Neuronal migration

Disorders of neuronal migration can occur and can be genetically determined. Filamin 1 is a large actin-binding / cross linking protein whose gene is located on chromosome Xq28. It plays an important role in migration. Defects may be inherited or due to sporadic mutations, and lead to migrational defects in females, while affected males foetuses generally do not survive to term. Other factors such as integrins, Ra1A and presenilin 1 may be involved in the initiation of migration

(reviewed by (Gleeson and Walsh, 2000)). Insight into the mechanisms of migration between the ventricular zone and the cortical plate comes from two disorders where migration is arrested part way between source and target, Lissencephaly type I and band heterotopia (BH).

1.5.3.2.1 Lissencephaly

Lissencephaly can be caused by mutations in at least two genes. The LIS1 gene is located on chromosome 17p13.3 (Cardoso et al., 2002; Dobyns et al., 1991). Its autosomal mode of inheritance causes haplo-insufficiency in affected individuals and the Lissencephaly phenotype (severe mental retardation and intractable epilepsy), suggesting that two wild type copies of the gene are necessary for normal cortical development. LIS1 probably exercises its role in migration through interaction with the microtubule cytoskeleton (Morris et al., 1998).

In males, a second Lissencephaly locus on the X chromosome, termed DCX gene, leads to a phenotype that is similar to the one caused by the LIS1 mutation. Affected females, however, retain a working copy of the gene and have a band heterotopia together with a milder phenotype.

Lissencephaly type II (cobblestone Lissencephaly) in humans, the related Fukuyama disease (Kobayashi et al., 1998) and Walker-Warburg syndrome (Kanoff et al., 1998) all produce disruptions of the architecture of the developing cerebral wall and severe disorders of neuronal migration. The pial limiting membrane is defective, and neurons migrate out of the CNS and into the meninges [reviews by (Gleeson and Walsh, 2000; Golden, 2001)].

1.5.3.2.2 Subependymal nodular heterotopia (SEH)

Grey matter accumulation between the ependyma lining the lateral ventricles and the cortex is described as heterotopic, as compared to the normotopic overlying cortical grey matter. SEH are characterised by periventricular (subependymal) collections of neurons which form nodules.

The nodules measure typically 2-10mm in diameter (Eksioglu et al., 1996), but may merge to form an irregular band of overlapping nodules (Raymond et al., 1994b). They may be unilateral or bilateral, and in published series comprising 7

(Huttenlocher et al., 1994), 8 (Barkovich and Kjos, 1992a), 13 (Raymond et al., 1994b), 20 (Raymond et al., 1995) and 33 patients (Dubeau et al., 1995), respectively, they were seen bilaterally in 40-100%. While the whole length of the ventricles may be involved, the trigones and occipital horns are more commonly involved (Raymond et al., 1995). Frontal and temporal horns are less frequently involved, and the third and fourth ventricles are spared.

SEH are among the more common forms of MCD encountered in adult epilepsy patients, accounting for 20/100 patients with MCD in the National Hospital series (Raymond et al., 1995), but again the true prevalence is not known. SEH has occasionally been seen in people undergoing MRI as “healthy controls” (Raymond et al., 1995) (Dubeau et al., 1995). There is a female preponderance. The gene, FLN1 (named after its gene product, filamin), has been linked to Xq28, and affected hemizygous males in typical pedigrees do not appear to survive gestation.

SEH can be associated with other CNS malformations, for example Chiari Type II malformations or agenesis of the corpus callosum, and metabolic disorders such as Zellweger’s syndrome or neonatal adrenoleukodystrophy [reviewed by (Kuzniecky and Barkovich, 2001)]. In Dubeau's series of 33 patients with SEH, 13 also had sub- cortical nodular heterotopia (Dubeau et al., 1995), and this combination was present in 2 of 20 patients in Raymond's series as well (Raymond et al., 1995). These cases were mostly unilateral, and abnormalities of the overlying cortex were frequently seen. Hippocampal sclerosis is described in association with SEH (Dubeau et al., 1995; Raymond et al., 1994b).

The heterotopia are composed of islands of relatively mature cells which resemble cortical neurons rather than the neurons of deep grey nuclei, in keeping with their likely provenance. They contain multiple neuronal types but no dysplastic nerve cells, and calcifications are not seen. Synaptophysin immunohistochemistry has shown dense pre-synaptic terminals around the heterotopic cells (Eksioglu et al., 1996) but the origin of these afferents is not established. A study of nodular heterotopia in four children using dye tracing methods has shown limited connectivity of neurons between nodules (Hannan et al., 1999), for which there is indirect evidence through functional imaging studies that show task-induced activation in heterotopic gray matter (Pinard et al., 2000; Richardson et al., 1998a;

Spreer et al., 2001). The detailed autopsy study in children (Hannan et al., 1999) showed abnormal calretinin-positive neurons in the nodules and far less arborisation of dendritic trees. The interneurons in the nodules appeared generally immature.

Epilepsy is common (Raymond et al., 1995). As the onset of seizures is typically in the second decade of life, relatively later than in other forms of MCD, the prevalence of epilepsy may be underestimated in series including young patients. Learning difficulties may not be present in milder cases (Raymond et al., 1995) but become more likely with bilateral and more extensive SEH (Kuzniecky and Barkovich, 2001).

Focal, multifocal and generalized seizures can occur and at the severe end of the spectrum, infantile spasms and Lennox-Gastaut syndrome are seen (Golden, 2001). Epileptic phenomena are frequently discordant or contralateral to the side or location of the lesion (Raymond et al., 1995). There is direct evidence for epileptogenicity of heterotopic neuronal clusters (Francione et al., 1994; Kothare et al., 1998; Mattia et al., 1995; Palmini et al., 1995; Sisodiya et al., 1999a).

On MRI, the isolated or confluent nodules are seen as isointense to normotopic grey matter on all standard MR sequences but are most readily seen on T1 weighted images (Raymond et al., 1995). Coexisting hippocampal sclerosis (dual pathology) is relatively frequent (Cendes et al., 1995; Raymond et al., 1995).

1.5.3.2.3 Subcortical heterotopia (SCH)

SCH are characterised by collections of neurons in the hemispheric white matter. These are separated from both the ventricles and the cortex through white matter. SCH are rare, accounting for only 3/100 malformations in the National Hospital series (Raymond et al., 1995).

The nodules are of widely varying size, from less than 5mm to 20 or more mm in diameter. Abnormalities of the overlying cortex may be present [e.g. (Battaglia et al., 1996; Guerrini et al., 1996)]. Histology shows unlayered neurons which may look normal on inspection (Battaglia et al., 1996), but closer study suggests an imbalance between excitation and inhibition within the heterotopia (Hannan et al.,

1999). SCH are often sporadic, indicating that somatic rather than germ line mutations may be involved (Kuzniecky and Barkovich, 2001).

Epilepsy is common and usually develops early in life (Kuzniecky and Barkovich, 2001). Patients with small unilateral subcortical heterotopia may be neurologically normal (Barkovich and Kjos, 1992a), whereas patients with extensive unilateral heterotopia are likely to present with hemi-plegia. At the severe end of the spectrum, patients with bilateral, large or spatially extended lesions may present with moderate to severe developmental delay and neurological deficits (Kuzniecky and Barkovich, 2001). Heterotopic grey matter (Francione et al., 1994; Kothare et al., 1998; Sisodiya et al., 1999a) may be intrinsically epileptogenic.

On MRI, the subcortical nodules are seen as isointense to normotopic grey matter (Raymond et al., 1995). The overlying cortex may look normal but may also be thin with small gyri and shallow sulci. Coexisting abnormalities are frequent, Kuzniecky and Barkovich claim that an agenetic or hypogenetic corpus callosum is present in approximately 70% of affected brains (Kuzniecky and Barkovich, 2001), and other malformations, particularly SEH, are frequently seen (Cendes et al., 1995; Raymond et al., 1995).

1.5.3.2.3 Band Heterotopia (BH)

BH usually affects the fronto-central and/or parieto-occipital areas with sparing of the temporal, inferior frontal and cingulate/medial frontal cortices. They are rare in adult epilepsy patients, accounting for 8/100 patients with MCD in the National Hospital series (Raymond et al., 1995).

The bands are composed of differentiated, randomly orientated neurons of all types, accompanied by glial cells. In most cases, the overlying cortex shows the normal six-layered architecture, but layers V and VI may be poorly delineated and merge with the subcortical white matter and the lateral parts of the bands.

A developmental link between Lissencephaly and BH was reported in a study of two families. Females had BH and hemizygous male offspring had Lissencephaly (Pinard et al., 1994). Subsequently, mutations of the gene, named DCX after its gene product, doublecortin, or XLIS after the mode of transmission, have been identified

on the X chromosome (Des Portes et al., 1998). Mutations have also been seen in some sporadic cases where DCX mutations account for some 85% of cases, whereas mutations have been found in 11 of 11 pedigrees with X-linked transmission of laminar heterotopia [reviewed by (Ross and Walsh, 2001)]. Doublecortin is a microtubule-associated protein expressed by migrating neurons (Gleeson et al., 1999). While its precise function is unknown, it is thought to play a role in regulation of the microtubule cytoskeleton (Gleeson and Walsh, 2000).

Most if not all subjects with BH develop epilepsy within the first two decades. A variety of seizure types is seen, including infantile spasms, Lennox-Gastaut syndrome, or other forms of secondary generalized, focal or multifocal epilepsy. On MRI, the BH are usually bilateral and approximately symmetrical. As with the other heterotopia, they are isointense to normotopic grey matter on all sequences. Typically, the medial border of the lamina is smooth, whereas the lateral border follows the white matter into the crowns of the gyri. The cortex overlying the laminae may appear macrogyric. Patients with the DCX/XLIS mutation show an anterior>posterior gradient of severity which is in contrast to that seen in LIS1 patients.

1.5.3.3 Abnormal post-migrational cortical organisation