DEVELOPMENTAL DEFECTS AND PATHOPHYSIOLOGY

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CHAPTER 49 DEVELOPMENTAL DEFECTS AND PATHOPHYSIOLOGY

Developmental defects are among the most frequent causes of epilepsy, particularly of refractory epilepsy. They constitute a very broad range of pathological processes occurring during brain development. Each step of brain maturation, from neurogenesis to cortical organization, may be affected, which leads to several cortical malformations and/or molecular/cellular defects affecting synapses, neurotransmitter receptors, or ion channels. Advances in research, mainly in the fields of neuroimaging, electrophysiology, and genetics, have yielded a better understanding of the pathophysiology of these developmental epilepsies. This chapter focuses on malformations caused by abnormalities of cortical development (MCDs) responsible for epilepsy. Several aspects are covered: (1) definition and classification, (2) neurogenetics, (3) neuroimaging, and (4) electrophysiological-clinical data and relevance to epilepsy surgery. Each section highlights specific data of relevance to the pathophysiology of developmental defects associated with epilepsy.

DEFINITION AND CLASSIFICATION

MCDs have become more easily recognized in vivo since the 1980s because of technical improvements in magnetic resonance imaging (MRI). The term malformations caused by abnormalities of cortical development1 encompasses many forms of developmental defect resulting in architectural alteration of the cerebral cortex with or without abnormal cells (neuron and/or aberrant cells). MCDs are also referred to as disorders of cortical development,2 cortical dysplasias, and cortical dysgenesis. However, malformations caused by abnormalities of cortical development appears to us to be the most useful label.

Focal cortical dysplasia (FCD) is a specific form of MCD. Although FCD is the type of MCD that most frequently causes drug-resistant epilepsy, the term should not be used generically to describe cortical malformations.

The term neuronal migration disorders has also been improperly confused with MCD; these disorders constitute a group of malformations occurring during only during the neuronal migration period of brain development.

MCDs comprise all architectural abnormalities occurring during the different processes involved in cortical formation that can be schematically divided into three overlapping steps (which are themselves not temporally separated): (1) cell proliferation, differentiation, and apoptosis; (2) neuronal migration; and (3) cortical organization. This scheme was used by Barkovich and colleagues to provide one of the most used classifications of MCD (Table 49-1).3 Other classifications based on either imaging aspects or etiology have also been proposed.4 However, the principal advantage of the Barkovich classification is that it incorporates several processes that combine to generate the complexity of clinical manifestations of MCDs, including embryological, genetic, anatomical, and neuropathological factors.

TABLE 49-1 Malformations Caused by Abnormalities of Cortical Development (MCDs): Classification Scheme

Focal cortical dysplasia* without dysmorphic neurons or balloon cells (type I* of Palmini’s classification [cf. Table 49-2])

* Classically associated with epilepsy.

Adapted from Barkovich AJ, Kuzniecky RI, Jackson GD, et al: Classification system for malformations of cortical development: update 2001. Neurology 2001 57:2168-2178.

This comprehensive classification includes all MCDs: not only those responsible for epilepsy but also those associated with encephalopathy with severe developmental delay. Thus, the spectrum of clinical manifestation of MCD is in fact very wide and heterogeneous.

This chapter focuses on MCD as a cause of localization-related refractory epilepsy, excluding clinical manifestations with severe mental retardation. Therefore, only the following focal forms of MCD are discussed in this chapter: FCDs, cortical hamartomas of tuberous sclerosis, neoplastic MCD (i.e., dysembryoplastic neuroepithelial tumors [DNETs], ganglioglioma, and gangliocytoma), subcortical band heterotopia, periventricular (subependymal) and subcortical heterotopia, polymicrogyria and schizencephaly, and mild MCD (replacing the term microdysgenesis; see later discussion). Drug-resistant partial epilepsies associated with MCD represent a critical issue in pediatric and adult clinical neurology. In such cases, modern surgical approaches to epilepsy may represent a unique and curative solution for patients. A careful comprehensive presurgical assessment is required and must take into account all aspects of the epilepsy, from lesion to seizure phenomena. Recognition of MCD by magnetic resonance techniques has dramatically modified presurgical assessment. However, two critical issues remain: the precise localization of an epileptogenic zone responsible for seizure onset and the relationship between MRI-defined lesions and the epileptogenic zone, which may be complex.5 Moreover, up to 20% of MRI scans appear normal on visual inspection in such patients.6

No specific epidemiological studies on the prevalence of MCD are available in the literature; therefore, the only estimates of the proportion of each MCD subtype come from specialized tertiary centers.7,8 Nevertheless, it appears that FCDs are the principal cause of MCDs responsible for drug-resistant partial epilepsy that is potentially treatable by surgery. Therefore, since the first description of surgical specimens from epileptic patients by Taylor and colleagues in 1971,9 FCD has been of interest to physicians and researchers working with epilepsy surgery. Today, it is well recognized that FCD is not a homogeneous entity but exhibits different histopathological features with variable cytological components and degrees of architectural disruption. This observation implies a range of genetic and molecular mechanisms and variable alterations in cortical connectivity. This variability affects the visibility of FCD on MRI scans. However, from such diversity, it is possible to describe correlations between histopathological and MRI features and, to some extent, clinical electrophysiological features.10,11 Thus, Palmini and colleagues proposed a specific classification of FCDs that is clinically particularly useful (Table 49-2).12,13

TABLE 49-2 Focal Cortical Dysplasia (FCD): Classification Scheme

MCD, malformation caused by abnormalities of cortical development; MRI, magnetic resonance imaging.

Adapted from Palmini A, Najm I, Avanzini G, et al: Terminology and classification of the cortical dysplasias. Neurology 2004 62(6, Suppl 3):S2-S8.

In the same report, the result of a panel discussion between epileptologists, neuroradiologists, and neuropathologists specializing in the field, Palmini and colleagues12 also brought clarity to the concept of microdysgenesis. This category of MCD is important because it represents another frequent cause of drug-resistant partial epilepsy in which MRI scans are normal.14 The term microdysgenesis has been used to describe microscopic changes that constitute cortical laminar disorganization; abnormal cortical myelinated fibers; neuronal clustering; and heterotopic or excessively numerous neurons in white matter, subcortical areas, or cortical layer I. Today, the term mild MCD is preferred to describe such microscopic histopathological changes. Palmini and colleagues classified mild MCD into type I (with ectopically placed neurons in or adjacent to layer I) and type II (with microscopic neuronal heterotopia outside layer I).

It is worth noting that several types of MCD may be observed in the same patient. This fact illustrates the complexity of this broad spectrum of pathological processes that affect cortical mantle formation.

NEUROGENETICS

Since the first reports of familial cases of lissencephaly and subcortical heterotopia2 in the early 1990s, the genetic basis of MCD has been increasingly recognized.15,16 Like many developmental neurological disorders, MCD is the result of a combination of genetic defect and gestational environmental insult.17 Thus, although genetic discoveries have brought new insights and a better understanding of the causes of MCD, they have also revealed more complexity as concerns an understanding of pathophysiology. Indeed, the same mutation may lead to different types of MCD, and conversely, the same phenotype may be linked to different mutations.7

Lissencephaly and subcortical band heterotopia are the first MCDs for which a genetic basis was found. However, these MCDs are not commonly associated with epilepsy. They represent a spectrum of abnormalities, and both can be encountered in the same families. Two genes have been discovered: LIS118 on chromosome 17 and DCX19 on chromosome X. LIS1 mutations can lead to isolated lissencephaly or a more severe phenotype (Miller-Dieker syndrome) in the case of heterozygous deletions. DCX mutations can lead to lissencephaly in boys, subcortical band heterotopia in girls, or mixed phenotypes.

Several familial forms of polymicrogyria have been linked to a number of genes, mainly on chromosome X.20,21 Familial schizencephaly linked to a mutation within the EMX2 gene has also been reported.21

Finally, one report linked a mutation of the TSC1 gene to molecular defects associated with FCD.22

NEUROIMAGING

Modern imaging based on magnetic resonance has dramatically modified not only the definition of MCD but also an understanding of the physiology and pathophysiology of MCD.

Conventional Magnetic Resonance Imaging

High-resolution conventional MRI used according to an optimal protocol defined by the Neuroimaging Commission of the International League against Epilepsy allows the diagnosis of most MCDs.

High-resolution MRI with specific sequences is required for presurgical evaluation for patients with drug-resistant epilepsy.

The MRI appearances in each type of epilepsy-associated MCD without severe developmental retardation can be summarized as follows.

Focal Cortical Dysplasia

Not all the subtypes of FCD (Fig. 49-1) can be identified on MRI. Type I FCD is almost always invisible on MRI and is usually discovered on neuropathological examination after surgery. The most commonly identified lesions on MRI are those associated with type II (Taylor-type) FCD. Several features can be observed: focal cortical thickening, blurring of the junction between gray and white matter, increased signal intensity on T2-weighted, proton density, or fluid-attenuated inversion recovery imaging (FLAIR), classically linked to the balloon cell content of the FCD (type IIB) and extension of this hypersignal from the cortex to the ventricle (also called transmantle dysplasia in the literature).

A distinction must be made with the hamartomas of tuberous sclerosis (a potentially very difficult differential diagnosis in the absence of other clinical or radiological symptoms suggestive of tuberous sclerosis), low-grade gliomas, and dysplastic MCDs such as DNETs and gangliogliomas.

Hamartomas of the Tuberous Sclerosis Complex

Typical cortical hamartomas (Fig. 49-2) potentially responsible for refractory epilepsy are usually called tubers and may mimic some of the features of FCD. However, they do not show regular cortical thickening or transmantle hypersignal spreading to the ventricle. The more typical findings are cortical or subcortical hyperintensity on T2-weighted images. Tubers are generally associated with other characteristic hamartomous lesions such as subependymal nodules and subependymal giant cell astrocytomas. They may also be calcified, and signal appearances may change with age.

Neoplastic MCDs

Dysembryoplastic neuroepithelial tumors

DNETs (Fig. 49-3

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