Epilepsy: A Comprehensive Textbook
2nd Edition
© 2008 Lippincott Williams & Wilkins
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Chapter 259
Malformations of Cortical Development
Ruben I. Kuzniecky
Graeme D. Jackson
Introduction
The development of the human brain is a long and complex process that begins with the induction of the neural plate from the undifferentiated surface ectoderm and continues after birth.115 Any disruption of the normal mechanisms responsible for the formation of the cerebral structures can result in malformations due to abnormal cortical development.81,85 A wide variety of genetic and environmental factors can cause disturbances in these developmental processes and can therefore lead to an abnormality in the mature brain.
Until the advent of high-resolution magnetic resonance (MR), malformative disorders of the nervous system were almost exclusively the domain of the pathologist. With magnetic resonance imaging (MRI), abnormalities of cortical development can be identified in life, and understanding these conditions, their clinical consequences, and outcome has become essential for appropriate management. The physician’s goal is to diagnose these disorders accurately, using information that is available in the clinical setting. This chapter presents an approach that we believe is helpful to clinicians dealing with these disorders, especially in the setting of epilepsy.
The clinical circumstances in which these disorders are encountered are many but primarily involve developmental delay, epilepsy, skin lesions in specific neurocutaneous disorders, and associated organ malformations. From the perspective of epilepsy, there are two common presentations. First, a patient with epilepsy has an abnormal MR brain scan suggesting a malformation of cortical development (MCD). In this case, the issue is largely one of diagnosis, appropriate classification, knowledge of the relevant condition, and genetic testing, if available. This is important for prognosis, treatment, and genetic counseling. Second, a patient with epilepsy has a “normal” brain MR scan, but the clinician suspects, perhaps on the basis of family history, seizure intractability, or other findings on clinical examination, that there may be an underlying abnormality of cortical development. In this case, one is usually dealing with a subtle, localized cortical malformation, and the challenge is to identify the abnormal brain region(s). This is not an uncommon problem for epilepsy centers that deal with surgical treatment.
Clinical Presentation
Disorders of cortical development encompass many types of malformations with a comparably wide range of etiologies that produce different effects depending on the stage of brain development that is affected. Not surprisingly, then, clinical presentations are quite heterogeneous and can manifest at almost any age. As a result, the practical problem is that because there are actually many disorders of cortical development, there are no specific clinical features associated with MCDs when considered as a group.
While MCDs are a common cause of epilepsy, there are many cases in which seizures are not a feature of these disorders. Why almost identical brain abnormalities can have such variable clinical phenotypes is not known. Yet while there are no clinical features that are specific for MCDs taken as a whole, there are within this group some specific syndromes recognized on the basis of characteristic patterns of genetic, clinical, and imaging findings.
Seizure type usually reflects the topology of the malformations. That is, focal seizures occur with focal or multifocal MCD, and secondarily generalized seizures with diffuse or bilateral MCDs.
Almost any epilepsy presentation, at almost any age, can be due to an MCD. However, in focal epilepsy, some features create a strong suspicion of an underlying MCD and encourage thorough investigation to exclude this possibility if no other cause has been identified. These features include developmental delay, static focal neurologic deficits, a family history of developmental delay or epilepsy, frequent seizures from onset, and focal status epilepticus. While the presence of such elements may raise the suspicion of an MCD, it must be emphasized that none of them is specific. In surgical series of patients, such characteristics will likely lead to detailed high-resolution MRI with special techniques in an effort to define an abnormality of cortical development.
The severity of seizures in patients with MCDs also varies greatly. There are many individuals with extensive cortical malformations who have no seizures. On the other hand, some individuals with apparently small developmental malformations have severe and intractable epilepsy. The mechanisms of epileptogenesis associated with these abnormalities are complex and generally poorly understood.
Epidemiology
Few studies have addressed the epidemiology of MCDs in detail, and little information can be obtained from studies using the modalities, including MRI, that are currently available. One series based on pathology findings revealed that 46.5% of patients had developmental malformations at autopsy.95 A case ascertainment study of lissencephaly showed a prevalence of 11.7 per million births.40 No data are available for heterotopia, focal cortical dysplasia, or other malformations of cortical development.
Recent clinical and neuroimaging studies in special populations have suggested that cortical malformations are much more common than was previously appreciated. In children referred to epilepsy centers for intractable seizures, more than half have some type of developmental abnormality, with focal cortical dysplasia discovered in approximately 25% of those with intractable focal seizures.79 The prevalence of these
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disorders in the adult population with intractable focal epilepsy is 15% to 20%.6,10
Terms and Definitions
A number of terms are commonly used in referring to patients with developmental malformations.10 For example, dysplasia in this context is an encompassing term that usually means abnormalities of the cortex that have a particular histopathology and are developmental in origin. Neuronal migration disorder is generally used in a similar context, but this is clearly incorrect as a general term, as it describes only one embryologic stage in cortical development. We consider all of these disorders to be malformations of cortical development and prefer this as the general term for referring to this category of conditions. All of these disorders seem to result from disturbed organogenesis (and, hence, are malformations), and all involve cells that under normal circumstances would participate in formation of the cerebral cortex. The most common malformative disorders involve abnormal stem cell formation in the germinative zone or abnormal cortical organization. Some result from faulty neuronal migration, whereas still others are postmigratory in origin.
We believe that establishing a single nomenclature and classification system for these disorders is essential to their understanding and management. The classification proposed in the following discussion provides a means by which similar disorders can be logically grouped together.10
Classification Principles
MCDs can be classified according to a number of different criteria emphasizing clinical phenotype, imaging findings, pathology, and genetic defects. The overall classification scheme that we favor (Table 1) is based on the three fundamental events of cortical formation: (a) proliferation of neurons and glia in the ventricular zone and subventricular zones; (b) multidirectional migration of immature but postmitotic neurons to the developing cerebral cortex; and (c) cortical organization, which consists of vertical and horizontal organization of neurons within the cortex and elaboration of axonal and dendritic ramifications. For those malformations with abnormalities involving more than one of these processes, classification is based on the first identified abnormal step. Diffuse and focal malformations that were classified separately in the past are no longer separated since genetic studies have shown that the same gene defects can cause focal or generalized MCDs.
Table 1 Classification Scheme of Malformations of Cortical Development
  1. Malformations due to abnormal neuronal and glial proliferation or apoptosis
    1. Decreased proliferation/increased apoptosis or increased proliferation/decreased apoptosis—abnormalities of brain size
      1. Microcephaly with normal to thin cortex
      2. Microlissencephaly (extreme microcephaly with thick cortex)
      3. Microcephaly with extensive polymicrogyria
      4. Macrocephalies
    2. Abnormal proliferation (abnormal cell types)
      1. Nonneoplastic
        1. Cortical hamartomas of tuberous sclerosis
        2. Cortical dysplasia with balloon cells
        3. Hemimegalencephaly
      2. Neoplastic (associated with disordered cortex)
        1. Dysembryoplastic neuroepithelial tumor
        2. Ganglioglioma
        3. Gangliocytoma
  2. Malformations due to abnormal neuronal migration
    1. Lissencephaly/subcortical band heterotopia spectrum
    2. Cobblestone complex/congenital muscular dystrophy syndromes
    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 or schizencephaly as part of multiple congenital anomaly/mental retardation syndromes
    2. Cortical dysplasia without balloon cells
    3. 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
Thus, with advances in molecular genetics, we have moved from a purely phenotypic approach to a combined phenotypic/genetic classification. The basis of this change has been the recognition that malformations of varying severity can result from the same underlying processes, specifically from mutations of the same causative genes. This was shown first for classical lissencephaly38,93,94,111,112,113,114,123 and more recently in the brain malformations associated with congenital muscular dystrophies.15,16,17,88,89,108,132,133,134 For example, patients with large deletions and truncations of the LIS1 and DCX mutations have diffuse or severe lissencephaly, while those with less severe LIS1 mutations may only have posterior pachygyria or posterior-predominant subcortical band heterotopia. Those with less severe DCX mutations have anterior pachygyria or frontal subcortical band heterotopia of variable thickness,27,49,50,51,87,92,111,114,123 or they may even have normal brain MRI scans.57 Further support for this approach has been the recent discovery of mutations of multiple genes each causing very similar clinical syndromes, and the finding that mutations of different genes can cause the phenotype of Walker-Warburg syndrome or muscle-eye-brain disease.123
Developmental Malformations Associated with Epilepsy: Specific Disorders
We have restricted the following discussion to an overview of the most common and relatively distinct entities that affect patients with epilepsy.
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Focal Cortical Dysplasia
Focal cortical dysplasia (FCD) is probably the most common form of focal developmental disorder diagnosed in patients with intractable focal epilepsy.24,67,83,86,100 The lesions consist of disruption of cortical lamination with poorly differentiated glial cell elements. Since its original description, FCD has been recognized to encompass a spectrum of changes.130 These range from mild cortical disruption without apparent giant neurons to the most severe forms in which cortical dyslamination, large bizarre cells, and astrocytosis are present.75,79,130 It is the presence of balloon cells that differentiates FCD type I (without balloon cells) from FCD type II (with balloon cells) and that lead to the distinction in our classification scheme (see Table 1).
FIGURE 1. Focal cortical dysplasia (FCD). Left frontal lobe shows in this coronal fluid-attenuated inversion recovery magnetic resonance image a subtle signal abnormality and thickened cortex representing FCD. Pathology showed balloon cells.
FIGURE 2. Hemimegalencephaly. Axial T2-weighted magnetic resonance image shows abnormal left hemisphere with smooth cortex and white matter changes.
The clinical manifestations of patients with cortical FCD are variable. Seizures usually begin between the ages of 2 and 10 years. Sometimes, however, seizures may be the presenting clinical problem in the second decade or even later. Focal and secondarily generalized attacks are common. Interestingly, seizures often occur in clusters, but generalized status epilepticus is rare except in patients with FCD involving the central region.76 In our experience, the majority of patients have extratemporal cortical dysplasias that affect the pre- and postcentral regions most often. Interictal scalp electroencephalography (EEG) may demonstrate focal subclinical ictal discharges over the dysplastic lesions, underscoring the high epileptogenicity of these lesions.103 FCD involving the frontal lobe has also been reported, and lesions can occur in both mesial and lateral neocortical structures as well.77
The MRI findings consist of abnormal gyral thickening with underlying T2-weighted white matter changes. These abnormalities are often circumscribed in nature, and they can sometimes be extensive, involving more than one gyrus or lobe. High-resolution MRIs with thin slices and multiplanar reconstruction are often necessary to identify these24,25,55 (Fig. 1). Location can be quite unpredictable, as in the example of a very small lesion that was restricted to the bottom of a sulcus. Correlating clinical manifestations with the spectrum of changes seen in FCD has been limited, because histopathology is usually required before subtypes of FCD (e.g., FCD without balloon cells and microdysgenesis) can be firmly established.10
Hemimegalencephaly
Hemimegalencephaly is a rare malformation characterized by predominantly unilateral cerebral pathology typically associated with an enlarged hemisphere. It can be seen in isolation or in association with epidermal nevus syndrome105 or hypomelanosis of Ito.91,104,128 Pathologic findings are diverse and include cortical dysplasia, white matter abnormalities with abnormal cell types, or polymicrogyria usually restricted to one hemisphere. Most children with hemimegalencephaly associated with cortical malformations have not had other associated congenital anomalies.
Seizures and hemiparesis are common presenting symptoms.101,107,118 Developmental delay is also common. Seizures usually appear within the first 6 months of life. They are often unilateral but can secondarily generalize, and they are frequently intractable to medical therapy. Continuing seizure activity is associated with the appearance or worsening of unilateral neurologic findings, such as hemiparesis and hemianopias. Occasionally there is only minimal neurologic dysfunction.
Diagnosis is based on the predominantly focal epileptic syndrome, the unilateral hemispheric EEG discharges, and the presence of unilateral neurologic abnormalities. MRI findings provide definitive diagnosis. Mild to severe enlargement of at least one lobe is present in all patients (Fig. 2). In more than half of the patients, the entire hemisphere is enlarged with thick gray
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matter and broad, flat gyri.23,83,136 The underlying hemispheric white matter usually demonstrates abnormal MRI signal intensity. Heterotopia and other malformations are sometimes detected throughout the abnormal hemisphere, and there may be ipsilateral ventricular enlargement.
Focal Transmantle Dysplasia
Transmantle dysplasia is a developmental malformation characterized by abnormal brain tissue that extends through the entire mantle of the cerebrum, from the pia to the ventricular surface.12 On MRI brain scans, areas of signal abnormality extend radially inward from the cortical surface toward the lateral ventricle. When the imaging plane is parallel to the tract, the T2 imaging signal abnormality involves the deep cortex and subcortical white matter.
Patients with this malformation present with focal seizures at different ages. Ictal semiology and neurologic deficits resemble those that accompany FCD. EEG abnormalities are usually lateralized to the areas of cortical malformations. Mild motor signs may be present if the lesions are in close proximity to the central cortical area. This malformation likely represents a subtype of FCD as pathology obtained during resections for epilepsy show a lack of normal cortical lamination, neuronomegaly, and hypomyelination with atypical reactive astrocytosis in the white matter.
Tuberous Sclerosis
Tuberous sclerosis (TS) is an autosomal dominant, genetically determined multisystem disorder with high penetrance and variable expression.35,36,37,71 Genetic heterogeneity is observed with gene defects reported in both chromosome 9q34 and chromosome 16p13 with genetic classification into TSC1 and TSC2.
Pathologically, TS is a disorder of cellular migration, proliferation, and differentiation, resulting in hamartomata formation that involves a large number of neural crest derivatives. Histologically, two major abnormalities are seen. Cortical tubers are characterized by cortical dyslamination, large cells (neurons and glial cells or neuroastrocytes), and abnormal neuropil with hypomyelination. Subcortically, subependymal nodules projecting into the ventricles are typical. Microscopically, densely aggregated larger cells are present, often resembling neoplasms. Electron microscopic (EM) studies of cortical tubers have demonstrated that glial cells predominate near the pial surface, whereas small neurons are more prevalent inferiorly. Underneath the tubers, a rudimentary cortical plate is seen. The presence of the most undifferentiated cell types in the subependymal zone (giant cells) and more differentiated cells in the cortical tubers with intermediate lesions between them suggest a spectrum of abnormalities in neural and glial differentiation and migration.
Seizures are the most common neurologic symptom in TS: More than 90% of patients have seizures during their lifetimes.71,120,142 Infantile spasms and partial seizures are highly prevalent, and secondary generalization occurs more often after age 2 years. Myoclonic seizures and mental retardation are very frequent. Over time, clinical deterioration is common, with seizures becoming more frequent and difficult to treat.
FIGURE 3. Tuberous sclerosis complex. Coronal fluid-attenuated inversion recovery magnetic resonance image shows multiple hamartomas and a large subependymal nodule.
MRI scans often demonstrate subependymal nodules with varying degrees of contrast enhancement. Calcifications are frequent and are best demonstrated using gradient-echo sequences. Cortical tubers, ranging in size from 1 to 2 cm, are located at the gray–white matter interface. The parietal and frontal lobes are affected most often (Fig. 3). Tubers are isointense on T1 images but hyperintense using T2 sequences. Gyral core tubers may resemble an empty gyrus due to hypointensity of the white matter.3,48,129
The location of certain size tubers appears to correlate with EEG epileptogenic foci and prognosis. Patients with posteriorly located lesions have early onset of seizures as opposed to those with frontal lesions.31 The presence of multiple and large cortical tubers, early onset of multiple seizure types, and multifocal EEG abnormalities correlate with unfavorable prognosis.
Lissencephalies
Lissencephaly refers to brains without normal sulcation (i.e., smooth brains).43,72 The lissencephalies are a group of different disorders with distinct pathologic substrates and multiple causes. The major distinction is between classical lissencephaly and cobblestone lissencephaly, terms that reflect the appearance of the brain and that, in turn, derive from different genes. The various types of lissencephaly are classified according to the gene defect and associated malformations. For example, instead of classifying LIS1 mutations and DCX mutations as subcategories of the isolated lissencephaly sequence, the classification includes Miller-Dieker syndrome, isolated lissencephaly syndrome, and subcortical band heterotopia as subcategories under LIS1 mutations.10 Instead of listing POMT1 mutations and FKRP mutations under Walker-Warburg syndrome, the classification lists muscle-eye-brain disease and Walker-Warburg syndrome under FKRP mutations. As a result of this reclassification, many syndromes are listed more than once. For example, isolated lissencephaly sequence and band heterotopia are listed under both LIS1 and DCX mutations and Walker-Warburg syndrome is listed under POMT, FKRP, and FCMD mutations.
Classical Lissencephaly
Classical lissencephaly or generalized agyria-pachygyria is a severe brain malformation manifested by a smooth cerebral surface, abnormally thick cortex with four abnormal layers,
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diffuse neuronal heterotopia, enlarged ventricles, and often hypoplasia of the corpus callosum. Mutations in the LIS1 gene result in Miller-Dieker syndrome (MDS), isolated lissencephaly sequence (ILS), and subcortical band heterotopia (SBH). Similar phenotypes also occur with DCX mutations, although in patients with DCX mutations, the frontal lobes are most affected; whereas in patients with LIS1 mutations, the posterior areas are more involved. Mutations of the ARX gene cause X-linked lissencephaly with ambiguous genitalia and anomalies of the corpus callosum.65,69,70,127
FIGURE 4. Lissencephaly. Miller-Dieker syndrome. LIS1 mutation. Axial T2-weighted image shows smooth cortex.
FIGURE 5. Subcortical band heterotopia (SBH). Coronal T1-weighted image shows typical subcortical band of gray matter with relative normal cortical infolding; DCX mutation.
Children with classical lissencephaly present with feeding difficulties or hypotonia. By 6 months of life, most of these children will have seizures, and the evolution of the epilepsy is similar in all patients. Infantile spasms with hypsarrhythmia and typical paroxysmal fast activity on the EEG appear in the first year of life. Response to treatment with adrenocorticotropic hormone (ACTH) or other anticonvulsants is variable, but most children will continue to have frequent seizures accompanied by severe developmental delay. Typical seizure types also include myoclonic, tonic, and tonic–clonic seizures. Profound mental retardation and spastic quadriplegia are present.
Diagnosis of classic lissencephaly is based on the typical clinical, EEG, and MRI features. MRI demonstrates a thickened cortex, loss of white matter, and vertical sylvian fissures, which result in the typical 8-shaped appearance of the brain (Fig. 4). Cortical thickness is in the range of 11 to 20 mm compared to 3.5 mm in normal controls.11 In some patients there are regions of pachygyric cortex. Barkovich et al.11 have also reported the presence of incomplete inversion of the hippocampi, a marker of arrest of neuronal migration.
Band Heterotopia (Double Cortex)
Subcortical band heterotopia or “double cortex syndrome” (Fig. 5) consists of symmetric and circumferential bands of gray matter located just beneath the cortex and separated from it by a thin band of white matter. The inner margin of the band is usually smooth, while the outer margin may be smooth or follow the interdigitations of the true cortex and white matter. Pathologic specimens have demonstrated normal lamination in cortical layers one through four; layers five and six usually cannot be seen; and layer six is merged with the U-fibers of the white matter.90 Underneath, clusters of ganglion cells are present. Cortical thickness overlying the heterotopia is mildly increased or normal, and the temporal lobes, in particular the hippocampal structures, are normal as opposed to lissencephaly.
Band heterotopia is an X-linked recessive trait, and thus it is usually found only in females, although a few affected males have survived.112 The risk for carrier females is high: 50% of their sons will have lissencephaly, and 50% of their daughters will have band heterotopia. Patients have mild to moderate developmental delay, upper motor neuron signs, and, in some, dysarthria. Full-scale IQs ranging from severely low to normal have been reported.5 EEG investigations usually demonstrate frequent bilateral focal and multifocal spikes, although generalized discharges are also seen, including slow spike-wave patterns.
MRI findings are fairly stereotyped and demonstrate a circumferential band of subcortical gray matter heterotopia underlying the cortical mantle and separated from it by a thin rim of white matter. This is usually more obvious over the frontocentral parietal region. Barkovich et al. have suggested that the thickness of the heterotopic gray matter correlates with severity of the clinical syndrome.5,66,90
Cobblestone Lissencephaly Complex
Cobblestone lissencephaly, so called because of the pebbled appearance of the cortical surface due to leptomeningeal neuronal and glial heterotopia, is less common than classical
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lissencephaly. It is a complex brain malformation that consists of cobblestone cortex, polymicrogyria, pachymicrogyria, abnormal white matter, enlarged ventricles, small brainstem, and cerebellar vermian atrophy with cerebellar polymicrogyria.43 It is often associated with eye malformations and congenital muscular dystrophy.
FIGURE 6. Cobblestone lissencephaly in Fukuyama congenital muscular dystrophy with FKTN mutation. Note white matter changes, smooth cortex, and cerebellar cyst.
Syndromes associated with cobblestone lissencephaly include Fukuyama congenital muscular dystrophy (FCMD) (Fig. 6), muscle-eye-brain disease (MEB), and Walker- Warburg syndrome (WWS). The classification of cobblestone lissencephalies changed significantly when it was discovered that congenital muscular dystrophies result from abnormalities of protein glycosylation.2,22,143 Mutations in any of the genes involved can cause several different clinical syndromes. For example, Fukutin-related protein (FKRP) mutations can cause the clinical phenotypes of limb-girdle muscular dystrophy, muscle-eye-brain disease, and Walker-Warburg syndrome.15 Fukuyama (FCMD) mutations can cause Walker-Warburg syndrome in addition to FCMD and MEB (Fukuyama CMD plus retinal abnormality) phenotypes.14,124 Thus, the clinical phenotype may be related more to the severity of the mutation than to the precise gene.
Most children with cobblestone lissencephaly have severe mental retardation and hypotonia, mild distal spasticity, and often poor vision. Most patients do not survive beyond the first decade. Seizures have not been well studied.
Heterotopia
Heterotopia is, by definition, the presence of normal cells in improper locations.8,47 In cases of epilepsy associated with MCDs, this definition usually refers to neurons within the periventricular or subcortical white matter. At the present time, there are two major groups of heterotopia that are recognized as syndromes: Periventricular nodular heterotopia (PNH) and focal subcortical heterotopia.
Periventricular Nodular Heterotopia
Periventricular nodular heterotopia, or subependymal nodular heterotopia, is the most common form of developmental disorder seen in patients with epilepsy.8,21,44,58,68 The condition is caused by the failure of a group of neurons to either initiate or complete the migration process toward the cortical mantle. PNH can range from a few nodular clusters of neurons to diffuse lining of the ependymal regions. Bilateral periventricular nodular heterotopias (BPNHs) are usually contiguous and symmetric but occasionally are isolated and asymmetric. Ninety percent of reported patients with PNH had diffuse, narrow involvement of all subventricular regions.44,63,84
Patients with PNH usually have normal neurologic development. A few have had symptoms that were probably overlooked, such as headaches or psychiatric complaints, while other persons discovered during family evaluations have been asymptomatic. The majority of patients have normal intellectual and motor function or mild mental retardation. Seizures are common, and epilepsy occurs in almost 80% of cases. Interestingly, seizures usually begin in adolescence. In patients with seizures, temporal and parieto-occipital symptomatology is common. EEG findings are generally nonspecific, and interictal discharges are infrequent.57
Typical MRI features consist of multiple smooth ovoid nodules of cortical gray matter lining the lateral ventricles but sparing the third and fourth ventricles (Fig. 7). Approximately 75% of patients have bilateral lesions, and 30% have additional focal subcortical heterotopia. Callosal and cerebellar malformations are present in 25% of cases. Signal intensity from the nodules is isointense with gray matter in all MRI sequences, and the nodules do not enhance with contrast, distinguishing features from subependymal hamartomas seen in tuberous sclerosis. In 20% of patients, other cortical malformations may be detected.
Classic PNH can be associated with FILA (Filamin) mutation on chromosome Xq28.46 Because it is an X-linked mutation, men are only rarely affected.45,57,59,97 Most pregnancies carrying male fetuses terminate in spontaneous abortions.
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FIGURE 7. Periventricular nodular heterotopia due to Filamin 1 mutation. Note periventricular gray matter nodules.
Focal Subcortical Heterotopia
Although the majority of patients with subependymal heterotopia have diffuse nodular lesions, occasionally patients may present with few focal lesions involving one hemisphere. According to reviews,13,45,83 the frequency of focal subcortical heterotopia is <20%. In a patient without neurologic symptoms, such lesions may be just coincidental findings, but the true incidence of seizures in these patients is unknown. Most patients have been sporadic occurrences, and subcortical heterotopias are probably secondary to mosaic mutations or to true environmental injuries.
Clinically, patients may present with normal development, but at times, depending on the size of the lesions, contralateral pyramidal signs may be present. Approximately 50% of patients with focal subcortical heterotopia are developmentally and cognitively delayed. Developmental delay is more common among patients who have concomitant callosal agenesis. Speech appears to be normal in some patients, but when lesions are extensive and involve the dominant hemisphere, speech delay is observed. Seizures in these patients are a mixture of focal motor and secondary generalized convulsions. Infantile spasms have also been described. The ultimate neurologic and seizure outcome not only depends on the type, location, and size of lesions, but also on the type of developmental disorder.
Imaging features in these patients are quite characteristic. Heterotopia appears as clusters of nodules of gray matter with irregular margins (Fig. 8). The surrounding white matter is usually normal and has normal-intensity signal. At times, the heterotopia may appear as masses with ventricular compression. On some occasions, cerebrospinal fluid (CSF) signal may be seen within these malformations. Corpus callosum abnormalities have also been reported.
Polymicrogyria
Polymicrogyria (PMG) refers to an abnormal macroscopic appearance of brain gyration that is characterized by excessive numbers of small gyri. In some cases, the gyri are shallow and very small, separated by slight sulci, whereas in other cases the gyri are wider.1,86,108
FIGURE 8. Subcortical nodular heterotopia. Axial T1-weighted magnetic resonance image shows large subcortical mass of gray matter in the mesial frontal lobe associated with partial agenesis of corpus callosum and ventricular changes.
The histologic changes in polymicrogyria are midcortical laminar necrosis in layer five resembling ischemic change. Superficial to this cortical band, the cortex consists of normal layers four, three, and two. Because late-migrating neurons reach their normal positions before laminar necrosis takes place, this type of malformation most likely originates in some cases after the 20th fetal week and is thus postmigratory in origin.
Histologic classification divides polymicrogyria into four-layered and unlayered types. Although most of the experimental data and pathologic findings in human fetuses suggest that polymicrogyria is the result of a postmigratory ischemic mechanism, this has been disputed and some investigators1,99 have postulated that at least some forms of PMG are premigratory in origin. In fact, the best known cause in humans is intrauterine cytomegalovirus (CMV) infection, which is also usually associated with diffuse or patchy white matter changes and often diffuse or multifocal calcifications.
Several new unilateral and bilateral polymicrogyria syndromes have recently been described, and several others have had the causative genes mapped or identified. Reports of bilateral perisylvian polymicrogyria had commented on a significant male preponderance.96 This was subsequently confirmed in a large series that localized a gene to Xq28.135 Unilateral and bilateral perisylvian polymicrogyria has been observed in several chromosomal aneuploidy syndromes, most prominently with deletion of the chromosome 22q11.2 DiGeorge syndrome critical region,18,19 and in families with presumed X-linked inheritance.20 Additional bilateral polymicrogyria syndromes include bilateral frontal polymicrogyria,60 bilateral parasagittal parieto-occipital polymicrogyria,61 bilateral lateral parietal polymicrogyria,7
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bilaterally generalized polymicrogyria,30 and two distinct malformations with periventricular nodular heterotopia and overlying polymicrogyria, one with frontal-perisylvian predominance and another with posterior-temporal predominance. A recent report described a malformation designated bilateral frontoparietal polymicrogyria associated with abnormalities of myelination and dysplasia of the cerebellum and brainstem.29 This has been mapped to chromosome 16q12.2-21 and subsequently associated with mutations of the GPR56 gene.109
FIGURE 9. A: Unilateral polymicrogyria (PMG). Note extensive atrophy and PMG cortex in the left hemisphere. B: Bifrontal PMG syndrome with GPR56 mutation. Note PMG and abnormal white matter changes.
FIGURE 10. Polymicrogyria (PMG), bilateral perisylvian syndrome. Coronal T1- weighted magnetic resonance image shows bilateral perisylvian PMG.
The clinical presentation depends on the location and extent of polymicrogyria, and whether the contralateral hemisphere is involved. It is thus highly variable. Diffuse polymicrogyria may present with severe developmental delay, microcephaly, and hypotonia. Polymicrogyria can be limited to one hemisphere (unilateral hemispheric polymicrogyria) (Fig 9); it can also be one of the pathologic changes associated with hemimegalencephaly.
MRI findings demonstrate a seemingly thick cortex that can be interpreted as pachygyria. However, cortical thickness in polymicrogyria is less than that observed in pachygyria. The sulci are shallow, and the underlying white matter may show abnormal T2 signal. (Figs. 9 and 10).
As indicated by the foregoing descriptions, PMG syndromes have been classified by the anatomic distribution of the abnormal gyri. Some syndromes can also now be identified on the basis of clinical and imaging features. The most common of these is bilateral perisylvian polymicrogyria, also known as congenital bilateral perisylvian syndrome (CBPS).52,56,73,74,98 Clinical features include congenital pseudobulbar paresis, intellectual delay, and characteristic bilateral lesions on computed tomography (CT) or MRI. Almost 90% of patients present with seizures, and half of them have intractable epilepsy. A unique seizure pattern consists of perioral and bilateral facial involvement. Other seizure types include atypical absences attacks, tonic/atonic seizures, and generalized tonic–clonic seizures. EEG findings include generalized spike-wave or multifocal abnormalities, but 20% have had localized epileptogenic discharges. The diagnosis can be made on the basis of the clinical features; brain MRI provides confirmation.74 The imaging findings are distinctive with involvement of the sylvian,
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opercular, and perisylvian regions (Fig. 10). Except for unilateral hemispheric polymicrogyria, the other bilateral polymic-rogyria syndromes do not have characteristic clinical or EEG features.
Schizencephaly
Although schizencephaly has been considered a condition different from polymicrogyria, most authorities today classify them as polymicrogyria/schizencephaly complex. The term schizencephaly is used to describe clefts in the cerebral hemispheres that are lined with gray matter and extend from the pia to the ependymal lining.42,54,64 The clefts may be in apposition to each other (closed lip or type I schizencephaly) or separated (open lip or type II schizencephaly).126 The cortex surrounding the clefts can be normal or have underlying polymicrogyria. The gray matter lining the cleft itself is usually composed of polymicrogyric cortex. Subependymal heterotopias are common. The pathogenesis of schizencephaly is probably similar to that of polymicrogyria and porencephaly. It is, rather, the extent of cortical injury that determines if a lesion becomes polymicrogyria or schizencephaly. Injuries that extend more deeply into the cortex and destroy the superficial portions of the glial fibers produce cortical infoldings lined by polymicrogyria. When the injury involves the entire thickness of the developing hemisphere, schizencephaly results. The septum pellucidum is absent in 70% to 90% of patients.9,117
Schizencephaly has many features resembling those of polymicrogyria. As with polymicrogyria, schizencephaly can be bilateral or unilateral. Furthermore, bilateral lesions can be either symmetric or asymmetric. In our experience, approximately 30% to 40% of patients with schizencephaly have bilateral lesions. They are often asymmetric, however, with type I schizencephalic lesions in one hemisphere and type II lesions in the opposite hemisphere (Fig 11).
Patients with bilateral schizencephaly often have a moderate to severe spastic quadriparesis. Severe mental retardation and language disorders are also common. Infantile spasms may be the presenting seizure type in these patients, and focal motor seizures with and without secondary generalization are common. A minority of patients with bilateral lesions are controlled on drugs.
Unilateral schizencephalies are evenly distributed between the two hemispheres. The frequency of type I versus type II lesions is similar. Developmental delay, intellectual impairment, and hemiparesis contralateral to the cleft are common findings. We have not observed any significant differences in language dysfunction between left and right dominance in persons with schizencephaly, probably because these patients most likely transfer language to the more normal hemisphere. Seizures are usually focal motor, but sensory and complex partial seizures also occur. EEG investigations may reveal focal temporal discharges when the lesions are localized to the temporal-parietal convexity. However, EEG spikes may occur beyond the area of malformation, including the opposite hemisphere (see below). The location of lesions by MRI appears to be evenly distributed, with the majority located in pre- and postcentral regions.
An interesting issue concerning patients with unilateral polymicrogyria or schizencephaly is the presence of subtle cortical developmental malformations of the opposite hemisphere. The contralateral lesions are usually present in the mirror regions of the opposite hemisphere. This may explain why some patients with unilateral lesions may present with severe developmental delay. These findings underscore the possible pathogenic mechanism for cortical dysplasia, polymicrogyria, and schizencephaly.
Management of Patients with Malformations of Cortical Development
The first step is to make a correct diagnosis of the specific MCD. This is important for several reasons. First, accurate identification of the underlying MCD permits proper genetic counseling. Second, a syndromic classification assists in making rational decisions about the medical and surgical treatment for seizures. The best example of such a case is the congenital bilateral perisylvian syndrome. Third, proper diagnosis may permit assessment of ultimate prognosis. In the following section we will discuss management issues pertaining to specific problems and conditions.
Infantile Spasms and Malformations of Cortical Development
MCD is recognized with increasing frequency in children with infantile spasms (ISs) because high-resolution imaging has permitted improvement in the detection of MCDs. In fact, MCDs are the most frequent cause of ISs. However, the ultimate prognosis for these children is variable and more likely to be associated with the extent and type of underlying MCD (see Chapter 229, West Syndrome).
A number of observations have modified the treatment options in patients with ISs and MCDs.36 It is likely that corticosteroids may be the treatment of choice in patients with focal developmental lesions and ISs associated with hypsarrhythmia. In contrast, open studies have shown that vigabatrin (VGB) is effective in patients with diffuse malformations such as TS. VGB in combination with carbamazepine or benzodiazepines is effective in TS. The response to drug treatment in patients with ISs and diffuse malformations such as lissencephaly is poor.
Surgical treatment of patients with ISs and MCDs is dependent on the underlying condition. The presence of a tumor or porencephalic cyst is usually associated with good results.4,138 Large multifocal resections have provided improvement in a number of children with ISs and focal features.32,33 Modified hemispherectomy is also effective in patients with ISs and hemimegalencephaly.39,106 Callosal sections performed in some children with diffuse MCDs and ISs have given disappointing results.140
Other Seizure Types
Apart from the clear difference in response of TS patients with ISs to VGB treatment, there have been no randomized drug trials to prove that any particular drug regimen is superior in treating patients with MCDs.
The response to antiepileptic drugs (AEDs) is generally dismal in diffuse malformations such as Aicardi syndrome; it is more variable among patients with lissencephaly. Among patients with bilateral lesions or focal malformations, about 35% respond to AEDs.125 It is estimated that the response rate to AEDs is approximately 35%. Valproic acid and other broad-spectrum drugs are generally chosen in patients with diffuse malformations.
FIGURE 11. Schizencephaly/polymicrogyria syndrome, bilateral symmetric clefts involving frontal and parietal regions.
Surgical Strategies
In some cases of MCDs, depending on the specific clinical and investigative findings, surgical procedures may be appropriate
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for treatment (see Chapters 178 and 179). In general, any defined abnormality (usually on MRI) is only a small part of the disturbance of the brain due to abnormal development. Therefore, resections need to extend beyond just the clearly defined abnormality; outcome is generally not as good as that following resections of focal lesions such as benign tumors or cavernomas.
Focal resections in patients with MCDs have been performed with variable results. Several groups78,80,102,137,139,141 reported good outcome if the visualized lesions were completely resected. In our experience, the best outcome is seen among patients with small developmental abnormalities in the temporal lobe. Unfortunately, focal MCDs are commonly localized in the perisylvian region, and thus, motor or language vital cortical areas limit resections. In such cases, outcome is more variable. Recent data have indicated that 52% of patients with temporal lobe dysplasias were seizure free compared with 29% of those with frontal lobe dysplasias.102 reported excellent outcome when ictal-like EEG activity was eliminated by surgery. Therefore, it would appear that the outcome following surgical resection of focal MCDs depends on the extent of lesion removal and elimination of highly epileptogenic discharges on EEG.
Table 2 Genetic Basis of Malformations of Cortical Development
Syndrome Locus Gene (Testing) Protein
ARMCPMCPH1 8p23 MCPH1(R) Microcephalin
ARMCPASPM 1q31 ASPM (R) Abnormal spindle—like microcephaly
ARMCPCDK5RAP2 9q34 CDK5RAP2 (R) Cyclin-dependent kinase 5 regulatory associated protein 2
ARMCPCENPJ 13q12.2 CENPJ (R) Centromere associated protein J
ARPHM 20q13.13 ARFGEF2 (R) ARFGEF2
MCPHA 17q25.3 SLC25A19 (R) Nuclear mitochondrial deoxynucleotide carrier
SCKL1 3q22-q24 ATR (R) FRAP-related protein 1
ILSDCX Xq22.3-q23 DCX=XLIS (C) DCX or doublecortin
SBHDCX Xq22.3-q23 DCX=XLIS (C) DCX or doublecortin
MDS 17p13.3 Several contiguous PAFAH1B1, 14-3-3ε, and others
ILSLIS1 17p13.3 LIS1 (C) PAFAH1B1
SBHLIS1 17p13.3 LIS1 (C) PAFAH1B1
LCHRELN 7q22 RELN (R) Reelin
XLAGARX Xp22.13 ARX (C) Aristaless-related homeobox protein
FCMDFCMD 9q31 FCMD (R) FCMD or Fukutin
MEBPOMGnT1 1p33-34 POMGnT1 (C) Unknown
MEBFKRP 19q13.3 FKRP (R) Fukutin-related protein
MDC1CFKRP 19q13.3 FKRP (R) Fukutin-related protein
MDC1DLARGE 22q12.3-q13.1 LARGE (R)  
WWSPOMT 9q34.1 POMT1 (R) O-mannosyl-transferase 1
WWSFKRP 19q13.3 FKRP (R) Fukutin-related protein
WWSFCMD 9q31 FCMD (R) FCMD
BPNHFLNA Xq28 FLNA (R) Filamin-A
BPNH with microcephaly 20q13.3 ARFGEF2 (R) BIG2
BPNH5p 5p15 Unknown Unknown
TSC1 9q32 TSC1 (C) Hamartin
TSC2 16p13.3 TSC2 (C) Tuberin
BFPP 16q13 GPR56 (R) Unknown
WARBM1 2q21.3 RAB3GAP (R)  
BPSP Xq28 Unknown Unknown
ARMCP, autosomal recessive microcephaly; ARPHM, autosomal recessive periventricular heterotopia and microcephaly; BFPP, bilateral frontoparietal polymicrogyria; BPNH, bilateral periventricular nodular heterotopia; BPSP, bilateral perisylvian polymicrogyria; C, clinical testing available for gene; FCMD, Fukuyama congenital muscular dystrophy; ILS, isolated lissencephaly sequence; LCH, lissencephaly with cerebellar hypoplasia; MCPHA, Amish lethal microcephaly; MDC, congenital muscular dystrophy; MDS, Miller-Dieker syndrome; MEB, muscle-eye-brain disease; R, research testing available for gene; SBH, subcortical band heterotopia; SCKL1, Seckel syndrome 1; WWS, Walker Warburg syndrome.
In cases of hemimegalencephaly, high seizure-free rates have been reported with early hemispherectomy.119 Although there has been controversy regarding the optimal timing of surgery, an increasing number of investigators advocate early surgical intervention with the aim of protecting the normal hemisphere from the damaging effects of seizures and subsequent abnormal development. Another point of contention has
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related to the type of surgery. Some have argued that complete hemispherectomy is the procedure of choice,34,119 whereas others recommend functional hemispherectomy.28,34,131 Unfortunately, there have been no randomized trials to assess this issue. The complications of complete hemispherectomy, which include hydrocephalus and hemosiderosis, appear to be higher than with functional hemispherectomy.
Callosotomy has been used in patients with severe diffuse MCDs, but the results have been disappointing. However, benefit has been observed in some patients with specific types of malformations. For example, we previously reported good outcome in cases of congenital bilateral perisylvian syndrome,73 although results have not been predictable. Recent experience with individual patients suggests that multiple subpial transactions may be a potential treatment for selected patients with bilateral lesions. In such cases, the surgical approach should be viewed as a palliative procedure that offers the possibility of a good outcome. Finally, vagus nerve stimulation (VNS) has been carried out in patients with various types of MCDs. Although some reports have described improved seizure control, there are no prospective studies. Our own experience indicates that outcome with VNS is unpredictable.
Genetic Counseling
MCDs often affect children, and thus, genetic counseling becomes extremely important for their families. Much has been learned about the genetics of MCDs, but diagnostic testing is available for only a few (Table 2). Among malformations of neuronal and glial proliferation/apoptosis, routine tests are only available for the two causal genes for tuberous sclerosis (TSC1 and TSC2).
All forms of lissencephaly/subcortical band heterotopia are genetic, and tests are available that are applicable to at least 80% of patients, although this varies with the specific phenotype. When lissencephaly is suspected, chromosome analysis and fluorescent in situ hybridization (FISH) using a probe that contains the LIS1 gene should be done followed by sequencing of LIS1 and then DCX if LIS1 is negative. When band
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heterotopia is suspected, the order of testing should be changed to sequencing of DCX, followed by FISH with a probe containing LIS1, and finally sequencing of LIS1. In a child with lissencephaly whose brain imaging also reveals callosal agenesis, or whose physical examination demonstrates abnormal genitalia, ARX testing should be done first. When mutations of any of the aforementioned genes are found, parents should generally be tested to determine their carrier status, as this is important for genetic counseling. Parental testing is especially important for the two X-linked genes, ARX and DCX, as mothers are often carriers. The frequency of postzygotic mosaicism is high in mothers, probably at least 5%, which must be taken into account for genetic counseling. When genetic tests for lissencephaly or band heterotopia are negative, later siblings have nonetheless been affected in several instances.41,50,82,116 Counseling should include acknowledging a 10% to 15% risk in such situations. Without testing, counseling is more difficult.
Two genes associated with PNH, FLNA and ARFGEF2, have been discovered, but no labs currently offer clinical testing. Classic PNH with cerebellar hypoplasia and no dysmorphic features occurs much more frequently in females than in males, and mutations of the X-linked FLNA gene account for >80% of familial PNH, ∼20% of sporadic PVNH in females, and ∼10% in sporadic males.121 The large size of the gene, which would make clinical testing very expensive, probably accounts for the lack of testing by clinical labs. Among women carriers, ∼50% have de novo mutations of FLNA, whereas the remaining 50% have inherited mutations. Although maternal transmission is much more likely, father-to-daughter transmission is possible, implying that either parent can transmit the mutation to a female proband.62 An affected man with PNH caused by an FLNA mutation would be expected to transmit the mutation to all of his daughters unless somatic mosaicism is present. To date, all individuals harboring FLNA mutations have been found to have PNH, although they can be asymptomatic. Because germline mosaicism of FLNA has never been reported in PNH, the recurrence risk is probably low when a mutation is found in the proband but neither parent is a carrier. Microcephaly with PNH is a rare malformation associated with mutations of ARFGEF2 in a few patients.122
So far, five genes have been identified that are associated with the cobblestone cortical malformation found in Fukuyama congenital muscular dystrophy, muscle-eye-brain disease, and Walker-Warburg syndrome (FCMD, FKRP, LARGE, POMGnT1, and POMNT1). Testing is not yet available clinically. However, enzyme analysis has been developed for POMGnT1 in muscle,144 and it should be possible to use the same assay in fibroblasts. Similar assays for other enzymes in this group could be developed as well.
There are few laboratory tests to identify genes associated with malformations of late migration and cortical organization. A few patients with perisylvian polymicrogyria have had small chromosomal deletions or duplications, the most common being deletion of chromosome 22q11.2. We therefore recommend chromosome analysis, FISH using a probe from 22q11.2, and FISH using a subtelomeric probe set. The yield with the 22q11.2 probe appears to be high if the polymicrogyria is asymmetric. The causal gene for bilateral frontoparietal polymicrogyria has been identified (GPR56),110 but it cannot yet be tested for clinically. Several years ago, mutations of the EMX2 gene were reported in a few patients with schizencephaly,26,53 but these results have not been confirmed. There is now doubt that EMX2 is a causal gene for schizencephaly.
Summary and Conclusions
Malformations of cortical development are an important cause of drug-resistant epilepsy. High-resolution MRI now permits detection and classification of MCDs, and advances in molecular genetics are identifying causal gene mutations. It is important today to view MCDs within a coherent framework that integrates the clinical phenotype, imaging findings, and genetic cause (if known). Antiepileptic drug treatment provides benefit in some cases, and surgical intervention is useful in others. However, treatment is often frustrating and the results of various therapeutic interventions unpredictable.
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