Hemimegalencephaly …

Developmental Malformations

Updated 03.29.2024
Released 04.11.1995
Expires For CME 03.29.2027

Hemimegalencephaly

Authors: Harvey B Sarnat MS MD FRCPC, Laura Flores-Sarnat MD

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Editor: Bernard L Maria MD

Hemimegalencephaly

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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 or overgrowth 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/PIK3CA. 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. It is a frequent complication of the two neurologic phenotypes of epidermal nevus syndromes and occasionally of tuberous sclerosis complex.

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 syndromes, and occasionally with tuberous sclerosis complex.
	• 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.
	• Epilepsy is often refractory to medical control, but early surgical intervention for intractable epilepsy may lead to improved epileptic and developmental prognoses.

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 one cerebral hemisphere (148; 43; 90; 17; 157; 44; 102; 97; 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 two brains of different sizes had been joined in the midline (64). Involvement of the infratentorial neural structures is now known as “total hemimegalencephaly” and is explained by somatic mutations 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 (60). 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” (49; 45; 48). A recounting of the inhumane Nazi medical euthanasia program and other Nazi physicians are well documented by Ronen (127).

Patients with hemimegalencephaly are divided into two groups: one in which hypertrophy is localized to the CNS (isolated) and the other when associated with neurocutaneous syndromes. In one phenotype, hyperplasia may involve the face ipsilaterally (Heide syndrome) or other parts of the body (33; 99; 158; 47; 49). Most early descriptions of hemimegalencephaly were of patients with both brain and somatic hemihypertrophy (168; 65; 130). 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 (124; 112) and resective or cerebral disconnection surgery; hemispherectomy remains the treatment of choice in many cases (161; 146; 36; 95; 133; 94; 78; 167; 169). 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 (84). Although seizure reduction was noted in the first observations following 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 (156; 118; 36). Motor deficits remain unchanged postoperatively, and, in some cases, cognitive functions may improve.

Clinical manifestations

Presentation and course

Epilepsy, development and cognitive delays, and contralateral hemiparesis are hallmarks of hemimegalencephaly, with symptoms typically presenting during the neonatal period but can have variability in its clinical presentation (142). Some patients may present with refractory seizures as early as the neonatal period (103). Patients with the onset of epilepsy after the neonatal period or in early infancy may exhibit subclinical epileptiform activity on EEG from birth. Seizure onset is often the first manifestation of hemimegalencephaly with earlier seizure presentation classically linked to increased severity of seizures in this patient population, with many having uncontrollable seizures and catastrophic epilepsy (86). Most infants have focal seizures involving the arm and leg contralateral to the side of hemimegalencephaly (112). In some cases, both epilepsia partialis continua (162; 51; 45) and secondary generalization occur over time in children with hemimegalencephaly. Other seizure types, such as infantile spasms and atonic seizures, may occur in addition to focal seizures (18; 154; 112; 163; 123). Hemimegalencephaly may also present as an infantile myoclonic epilepsy (16; 110; 119), Ohtahara syndrome (13; 80), or later evolve to Lennox-Gastaut syndrome (87).

Macrocephaly and cranial asymmetry is apparent during the neonatal period, but commonly missed if the skull is not examined carefully and viewed from the vertex (164). Various degrees of hemiparesis are present, as a result of both malformation of the involved motor cortex and frequent focal motor seizures. Hemianopsia may also be detected in older children. Localized asymmetrical hypertrophy of the extremities as well as hemimegalencephaly are characteristic of Proteus syndrome, a keratinocytic variety of epidermal nevus syndrome caused by somatic mutation of the AKT1 gene affecting mTOR (92; 45). Facial asymmetry is due to infiltrative lipomatosis, which is distinct from and more severe than encapsulated lipoma (49; 45; 134).

Milder symptoms and later onset of seizures may occur presumably due to less severe cytoarchitectural abnormalities (162; 119; 29), especially if hemimegalencephaly occurs in the context of neurofibromatosis or tuberous sclerosis complex (32; 23; 131). Rarely, early developmental motor and cognitive function may be normal (52; 29).

Rarely, an adult with undiagnosed hemimegalencephaly was found by imaging ordered for another reason, such as recurrent migraine headaches (93), though migraine is probably unrelated.

Prognosis and complications

The prognosis of children with hemimegalencephaly is variable given the variable extent of neuronal malformation seen across the spectrum of this disease (158). However, it has been noted that the appearance of seizures prior to 1 month of age foreshadows a poor prognosis (154; 76), whereas seizures beginning after the age of 7 portend a better functional outcome. Additionally, status epilepticus may be a cause of early death (79; 124). Patients with hemimegalencephaly surviving to adulthood without hemispherectomy are uncommon (68). For patients who are not good surgical candidates or decline surgical intervention, relative seizure control may be achieved through medical management, but seizure freedom is rarely achieved. Ikeda and colleagues reported one case of hemimegalencephaly in a 26-year-old-male with severe epilepsy, albeit poorly controlled, who was managed medically; however, these cases are most often associated with a milder seizure disorder and are rarely reported in the literature (68).

Clinical vignette

A Caucasian girl presented to the neurology clinic at age 2 years with a nonprogressive right hemiparesis. Parents had noted weakness of her right hand greater than leg since shortly after birth. She was developmentally delayed, most notably with delayed walking at 15 months and delayed expressive language, and she had been receiving physical and speech therapies. Exam showed an alert, interactive child without neurocutaneous markers or neurometabolic odors. Head circumference was at the 75th percentile for age, with noted cranial asymmetry, left hemicranium much larger than the right. Right spastic hemiparesis was demonstrated with hemiparetic gait, decreased muscle power (4-/5), increased tone, and increased deep tendon reflexes in the right arm greater than the right leg. Further, family and social histories were negative, and no history of seizures was reported. Brain MRI was consistent with left hemimegalencephaly. Two weeks after MRI, she presented to her local emergency room in focal status epilepticus. AED therapy was begun. She was started on phenytoin but was soon changed to oxcarbazepine. Epilepsy surgery planning was started. Right focal seizures persisted, and she was transitioned to topiramate. Continued seizures persisted despite addition of valproate. Within 2 months of initial seizure, left hemispherectomy was successfully performed. The patient has been postoperatively seizure-free for 5 years and continues to make substantial neurodevelopmental gains.

Biological basis

Etiology and pathogenesis

Hemimegalencephaly is a postzygotic somatic mutation in undifferentiated premigratory neuroepithelial cells, with involvement of the mTOR signaling pathway or related pathways that influence mTOR, such as AKT (91; 139; 106). This pathogenesis has been shown neuropathologically and has been confirmed as etiology in genetic studies (31; 08; 37; 38; 71). Small focal cortical dysplasias exhibit somatic mutations only in neurons; large lesions involve glial cells as well. Dysplastic clones disperse across the cortex at relatively low levels of mosaicism, and small lesions involve neuroblasts only; larger lesions involve glial cells as well (125). Increased levels of nonphosphorylated beta-catenin occur in hemimegalencephaly, which transcriptionally activates cyclin D7 and c-myc genes but reduced levels of Ser33/Ser37/Thr41 phospho-beta-catenin, which is essential for beta-catenin inactivation (176).

Neuropathology. Timing is the essence of determining the size of the lesion because hemimegalencephaly is within the same spectrum as focal cortical dysplasia type IIb (138; 140). Neuropathological confirmation has been made in the midgestation fetus (96). There are approximately 33 mitotic cycles of the human ventricular neuroepithelium that produce all neurons of the cerebral cortex because of logarithmic exponential increase (24). If the somatic mutation, which involves some but not all neuroepithelial cells, is first expressed in a late cycle, a small lesion of focal cortical dysplasia is produced. A somewhat earlier onset yields a wider lesion of several adjacent gyri, and an even earlier onset produces hemimegalencephaly. If the onset is in the first few mitotic cycles, when the neuroepithelium of the supratentorial and infratentorial compartments are still continuous, the result is “total hemimegalencephaly” that not only involves the cerebral hemisphere but also the ipsilateral cerebellar hemisphere and hemi-brainstem (138; 140).

Thus, hemimegalencephaly is characterized by excessive proliferation of both neurons and astrocytes. The principal lesion is histologically classified as a hamartoma because it involves not only disorganization of tissue architecture but abnormal cellular morphology as well.

Hemimegalencephaly in 3-D

Three-dimensional MRI rendering of cortex showing an enlarged hemisphere with pachygyria. (Contributed by Dr. David Griesemer.)

Involved cortex is thickened, with a flattened inner cortical border, associated with a lack of lamination. There are an increased number of miniature, shallow gyri over the cortical surface, and in some places adjacent microgyri fuse and the cortical surface appears paradoxically smooth (11; 46; 50).

Hemimegalencephaly (MRI) (1)

A T1-weighted MRI of a child with left hemimegalencephaly demonstrating an enlarged hemisphere with diffuse unilateral polymicrogyria and pachygyria, associated with distortion of underlying white matter and incomplete neuronal mi...

In addition to diffuse enlargement of the cerebral cortex, there is typically dilatation of the ipsilateral occipital horn of the lateral ventricle (46) and expansion of the hemisphere beyond the midline.

Hemimegalencephaly (MRI) (2)

A T2-weighted MRI of a child with left hemimegalencephaly demonstrating an enlarged left lateral ventricle as well as unilateral cortical and subcortical abnormalities. (Contributed by Dr. David Griesemer.)

Neuropathological findings also include abnormal neuronal growth and cytomorphology in both gray and white matter (50), abnormal neuronal lamination (90; 34; 06), abnormal neuronal orientation (60), and neuronal and leptomeningeal glioneuronal heterotopia (108; 96). Note that “heterotopia” is the plural form of this Greek derivative; the singular form is “heterotopion.”

No abnormality is known in the density of synapses, although there is an increased number in a given cytoarchitectural area because of increased cortical thickness (111). Most cases are also characterized by gliosis (154; 162).

Balloon cells are large globoid cells with eccentric nuclei and coarse, short radiating processes and are of mixed cellular lineage or incomplete differentiation, expressing both neuronal and glial proteins as well as primitive proteins of progenitor cells (175; 136). Balloon cells are immunoreactive for the mTOR substrates phospho-ribosomal S6 protein, similar to cells in tuberous sclerosis (15). Occasionally, however, the cortical dysplasia appears mild (34). Balloon cells are common in focal cortical dysplasia type IIb, hemimegalencephaly, and tuberous sclerosis complex (157; 124; 34; 135; 136).

Immunoreactivity studies have demonstrated that such abnormal neurons in the white matter demonstrate interactions with synaptophysin-reactive axons and are not “isolated islands” of neuronal heterotopia. Such neurons may also contribute to the epileptogenicity associated with clinical hemimegalencephaly (50).

An additional neuropathological lesion demonstrated in both focal cortical dysplasia type II and hemimegalencephaly is a cortical and hippocampal accumulation of an abnormally phosphorylated tau protein similar to that demonstrated in adult Alzheimer disease and certain other adult neurodegenerative diseases with dementia (139; 137). Furthermore, there is a neutral lipid storage in many cortical neurons in at least some cases of hemimegalencephaly, the significance of which remains uncertain (139).

Cortical lesions of hemimegalencephaly resemble the cerebral lesions (ie, tubers) of tuberous sclerosis (ie, tubers). Neuroblast migratory disturbances are accompanied by abnormal gyration (174; 50). Coexistence of hemimegalencephaly and tuberous sclerosis complex has been described (53; 115; 61; 20; 147), but most cases of tuberous sclerosis do not have hemimegalencephaly despite numerous cortical tubers. Tuberous sclerosis is another disorder of the mTOR signaling pathway, and the TSC1 and TSC2 genes are closely related to it, so it is not surprising. Tuberous sclerosis complex genes are both germline mutations as autosomal dominant traits and also postzygotic somatic mutations not of Mendelian inheritance. Immunocytochemical studies show similarities in the megalocytic dysplastic neurons in both, and glial cell involvement also occurs in both. Furthermore, both show similar abnormal tau protein expression (137). A subtle difference is that cortical tubers may exhibit microcalcifications that are rare in hemimegalencephaly and do not occur in focal cortical dysplasia type II. Balloon cells are similar in all. Periventricular nodules and giant cell astrocytomas in tuberous sclerosis, by contrast, contain glial elements but no neurons or balloon cells. Hemimegalencephaly in tuberous sclerosis complex can sometimes be diagnosed by prenatal imaging as early as midgestation (20).

Neoplastic transformation of the hamartoma of hemimegalencephaly into glioblastoma multiforme is rare but has been described in isolated patients (28). The authors have also seen one such case, which has not yet been published.

Genetics. The fundamental genetic defect in hemimegalencephaly is a disorder of the mTOR signaling pathway, including any of the various associated pathways that affect mTOR, such as PIK3CA, AKT, DEPDC5, and GATOR (91; 74; 54; 56). Mutation of the NPRL3 gene also was described in hemimegalencephaly with refractory status epilepticus followed by cerebral atrophy (160). This genetic basis occurs in both isolated hemimegalencephaly and when this malformation is associated with epidermal nevus syndromes, tuberous sclerosis complex, and also in focal cortical dysplasia type IIb (106).

Neuronal heteroploidy has been suggested by quantitative histochemical studies demonstrating enlarged nucleoli, nuclei, and increased DNA and RNA content in neurons of the involved hemispheres of two patients (17; 97). The first cultured cell line developed from cerebral cortex came from a patient with hemimegalencephaly (128), suggesting that hyperdiploidy may confer a proliferative enhancement to neurons. In addition to the primary genetic etiology of postzygotic somatic mutation due to an mTOR defect, DNA from a case of isolated hemimegalencephaly showed a heterozygous deletion of 15q11.2-15q13.1. The region of the deletion includes at least 30 known genes and could present a susceptibility locus for hemimegalencephaly (15). Studies also suggest a possible correlation with platelet activating factor and cell adhesion molecule L1, two substances thought to be involved in neuronal migration, but no precise mechanism for this brain malformation has been elucidated (159; 66). One case study identified somatic uniparental disomy of the ZNF597 gene of chromosome 16 in patients with hemimegalencephaly, indicating that overexpression of maternally expressed ZNF597 may play a role in aberrant hemispheric development (59).

In a female neonate with refractory seizures since birth and hemimegalencephaly, whole genome sequencing revealed a novel, maternally inherited 3Kb deletion encompassing exon 5 of the NPRL3 gene of chromosome 16, which encodes a subunit of the GATOR complex (26). GATOR is a regulator of the mTOR signaling pathway, and, thus, this variant is consistent with a mutation of one of several pathways affecting mTOR.

Neuroimaging. Advanced MRI technology with diffusion tensor imaging has shown asymmetry in interhemispheric fiber tracts and white matter of not only the enlarged hemisphere but also the “normal” hemisphere in patients with hemimegalencephaly (72). Fiber tracts passing through the corpus callosum showed aberrant pathways from the unaffected side to incorrect areas of the corresponding lobe and to noncorresponding lobes. Abnormal projections of the cortico-ponto-cerebellar pathway are also demonstrated by diffusion tensor imaging (41). These images also demonstrated abnormal fiber tract volumes on the affected side when compared to the unaffected side.

Dysplasia of the corpus callosum was also confirmed neuropathologically (50). Takahashi and colleagues hypothesize that the abnormal fiber tracts could be due to immature neuronal cells connecting with abnormal axonal projections during development (152). Transcranial magnetic stimulation has shown abnormal axon orientation and excess spread of corticospinal excitation associated with multiple defects of cortical inhibition in the affected hemisphere in a patient with hemimegalencephaly (29).

In addition to the more clinically obvious enlarged hemisphere, abnormal findings outside the involved hemisphere have been reported. MRI and neuropathological abnormalities reported include enlargement of ipsilateral olfactory bulb (124) and optic nerves, ipsilateral cerebral vascular dilations, ipsilateral cerebellar and brainstem enlargements, and abnormal cerebellar folia (both ipsilateral and contralateral). These findings confirm the great importance of high-quality performance and interpretation of diagnostic neuroimaging studies (143).

The diagnosis of hemimegalencephaly can sometimes be demonstrated prenatally by fetal ultrasound confirmed by fetal MRI (170; 144) and as observed in the authors’ practice (49). Prenatal imaging criteria of the diagnosis are becoming better recognized and may differ from some postnatal features because of differences in the developmental stages (75; 144).

Ictal and interictal single photon emission computed tomography (SPECT) and positron imaging tomography (PET) often detect hypometabolism in the overgrown cerebral hemisphere. Another special MRI sequence, arterial spin labelling, is an additional noninvasive functional imaging biomarker of cerebral perfusion using magnetically labelled blood as an endogenous contrast agent; it shows reduced cerebral blood flow that correlates with the hypometabolism of PET and SPECT, except for ictal increased blood flow during peri-ictal phases in hemimegalencephaly (153).

Differential diagnosis

Megalencephaly (but not hemimegalencephaly) may also occur with a variety of metabolic disorders, including leukodystrophies such as Canavan disease and Alexander disease, lipidoses such as Tay-Sachs disease, or mucopolysaccharidoses. In addition, general disturbances of growth, such as Sotos syndrome (cerebral gigantism), Beckwith syndrome, or achondroplasia, may cause megalencephaly, but these typically have other distinguishing features (101; 165). Megalencephaly occurring with neurocutaneous syndromes, such as neurofibromatosis (129; 32) or tuberous sclerosis (23; 131; 155), present a more difficult diagnostic challenge, particularly if there is asymmetrical hypertrophy, as may be seen with intracerebral hemangiomatosis of Sturge-Weber syndrome, Klippel-Trenaunay-Weber syndrome (99; 21; 109; 166), or “cutis marmorata telangiectatica congenita” (57), which is now known as “megalencephaly capillary malformation or MCAP.” In a Japanese nationwide survey, 16 of 44 patients with hemimegalencephaly had underlying neurocutaneous syndromes (142); this has been confirmed by others (45).

Neurocutaneous syndromes and hemimegalencephaly. The most frequent neurocutaneous syndromes associated with hemimegalencephaly are the neurologic phenotypes of epidermal nevus syndromes, both the linear nevus sebaceous and keratinocytic types, in approximately one half of cases (117; 69; 116; 45). They are distinguished by a midline facial nevus, occasional facial hemihypertrophy caused by hamartomatous-lipomatous lesions, and venous sinus dysplasias (25; 12; 19; 177; 30; 141; 63). Hemimegalencephaly has also been reported with both keratinocytic and sebaceous types of epidermal nevus syndrome associated with severe epilepsies (39; 132; 40; 62; 94; 45).

Hypomelanosis of Ito is another neurocutaneous syndrome that is inconstantly associated with hemimegalencephaly and epilepsy (120; 14; 149; 27; 122) and Proteus syndrome (100; 05; 13; 92; 49). Still another neurocutaneous syndrome that may present with hemimegalencephaly is neurocutaneous melanocytosis (85).

Diagnostic workup

The diagnosis of hemimegalencephaly is often suspected because of an enlarged hemicalvarium. Though hemimegalencephaly may be detected prenatally by ultrasound or magnetic resonance imaging, post-natal high-resolution imaging remains the current standard in the diagnostic evaluation (67; 02).

MRI is the most sensitive study for diagnosing hemimegalencephaly (01), which occurs in association with pachygyria, polymicrogyria, nodular heterotopia, and a small hippocampus in some patients (105; 104).

Hemimegalencephaly (MRI) (1)

A T1-weighted MRI of a child with left hemimegalencephaly demonstrating an enlarged hemisphere with diffuse unilateral polymicrogyria and pachygyria, associated with distortion of underlying white matter and incomplete neuronal mi...
Left hemimegalencephaly (1)

T1-weighted image of left hemimegalencephaly. (Contributed by Dr. Robert Turner.)

Unilateral lissencephaly or agyria may also occur in some cases (88). Ipsilateral ventricular enlargement occurs in most cases, often with a straightened and uplifted frontal horn.

Hemimegalencephaly (MRI) (2)

A T2-weighted MRI of a child with left hemimegalencephaly demonstrating an enlarged left lateral ventricle as well as unilateral cortical and subcortical abnormalities. (Contributed by Dr. David Griesemer.)
Left hemimegalencephaly (2)

T2-weighted image of left hemimegalencephaly. (Contributed by Dr. Robert Turner.)

Greater enlargement of the involved cerebral hemisphere is seen in patients with polymicrogyria and normal subcortical white matter, whereas patients with significant subcortical gliosis have less enlargement (88). Because hemicalvarial enlargement does not occur in all patients with hemimegalencephaly, CT or MRI studies may be required to demonstrate enlargement of at least one lobe of one hemisphere.

Hemimegalencephaly in 3-D

Three-dimensional MRI rendering of cortex showing an enlarged hemisphere with pachygyria. (Contributed by Dr. David Griesemer.)

This is particularly true for normocephalic infants being evaluated for refractory partial seizures. In addition, the abnormally enlarged hemisphere over time may show impairment of growth, causing a later relative micrencephaly. MR imaging, especially with gadolinium enhancement, is useful in distinguishing hemimegalencephaly from disorders characterized by leptomeningeal angiomatosis or intraparenchymal vascular malformations.

Evaluation of the contralateral nonmegalencephalic hemisphere is also important, not only to assess improvement following hemispherectomy of the abnormal cortex, but also to identify possible dysgenesis of the nonmegalencephalic hemisphere. SPECT (83) and PET (123) may be used to identify possible hypometabolism of "normal" cortex. Neuropathological examination of the “normal” hemisphere may disclose mild histopathological abnormalities (139).

Electroencephalography is essential for localizing zones of epileptic activity. This is important because seizures may rarely originate from cortex other than that which is considered abnormal on the basis of neuroimaging studies (162). EEG findings over the involved hemisphere typically demonstrate depression of background voltage with bursts of numerous spikes during wakefulness, and unilateral suppression-burst during sleep (161). This has been labeled hemihypsarrhythmia (154; 87; 30), though a good response to ACTH is not assured (119). In neonates and infants, interictal fast oscillations on the affected hemisphere may represent an epileptic tendency (173). There is no consensus concerning the prognostic value of EEG (82; 83; 158). Nevertheless, video EEG is considered important to verify the stereotypic pattern of seizures and to demonstrate the onset of seizures from the malformed cerebral hemisphere (161).

Cerebral angiography, although not typically required for diagnosis, may demonstrate arteriovenous abnormalities in areas of aberrant neuronal migration, as normal vessels that coalesce from venules and venous channels within fully developed cortex do not form (10). Ultrasonographic studies have also provided descriptive information (89; 42); however, these are not likely to provide as much specificity and prognostic information as MRI (113).

Literature has documented the superiority of MRI over neurosonography in accurate diagnosis and avoidance of misdiagnosis of hemimegalencephaly, particularly prenatally (107). In a case report by Romero and colleagues, MRI was done as early as 22 weeks gestational age, resulting in a definitive diagnosis of hemimegalencephaly (126). In older patients who do not present with hemiparesis, cortical mapping studies can be performed prior to epilepsy surgery for counseling on prognosis. Transcranial magnetic stimulation performed on a patient with hemimegalencephaly showed enlargement of the cortical motor map (29).

Management

Antiseizure medication is typically required for infants or children with hemimegalencephaly, although a few patients with milder cytoarchitectural abnormalities may not develop early seizures until later in childhood, or not at all. Antiseizure medications used in this age population seldom result in seizure freedom, even with the newer agents available since 1993. Seizures may improve with ketogenic diets, including a modified Atkins diet (27).

Though medical control of seizures is desirable (158), surgery is most likely to be the best option for infants and children with refractory seizures, even in early infancy (79; 156; 161; 55; 07; 150; 35; 03; 73; 121; 142; 146; 36; 95; 20; 70; 145; 58) and should not be considered a last resort. The surgical strategy for these patients depends in large part on the extent of neuroimaging abnormalities as well as motor impairment (114; 146; 36; 95). For infants and young children with significant hemiparesis, cerebral hemispherectomy is recommended (79; 161; 142; 146; 36; 95). In a large multicenter study of 1267 hemispherectomies for intractable epilepsy in 32 centers of 12 countries, 85% were seizure-free at 12 months postoperatively, though not all patients in this cohort had hemimegalencephaly (169). Hemisphectomy also may be beneficial for patients with infantile epilepsies such as Ohtahara syndrome (80).

With mild hemiparesis, resection of more clearly demarcated structural or electrical abnormalities is appropriate (113); however, postoperative seizure control may be less satisfactory than that achieved following hemispherectomy (04; 73; 146; 36). Hemispherotomy has also been described and attempted for patients with hemimegalencephaly (98). Results were not favorable, possibly due to incomplete disconnection of the affected hemisphere. Early surgical intervention is thought advisable to permit brain "plasticity" maximum benefit, but it is not likely to be helpful in patients with cortical dysplasia or hypometabolism of the nonmegalencephalic hemisphere (83; 123; 151; 142). Kawai and colleagues reported a modification of the vertical hemispherectomy for refractory epilepsy in seven patients (77). Four patients were children with hemimegalencephaly and the other three were adults with ulegyric hemisphere. Surgical procedure was completed without complication in all cases, and there was no case that required CSF shunting. Seizure outcome was Engel's class I in six and class IV in one. For patients that are poor surgical candidates in which the seizures arise from the contralateral hemisphere or if the risk of a hemispherectomy is unacceptably high, implantation with vagus nerve stimulation may also be considered. Vagal nerve stimulation in this population can lead to significant reduction in partial and generalized seizures (greater than 60%) as well as psychological improvement in the form of calmer effect and improved communication in patients with severe cognitive impairments (28).

A promising treatment that has not yet been officially approved but has been successful in some isolated cases is the use of mTOR inhibitors, such rapamycin (172).

Outcomes

Early hemispherectomy, at a few months of age, has been associated with a significantly improved outcome, including seizure freedom or more than 75% seizure reduction, as well as developmental and cognitive improvements (161; 162; 123; 35; 94; 169). Even infants just beyond the neonatal period have undergone hemispherectomy for retractable seizures in hemimegalencephaly, either isolated (139) or complicating tuberous sclerosis complex (145).

Improvement of cognitive function of the remaining hemisphere, following surgery for intractable epilepsy, is a function of preoperative glucose metabolism as determined by PET (22; 123). Some patients with hemimegalencephaly seem to experience poorer outcomes following hemispherectomy presumably because of greater involvement of the non-megalencephalic hemisphere. An explanation for this is that there are bilateral cerebral hemispheric abnormalities, though significantly less in the “non-megalencephalic” hemisphere (133). Postnatal evolution of cortical malformation in the previously unaffected hemisphere has been reported following hemispherectomy for intractable hemitonic and asymmetrical epileptic spasms (81).

As the child with hemimegalencephaly grows, the involved hemisphere may fail to grow normally as does the nonmegalencephalic hemisphere. This results in an eventual hemiatrophy of the previous megalencephalic hemisphere (171), and may ultimately lead to macrocephaly, though the pathogenesis for such aberrant growth remains unknown (131).

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References

01: Abdel Razek AA, Castillo M. Magnetic resonance imaging of malformations of midbrain-hindbrain. J Comput Assist Tomogr 2016;40(1):14-25. PMID 26599961
02: Agid R, Lieberman S, Nakjari M, Gomori JM. Prenatal MR diffusion-weighted imaging in a fetus with hemimegalencephaly. Ped Radiol 2006;36(2):138-40. PMID 16292644
03: Alfonso I, Vasoncellos E, Shuhaiber HH, Yaylali I, Papazian O. Bilateral decreased oxygenation during focal status epilepticus in a neonate with hemimegalencephaly. J Child Neurol 2004;19(5):394-6. PMID 15224715
04: Andermann F, Palmini A. Neuronal migration disorders, tuberous sclerosis, and Sturge-Weber syndrome. In: Luders HO, editor. Epilepsy surgery. New York: Raven, 1992:203-11.
05: Anik Y, Anik I, Gonullu E, Inan N, Demirci A. Proteus syndrome with syringohydromyelia and arachnoid cyst. Childs Nerv Syst 2007;23(10):199-202. PMID 17593376
06: Antonelli A, Chiaretti A, Amendola T, Piastra M, Di Rocco C, Aloe L. Nerve growth factor and brain-derived neurotrophic factor in human paediatric hemimegalencephaly. Neuropediatrics 2004;35(1):39-44. PMID 15002051
07: Appleton R, Gardner-Medwin D, Mendelow D. Hemispherectomy for intractable seizures. Dev Med Child Neurol 1991;33:273-6. PMID 1902804
08: Baek ST, Gibbs EM, Gleeson JG, Mathern GW. Hemimegalencephaly, a paradigm for somatic postzygotic neurodevelopmental disorders. Curr Opin Neurol 2013;26(2):122-7. PMID 23449172
09: Bahuleyan B, Robinson S, Nair AR, Sivanandapanicker JL, Cohen AR. Anatomic hemispherectomy: historical perspective. World Neurosurg 2013;80(3-4):396-8. PMID 22480976
10: Barkovich AJ. Abnormal vascular drainage in anomalies of neural migration. AJNR Am J Neuroradiol 1988;9:939-42. PMID 3140639
11: Barkovich AJ, Chuang SH, Norman D. MR of neuronal migration anomalies. AJNR Am J Neuroradiol 1987;8:1009-17. PMID 3257118
12: Barth PG, Valk J, Kalsbeek GL, Blom A. Organoid nevus syndrome (linear nevus sebaceous of Jadassohn): clinical and radiological study of a case. Neuropediatrie 1977;8:418-28. PMID 579439
13: Bastos H, Sobral da Silva PF, Veloso de Albuquerque MA, et al. Proteus syndrome associated with hemimegalencephaly and Ohtahara syndrome: Report of two cases. Seizure 2008;17:378-82. PMID 18082431
14: Battistella PA, Peserico A, Bertoli P, Drigo P, Laverda AM, Casara GL. Hypomelanosis of Ito and hemimegalencephaly. Childs Nerv Syst 1990;6:421-3. PMID 1669255
15: Baybis M, Aronica E, Nathanson KL, Crino PB. Deletion of 15q11.2-15q13.1 in isolated human hemimegalencephaly. Acta Neuropathol 2009;118:821-3. PMID 19851776
16: Bermejo AM, Martin VL, Arcas J, Perez-Higueras A. Early infantile epileptic encephalopathy: a case associated with hemimegalencephaly. Brain Dev 1992;14:425-8. PMID 1492660
17: Bignami A, Palladini G, Zappella M. Unilateral megalencephaly with nerve cell hypertrophy: an anatomical and quantitative histochemical study. Brain Res 1968;9:103-14. PMID 5699812
18: Bignami A, Zappella M, Benedetti P. Infantile spasms with hypsarrhythmia: a pathological study. Helv Paediatr Acta 1964;4:326-42. PMID 14229912
19: Boltshauser E, Navratil F. Organoid nevus syndrome in a neonate with hemimacrocephaly. Neuropediatrie 1978;9:195-6. PMID 581224
20: Bruet S, Francannet C, Marguet F, Biard M, Sarret C, Laurichesse Delmas H. Prenatal diagnosis of hemimegalencephaly revealing tuberous sclerosis complex. Ultrasound Obstet Gynecol 2020;55(5):688-9. PMID 31568608
21: Burke JP, West NF, Strachan IM. Congenital nystagmus, anisomyopia, and hemimegalencephaly in the Klippel-Trenaunay-Weber syndrome. J Pediatr Ophthalmol Strabismus 1991;28:41-4. PMID 1850461
22: Caplan R, Chugani HT, Messa C, et al. Hemispherectomy for intractable seizures: presurgical cerebral glucose metabolism and post-surgical non-verbal communication. Dev Med Child Neurol 1993;35:582-92. PMID 9435774
23: Cartwright MS, McCarthy SC, Roach ES. Hemimegalencephaly and tuberous sclerosis complex. Neurology 2005;64(9):1634. PMID 15883333
24: Caviness VS, Pinto-Lord M, Evrard P. The development of laminated patterns in the mammalian neocortex. In: Connelly TG, editor. Morphogenesis and pattern formation. New York: Raven Press, 1981:103-26.
25: Chalhub EG, Volpe JJ, Gado MH. Linear nevus sebaceous syndrome associated with porencephaly and nonfunctioning major cerebral venous sinuses. Neurology 1975;25:857-60. PMID 1172209
26: Chandrasekar I, Tourney A, Loo K, et al. Hemimegalencephaly and intractable seizures associated with the NPRL3 gene variant in a newborn: a case report. Am J Med Genet A 2021;185(7):2126-30. PMID 33749980
27: Chapman K, Cardenas JF. Hemimegalencephaly in a patient with a neurocutaneous syndrome. Semin Pediatr Neurol 2008;15:190-3. PMID 19073327
28: Chrastina J, Novak Z, Brazdil N, Hermanova M. Glioblastoma multiforme in a patient with isolated hemimegalencephaly. J Neurol Surg Rep 2015;76(1):e160-3. PMID 26251796
29: Civardi C, Vicentini R, Collini A, Boccagni C, Cantello R, Monaco F. Motor cortical organization in an adult with hemimegalencephaly and late onset epilepsy. Neurosci Let 2009;460:126-9. PMID 19450654
30: Clancy RR, Kurtz MB, Baker D, Sladky JT, Honig PJ, Younkin DP. Neurologic manifestations of the organoid nevus syndrome. Arch Neurol 1985;42:236-40. PMID 3977653
31: Crino PB. Molecular pathogenesis of focal cortical dysplasia and hemimegalencephaly. J Child Neurol 2005;20(4):330-6. PMID 15921235
32: Cusmai R, Curatalo P, Mangano S, Cheminal R, Echenne B. Hemimegalencephaly and neurofibromatosis. Neuropediatrics 1990;21:179-82. PMID 2127080
33: Dekaban AS, Sakuragawa N. Megalencephaly. In: Vinken PJ, Bruyn GW, editors. Handbook of clinical neurology. Amsterdam: North-Holland, 1977;30:647-60.
34: De Rosa MJ, Secor DL, Barsom M, Fisher RS, Vinters HV. Neuropathological findings in surgically treated hemimegalencephaly: immunohistochemical, morphometric, and ultrastructural study. Acta Neuropathol 1992;84:250-60. PMID 1414279
35: Devlin AM, Cross JH, Harkness W, et al. Clinical outcomes of hemispherectomy for epilepsy in childhood and adolescence. Brain 2003;126(Pt. 3):556-66. PMID 12566277
36: Di Rocco C, Battaglia D, Pietrini D, Piastra M, Massimi L. Hemimegalencephaly: clinical implications and surgical treatment. Childs Nerv Sys 2006;22(8):852-66. PMID 16821075
37: D’Gama AM, Geng Y, Couto JA, et al. Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann Neurol 2015;77(4):720-5.** PMID 25599672
38: D’Gama AM, Woodworth MB, Hossain AA, et al. Somatic mutations activating the mTOR pathway in dorsal telencephalic progenitors cause a continuum of cortical dysplasias. Cell Rep 2017;21(13):3754-66. PMID 29281825
39: Dobyns WB, Garg BP. Vascular abnormalities in epidermal nevus syndrome. Neurology 1991;41:276-8. PMID 1992375
40: El-Shanti H, Bell WE, Waziri MH. Epidermal nevus syndrome: subgroup with neuronal migration defects. J Child Neurol 1992;7:29-34. PMID 1552148
41: Enokizono M, Sato N, Ota M, et al. Disrupted cortico-ponto-cerebellar pathway in patients with hemimegalencephaly. Brain Dev 2019;41(6):507-15. PMID 30665821
42: Fariello G, Malena S, Lucigrai G, Toma P. Hemimegalencephaly: early sonographic pattern. Pediatr Radiol 1993;23:151-2. PMID 8516043
43: Feld M, Gruner J, Heuyer G. Hétérotopies volumineuses et malformations de l'hémisphère droit. Hydrocéphalie avec lésions destructives de l'hemisphère gauche, seules cliniquement traduites. Rev Neurol 1955;92:26-35.
44: Fitz CR, Harwood-Nash DC, Boldt DW. The radiographic features of unilateral megalencephaly. Neuroradiology 1978;15:145-8. PMID 673168
45: Flores-Sarnat L. Epilepsy in neurological phenotypes of epidermal nevus syndrome. J Pediatr Epilepsy 2016a;5:97-110.**
46: Flores-Sarnat L. Hemimegalencephaly: part 1. Genetic, clinical, and imaging aspects. J Child Neurol 2002;17(5):373-84. PMID 12150586
47: Flores-Sarnat L. Hemimegalencephaly syndrome. In: Sarnat HB, Curatolo P, editors. Malformations of the nervous system. Amsterdam: Elsevier, 2007:153-76.
48: Flores-Sarnat L. Heide’s syndrome: infantile spasms, epidermal nevus, PIK3CA-related overgrowth spectrum. Presented at: 70th Annual Meeting of the American Epilepsy Society; December 2-6, 2016b; Houston, Texas.
49: Flores-Sarnat L. Epidermal nevus syndrome. Handb Clin Neurol 2013;111:349-68. PMID 23622186
50: Flores-Sarnat L, Sarnat HB, Davila-Gutierrez G, Alvarez A. Hemimegalencephaly: part 2. Neuropathology suggests a disorder of cellular lineage. J Child Neurol 2003;18(11):776-85. PMID 14696906
51: Fusco L, Bertini E, Vigevano F. Epilepsia partialis continua and neuronal migration anomalies. Brain Dev 1992b;14:323-8. PMID 1456388
52: Fusco L, Ferracuti S, Fariello G, Manfredi M, Vigevano F. Hemimegalencephaly and normal intellectual development. J Neurol Neurosurg Psychiatry 1992a;55:720-2. PMID 1326602
53: Galluzzi P, Cerase A, Strambi M, Buoni S, Fois A, Venturi C. Hemimegalencephaly in tuberous sclerosis complex. J Child Neurol 2002;17(9):677-80. PMID 12503644
54: Garcia CAB, Carvalho SCS, Yang X, et al. mTOR pathway somatic variants and the molecular pathogenesis of hemimegalencephaly. Epilepsia Open 2020;5(1):97-106. PMID 32140648
55: George RE, Hoffman HJ, Hwang PA, Becker LE, Chuang SH. Management of intractable seizures in unilateral megalencephaly. J Epilepsy 1990;3:305-13.
56: Gerasimenko A, Baldassan S, Baulac S. mTOR pathway: insights into an established pathway for brain mosaicism in epilepsy. Neurobiol Dis 2023;182:106144. PMID 37149062
57: Giuliano F, David A, Edery P, et al. Macrocephaly-cutis marmorata telangiectatica congenital: seven cases including two with unusual cerebral malformations. Am J Med Genet A 2004;126(1):99-103. PMID 15039980
58: Goel K, Ghadiuyaram A, Krishnaakumar A, et al. Hemimegalencephaly: a systematic comparison of functional and anataomic hemispherectomy for drug-resistant epilepsy. Neurosurgery 2024;94(4):666-78. PMID 37975663
59: Griffin NG, Cronin KD, Walley NM, et al. Somatic uniparental disomy of Chromosome 16p in hemimegaloencephaly. Cold Spring Harb Mol Case Stud 2017;3(5). PMID 28864461
60: Gross H, Uiberrak B. Klinisch-anatomische befunde bei hemimegalencephalie: Über die stellung der cerebralen hyperplasie und des örtlichen riesenwuchses innerhalab der phakomatosen. Virchows Arch [A] 1955;327:577-89.
61: Guerra MP, Cavalleri F, Migone N, et al. Intractable epilepsy in hemimegalencephaly and tuberous sclerosis complex. J Child Neurol 2007;22(1):80-4. PMID 17608312
62: Gurecki PJ, Holden KR, Sahn EE, Dyer DS, Cure JK. Developmental neural abnormalities and seizures in epidermal nevus syndrome. Dev Med Child Neurol 1996;38:716-23. PMID 8761167
63: Hager BC, Dyme IZ, Guertin SR, Tyler RJ, Tryciecky EW, Fratkin JD. Linear nevus sebaceous syndrome: megalencephaly and heterotopic gray matter. Pediatr Neurol 1991;7:45-9. PMID 2029293
64: Hallervorden J. Angeborene Hemihypertrophie der linken Körperhälfte einschlie(lich des Gehirns. Zentralbl Neurol Psychiatr 1923;33:518-9.
65: Hallervorden J. Microscopic findings in brain in case of congenital hemihypertrophy of left side of body including brain. Dtsh Z Nervenheilkd 1926;89:28-42.
66: Hirashima Y, Endo S, Karasawa K, et al. Deficient platelet-activating factor and related enzymes in hemimegalencephaly. Childs Nerv Syst 1999;15:98-101. PMID 10230665
67: Hung PC, Wang HS. Hemimegalencephaly: cranial sonographic findings in neonates. J Clin Ultra 2005;33(5):243-7. PMID 16047376
68: Ikeda KM, Mirsattari SM. Evolution of epilepsy in hemimegalenchephaly from infancy to adulthood: case report and review of the literature. Epilepsy Behav Case Rep 2017;7:45-8. PMID 28377884
69: Jachowicz-Jeszka J, Juchniewicz B, Torsztejn H, Wilkowski J, Wendorff J. Linear nevus sebaceous syndrome with hemimegalencephaly diagnosis in a child in the neonatal period. Polski Merkuriusz Lekarski 2005;18(105):310-3. PMID 15997640
70: Jaiswal V, Hanif M, Sarfraz Z, et al. Hemimegalencephaly: a rare congenital malformation of cortical development. Clin Case Rep 2021;9:e05238. PMID 34976397
71: Jansen LA, Mirzaa GM, Ishak GE, et al. PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain 2015;138(Pt 6):1613-28. PMID 25722288
72: Jeon TY, Poliakov AV, Friedman SD, et al. Structural MRI and tract-based spatial statistical analysis of diffusion tensor imaging in children with hemimegalencephaly. Neuroradiology 2020;62(11):1467-74. PMID 32651620
73: Jonas R, Nguyen S, Hu B, et al. Cerebral hemispherectomy: hospital course, seizure, developmental, language, and motor outcomes. Neurology 2004;62(10):1712-21. PMID 15159467
74: Juric-Sekhar G, Hevner RF. Malformations of cerebral cortex development: molecules and mechanisms. Annu Rev Pathol 2019;14:293-318. PMID 30677308
75: Kakish D, Tominna M, Krishnan A. Hemimegalencephaly: evolution from an atypical focal early appearance on fetal MRI to more conventional MR findings. Cureus 2022;14(8):e27976. PMID 36120272
76: Kalifa G, Chiron C, Sellier N, et al. Hemimegalencephaly: MR imaging in five children. Radiology 1987;165:29-33. PMID 3628788
77: Kawai K, Morino M, Iwasaki M. Modification of vertical hemispherotomy for refractory epilepsy. Brain Dev 2014;36(12):124-9. PMID 23422258
78: Kiehna EN, Widjaja E, Holowka S, et al. Utility of diffusion tensor imaging studies linked to neuronavigation and other modalities in repeat hemispherotomy for intractable epilepsy. J Neurosurg Pediatr 2016;17(4):483-90. PMID 26651159
79: King M, Stephenson JB, Ziervogel M, Doyle D, Galbraith S. Hemimegalencephaly: a case for hemispherectomy. Neuropediatrics 1985;16:46-55. PMID 3974804
80: Klancir KP, Habek D, Duranovic V, Batos AT, Rosko SP, Stanojevic M. Hemispherectomy in an infant with hemimegalencephaly and Ohtahara syndrome. Wien Med Wochenschr 2024;174(5-6):107-10. PMID 37071300
81: Komenati H, Sugai K, Yoshiaki S, et al. Postnatal evolution of cortical malformation in the "non-affected" hemisphere of hemimegalencephaly. Brain Dev 2010;32:412-6. PMID 19345027
82: Konkol RJ, Maister BH. Relevance of EEG to prognosis in hemimegalencephaly. Dev Med Child Neurol 1989;31:827-8. PMID 2599276
83: Konkol RJ, Maister BH, Wells RG, Sty JR. Hemimegalencephaly: clinical, EEG, neuroimaging, and IMP-SPECT correlation. Pediatr Neurol 1990;6:414-8. PMID 2073303
84: Krynauw RA. Infantile hemiplegia. Proc R Soc Med 1950;46:431-4.
85: Kumar I, Aggarwal P, Rai T, Gupta V. Posterior quadrantic dysplasia with localized hemimegalencephaly in a patient with giant congenital melanocytic nervus: first case report. Neuroradiol J 2019;32(3):210-4. PMID 30794039
86: Kumar RM, Koh S, Knupp K, Handler MH, O'Neill BR. Surgery for infants with catastrophic epilepsy: an analysis of complications and efficacy. Childs Nerv Syst 2015;31(9):1479-91. PMID 26022500
87: Kurokawa T, Sasaki K, Hanai T, Goya N, Komaki S. Linear nevus sebaceous syndrome: report of a case with Lennox-Gastaut syndrome following infantile spasms. Arch Neurol 1981;38:375-7. PMID 6972208
88: Kuzniecky RI. Magnetic resonance imaging in developmental disorders of the cerebral cortex. Epilepsia 1994;35(Suppl 6):S44-56. PMID 8206014
89: Lam AH, Villanueva AC, De Silva M. Hemimegalencephaly. Cranial sonographic findings. J Ultrasound Med 1992;11:241-4. PMID 1588696
90: Laurence KM. A case of unilateral megalencephaly. Dev Med Child Neurol 1964;6:585-90. PMID 14248476
91: Lee JH, Huynh M, Silhavy JL, et al. De novo somatic mutations in components of the P13K-AKT3-mTOR pathway cause hemimegalencephaly. Nature Genet 2012;44(8):941-5. PMID 22729223
92: Lindhurst MJ, Sapp JC, Teer JK, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 2011;365(7):611-9. PMID 21793738
93: Liu Q, Zhao W, Zhou G. Adult hemimegalencephaly with migraine as the first symptom. Neurol India 2022;70(2):788-9. PMID 35532662
94: Loddenkemper T, Alexopoulos AV, Kotagal P, et al. Epilepsy surgery in epidermal nevus syndrome variant with hemimegalencephaly and intractable seizures. J Neurol 2008;255;1829-31. PMID 19009333
95: Luders H, Schuele SU. Epilepsy surgery in patients with malformations of cortical development. Cur Op Neurol 2006;19(2):169-74. PMID 16538092
96: Manoranjan B, Provias JP. Hemimegalencephaly: a fetal case with neuropathological confirmation and review of the literature. Acta Neuopathol 2010;120:117-30. PMID 20237789
97: Manz HJ, Phillips TM, Rowden G, McCullough DC. Unilateral megalencephaly, cerebral cortical dysplasia, neuronal hypertrophy, and heterotopia: cytomorphometric, fluorometric, cytochemical, and biochemical analyses. Acta Neuropathol 1979;45:97-103. PMID 419942
98: Marras CE, Granata T, Franzini A, et al. Hemispherotomy and functional hemispherectomy: indications and outcome. Epil Res 2010;89:104-12. PMID 19883995
99: Matsubara O, Tanaka M, Ida T, Okeda R. Hemimegalencephaly with hemihypertrophy: Klippel-Trenaunay-Weber syndrome. Virchows Arch A Pathol Anat Histopathol 1983;400:155-62. PMID 6310854
100: McCall S, Ramzy MI, Curé JK, Pai GS. Encephalocraniocutaneous lipomatosis and the Proteus syndrome: distinct entities with overlapping manifestations. Am J Med Genet 1992;43:662-8. PMID 1621755
101: Menkes JH. Textbook of child neurology. Philadelphia: Lea & Febiger, 1990.
102: Mikhael MA, Mattar AG. Malformation of the cerebral cortex with heterotopia of the gray matter. J Comput Assist Tomogr 1978;2:291-6. PMID 263492
103: Mohamed K, Elmalik EE, Bakry M, Bayoumi MAA. Refractory neonatal seizures caused by hemimegalencephaly. BMJ Case Rep 2022;15(9):e251587. PMID 36104033
104: Montenegro MA, Kinay D, Cendes F, et al. Patterns of hippocampal abnormalities in malformations of cortical development. J Neuro Neurosurg Psych 2006;77(3):367-71. PMID 16484646
105: Mori H, Aoki S, Abe O, et al. Diffusion property following functional hemispherectomy in hemimegalencephaly. Acta Radiologica 2004;45(7):778-81. PMID 15624522
106: Muhlebner A, Bongaarts A, Sarnat HB, Scholl T, Aronica E. New insights into a spectrum of developmental malformations related to mTOR dyregulations: challenges and perspectives. J Anat 2019;235(3):521-42. PMID 30901081
107: Nishimaki S, Endo M, Seki K, Yokota S. Hemimegalencephaly misdiagnosed as a congenital brain tumor by fetal cerebral ultrasonography. Prenat Diagn 2004;24(4):257-9. PMID 15065098
108: Norman RM. Malformations of the nervous system, birth injury and diseases of early life. In: Blackwood W, McMenemey WH, Meyer A, Norman RM, Russell DS, editors. Greenfield's neuropathology. 2nd ed. Baltimore: Williams & Wilkins, 1963:324-440.
109: Obradocic S, Belutic B, Stojkovic-Andelkovic A, Igrutinovic Z. Report of a newborn with hemimegalencephaly in association with Klippel-Trenaunay-Weber syndrome. Srpski Arhiv Za Celojupno Lekarstvo 2005;133(1-2):62-4. PMID 16053178
110: Ogihara M, Kinoue K, Takamiya H, Nemoto S. A case of early infantile epileptic encephalopathy (EIEE) with anatomical cerebral asymmetry and myoclonus. Brain Dev 1993;15:133-9. PMID 8214333
111: O’Kusky JR, Akers MA, Vinters HV. Synaptogenesis in hemimegalencephaly: the numerical density of asymmetric and symmetric synapses in the cerebral cortex. Acta Neuropathol 1996;92:156-163. PMID 8841661
112: Paladin F, Chiron C, Dulac O, Plouin P, Ponsot G. Electroencephalographic aspects of hemimegalencephaly. Dev Med Child Neurol 1989;31:377-83. PMID 2753242
113: Palmini A, Andermann F, Olivier A, et al. Neuronal migration disorders: a contribution of modern neuroimaging to the etiologic diagnosis of epilepsy. Can J Neurol Sci 1991;18(Suppl 4):580-7. PMID 1777874
114: Palmini A, Gambardella A, Andermann F, et al. Operative strategies for patients with cortical dysplastic lesions and intractable epilepsy. Epilepsia 1994;35(Suppl 6):S57-71. PMID 8206015
115: Parmar H, Parkar D, Shah J, Patankar T. Hemimegalencephaly with tuberous sclerosis: a longitudinal imaging study. Australas Radiol 2003;47(4):438-42. PMID 14641199
116: Pavlidis E, Cantalupo G, Boria S, Cossu G, Pisani F. Hemimegalencephalic variant of epidermal nevus syndrome: case report and literature review. Eur J Paediatr Neurol 2012;16:332-42. PMID 22200538
117: Pavone L, Curatolo P, Rizzo R, et al. Epidermal nevus syndrome: a neurologic variant with hemimegalencephaly, gyral malformation, mental retardation, seizures, and facial hemihypertrophy. Neurology 1991;41:266-71. PMID 1992373
118: Peacock WJ, Comair YG, Hovda S. Hemispherectomy for intractable seizures. In: Apuzzo MLJ, editor. Neurosurgical aspects of epilepsy. Park Ridge (IL): American Association of Neurological Surgeons Publications Committee, 1991.
119: Pelayo R, Barasch E, Kang H, Marion R, Moshé SL. Progressively intractable seizures, focal alopecia, and hemimegalencephaly. Neurology 1994;44:969-71. PMID 8190309
120: Peserico A, Battistella PA, Bertoli P, Drigo P. Unilateral hypomelanosis of Ito with hemimegalencephaly. Acta Paediatr Scand 1988;77:446-7. PMID 3389141
121: Piastra M, Pietrini D, Caresta E, et al. Hemispherectomy procedures in children: haematological issues. Childs Nerv Syst 2004;20(7):453-8. PMID 15503368
122: Ream M. Hypomelanosis of Ito. Handb Clin Neurol 2015;132:281-9. PMID 26564088
123: Rintahaka PJ, Chugani HT, Messa C, Phelps ME. Hemimegancephaly: evaluation with positron emission tomography. Pediatr Neurol 1993;9:21-8. PMID 8452595
124: Robain O, Floquet CH, Heldt N. Rozenberg F. Hemimegalencephaly: a clinicopathological study of four cases. Neuropathol Appl Neurobiol 1988;14:125-35. PMID 3399023
125: Rodin RE, Walsh CA. Somatic mutation in pediatric neurological diseases. Pediatr Neurol 2018;87:20-2. PMID 30249355
126: Romero XC, Molina FS, Pastor E, Amaya F. Hemimegalencephaly: 2D, 3D ultrasound and MRI correlation. Fetal Diagn Ther 2011;29(3):257-60. PMID 21109730
127: Ronen GM, Meaney B, Dan B, Zimprich F, Stogmann W, Neugebauer W. From eugenic euthanasia to habilitation of “disabled” children: Andreas Rett’s contribution. J Child Neurol 2009;24(1):115-27. PMID 19168827
128: Ronnett GV, Hester LD, Nye JS, Connors K, Snyder SH. Human cortical neuronal line: establishment from a patient with unilateral megalencephaly. Science 1990;248:603-5. PMID 1692158
129: Ross GW, Miller JQ, Persing JA, Urich H. Hemimegalencephaly, hemifacial hypertrophy and intracranial lipoma: a variant of neurofibromatosis. Neurofibromatosis 1989;2:69-77. PMID 2516459
130: Rugel SJ. Congenital hemihypertrophy: report of a case with postmortem observations. Am J Dis Child 1946;71:530-6. PMID 20986607
131: Sakuma H, Iwata O, Sasaki M. Longitudinal MR findings in a patient with hemimegalencephaly associated with tuberous sclerosis. Brain Dev 2005;27(6):458-61. PMID 16122638
132: Sakuta R, Aikawa H, Takashima S. Epidermal nevus syndrome with hemimegalencephaly: neuropathological study. Brain Dev 1991;13:260-5. PMID 1957975
133: Salamon N, Andres M, Chute DJ, et al. Contralateral hemimicrencephaly and clinical-pathological correlations in children with hemimegalencephaly. Brain 2006;129(Pt2):253-65. PMID 16291806
134: Santana-Ramírez A, Farias Serratos F, Sánchez-Corona J, Castaneda-Cisneros G, Farias-Serratos NM. Hemimegalencephaly with facial congenital infiltrating lipomatosis in a child. Iranian J Publ Health 2014;43(12):1702-9. PMID 26171364
135: Sarnat HB. Cerebral dysgenesis: embryology and clinical expression. New York: Oxford Univ Pr, 1992:348-54.
136: Sarnat HB. New neuropathological concepts in focal cortical dysplasias. In: Wyllie E, editor. Wyllie’s treatment of epilepsy. 7th edition. Philadelphia: Lippincott Williams & Wilkins, 2021:263-71.
137: Sarnat HB, Flores-Sarnat L. Infantile tauopathies: hemimegalencephaly; tuberous sclerosis complex; focal cortical dysplasia 2; ganglioglioma. Brain Dev 2015;37(6):553-62. PMID 25451314
138: Sarnat HB, Flores-Sarnat L. Morphogenesis timing of genetically programmed brain malformations in relation to epilepsy. Prog Brain Res 2014;213:181-98. PMID 25194490
139: Sarnat HB, Flores-Sarnat L, Crino PB, Hader W, Bello-Espinosa L. Hemimegalencephaly: fetal tauopathy with mTOR hyperactivation and neuronal lipidosis. Folia Neuropathol 2012:50(4):330-45.** PMID 23319189
140: Sarnat HB, Philippart M, Flores-Sarnat L, Wei XC. Timing in neural maturation: arrest, delay, precociousness, and temporal determination of malformations. Pediatr Neurol 2015;52(5):473-86.** PMID 25797487
141: Sarwar M, Schafer ME. Brain malformations in linear nevus sebaceous syndrome: an MR study. J Comput Assit Tomogr 1988;12:338-40. PMID 3351053
142: Sasaki M, Hashimoto T, Furushima W, et al. Clinical aspects of hemimegalencephaly by means of a nationwide survey. J Child Neurol 2005;20(4):337-41. PMID 15921236
143: Sato N, Yagishita A, Oba H, et al. Hemimegalencephaly: a study of abnormalities occurring outside the involved hemisphere. AJNR Am J Neuroradiol 2007;28(4):678-82. PMID 17416820
144: Sepulveda W, Sepulveda F, Schonstedt V, Stern J, Diaz-Serani R. Neuroimaging findings in fetal hemimegalencephaly: case study and review. Fetal Diagn Ther 2024;51(2):133-44. PMID 38008087
145: Serletis D, MacDonald C, Xu Q, et al. Hemispherectomy for hemimegalencephaly in a 6.5-week-old infant with tuberous sclerosis complex. Childs Nerv Syst 2022;38(7):1415-9. PMID 35022853
146: Shimizu H. Our experience with pediatric epilepsy surgery focusing on corpus callosotomy and hemispherotomy. Epilepsia 2005;46 Suppl 1:30-1. PMID 15816976
147: Sidira C, Vargiami E, Dragoumi P, Zafeiriou DI. Hemimegalencephaly and tuberous sclerosis complex: a rare yet challenging association. Eur J Paediatr Neurol 2021;30:58-65. PMID 33387903
148: Sims JM. On hypertrophy and atrophy of the brain. Med Chir Trans 1835;19:315-80. PMID 20895622
149: Singh SA, Sampath S, Nathan R, Nair M. Hypomelanosis of Ito. Indian J Pediatr 2004;71(10):947. PMID 15531845
150: Smith S, Andermann F, Villemure JG, Rasmussen TB, Quesney LF. Functional hemispherectomy: EEG findings, spiking from isolated brain and prediction of outcome. Neurology 1991;41:1790-4. PMID 1944910
151: Soufflet C, Bulteau C, Delanlande O, et al. The non-malformed hemisphere is secondarily impaired in young children with hemimegalencephaly: a pre- and postsurgery study with SPECT and EEG. Epilepsia 2004;45(11):1375-82. PMID 15509238
152: Takahashi T, Sato N, Ota M, et al. Asymmetrical interhemispheric fiber tracts in patients with hemimegalencephaly on diffusion tensor magnetic resonance imaging. J Neuroradiol 2009;36:249-54. PMID 19783304
153: Thakor B, Deshmukh Y, Japtap SA, Kurwale N. Ictal and interictal arterial spin labelling (ASL) in hemimegalencephaly. Ann Indian Acad Neurol 2021;24(5):763-4. PMID 35002138
154: Tijiam AT, Stefando S, Schenk VWD, de Vlieger M. Infantile spasms associated with hemihypsarrhythmia and hemimegalencephaly. Dev Med Child Neurol 1978;20:779-89. PMID 729931
155: Tinkle BT, Schorry EK, Franz DN, Crone KR, Saal HM. Epidemiology of hemimegalencephaly: a case series and review. Am J Med Genet A 2005;139(3):204-11. PMID 16283674
156: Tinuper P, Andermann F, Villemure J, Rasmussen TB, Quesney LF. Functional hemispherectomy for treatment of epilepsy associated with hemiplegia: rationale, indications, results, and comparison with callosotomy. Ann Neurol 1988;24:27-34. PMID 3137858
157: Townsend JJ, Nielsen SL, Malamud N. Unilateral megalencephaly: hamartoma or neoplasm. Neurology 1975;25:448-53. PMID 1169702
158: Trounce JQ, Rutter N, Mellor DH. Hemimegalencephaly: diagnosis and treatment. Dev Med Child Neurol 1991;33:261-6. PMID 1902803
159: Tsuru A, Mizuguchi M, Uyemura K, Becker L, Takashima S. Immunohistochemical expression of Cell Adhesion Molecule L1 in hemimegalencephaly. Pediatr Neurol 1997;16:45-9. PMID 9044401
160: Vásquez A, Miller KJ, Youssef PE, Selcen D, Patterson MC, Starnes K. A case report of hemimegalencephaly with super-refractory status epilepticus and brain atrophy associated with NPRL3 gene mutation. Seizure 2024;116:156-8. PMID 36842889
161: Vigevano F, Bertini E, Boldrini R, et al. Hemimegalencephaly and intractable epilepsy: benefits of hemispherectomy. Epilepsia 1989;30:833-4. PMID 2591346
162: Vigevano F, Di Rocco C. Effectiveness of hemispherectomy in hemimegalencephaly with intractable seizures. Neuropediatrics 1990;21:222-3. PMID 2290487
163: Vinters HV, Fisher RS, Cornford ME, et al. Morphological substrates of infantile spasms: studies based on surgically resected cerebral tissue. Childs Nerv Syst 1992;8:8-17. PMID 1315619
164: Volpe JJ. Brain injury in the premature infant: is it preventable. Pediatr Res 1990;27(6 Suppl):S28-33. PMID 2192350
165: Volpe JJ. Neurology of the newborn. 3rd ed. Philadelphia: WB Saunders, 1995:50-86.
166: Vurucu S, Battal B, Kocaoglu M, Akin R. Klippel-Trenaunay syndrome with hemimegalencephaly, retroperitoneal lymphangioma and double inferior vena cava. Brit J Rad 2009;82:e102-4. PMID 19386952
167: Wang DD, Knox R, Rolston JD, et al. Surgical management of medically refractory epilepsy in patients with polymicrogyria. Epilepsia 2016;57(1):151-61. PMID 26647903
168: Webster JHD. A case of unilateral cerebral hyperplasia, with co-existent "acromegaly" of the feet, and a slight degree of unilateral gigantism. J Pathol Bacteriol 1908;12:306-21.
169: Weil AG, Lewis EC, Ibrahim GM, et al. Hemispherectomy outcome prediction scale; development and validation of a seizure freedom prediction tool. Epilepsia 2021;62(5):1064-73. PMID 33713438
170: Wojtowicz A, Duczkowska A, Huras H. A rare case of hemimegalencephaly diagnosed prenatally. Ginekol Pol 2022;93(8):677-8. PMID 35894497
171: Wolpert SM, Cohen A, Libenson MH. Hemimegalencephaly: a longitudinal MR study. Am J Neuroradiol 1994;15:1479-82. PMID 7985566
172: Xu Q, Uliel-Sibony S, Dunham C, et al. mTOR inhibitors as a new therapeutic strategy in treatment resistant epilepsy in hemimegalencephaly: a case report. J Child Neurol 2019;34(3):132-8. PMID 30514132
173: Yamazaki M, Chan D, Tovar-Spinoza Z, et al. Interictal epileptogenic fast oscillations on neonatal and infantile EEGs in hemimegalencephaly. Epilepsy Res 2009;83:198-206. PMID 19118979
174: Yasha TC, Santosh V, Das S, Shankar SK. Hemimegalencephaly—morphological and immunocytochemical study. Clin Neuropathol 1997;16:17-22. PMID 9020389
175: Yasin SA, Latak K, Becherini F, et al. Balloon cells in human cortical dysplasia and tuberous sclerosis: isolation of a pathological progenitor-like cell. Acta Neuropathol 2010;120(1):85-96. PMID 20352236
176: Yu J, Baybis M, Lee A, et al. Targeted gene expression analysis in hemimegalencephaly: activation of beta-catenin signaling. Brain Pathol 2005;15(3):179-86. PMID 16196383
177: Zaremba J, Wislawski J, Bidzinski J, Kansy J, Sidor B. Jadassohn's naevus phakomatosis: a report of two cases. J Ment Defic Res 1978;22:91-102. PMID 671535

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Harvey B Sarnat MS MD FRCPC

Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.
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Laura Flores-Sarnat MD

Dr. Flores-Sarnat of the University of Calgary has no relevant financial relationships to disclose.
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Editor

Bernard L Maria MD

Dr. Maria of Thomas Jefferson University has no relevant financial relationships to disclose.
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Former Authors

David A Griesemer MD
Thea J Williams MD
Robert P Turner MD
G Nicole Brockway MD
Yong D Park MD
Kimon Bekelis MD
Robert J Singer MD
H Westley Phillips MD
Nicholas Macaluso BS
Aria Fallah MD

Patient Profile

Age range of presentation: 0 month to 5 years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

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Hemimegalencephaly

Associated Disorders

Epidermal nevus syndrome
Klippel-Trenaunay-Weber syndrome
Linear nevus sebaceous syndrome
Neurofibromatosis
Hypomelanosis of Ito
- Proteus syndrome

Differential Diagnosis

craniosynostosis
obstructive hydrocephalus
communicating hydrocephalus
subdural hematoma
subdural effusion
- benign external hydrocephalus
- Canavan disease
- Alexander disease
- Tay-Sachs disease
- mucopolysaccharidoses
- Sotos syndrome (cerebral gigantism)
- Beckwith syndrome
- Neurofibromatosis
- neurocutaneous syndromes
- tuberous sclerosis
- achondroplasia
- Sturge-Weber syndrome
- Klippel-Trenaunay-Weber syndrome
- cutis marmorata telangiectasia congenital
- megalencephaly capillary malformation
- linear nevus sebaceous syndrome
- epidermal nevus syndrome
- hypomelanosis of Ito
- Proteus syndrome

Also Relevant

Aicardi syndrome
Colpocephaly
Epidermal nevus syndromes: neurologic phenotypes
Epilepsy
Epilepsy surgery in children
- Focal cortical dysplasias
- Hypomelanosis of Ito
- Megalencephaly
- Neurocutaneous syndromes

Clinical Categories

Developmental Malformations

Hemimegalencephaly …

Hemimegalencephaly

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Also in This Category

X-linked hydrocephalus (L1 syndrome)

Cerebro-oculo-facio-skeletal syndrome

Schizencephaly

Fetal anticonvulsant syndrome

Rhombencephalosynapsis

Malformations of the brain

Von Hippel-Lindau disease

Vein of Galen malformations

Hemimegalencephaly

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

X-linked hydrocephalus (L1 syndrome)

Cerebro-oculo-facio-skeletal syndrome

Schizencephaly

Fetal anticonvulsant syndrome

Rhombencephalosynapsis

Malformations of the brain

Von Hippel-Lindau disease

Vein of Galen malformations

This is an article preview.
Start a Free Account
to access the full version.