Hemimegalencephaly with tuberous sclerosis: A longitudinal imaging study

Hemimegalencephaly is a rare cerebral malformation characterized by asymmetry of the hemispheres and cortical dysplasias. We report clinical and imaging findings in a child with hemimegalencephaly involving the right cerebral hemisphere with associated manifestations of tuberous sclerosis complex. Gross abnormal myelination pattern and gyral abnormalities were seen in the enlarged hemisphere. Subsequent scans showed atrophy of the frontoparietal region in the enlarged hemisphere and normal growth of the opposite hemisphere exceeding the size of the abnormal hemisphere in the frontoparietal region. A few white‐matter lesions that were seen in the normal hemisphere on neonatal scan were difficult to appreciate on subsequent MR studies. The white‐matter lesions were better seen in the neonatal period, whereas cortical tubers were better detected at a later age.     

Status epilepticus and frequent seizures: incidence and clinical characteristics in pediatric epilepsy surgery patients

PURPOSE: The literature suggests that pediatric epilepsy surgery cases that present in status epilepticus (SE) are an unusual occurrence. However, this concept is based on case reports, and the incidence and clinical characteristics of these patients have not been systematically assessed. METHODS: The cohort consisted of resective epilepsy surgery cases from 2000 to 2005 (n = 115), and they were classified as presenting with continuous SE requiring medical suppression therapy (n = 6) or intermittent SE (greater than 3 seizures/hour; n = 17). The SE categories were compared with extratemporal surgery patients without SE (non-SE; n = 64) for differences in clinical variables abstracted from the medical record. RESULTS: Continuous SE was noted in 5% and intermittent SE in 15% of resective surgery cases, and all had extratemporal cortical involvement. Compared with continuous SE and non-SE cases, intermittent SE patients were younger at surgery with shorter duration of seizures, and had an increased incidence of active infantile spasms during video scalp EEG monitoring. Compared with non-SE cases, the continuous and intermittent SE groups required a larger number of antiepileptic medications presurgery and 6-months postsurgery, underwent hemispherectomy more frequently, and had an increased incidence of hemimegalencephaly and Rasmussen encephalitis and a lower occurrence of infarct/ischemia and infectious etiologies. Seizure control was over 71% up to 2 years postsurgery, and there were no differences between patient groups. Finally, seizure frequency per hour was greater in continuous SE cases compared with the intermittent SE group. CONCLUSIONS: Children presenting with continuous or intermittent SE are not rare in pediatric epilepsy surgery centers, and such cases are more commonly associated with infantile spasms, Rasmussen's syndrome, and hemimegalencephaly pathologies. Seizure outcome after surgery was not altered in pediatric patients because they had presented with continuous or intermittent SE.     

Epilepsy and anomalies of neuronal migration: MRI and clinical aspects

Neuronal migration disorders are the result of disturbed brain development. In such disorders, neurons are abnormally located. In diagnosing these conditions, magnetic resonance imaging is superior to any other imaging technique. This enables us to improve our knowledge of the clinical correlates of neuronal migration. With reference to migrational disorder, a retrospective study of all 303 patients with epileptic seizures referred for magnetic resonance imaging during a 3-year period was performed, 13 patients (aged 12-41, mean age 27) were identified. They represent 4.3% of the entire study group. Of the patients with known epilepsy, 6.7% and of the mentally retarded, 13.7% had migrational disorders. Four patients had schizencephaly as the dominant finding, one was classified as hemimegalencephaly, 2 had isolated heterotopias, and 6 had localized pachy- and/or poly-microgyria. The clinical pictures are complex. Ectopias of grey matter are recognised foci of epilepsy, but from an epileptological and a clinical viewpoint little attention has been given to these disorders. The present study shows that malmigration is not rare in epilepsy patients, especially not in the mentally retarded.     

Inclusion of hemimegalencephaly into the phenotypic spectrum of NPRL3 pathogenic variants in familial focal epilepsy with variable foci

Despite tremendous progress through next generation sequencing technologies, familial focal epilepsies are insufficiently understood. We sought to identify the genetic basis in multiplex Palestinian families with familial focal epilepsy with variable foci (FFEVF). Family I with 10 affected individuals and Family II with five affected individuals underwent detailed phenotyping over three generations. The phenotypic spectrum of the two families varied from nonlesional focal epilepsy including nocturnal frontal lobe epilepsy to severe structural epilepsy due to hemimegalencephaly. Whole‐exome sequencing and single nucleotide polymorphism array analysis revealed pathogenic variants in NPRL3 in each family, a partial ~38‐kb deletion encompassing eight exons (exons 8‐15) and the 3′‐untranslated region of the NPRL3 gene in Family I, and a de novo nonsense variant c.1063C>T, p.Gln355* in Family II. Furthermore, we identified a truncating variant in the PDCD10 gene in addition to the NPRL3 variant in a patient with focal epilepsy from Family I. The individual also had developmental delay and multiple cerebral cavernomas, possibly demonstrating a digenic contribution to the individual's phenotype. Our results implicate the association of NPRL3 with hemimegalencephaly, expanding the phenotypic spectrum of NPRL3 in FFEVF and underlining that partial deletions are part of the genotypic spectrum of NPRL3 variants.     

Hemimegalencephaly: A rare congenital malformation of cortical development

Hemimegalencephaly is a rare congenital malformation of cortical development usually associated with developmental delay and refractory epilepsy that sooner or later require hemispherectomy.     

Muenke syndrome with pigmentary disorder and probable hemimegalencephaly: An expansion of the phenotype

We describe a 2‐year‐old boy born to healthy, consanguineous parents. He had craniofacial asymmetry with left frontal bossing, midface hypoplasia, proptosis, and low‐set ears. In addition, he had curly, light hair, and oval hypomelanotic patches in the abdomen, lower limbs and back and one hyperpigmented patch in the groin without acanthosis nigricans. Cranial three‐dimensional CT scan showed right‐coronal, sagittal, and lambdoid suture synostoses. His cranial MRI at 2‐months of age showed left hemimegalencephaly, hypoplasia of corpus callosum, and an abnormal configuration of hippocampus. In spite of these cranial findings, he had mild developmental delay and his neurological examination showed symmetric strength, tone and reflexes. Apart from febrile seizures, there was no history of epilepsy. The proband developed asymmetric hydrocephalus at the age of 18 months that required third ventriculostomy. Post‐operative cranial MRI showed Chiari I‐ like malformation and asymmetry of cerebral hemispheres but less dysplastic cerebral cortex. Mutation analysis of FGFR3 showed a c.749C > G, p.Pro250Arg substitution. To the best of our knowledge, these manifestations have not been reported in patients with Muenke syndrome. © 2010 Wiley‐Liss, Inc.     

Widespread frontal lobe cortical dysplasia or partial hemimegalencephaly: a continuum of the spectrum

Focal cortical dysplasia (FCD) type II and hemimegalencephaly (HME) are currently considered as a continuum of pathology, the most important distinction being the extent or the size/volume of the lesion. While partial HME involving the posterior cortex has been well described, we present an unusual case with a dysplastic lesion of the whole frontal lobe. A 17‐year‐old boy had focal seizures from the age of nine years. Apart from diminished right‐hand dexterity, his neurological and cognitive status were unremarkable. The course of his epilepsy exhibited a relapsing‐remitting pattern, with prolonged periods of remission. Imaging showed dysplastic left frontal lobe (including paracentral lobule) thickened cortex with an abnormal gyration pattern resembling polymicrogyria, as well as dystrophic calcifications and hypodensity scattered throughout the white matter. This patient represents an intermediate case within the FCD type II/HME spectrum. Localization of the lesion in the frontal lobe as well as clinical characteristics (childhood onset, relapsing‐remitting epilepsy, without hemiparesis and overt cognitive impairment) are more consistent with FCD type II, while a range of MRI features is shared between HME and FCD type II.     

Human cortical dysplasia and epilepsy: an ontogenetic hypothesis based on volumetric MRI and NeuN neuronal density and size measurements

In epilepsy patients with cortical dysplasia (CD), this study determined the probable ontogenetic timing of pathogenesis based on the number, location and appearance of neurons. Magnetic resonance imaging (MRI) determined gray and white matter volumes of affected and non-affected cerebral hemispheres, and gray and white matter neuronal-nuclear protein (NeuN) densities and sizes were assessed in epilepsy surgery patients (0.2-38 years) with CD (n = 25) and non-CD etiologies (n = 14), and compared with autopsy cases (n = 13; 0-33 years). Pathology group, seizure type and age at surgery were compared against MRI and NeuN data. CD patients demonstrated increased MRI cerebral (3%) and gray matter (8%) volumes of the affected compared with non-affected cerebral hemisphere, and increased layer 1 (131%), upper cortical (9-23%) and white matter (28-77%) NeuN densities compared with autopsy cases. Non-CD cases showed decreased cerebral volumes of the affected hemisphere (14-18%) without changes in NeuN densities. Compared with autopsy cases, in CD and non-CD patients, cortical neurons were hypertrophied. Patients with a history of infantile spasms had a 40% increase in the size of layer 1 neurons compared with cases without spasms. By age, regardless of pathology group, there were logarithmic increases in MRI cerebral and white matter volumes, logarithmic increases in the size of lower gray and superficial white matter neurons, and logarithmic decreases in gray and white matter neuronal densities. These results support the concept that there were more neurons than expected in layer 1, gray, and white matter of CD patients compared with non-CD and autopsy cases. In addition, the location and appearance of neurons are consistent with the hypothesis that CD is the consequence of abnormalities occurring late in corticoneurogenesis that involve excessive neurogenesis with retention of pre-plate cells in the molecular layer and subplate regions.     

Maturation and Dysgenesis of the Human Olfactory Bulb

The olfactory bulb with its unique architecture was studied for neuronal maturation in human fetuses. Neuroblasts stream into the olfactory bulb from the rostral telencephalon and secondarily migrate radially. The transitory olfactory ventricular recess regresses postnatally. Olfactory is the only sensory system without thalamic projections but incorporates intrinsic thalamic equivalents. The bulb is a repository of progenitor cells. Maturation of the bulb and tract was studied in 18 normal human fetuses of 16–41 weeks gestation; mid‐gestational twins with hydrocephalus; 7 arrhinencephaly/holoprosencephaly; 2 olfactory dysgeneses. Multiple immunoreactivities were performed. Synaptophysin around mitral neurons, in a few synaptic glomeruli and concentric lamination of the outer granular layer, was seen at 16 weeks. Outer granular neurons exhibited NeuN at 16 weeks, only 2/3 were reactive at term. Concentric alternating sheets of granular neurons and their dendrodendritic synapses are seen during maturation. Calretinin reactivity is seen in neurons and neurites, primary olfactory nerve axons, periglomerular cells and neuroepithelial cells surrounding the ventricular recess; reactivity occurs later in synaptic glomeruli than with synaptophysin; not all glomeruli are strongly reactive even at term. Nestin‐ and vimentin‐reactive bipolar progenitor cells were demonstrated at all ages and extend into the olfactory tract. Myelin is demonstrated by Luxol fast blue (LFB) only postnatally. In hydrocephalus, the olfactory recess is dilated. Mitral cell dispersion, disrupted glomeruli, heterotopia and maturational delay are seen in some dysgeneses. Malformations exhibit unique findings. Fusion of hypoplastic bulbs can occur. Abnormal architecture is seen in hemimegalencephaly. More documentation of olfactory dysgenesis is needed in other major brain malformations.