Hemimegalencephaly: Part 1. Genetic, Clinical, and Imaging Aspects

Abstract

Hemimegalencephaly is a rare hamartomatous malformation of the brain, remarkable for its extreme asymmetry. It can be isolated or associated with several neurocutaneous syndromes; less frequently, it also involves the brain stem and cerebellum. Traditionally, hemimegalencephaly has been considered a primary neuroblast migratory disturbance. At present, genetic theories of pathogenesis and modern histopathology provide a basis for this complex malformation as a primary disturbance in cellular lineage, differentiation, and proliferation, interacting with a disturbance in gene expression of body symmetry, with earlier onset than radial neuroblast migration. From my personal experience with 10 patients with hemimegalencephaly and review of the literature, I have found the same clinical neurologic, neuroimaging, and neuropathologic features in isolated and syndromic hemimegalencephaly. Magnetic resonance imaging (MRI) reveals abnormal gyration, ventriculomegaly, colpocephaly, an "occipital sign" (displacement of the occipital lobe across the midline), and increased volume and T2 signal of white matter, in addition to the overall increased size of the involved hemisphere. Mild, moderate, and severe grades of severity can be recognized, providing a functional neurologic prognosis and therapeutic plan. Early diagnosis is crucial because despite neuroimaging and pathologic evidence, hemimegalencephaly sometimes still is unrecognized. Also, misdiagnosis of obstructive hydrocephalus or cerebral neoplasm can lead to unnecessary surgical procedures. Although hemispherectomy has a high morbidity, it is recommended early for patients with severe, intractable epilepsy. The mildest forms of hemimegalencephaly are infrequent and the least recognized.

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…Epilepsy is often resistant to pharmacological treatment, requiring surgical intervention to remove or functionally disconnect the epileptogenic area within the affected hemisphere [232]. HME can occur as an isolated malformation or associated with several syndromes [230,231,233,234]. A large spectrum of central nervous system structural abnormalities have been reported, including cases variously defined as "hemimegalencephaly", "focal megalencephaly" "lobar dysplasia", or "localized megalencephaly", in which the abnormalities are detected only over a partial area of one hemisphere [235][236][237].…”

“…In these cases, the detection of associated extracerebral abnormalities (e.g., ipsilateral olfactory nerve enlargement, cerebral vascular dilations, cerebellar enlargement with abnormal architecture of the cerebellar folia) has been suggested to provide help in differentiating localized megalencephaly from multilobar cortical dysplasia [237]. Histopathologically, a large spectrum of morphologic alterations with a combination of different features of MCD (i.e., pachygyria, polygyria, polymicrogyria) can be observed in both isolated and syndromic forms (for reviews see [233,238] and [239]). Microscopically, the cortex displays alterations in cortical dyslamination with the presence of hypertrophic and dysmorphic neurons, as well as heterotopic neurons in the white matter and leptomeningeal glioneuronal heterotopia (Fig.…”

“…Microscopically, the cortex displays alterations in cortical dyslamination with the presence of hypertrophic and dysmorphic neurons, as well as heterotopic neurons in the white matter and leptomeningeal glioneuronal heterotopia (Fig. 1o) [238,[240][241][242][243][244][245] (for reviews see [233,238] and [239]). The presence of balloon cells has been also reported in HME [244,246].…”

“…On the basis of the histopathologic features, it has been suggested as a primary deregulation of proliferation [247], or a disturbance of cellular growth and cellular lineage [233,234]. Salamon et al [244] indicate an increased proliferation of the progenitor cells together with partial failure of postneurogenesis apoptosis in the molecular layer and subplate as possible mechanisms underlying the pathogenesis of HEM.…”

“…As HME has been reported in patients with various syndromes [e.g., Proteus syndrome, neurofibromatosis, hypomelanosis of Ito, Klippel-Weber-Trenauany syndrome, TSC, linear sebaceous nevus syndromes (for reviews see [233,238] and [239])], one longstanding question is whether syndromic HME is distinct from the sporadic forms or reflects a spectrum of hemispheric brain malformations, sharing common mechanism(s) of pathogenesis.…”