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Serious hyperinsulinemic hypoglycemia (HH) is generally the main initial symptom of hyperinsulinism. Epilepsy, without any overt feature of hypoglycemia, might be a very rare initial presentation of late-onset isolated hyperinsulinism. We describe a case of late-onset HH in a 15-year-old boy with a history of idiopathic generalized epilepsy, now named genetic generalized epilepsy (IGE/GGE), beginning with a tonic–clonic seizure at the age of 11 years. Subsequently, absences with rare eyelid myoclonia were recorded on electroencephalogram (EEG), followed by episodes of impaired consciousness with facial myoclonia. Neurological status was normal except attention-deficit hyperactivity disorder (ADHD). At the age of 15 years, an episode of slight alteration of consciousness with neurovegetative signs could be recorded, which did not correspond to an absence status. Hypoglycemia due to hyperinsulinism was documented (clinically, biologically, and genetically). Diazoxide treatment resolved the glycopenic symptoms, the non-hypoglycemic seizures and normalized brain electrical activity allowing complete withdrawal of antiepileptic medication. Epilepsy can be a very rare initial feature of HH starting in childhood. The occurrence of atypical features in the context of GGE as "absence statuses" with unusual vegetative symptoms and facial myoclonia might be suggestive for HH. Careful assessment and specific treatment are necessary to prevent hyperinsulinism related brain damage. Our case showed that diazoxide might also resolve seizures and normalize EEG. [ABSTRACT FROM AUTHOR]

Mutations that disrupt the TBC1D24 presynaptic protein have been implicated in various neurological disorders including epilepsy, chronic encephalopathy, DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures) syndrome, nonsyndromic hearing loss, and myoclonus. We present the case of a 22-month-old male with infantile-onset paroxysmal episodes of facial and limb myoclonus. The episodes were linked to biallelic variants in exon 2 of the TBC1D24 gene that lead to amino acid changes (c.304C >T/p.Pro102Ser and c.410T > C/p.Val137Ala), each variant being inherited from a parent. Follow-up imaging in adolescence revealed widened right cerebellar sulci. We discuss the evolving landscape of TBC1D24 associated phenotypes; this case adds to a growing body of evidence linking this gene to movement disorders in children. [ABSTRACT FROM AUTHOR]

Objectives The aim of our study was to explore the functional connectivity between the insula and other cortical regions, in human, using cortico-cortical evoked potentials (CCEPs) Experimental design We performed intra-cerebral electrical stimulation in eleven patients with refractory epilepsy investigated with depth electrodes, including 39 targeting the insula. Electrical stimulation consisted of two series of 20 pulses of 1-ms duration, 0.2-Hz frequency, and 1-mA intensity delivered at each of the 39 insular bipoles. Rates of connectivity were reported whenever a noninsular cortical region was tested by at least ten stimulating/recording electrode pairs in three or more patients Results Significant CCEPs were elicited in 193 of the 578 (33%) tested connections, with an average latency of 33 ± 5 ms. The highest connectivity rates were observed with the nearby perisylvian structures (59%), followed by the pericentral cortex (38%), the temporal neocortex (28%), the lateral parietal cortex (26%), the orbitofrontal cortex (25%), the mesial temporal structures (24%), the dorsolateral frontal cortex (15%), the temporal pole (14%), and the mesial parietal cortex (11%). No connectivity was detected in the mesial frontal cortex or cingulate gyrus. The pattern of connectivity also differed between the five insular gyri, with greater connectivity rate for the posterior short gyrus (49%), than for the middle short (29%), and two long gyri (28 and 33%) Conclusion The human insula is characterized by a rich and complex connectivity that varies as a function of the insular gyrus and appears to partly differ from the efferences described in nonhuman primates. Hum Brain Mapp 35:5279-5294, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objectives The anatomical organization of the insular cortex is characterized by its rich and heterogeneous cytoarchitecture and its wide network of connections. However, only limited knowledge is available regarding the intrainsular connections subserving the complex integrative role of the insular cortex. The aim of this study was to analyze the functional connectivity within- and across-insular subregions, at both gyral and functional levels. Experimental design We performed intracerebral electrical stimulation in 10 patients with refractory epilepsy investigated with depth electrodes, 38 of which were inserted in the insula. Bipolar electrical stimulation, consisting of two series of 20 pulses of 1-ms duration, 0.2-Hz frequency, and 1-mA intensity, was delivered at each insular contact. For each stimulated insular anatomical region, we calculated a rate of connectivity, reflecting the proportion of other insular contacts, showing significant evoked potentials. Results Statistically significant evoked potentials were recorded in 74% of tested connections, with an average latency of 26 ± 3 ms. All insular gyri were interconnected, except the anterior and posterior short gyri. Most connections were reciprocal, showing no clear anterior to posterior directionality. No connection was observed between the right and the left insula. Conclusions These findings point to specific features of human insula connectivity as compared to non-Human primates, and remain consistent with the complex integration role devoted to the human insula in many cognitive domains. Hum Brain Mapp 35:2779-2788, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Benign childhood epilepsy with centro-temporal spikes (BCECTS) is associated with cognitive disturbances thought to reflect interference between the epileptic focus and brain development. Using diffusion tensor imaging, Ciumas et al. demonstrate abnormal maturation of white matter at the epileptic focus, which correlates with duration of epilepsy and cognitive performance.Benign childhood epilepsy with centro-temporal spikes (BCECTS) is a unique form of non-lesional age-dependent epilepsy with rare seizures, focal electroencepalographic abnormalities affecting the same well delineated cortical region in most patients, and frequent mild to moderate cognitive dysfunctions. In this condition, it is hypothesized that interictal electroencepalographic discharges might interfere with local brain maturation, resulting in altered cognition. Diffusion tensor imaging allows testing of this hypothesis by investigating the white matter microstructure, and has previously proved sensitive to epilepsy-related alterations of fractional anisotropy and diffusivity. However, no diffusion tensor imaging study has yet been performed with a focus on BCECTS. We investigated 25 children suffering from BCECTS and 25 age-matched control subjects using diffusion tensor imaging, 3D-T1 magnetic resonance imaging, and a battery of neuropsychological tests including Conner’s scale and Wechsler Intelligence Scale for Children (fourth revision). Electroencephalography was also performed in all patients within 2 months of the magnetic resonance imaging assessment. Parametric maps of fractional anisotropy, mean-, radial-, and axial diffusivity were extracted from diffusion tensor imaging data. Patients were compared with control subjects using voxel-based statistics and family-wise error correction for multiple comparisons. Each patient was also compared to control subjects. Fractional anisotropy and diffusivity images were correlated to neuropsychological and clinical variables. Group analysis showed significantly reduced fractional anisotropy and increased diffusivity in patients compared with control subjects, predominantly over the left pre- and postcentral gyri and ipsilateral to the electroencephalographic focus. At the individual level, regions of significant differences were observed in 10 patients (40%) for anisotropy (eight reduced fractional anisotropy, one increased fractional anisotropy, one both), and 17 (56%) for diffusivity (13 increased, one reduced, three both). There were significant negative correlations between fractional anisotropy maps and duration of epilepsy in the precentral gyri, bilaterally, and in the left postcentral gyrus. Accordingly, 9 of 12 patients (75%) with duration of epilepsy >12 months showed significantly reduced fractional anisotropy versus none of the 13 patients with duration of epilepsy ≤12 months. Diffusivity maps positively correlated with duration of epilepsy in the cuneus. Children with BCECTS demonstrate alterations in the microstructure of the white matter, undetectable with conventional magnetic resonance imaging, predominating over the regions displaying chronic interictal epileptiform discharges. The association observed between diffusion tensor imaging changes, duration of epilepsy and cognitive performance appears compatible with the hypothesis that interictal epileptic activity alters brain maturation, which could in turn lead to cognitive dysfunction. However, such cross-sectional association does not demonstrate causality, and other hitherto unidentified factors could represent the common cause to part or all of the observed findings. [ABSTRACT FROM PUBLISHER]

Objectives Rolandic epilepsies (REs) represent the most frequent epilepsy in childhood. Patients may experience cognitive, speech, language, reading, and behavioral issues. The genetic origin of REs has long been debated. The participation of rare copy number variations (CNVs) in the pathophysiology of various human epilepsies has been increasingly recognized. However, no systematic search for microdeletions or microduplications has been reported in RE so far. Methods Array comparative genomic hybridization (aCGH) and quantitative polymerase chain reaction (qPCR) were used to analyze the genomic status of a series of 47 unrelated RE patients who displayed various types of electroclinical manifestations. Results Thirty rare CNVs were detected in 21 RE patients. Two CNVs were de novo, 12 were inherited, and 16 were of unknown inheritance. Each CNV was unique to one given patient, except for a 16p11.2 duplication found in two patients. The CNVs of highest interest comprised or disrupted strong candidate or confirmed genes for epileptic and other neurodevelopmental disorders, including BRWD3, GRIN2A, KCNC3, PRKCE, PRRT2, SHANK1, and TSPAN7. Significance Patients with REs showed rare microdeletions and microduplications with high frequency and heterogeneity. Whereas only a subset of all genomic alterations found here may actually participate in the phenotype, the novel de novo events as well as several inherited CNVs contain or disrupt genes, some of which are likely to influence the emergence, the presentation, or the comorbidity of RE. The future screening of cohorts of larger size will help in detecting more de novo or recurrent events and in appreciating the possible enrichment of specific CNVs in patients with RE. [ABSTRACT FROM AUTHOR]

Epileptic encephalopathies are severe brain disorders with the epileptic component contributing to the worsening of cognitive and behavioral manifestations. Acquired epileptic aphasia (Landau-Kleffner syndrome, LKS) and continuous spike and waves during slow-wave sleep syndrome (CSWSS) represent rare and closely related childhood focal epileptic encephalopathies of unknown etiology. They show electroclinical overlap with rolandic epilepsy (the most frequent childhood focal epilepsy) and can be viewed as different clinical expressions of a single pathological entity situated at the crossroads of epileptic, speech, language, cognitive and behavioral disorders. Here we demonstrate that about 20% of cases of LKS, CSWSS and electroclinically atypical rolandic epilepsy often associated with speech impairment can have a genetic origin sustained by de novo or inherited mutations in the GRIN2A gene (encoding the N-methyl-D-aspartate (NMDA) glutamate receptor α2 subunit, GluN2A). The identification of GRIN2A as a major gene for these epileptic encephalopathies provides crucial insights into the underlying pathophysiology. [ABSTRACT FROM AUTHOR]

Purpose: The continuous spike and waves during slow-wave sleep syndrome (CSWSS) and the Landau-Kleffner (LKS) syndrome are two rare epileptic encephalopathies sharing common clinical features including seizures and regression. Both CSWSS and LKS can be associated with the electroencephalography pattern of electrical status epilepticus during slow-wave sleep and are part of a clinical continuum that at its benign end also includes rolandic epilepsy (RE) with centrotemporal spikes. The CSWSS and LKS patients can also have behavioral manifestations that overlap the spectrum of autism disorders (ASD). An impairment of brain development and/or maturation with complex interplay between genetic predisposition and nongenetic factors has been suspected. A role for autoimmunity has been proposed but the pathophysiology of CSWSS and of LKS remains uncharacterized. Methods: In recent years, the participation of rare genomic alterations in the susceptibility to epileptic and autistic disorders has been demonstrated. The involvement of copy number variations (CNVs) in 61 CSWSS and LKS patients was questioned using comparative genomic hybridization assays coupled with validation by quantitative polymerase chain reaction (PCR). Key Findings: Whereas the patients showed highly heterogeneous in genomic architecture, several potentially pathogenic alterations were detected. A large number of these corresponded to genomic regions or genes ( ATP13A4, CDH9, CDH13, CNTNAP2, CTNNA3, DIAPH3, GRIN2A, MDGA2, SHANK3) that have been either associated with ASD for most of them, or involved in speech or language impairment, or in RE. Particularly, CNVs encoding cell adhesion proteins (cadherins, protocadherins, contactins, catenins) were detected with high frequency (≈20% of the patients) and significant enrichment (cell adhesion: p = 0.027; cell adhesion molecule binding: p = 9.27 × 10−7). Significance: Overall our data bring the first insights into the possible molecular pathophysiology of CSWSS and LKS. The overrepresentation of cell adhesion genes and the strong overlap with the genetic, genomic and molecular ASD networks, provide an exciting and unifying view on the clinical links among CSWSS, LKS, and ASD. [ABSTRACT FROM AUTHOR]

We report four infants (two males, two females) with ring 14 chromosome presenting with early-onset partial epilepsy. The first seizure occurred between 3 and 6 months (3, 3, 4, and 6mo respectively). In all four cases, diagnosis was based on early focal seizures, rather than on psychomotor retardation or morphological features, which were not prominent at seizure onset. Moreover, despite the young age of the patients and the high frequency of seizures, neither epileptic spasms nor progression to ‘epileptic encephalopathy’, such as hypsarrhythmia, were observed. Epilepsy remained partial in these patients. At the most recent follow-up, all four children had slight or mild psychomotor delay, and two of them had moderate non-specific dysmorphic traits. Data from the literature about epilepsy in ring 14 chromosome syndrome were also reviewed. Ring 14 chromosome syndrome may be revealed by isolated, early-onset focal epilepsy suggestive of focal lesions with only mild mental retardation and morphological features at the time of diagnosis. The characteristics of these observations differ from classic ring 14 syndrome, and may enlarge this clinical spectrum. Many unanswered questions remain concerning phenotype–genotype correlation and identification of the potential genes and molecular mechanisms responsible for epilepsy in patients with ring 14 syndrome. [ABSTRACT FROM AUTHOR]