Classification of Malformations of Cortical Development

The majority of patients with MCDs do not have a known specific genetic syndrome. Development of the normal six-layered human cortex results from a complex series of events, in large part controlled by known and as yet unknown genes.^8–11 Disruptions in these developmentally regulated genes can result in cortical malformations. A number of new genes have been discovered that cause certain forms of MCD (Table 51-1).^12–52 The specific malformation resulting from each mutation is related to the normal temporal and anatomic expression of the gene product that has been lost.

The dynamic process of cortical development can be disrupted at many time points by gene mutation or environmental events. Formation of the normal cerebral cortex extends from weeks 8 to 26 of human gestation and is orchestrated by a complex array of genes^5–11 that ultimately result in the correct cortical laminar organization. The cortex forms from neuroglial progenitor (stem) cells born in the ventricular and subventricular zones that undergo successive rounds of mitosis. Once exiting the cell cycle, neurons migrate via both radial and tangential pathways in response to various trophic and repulsive cues to form the cortical plate (the nascent cortex). Excitatory neurons follow a radial inside-out migratory gradient along radial glial cells from layer VI to layer II. Layer I is an early embryonic layer that predates the deeper layers. Inhibitory neurons are born in the ganglionic eminences and migrate by tangential pathways into the cortical plate. Cells arriving at their appropriate cortical laminar destination cease migration, begin to extend axons and dendrites, and form early functional synapses. Conceptually, normal corticogenesis can be broadly divided into three stages: proliferation, migration, and organization.

Based on the proposed steps for normal cortical development and the recent identification of single genes responsible for many MCDs, a classification scheme for abnormal cortical development (i.e., MCDs) was defined in 1996 and later modified in 2001 and 2004.^53–55 The MCD taxonomy is organized according to the putative cellular mechanisms that are disrupted in development. These groups include (1) disorders of cellular proliferation, (2) disorders of neuronal migration, (3) disorders of cortical organization, and (4) disorders with unknown mechanisms (Table 51-2). Functional in vitro studies have been used to mechanistically support parcellation of particular MCDs into each category.

TABLE 51-2 Classification of Malformations of Cortical Development

FCD, focal cortical dysplasia; TSC, tuberous sclerosis complex.

Adapted from Barkovich AJ, Kuzniecky RI, Jackson GD, et al. A developmental and genetic classification for malformations of cortical development. Neurology. 2005;65:1873-1887.

Disorders of Cellular Proliferation

Malformations in this group include disorders that result in either increased or decreased growth or in increased or decreased apoptosis. These disorders are often manifested as abnormal brain size or localized areas of enlargement. Abnormalities in brain size can be manifested as microcephaly with a normal to thin cortex, microlissencephaly, microcephaly with polymicrogyria, or macrocephaly.^15,17,32,47

Microcephaly is defined as a head circumference that is more than 2 SD smaller than normal.⁵⁶ Patients with this condition have a brain that may be up to 70% smaller than normal, but the brain has essentially normal cortical laminar architecture. In some cases of microcephaly, a simplified gyral folding pattern is observed on MRI. Because any process that interferes with brain growth can lead to reduced head/brain size, microcephaly is associated with a highly heterogeneous group of disorders. It can result from a number of prenatal insults, including hypoxia-ischemia and fetal alcohol exposure. Additionally, a number of genes (ASPM, MCPH1, CENPJ, and CDK5RAP2) have been shown to result in autosomal recessive forms of microcephaly.^{15–17,32,57,58} Rare syndromic forms include Amish lethal microcephaly and Seckel’s syndrome.^16,46 The ASPM (abnormal spindle-like microcephaly associated) gene is of particular interest because it is the single most common genetic mutation associated with microcephaly and has provided new insight into evolutionary mechanisms governing brain size across species. ASPM is an orthologue of a Drosophila gene that has been shown to be essential for normal mitotic spindle function in embryonic neuroblasts. When absent, neuroblasts are arrested in the cell cycle and fail to proliferate, which results in a reduction in the number of cells in the brain and consequently a smaller brain size. When the human ASPM gene sequence was compared with that of primates, there was a correlation between sequence and brain size.⁵⁹ Thus, ASPM appears to have played a central role in the genetic component of the evolutionary expansion in brain size from primates to Homo sapiens.

Macrocephaly, defined as measurable enlargement of the head (>2 SD), can occur in conjunction with a large number of syndromes and conditions that are not associated with MCDs, including hydrocephalus, autism, leukodystrophies, and organic acidurias.⁶⁰ Hemimegalencephaly (HME) is a malformation characterized by the abnormal enlargement of one entire hemisphere (Fig. 51-1); a variant of HME is lobar dysplasia, in which an entire brain lobe is enlarged. HME may be seen in isolation or in the setting of a known syndrome such as linear sebaceous nevus (of Jadassohn), hypomelanosis of Ito, tuberous sclerosis complex (TSC), or Proteus syndrome. HME is highly associated with intractable seizures and, frequently, infantile spasms. Pathologic analysis of HME brain demonstrates loss of cortical lamination, dysmorphic neurons, and cytomegalic cells similar to those seen in focal cortical dysplasia (FCD) and TSC (see later).^61–63 As yet, no specific gene has been associated with HME, although reports suggest an association with PTEN mutations in Proteus syndrome.^64–67

FIGURE 51-1 Postmortem specimen of hemimegalencephaly. Brain tissue stained with cresyl violet reveals massive enlargement of the left hemisphere.

In addition to changes across broad cortical areas, disorders of cellular proliferation can result in focal malformations or dysplasias. Such lesions include FCDs, in particular, cortical dysplasias containing balloon cells, tubers in TSC, and low-grade neoplastic lesions such as dysembryoplastic neuroepithelial tumor, ganglioglioma (Fig. 51-2), and gangliocytoma.^{24,29,30,33,44,61–63,68} TSC results from mutations in TSC1, which encodes TSC1 or hamartin, or from mutations in TSC2, which encodes TSC2 or tuberin.^24,29,30,33 TSC1 and TSC2 are known modulators of the mammalian target of rapamycin (mTOR) pathway, which governs cell size and proliferation. Neurological manifestations of TSC include epilepsy, infantile spasms, cognitive disabilities, and autism.⁶⁹ Cortical tubers are focal areas of disorganized cortical lamination characterized by the presence of cytomegalic cells known as giant cells.^69,70 The number of tubers across patients is variable and does not seem to vary with mutation type, patient age, or necessarily, neurological phenotype.

FIGURE 51-2 Magnetic resonance image depicting a left frontal ganglioglioma (arrow; T1-weighted image after intravenous gadolinium).

FCD with balloon cells (so-called Palmini type 2B dysplasia; Fig. 51-3) is a sporadic condition for which no specific gene mutation has been found.^68,71 Like the tubers in TSC, FCD 2B consists of focal areas of cortical laminar disorganization characterized histopathologically by neuronal dysmorphism and pathognomonic enlarged cells, known as balloon cells, that are similar to the giant cells found in TSC. In addition to appearance, balloon cells and giant cells share many immunohistochemical features.^{62,70,72–74}

FIGURE 51-3 Histopathology of Palmini type II cortical dysplasia. Left, Fresh specimen demonstrating thickened cortex (arrow). Right, Balloon cells (double arrows), dysmorphic neurons (single arrows and asterisk), and glial cells (arrowhead) (labeled with glial fibrillary acidic protein).

Disorders of Neuronal Migration

Disorders of migration are a heterogeneous set of syndromes characterized by altered gyral patterning and cortical laminar organization or the presence of ectopic neurons in the subcortical white matter or periventricular region. Such disorders include lissencephaly, subependymal/periventricular heterotopia, marginal glioneuronal heterotopia, subcortical band heterotopia, and heterotopia syndromes.^75,76 Disorders of neuronal migration can exhibit various clinicopathologic phenotypes, depending on the timing and location of the migratory disruption.

Lissencephaly (“smooth brain”) refers to a heterogeneous group of disorders characterized by loss of the normal gyral pattern and significant disorganization of cortical laminar cytoarchitecture (Fig. 51-4). Lissencephaly is separated into two pathologic subtypes: type 1 or classic and type II or cobblestone lissencephaly. In type I lissencephaly, the gyral patterning across the entire cortex is altered. Because of abnormal neuronal migration, neuronal progenitor cells fail to move to their correct laminar location and the normal six-layer cortex is reduced to a four-layered pattern.

FIGURE 51-4 Unfixed specimen of lissencephaly. Note the thickened cortex (arrow) and absence of cortical gyri.

Several autosomal recessive and X-linked forms of type I lissencephaly exist and result from mutations in the LIS1, DCX, ARX, or RELN genes.* These genes are believed to be involved in important cell processes, such as movement of the neuronal nucleus or dynamic changes in the neuronal cytoskeleton, that are required for neuronal progenitor cells to migrate properly from the ventricular zone into the cortical plate.^77–79 LIS1 mutations are seen in isolated lissencephaly, as well as in association with Miller-Dieker lissencephaly syndrome.

Syndromic forms of type II or cobblestone lissencephaly are associated with rare congenital forms of muscular dystrophy, muscle-eye-brain disease, and Walker-Warburg syndrome.12–14,19–21,36,37,48–50 In type II lissencephaly, the altered gyral patterning is more heterogeneously distributed across the cortical mantle. The combination of a muscular dystrophy and lissencephaly should prompt a search for one of these syndromes.

Subcortical band heterotopia (Fig. 51-5) and periventricular nodular heterotopia (Fig. 51-6) syndromes are X-linked disorders that are manifested as sexually dimorphic phenotypes. For example, in females, mutations in the DCX (doublecortin) gene are associated with a type of subcortical band heterotopia in which a broad focal band of cortical neurons is trapped within the subcortical white matter bilaterally.^26,41,79,80 The band consists of neurons of both excitatory and inhibitory phenotypes and makes connections with the overlying cortices. In males, the DCX mutation is associated with lissencephaly. Periventricular nodular heterotopia is a disorder resulting from mutations in the filamin-1 (FLN1) gene in which focal nodules of cortical neurons are observed within the walls of the lateral ventricles. These collections are also composed of both excitatory and inhibitory neurons, and recent tensor tract imaging techniques have revealed that these cells make connections with the overlying cortex. FLN1

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