erative or encephaloclastic insults to the developing brain.389 Its many causes range from destructive injuries (usually due to white matter injury in prematurity) and developmental dysgenesis (as with lissencephaly and callosal agenesis). Clinically, it is often associated with seizures, spasticity, and mental retardation, but some children are neurodevelopmentally normal.389 Colpocephaly and associated callosal agenesis may accompany a variety of congenital optic disc anomalies, most notably optic nerve hypoplasia, the morning glory disc anomaly, and other optic disc dysplasias in children with transsphenoidal encephalocele and Aicardi syndrome.163 It has also been described with bilateral cortical visual loss and with congenital homonymous hemianopia.329

Malformations Due to Abnormal Stem Cell Proliferation or Apoptosis

Schizencephaly

Schizencephaly (sometimes termed agenetic porencephaly) refers to an abnormal gray matter-lined cleft that extends through the cerebral hemisphere, from the lateral ventricle to the cortical surface (Fig. 11.28).58 The gray matter lining the cleft is usually abnormal in the form of polymicrogyria (small, irregular gyri without intervening sulci). Unlike porencephaly, however, schizencephaly is believed to result from destruction of a portion of the germinal matrix before the hemispheres form.58 Schizencephaly occurs most commonly in the parasylvian region and in the precentral and postcentral gyri.21 Schizencephaly can be unilateral or bilateral, and open-lipped (the walls of the cleft do not appose each other) or closed-lipped (the walls of the cleft do not appose each other and are often fused).530 Pathological studies suggest that it results from a hemispheric injury early in the second trimester.54 Children with schizencephaly present with seizures, hemiparesis, and variable developmental delay, with the severity of disability related to the amount of

involved brain.21,47,55,362,604

Barkovich and Kjos55 reviewed neurodevelopmental records from 20 patients with schizencephaly and found bilaterality, large cleft size, and frontal lobe involvement to be associated with more severe intellectual and neurological deficits. As is the case with many malformations, schizencephaly seems to result from both genetic and acquired causes. For example, some cases may be familial363,384,746 and may be associated with mutations of the EMX2 homeobox gene, located on chromosome 10q26,139 which is expressed in the germinal matrix of the developing cerebral neocortex. Several attempts to verify EMX2 mutations in schizencephaly have heretofore been unsuccessful.591 Acquired causes include congenital CMV infection and in utero ischemic

insults that produce transmantle injury during the middle of the second trimester.47,530

Schizencephaly is of neuro-ophthalmologic interest primarily because of its strong association with septo-optic dysplasia.48,54,128,180,494 In some cases, this association may reflect a disruption of normal guidance mechanisms involved in the migration of both neurons and optic nerve axons in utero, preventing them from forming appropriate connections at their target sites. Alternatively, a prenatal hemispheric injury or malformation that directly involves the optic radiations can lead to transsynaptic degeneration and homonymous hemioptic hypoplasia. In some children, these two mechanisms may coexist.

Hemimegalencephaly

Hemimegalencephaly (also termed unilateral megalencephaly) is a rare brain malformation characterized by congenital hamartomatous overgrowth of one cerebral hemisphere, with increased white matter volume and dilation of the lateral ventricle on the affected side (Fig. 11.28).47,244 MR imaging and histopathological examination show a wide array of migration anomalies, including pachygyria, polymicrogyria, and cortical heterotopias in the enlarged hemisphere.47,244 Hemimegalencephaly may accompany a number of neurocutaneous disorders of neuro-ophthalmologic interest; however, its frequency in the linear sebaceous nevus syndrome is particularly high.374,780 In this context, it can be associated with a variety of optic disc anomalies, including peripapillary staphyloma,133,814 coloboma,185,254,615 optic nerve hypoplasia,457 pseudopapilledema,159 and peripapillary chorioretinal­ lacunae.615,683 In retrospect, many early descriptions of unilateral “cerebral atrophy” in linear sebaceous nevus syndrome undoubtedly represented hemimegalencephaly affecting the contralateral hemisphere.133 It has been occasionally reported in neurofibromatosis,218 Klippel– Trenauney–Weber syndrome,146 and hypomelanosis of Ito,530 and linear nevus sebaceous syndrome.133

The clinical picture is usually dominated by severe, drugresistant epilepsy. Clinical features include early-onset seizures, severe encephalopathy, hemiplegia, and hemianopia.133,530 Because the affected hemisphere has essentially no function, partial or complete hemispherectomy may be indicated in children with intractable seizures and a normal contralateral hemisphere.45 Despite its high complication rate and significant mortality risk, hemispherectomy or hemispherotomy is the most effective treatment to control seizures, and it also seems to provide good results on psychomotor development when performed early.770 Patients with hemimegalencephaly actually have bilateral cerebral hemispheric abnormalities and contralateral hemimicrencephaly, which is the likely explanation for the poorer seizure control and cognitive outcomes in this group following surgical hemispherectomy.244

Fig. 11.28  (a and b) Examples of abnormal stem cell proliferation. (a) Schizencephaly.Arrowsdenotegraymatterliningbilateralschizencephalic clefts; (b) hemimegalencephaly – note larger right hemisphere with ipsilateral ventriculomegaly. (c and d) Two often coexisting malformations

secondary to abnormal neuronal migration. (c) Lissencephaly. Note smooth, featureless cortex with thickened cortical mantle and no visible gyrations. (d) Pachygyria. Note areas of large, thickened poorly formed gyri (e) Isolated gray matter heterotopia (arrow)

Malformations Due to Abnormal

Neuronal Migration

Lissencephaly

The terms lissencephaly (smooth brain) or agyria–pachygyria, are applied to several disorders of neuronal migration that result in a smooth cortex with absent sulci (agyria) or in a paucity of broad cortical gyri (pachygyria) (Fig. 11.28).3,53 In this condition, the architecture of the cortical plate is severely disturbed because of altered or arrested neuronal migration during corticogenesis.5 Lissencephaly can result from many causes, including congenital infection, (especially cytomegalovirus), impaired stem cell formation, and abnormal neuronal migration.47

Pachygyria results when neuronal migration is disrupted at a later stage. Classical lissencephaly is characterized by a thickened cortex with reduced numbers of gyri and cortical neurons (Fig. 11.28). Microscopic examination shows a thick disorganized cortex that has four layers rather than the normal six layers.530 Lissencephaly is often accompanied by areas of pachygyria, and genetic studies have confirmed that these two malformations exist on a continuum of migratory derangements caused by gene mutations.660,661 Mutations in six genes (LIS1, DCX, TUBA1A, RELN, VLDLR, and ARX) have to date been associated with lissencephaly, with mutations in LIS1 by far the most common.369 An autosomal recessive form of lissencephaly with severe abnormalities of the cerebellum, hippocampus, and brainstem has been mapped to chromosome 7q22, with mutations mapped to the RELN gene, which acts on migrating cortical neurons.370,402 A syndrome of lissencephaly with agenesis of the corpus callosum and a rudimentary dysplastic cerebellum has also recently been described.370,755

Classical lissencephaly (previously known as type 1) and cobblestone lissencephaly (previously known as type II) constitute the two major subtypes. Because of its associated ocular malformations, cobblestone lissencephaly is of greater importance to ophthalmologists. The “cobblestone cortex” of lissencephaly is characterized by multiple coarse gyri with agyric regions, a disorganized cortex of variable thickness in both the cerebral hemispheres and the cerebellum, and deficient neuronal migration.204,265,377 Other associated features include enlarged lateral ventricles, a flat brainstem, and cerebellar hypoplasia. The term lissencephaly type 2 has previously been described to characterize the brain malformation associated with Walker–Warburg syndrome.256 However, on pathologic examination, the disorganized cortical layers clearly distinguish this malformation from classic four-layered lissencephaly.204 The neuropathologic distinction of the cobblestone cortex in Walker–Warburg syndrome and muscle–eye–brain disease is based mainly on the degree of severity although additional features such as occipital enceph-

alocele, fusion of the hemispheres, and absent corpus callosum may occur in some patients with Walker–Warburg syndrome.

Clinically, the cobblestone lissencephalies are characterized by hypotonia starting at birth, generalized muscle weakness, joint contractures, and associated CNS and ocular abnormalities. The three autosomal recessive disorders that share this combination of muscular dystrophy and brain malformations secondary to a neuronal migration defect are muscle–eye–brain disease, Walker–Warburg syndrome, and Fukuyama congenital muscular dystrophy. All muscle–eye– brain disease and Walker–Warburg syndrome patients present as retarded, floppy infants with suspected blindness and elevated creatine kinase values. Walker–Warburg syndrome usually causes death in infancy, while children with muscle– eye–brain disease may survive later into childhood. Ocular abnormalities are a consistent feature of Walker–Warburg syndrome and muscle–eye–brain disease. Although the phenotypic distinction between muscle–eye–brain disease and Walker–Warburg syndrome has remained controversial, these disorders are now considered to be distinct, both on clinical and genetic grounds.46,204,256,624,776,898

Walker–Warburg syndrome is an autosomal recessive disorder that is of neuro-ophthalmologic interest because of its association with hydrocephalus and optic disc anomalies and its overlap with hydrocephalus and septo-optic dysplasia. Diagnostic features consist of type II lissencephaly, cerebellar malformations, retinal abnormalities, and congenital muscular dystrophy.466 Other ocular findings include anterior chamber malformations (Peters anomaly), cataracts, persistent pupillary membrane, persistent fetal vasculature, retinal detachment, optic nerve hypoplasia, coloboma, and hypertelorism. Ophthalmologic abnormalities in Walker–Warburg syndrome have been congenital in origin and involve both the anterior and posterior segments. These include optic nerve coloboma, cataracts, microphthalmia, buphthalmos, persistent hyperplastic primary vitreous, Peters anomaly, retinal dysplasia with rosette formation, and retinal detachment.255,919,920,922 Affected infants may present with microphthalmos or buphthalmos (secondary to congenital glaucoma).

Histologically, Walker–Warburg syndrome is characterized by a chaotic and unlayered cortical architecture. Hydrocephalus is attributed to proliferation of glio-mesenchymal tissue in the leptomeninges and around the brainstem, such that the subarachnoid space is often totally obliterated. MR imaging shows a smooth cerebral surface and a cortex that is abnormally thick, with absent white matter interdigitations.255 The appearance of the cortex is also distinctive, with an irregular gray matter–white matter junction, possibly reflecting the extension of bundles of disorganized cortical neurons into the underlying white matter49 and producing the classic cobblestone appearance of the cortex.47 The cerebellum is hypoplastic and usually lacks a posterior vermis. However, the posterior fossa is not enlarged, which distinguishes