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  • Updated 08.24.2021
  • Released 04.11.1995
  • Expires For CME 08.24.2024

Hemimegalencephaly

Introduction

Overview

Hemimegalencephaly is a rare central nervous system disorder of neuronal cell lineage, proliferation, maturation, and migration characterized by in utero enlargement of all or most of one cerebral hemisphere. The clinical hallmark is early-onset intractable epilepsy with associated hemiparesis and developmental delays. Hemimegalencephaly may occur in isolation or within the context of a defined syndrome. Occasionally, unilateral cerebral enlargement may also involve the ipsilateral brainstem and cerebellum, as well as rare hypertrophy of half of the face or body. Epilepsy is usually refractory to antiepileptic medications, and cerebral hemispherectomy or disconnection surgery is often a treatment of choice. Outcomes vary depending on the extent of neural dysplasia, association with a neurocutaneous syndrome, and surgical intervention. Currently, pharmacologic, surgical, and early developmental interventions remain at the forefront of long-term treatment strategies. The etiology and pathogenesis have been shown by neuropathological and genetic studies to be a postzygotic somatic mutation involving gain of function in the mammalian target of rapamycin (mTOR) signaling pathway and related genetic and metabolic pathways, such as AKT/PI3K. The extent of the cerebral lesion is determined by the timing of the onset of genetic expression in embryonic and fetal life. Hemimegalencephaly is part of a continuum in the spectrum of focal cortical dysplasia type IIb.

Key points

• Hemimegalencephaly is a disorder characterized by the enlargement of one hemisphere or side of the brain and abnormal cellular structure with megalocytic, dysplastic neurons and balloon cells.

• Patients can present from birth to young adulthood but can be diagnosed prenatally or in the neonatal period.

• Common presenting symptoms include hemiparesis, hemianopia, intractable epilepsy, cognitive impairment, and global developmental delay.

• Hemimegalencephaly may be associated with neurocutaneous syndromes, particularly the keratinocytic and sebaceous types of epidermal nevus syndrome.

• Hemimegalencephaly is both neuropathologically and genetically part of the spectrum of focal cortical dysplasia type IIb as a disorder of the mTOR signaling pathway, with onset of the postzygotic somatic mutation earlier in neuroepithelial mitotic cycles than in the smaller, more localized lesions of focal cortical dysplasia type II.

• As with other mTOR disorders, phosphorylated tau protein is upregulated in hemimegalencephaly

• Balloon cells are common to focal cortical dysplasia type IIb, hemimegalencephaly, and cortical tubers of tuberous sclerosis complex.

• Early surgical intervention for intractable epilepsy may lead to improved epileptic and developmental prognosis.

Historical note and terminology

First described by Sims in 1835, hemimegalencephaly is a rare central nervous system disorder of neuronal proliferation and migration characterized by congenital enlargement of all or most of 1 cerebral hemisphere (132; 41; 80; 17; 140; 42; 90; 85; 06). Clinically, hemiparesis, developmental delays, and intractable seizures are characteristic. In some cases, unilateral cerebral enlargement may also involve brainstem and cerebellum, creating the appearance that 2 brains of different sizes had been joined in the midline (59). Involvement of the infratentorial neural structures is now known as “total hemimegalencephaly” and is explained by somatic mutation in an early mitotic cycle of the neuroepithelium.

The term “hemimegalencephaly” was coined by Gross and Uiberrak, who performed and published the autopsy of an innocent 7-year-old German girl named Heide who had epilepsy, cognitive impairment, and a facial keratinocytic nevus ipsilateral to the dysplastic cerebral hemisphere (55). However, there is an ethical issue because she did not die of natural causes but was euthanized in a mental institution in Vienna in 1944. She had a form of epidermal nevus syndrome (triad of facial verrucous nevus, ipsilateral hemifacial lipomatosis, and ipsilateral hemimegalencephaly) that is now called “Heidi syndrome” (47; 43; 46). A recounting of the inhumane Nazi medical euthanasia program and other Nazi physicians are well documented by Ronen (113).

Patients with hemimegalencephaly are divided into 2 groups, 1 in which hypertrophy is localized to the CNS and the other in which hypertrophy may involve the face or other parts of the body (32; 87; 141; 45; 47). Most early descriptions of hemimegalencephaly were of patients with both brain and somatic hemihypertrophy (150; 60; 116). Thus, comprehensive history and examination remain the foundation of evaluation of any patient with apparent hemimegalencephaly.

Epilepsy, which develops in nearly all children with hemimegalencephaly, is typically refractory to medical management (110; 99) and resective or cerebral disconnection surgery; hemispherectomy remains the treatment of choice in many cases (143; 130; 35; 83; 119; 82; 69; 149; 151). Anatomic hemispherectomy (AH) was first introduced by Dandy in 1928 for the treatment of malignant gliomas and was expanded for the treatment of seizures by McKenzie in 1938 (09). This was initially deemed a last resort for patients with “catastrophic epilepsy,” an uncommon subset of seizure disorders marked by uncontrollable seizures and severe cognitive deficits. Later, Krynauw employed anatomic hemispherectomy in cases of intractable seizures in patients with unilateral CNS abnormalities (74). Although seizure reduction was noted in the first iterations of the anatomic hemispherectomy procedure, complications such as hemorrhage, hemosiderosis, and hydrocephalus minimized its utility for the treatment of epilepsy. Today, modern variants, including functional hemispherectomy, first introduced by Rassmusen in 1978, have minimized complications while still achieving comparable seizure outcomes (139; 104; 35). Motor deficits remain unchanged postoperatively, and, in some cases, cognitive functions may improve.

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