seizure onset and are more likely to develop Lennox-Gastaut syndrome or other generalized symptomatic epilepsy. Using depth electrodes, Morrell et al.[103] demonstrated that epilepti form activity may originate directly from the heterotopic neurons, independently of the activity of the overlying cortex. Callosotomy has been associated with worthwhile improvement in drop attacks in a few patients.[101, 104] Autosomal recessive lissencephaly with cerebellar hypoplasia

Two recessive pedigrees, each with three affected sibs showing moderately severe pachygyria and severe cerebellar hypoplasia, have been associated with mutations of the reelin gene.[105] Affected children in one family had congenital lymphedema, hypotonia, severe developmental delay and generalized seizures that were controlled by drugs. Severe hypotonia, delay and seizures were reported also in the other pedigree.

Malformations due to abnormal cortical organisation

Aicardi syndrome

Aicardi syndrome[106, 107] has been reported only in females, except for two males who each had two X chromosomes.[108] There has been a report of two affected sisters.[109] It may be caused by an X-linked gene with lethality in the hemizygous male. Eye abnormalities and agenesis of the corpus callosum are frequently associated with translocations involving Xp22.3, suggesting a possible linkage of Aicanli syndrome to the short arm of chromosome X. The neuropathological findings include a thin unlayered cor tex, diffuse unlayered polymicrogyria with fused molec ular layers, and nodular heterotopias in the periventricular region and in the centrum semiovale.[110, 111] No laminar organization is recognizable in the cortex beyond the molecular layer, and neurons have a radial disposition. As a result of the fusion of the molecular layers, the microgyri are packed and not visible on MRI. Less frequent mal formations include agenesis of the anterior commissure, the fornix, or both, choroid plexus cysts, colobomata, and vertebral and costal abnormalities.

The clinical picture includes severe mental retardation, infantile spasms, chorioretinal lacunae and agenesis of the corpus callosum. There is often an early onset of infantile spasms and partial seizures. Spasms were the only seizure type in 47 per cent and were accompanied by partial seizures in 35 per cent of 184 patients.[112] The partial seizures involved mainly the eyes and face, and often began in the first days of life. Hypsarrhythmia is observed in only about 18 per cent of patients.[108] Interietal FFG abnormalities are typically asymmetric and asynchronous and may include suppression bursts during wakefulness and sleep. The seizures are almost always resistant to medication and the seizure types and EEG patterns change little over time. Life expectancy is shortened, with an estimated survival rate of 75 per cent at 6 years and 40 per cent at 15 years.[113]

Schizencephaly

Schizencephaly (cleft brain) consists of a unilateral or bilateral full-thickness cleft of the cerebral hemispheres with communication between the ventricle and extra-axial subarachnoid spaces . The walls of the clefts may be widely separated (open-lip schizencephaly) or closely adjacent (closed-lip schizencephaly). The clefts may be located in any region of the hemispheres, but are most often found in the perisylvian area.[114] Bilateral clefts are usually symmetric in location, but not necessarily in size. Septo-optic dysplasia (agenesis of the septum pellu-cidum and optic nerve hypoplasia) is seen in up to one third of patients.[115] Schizencephaly is a malformation that is difficult to classify. This disorder may be due to a regional absence of proliferation of neurons and glia or to defective cortical organization.[12] The cortex surrounding the deft consists of polymicrogyric convolutions with a stellate aspect.[116, 117] Yakovlev and Wadsworth[116] sug gested that the pathogenesis involved a local failure of induction of neuronal migration. In contrast, Barkovich and Kjos[114] considered that ischemic damage during early gestation could cause focal necrosis with destruction of the radial glial fibers and consequent abnormalities of neu ronal migration, such as unlayered polymicrogyria and gray matter heterotopia. However, recent reports from the same group indicate that familial occurrence [118] and a specific genetic origin due to germline mutations in the homeobox gene EMX2 (human), may be responsible in rare cases.[119, 120] Severe mutations were associated with severe bilateral schizencephaly, whereas missense mutations were associated with a milder cortical abnormality.[121]

The broad range of clinical findings mirrors the wide spectrum of anatomic abnormalities in schizencephaly. Unilateral clefts and closed-lip clefts are associated with a less severe clinical phenotype. Small, unilateral closed-lip clefts may be demonstrated on MRI scans performed after the onset of seizures in otherwise normal individuals.[114] Patients with bilateral clefts usually have microcephaly, severe developmental delay and spastic quadripare sis.[114, 122] . Partial seizures occur in 81 per cent of patients and usually begin before 3 years of age. The incidence of seizures is similar in those with unilateral and bilateral clefts but seizures are more often intractable when the malformation is bilateral.[122]

Polymicrogyria

Polymicrogyria is characterized by an excessive number of small and prominent convolutions spaced out by shallow and enlarged sulci, giving the cortical surface a lumpy aspect.89 Cortical infolding and secondary, irregular, thickening due to packing of microgyri are quite distinctive MRI characteristics of polymicrogyria .[12, 123] However, polymicrogyria may be diffi cult to recognize on MRI because the microconvolutions are often packed and merged.44 Two histologic types of polymicrogyria are recognized. In unlayered polymicro gyria, the external molecular layer is continuous and does not follow the profile of the convolutions, and the underlying neurons have radial distribution but no laminar organization.[117] These features suggest an early disruption of normal neuronal migration with subsequent disordered cortical organization. In contrast, four-layered polymicrogyria is believed to result from perfusion failure, occurring between weeks 20 and 24 of gestation, which leads to intracortical laminar necrosis with consequent late migration disorder and postmigratory disruption of cortical organization.[124] The two types of polymicrogyria may co-occur in contiguous cortical areas ,[125] indicating that they may comprise a single spectrum. The extent of polymicrogyria varies greatly and there is a broad range of clinical manifestations from severe encephalopathy with intractable epilepsy to individuals with only selective impairment of cognitive functions.[126] Several syndromes featuring bilateral polymicrogyria have been described, including bilateral perisylvian poly microgyria ,[127] bilateral parasagittal parietooccipital polymicrogyria ,[128] bilat eral frontal polymicrogyria [129] and unilat eral perisylvian or multilobar polymicrogyria .[130] These may represent distinct entities that reflect the influence of regionally expressed developmental genes. However, consistent familial recurrence has been reported only for BPP,[130] which is sporadic in the great majority of patients. Genetic factors may also play a role in the pathogenesis of unilateral polymicrogyria, at least in some cases.[131]

Bilateral perisylvian polymicrogyria (BPP)

This malformation involves the gray matter bordering the sylvian fissure bilaterally. Neuropathologic studies in four sporadic cases demonstrated four-layered polymicro gyria in three[127, 132] and unlayered polymicrogyria in one.[133] It is unclear whether these cases represent a spectrum of changes within a single malformation with the same etiology or different malformations with the same topography. Several families with multiple affected members have been reported, indicating genetic heterogeneity with possible autosomal recessive,[130] X-linked dominant[134] and X-linked recessive[135] inheritance. Recently a locus for X-linked BPP was mapped to Xq28.[136] Polymicrogyria, including BPP, has been reported in association with a deletion at 22ql 1.2,[137] although most patients with 22ql 1.2 deletion do not have any brain abnormality.[138] BPP has also been reported in children born from mono-chorionic biamniotic twin pregnancies which were complicated by twin-twin transfusion syndrome,[139, 140] indicating causal heterogeneity.

Key points

• Malformations of the cerebral cortex are the cause of some of the most severe forms of childhood epilepsy, but there is a broad range of seizure severity
• Early onset severe epilepsy in children with cortical dysplasia significantly reduces the potential for an independent adult life. Seizure improvement is possible, but long-lasting remission is exceptional
• MRI has demonstrated that brain malformations are common in children with epilepsy. However, MRI is often normal in patients with malformations and often tails to demonstrate the full extent of the abnormality
• Abnormally connected neurons in malformations have a high intrinsic epileptogenicity and some electrographic patterns are highly suggestive of an underlying area of cortical dysplasia
• Co-localization of the abnormality on neu-roimaging with epileptogenic EEG activity may help considerably in planning a surgical resec tion. Functional neuroimaging, particularly PET and ictal SPECT, may also help to establish the location of the epileptogenic dysplastic cortex

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     4C.Abnormalities of brain development RENZO GUERRINI AND LUCIO PARMEGGIANI

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