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X-linked myotubular (centronuclear) myopathy is a severe muscle disorder mainly affecting newborn boys, but sometimes it can also affect girls. Diagnostic
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This article includes discussion of hemimegalencephaly, hemimacrocephaly, unilateral macrocephaly, and unilateral megalencephaly. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
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 1 cerebral hemisphere of the developing baby. The clinical hallmark is early onset intractable focal epilepsy with associated hemiparesis and developmental delays. Hemimegalencephaly may occur in the context of a defined syndrome, emphasizing the importance of comprehensive history and examinations being performed. Occasionally, unilateral cerebral enlargement may also involve brainstem and cerebellum, as well as rare hypertrophy of the face or body. Intractable epilepsy is virtually universally refractory to antiepileptic medications, and cerebral hemispherectomy is almost always the treatment of choice. As this update demonstrates, hemimegalencephaly is likely a heterogeneous group of disorders with distinct pathophysiologic characteristics resulting in a shared clinical presentation. Outcomes are variable, are dependent on degree of neuronal abnormalities, and are often dependent on surgical intervention. Initial studies investigating the genetic and histologic footprint of hemimegalencephaly are promising, but further studies are required to better understand the underlying mechanisms of the disease. Currently, pharmacologic, surgical, and developmental interventions remain at the forefront of long-term treatment strategies.
• Hemimegalencephaly is likely a diverse group of disorders with the common feature of enlargement and abnormal cellular structure of one cerebral hemisphere.
• Patients can present from birth to young adulthood.
• Common presenting symptoms include hemiparesis, intractable epilepsy, and developmental delay.
• Hemimegalencephaly may be associated with neurocutaneous syndromes.
• Early surgical intervention for intractable epilepsy may lead to improved epileptic and developmental prognosis.
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 (120; 43; 76; 20; 128; 44; 86; 80; 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 (57).
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 (36; 83; 129). Most early descriptions of hemimegalencephaly were of patients with both brain and somatic hemihypertrophy (138; 58; 111). Thus, comprehensive history and examination remain the foundation of evaluation of any patient with apparent hemimegalencephaly. Though rare, misdiagnosis of hemimegalencephaly may occur in the context of a contralateral small hemisphere (hemimicrencephaly) secondary to ischemia, heterotopias, or other neuronal migrational abnormalities (104; 114; 118).
Epilepsy, which develops in most children with hemimegalencephaly, is typically refractory to medical management (107; 94), and resective epilepsy surgery (hemispherectomy) remains the treatment of choice in most cases (131; 119; 39; 78; 114; 77; 66; 137). 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 (71). 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 (127; 99; 39).
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 (117). 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 (72). Most infants have focal seizures involving the arm and leg contralateral to the side of hemimegalencephaly (94). In some cases, both epilepsia partialis continua (132; 47) 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 (21; 125; 94; 133; 105). Hemimegalencephaly may also present as an infantile myoclonic epilepsy (19; 92; 100), Ohtahara syndrome (15), or later evolve to Lennox-Gastaut syndrome (73).
Cranial asymmetry is apparent during the neonatal period, but commonly missed if the skull is not examined carefully from above (134). 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.
Milder symptoms and later onset of seizures may occur presumably due to less severe cytoarchitectural abnormalities (132; 100; 32), especially if hemimegalencephaly occurs in the context of neurofibromatosis or tuberous sclerosis complex (35; 27; 112). In occasional patients, intellectual function may be normal (48; 32).
The prognosis of children with hemimegalencephaly is variable given the heterogeneous amounts of neuronal malformation seen across the spectrum of this disease (129). However, it has been noted that the appearance of seizures prior to 1 month of age foreshadows a poor prognosis (125; 64), whereas seizures beginning after the age of 7 portend a better functional outcome. Additionally, status epilepticus may be a cause of early death (67; 107). Patients with hemimegalencephaly surviving to adulthood without hemispherectomy is uncommon (61). 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 report 1 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 (61).
A Caucasian female 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 had had developmental delays, most notable with delayed walking at 15 months and delayed expressive language, and had been receiving physical and speech therapies. Exam showed an alert, interactive female without neurocutaneous markers or neurometabolic odors. Head circumference was 75% 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, the patient 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 safely and successfully completed and patient has been seizure free for 5 years postsurgery, continuing to make substantial gains in neurodevelopmental profile.
The etiology of hemimegalencephaly is currently unknown.
Hemimegalencephaly is characterized by excessive proliferation of both neurons and astrocytes.
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 (12; 45; 46).
In addition to diffuse enlargement of the cerebral cortex, there is typically dilatation of the ipsilateral ventricle and expansion of the hemisphere beyond the midline.
Neuropathological findings also include abnormal neuronal growth and cytomorphology in both gray and white matter (46), abnormal neuronal lamination (76; 37; 06), abnormal neuronal orientation (53), and neuronal and leptomeningeal glioneuronal heterotopias (90; 79).
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 (93). Most cases are also characterized by gliosis (125; 132). Giant neurons and glial cells ("balloon cells"), reminiscent of those seen in tuberous sclerosis, are commonly seen (128; 107; 37; 115), but in a generalized rather than nodular or periventricular distribution; excessive dendritic development is also seen (106). Studies have shown these balloon cells to be immunoreactive for the mTor substrates phospho-ribosomal S6 protein similar to cells in tuberous sclerosis (17). Occasionally, however, the cortical dysplasia appears mild (37). Pathological or autopsy findings often reveal a variety of complex histologic and phenotypic manifestations in hemimegalencephaly, which, when understood better, may lead to a better understanding of the molecular pathogenesis and epileptogenesis (22; 79).
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 heterotopias. Such neurons may also contribute to the epileptogenicity associated with clinical hemimegalencephaly (46).
Mechanisms underlying development of hemimegalencephaly are not known. However, there appear to be several pathomorphological patterns—the first with lesions resembling cerebral lesions of tuberous sclerosis and the second with disturbances of neuronal migration accompanied by abnormal gyration (141; 46). In fact, the clinical association of hemimegalencephaly and tuberous sclerosis complex has been reported (49; 97; 54). This association has been reported despite immunohistochemical studies that suggest that abnormal neurons in hemimegalencephaly are distinct from those of tuberous sclerosis in that the former show no immunoreactivity for glial markers, whereas those for tuberous sclerosis express glial markers (24).
An insult to the developing brain during the first or second trimester has been suggested in order to explain polymicrogyria, overgrowth of glial structures, and accelerated neuronal differentiation that occur in the context of disorganized axonal migration (30; 103; 11; 79). However, this growth disturbance, sometimes involving somatic structures as well as brain, has been postulated to originate during the earliest mitotic divisions of the embryo (13). 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 2 patients (20; 80). Interestingly, the first cultured cell line developed from cerebral cortex came from a patient with hemimegalencephaly (109), suggesting that hyperdiploidy may confer a proliferative advantage to neurons. 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 novel susceptibility locus for hemimegalencephaly (17). Studies also suggest a possible correlation with platelet activating factor and cell adhesion molecule L1, 2 substances thought to be involved in neuronal migration, but no precise mechanism for this brain malformation has been elucidated (130; 59). One case study identified somatic uniparental disomy of the ZNF597 gene of chromosome 16 in patients with hemimegaloencephaly, indicating that overexpression of maternally expressed ZNF597 may play a role in aberrant hemispheric development (52). The mechanism is still being explored, but modulation of mTOR signaling is thought to be involved.
Research into the possible mechanisms or pathogenesis and epileptogenesis of hemimegalencephaly demonstrate increased neuronal-nuclei cell densities (surgical specimens) in the molecular layer, upper grey matter, and white matter of patients with cortical dysplasias and hemimegalencephaly. These findings suggest increased neurogenesis in the late phases of cortical formation as well incomplete programmed cell death in the remnant cells occupying the pre-plate and sub-plate regions. Concomitant epilepsy, so prevalent in patients with hemimegalencephaly, may, therefore, be the consequence of incomplete cerebral development with abnormal interactions between immature and mature cells and cellular networks (82).
Advanced MRI technology with diffusion tensor imaging has shown asymmetry in interhemispheric fiber tracts in patients with hemimegalencephaly. 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. These images also demonstrated abnormal fiber tract volumes on the affected side when compared to the unaffected side. Takahashi and colleagues hypothesize that the abnormal fiber tracts could be due to immature neuronal cells connecting with abnormal axonal projections during development (124). 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 (32).
In addition to the more clinically obvious enlarged hemisphere, abnormal findings outside the involved hemisphere have been reported. MRI abnormalities reported include enlargement of ipsilateral olfactory 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 (118).
Continued investigations into the genetic basis of hemimegalencephaly using cDNA array analysis have suggested altered expression of mRNAs from selected families, which may lead to aberrant cell growth and hemispheric enlargement during brain development (18; 34; 142) Additionally, epileptogenesis noted in hemimegalencephaly may result, at least in part, from selective alterations in distinct neurotransmitter-receptor and -uptake sites (18). Research has also shown that somatic mutations of the PI3K-AKT-mTOR pathway limited to the brain may represent one cause of hemimegalencephaly. The gene mutations involve components of the phosphatidylinositol 3-kinase (PI3K)-AKT (also known as protein kinase B)-mammalian target of rapamycin (mTOR) pathway and include PIK3CA, PIK3R2, AKT3, and MTOR. These mutations were identified by comparing genomic data obtained from surgically resected brain tissue with nondiseased tissue, and by single-neuron sequencing in combination with molecular biology techniques. The association between the somatic mutations and downstream activation of the PI3K-mTOR pathway suggests that hemimegalencephaly is a neurodevelopmental disease caused by gain-of-function activation of the PI3K-AKT-mTOR pathway (08). Another paper from Yu and colleagues demonstrated increased levels of non-phosphorylated beta-catenin, 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, in hemimegalencephaly (142). Altered expression of 31 mRNAs from 4 gene families in human hemimegalencephaly may lead to aberrant cell growth and hemispheric enlargement during brain development. Enhanced cyclin D1 and c-myc transcription likely reflects increased transcriptionally active beta-catenin due to decreased Ser33/Ser37/Thr41 phospho-beta-catenin and suggests activation of the Wnt-1/beta-catenin cascade in hemimegalencephaly.
Hemimegalencephaly remains a relatively rare disorder reported worldwide and may be occasionally associated with many different syndromes, making comprehensive, unbiased, and detailed epidemiological studies difficult (126). Thus, longitudinal assessment of all patients with hemimegalencephaly is essential for long-term understanding of the epidemiology of this disorder.
Because hemimegalencephaly is presumed to have a developmental pathogenesis related to altered gene expression, no current methods of prevention are available to the developing infant (142).
Cranial asymmetry may be caused by craniosynostosis, a disorder of calvarial bone growth that occurs with or without underlying brain or facial anomalies. Specific types of this disorder can be distinguished by clinical examination and, when necessary, CT imaging of the skull, which is also helpful in excluding subdural hematoma or effusion as a cause of cranial asymmetry. Symmetric cranial enlargement may occur with obstructive or communicating hydrocephalus or in children with benign "external" hydrocephalus. Unlike infants with hemimegalencephaly, however, these patients rarely present with focal seizures.
Megalencephaly 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 (85; 135). Megalencephaly occurring with neurocutaneous syndromes, such as neurofibromatosis (110; 35) or tuberous sclerosis (27; 112; 126), 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 (83; 25; 91; 136), or cutis marmorata telangiectatica congenital (51). In a Japanese nationwide survey, 16 of 44 patients with hemimegalencephaly had underlying neurocutaneous syndromes (117).
Another neurocutaneous syndrome, the linear nevus sebaceous syndrome, is associated with hemimegalencephaly in approximately one half of cases (98; 62). This disorder is distinguished by a midline facial nevus, occasional facial hemihypertrophy caused by hamartomatous-lipomatous lesions, and venous sinus dysplasias (28; 14; 23; 143; 33; 116; 56). Hemimegalencephaly has also been reported with epidermal nevus syndrome (40; 113; 41; 55; 77), hypomelanosis of Ito (101; 16; 121; 29), and Proteus syndrome (84; 05; 15).
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 (60; 02).
MRI, with diffusion-tensor imaging, is the most sensitive study for diagnosing hemimegalencephaly (01), which occurs in association with pachygyria, polymicrogyria, nodular heterotopias, and a small hippocampus in some patients (88; 87).
Unilateral lissencephaly or agyria may also occur in some cases (74). Ipsilateral ventricular enlargement occurs in most cases, often with a straightened and uplifted frontal horn.
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 (74). Because hemicalvarial enlargement does not occur in all patients with hemimegalencephaly, CT or MRI studies may be required to demonstrate enlargement of at least 1 lobe of 1 hemisphere.
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 nonmegalencephalic hemisphere is also important, in order to anticipate the extent of improvement following hemispherectomy of the abnormal cortex. MRI should be used to identify possible dysgenesis of the nonmegalencephalic hemisphere, and SPECT (70), or, where available, PET (105) may be used to identify possible hypometabolism of "normal" cortex.
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 (132). 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 (131). This has been labeled hemihypsarrhythmia (125; 73; 33), although a good response to ACTH is not assured (100). In neonates and infants, interictal fast oscillations on the affected hemisphere may represent an epileptic tendency (140). There is no consensus concerning the prognostic value of EEG (69; 70; 129). 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 (131).
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 (75; 42); however, these are not likely to provide as much specificity and prognostic information as MRI (95).
Literature has documented the superiority of MRI over neurosonography in accurate diagnosis, and avoidance of misdiagnosis, of hemimegalencephaly (Mallinger et al 2004; 89). 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 (Romero et at 2011). In older patients who do not present with hemiparesis, cortical mapping studies should 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 (32).
Anticonvulsant 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. Anticonvulsants used in this age population seldom result in seizure freedom, even with the newer agents available since 1993. Seizures may improve with a modified Atkins diet (29).
Although medical control of seizures is desirable (129), surgery is most likely to be the best option for children with refractory seizures (67; 127; 131; 50; 07; 122; 38; 03; 63; 102; 117; 119; 39; 78) 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 (96; 119; 39; 78). For infants and young children with significant hemiparesis, cerebral hemispherectomy is recommended (67; 131; 117; 119; 39; 78). With mild hemiparesis, resection of more clearly demarcated structural or electrical abnormalities is appropriate (95); however, postoperative seizure control may be less satisfactory than that achieved following hemispherectomy (04; 63; 119; 39). Hemispherotomy has also been described and attempted for patients with hemimegalencephaly (81). 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 (70; 105; 123; 117). Kawai and colleagues reported a modification of the vertical hemispherectomy for refractory epilepsy in 7 patients (65). Four patients were children with hemimegalencephaly and the other 3 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 6 and class IV in 1. 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. Vagus 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 affect and improved communication in patients with severe mental retardation (31).
Early hemispherectomy, even 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 (131; 132; 105; 38; 77).
Improvement of cognitive function of the remaining hemisphere, following surgery for intractable epilepsy, is a function of preoperative glucose metabolism as determined by PET (26; 105). 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 (114). Postnatal evolution of cortical malformation in the previously unaffected hemisphere has been reported following hemispherectomy for intractable hemitonic and asymmetrical epileptic spasms (68).
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 (139), and may ultimately lead to macrocephaly, though the pathogenesis for such aberrant growth remains unknown (112).
H Westley Phillips MD
Dr. Phillips of the David Geffen School of Medicine at UCLA has no relevant financial relationships to disclose.See Profile
Nicholas Macaluso BS
Mr. Macaluso of the David Geffen School of Medicine at UCLA has no relevant financial relationships to disclose.See Profile
Aria Fallah MD
Dr. Fallah of the David Geffen School of Medicine at UCLA has no relevant financial relationships to disclose.See Profile
Bernard L Maria MD
Dr. Maria of Thomas Jefferson University has no relevant financial relationships to disclose.See Profile
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