Search

Purpose: Spatial patterns of long-range seizure propagation in epileptic networks have not been well characterized. Here, we use ictal high-gamma activity (HGA) as a proxy of intense neuronal population firing to map the spatial evolution of seizure recruitment., Methods: Ictal HGA (80-150 Hz) was analyzed in 13 patients with 72 seizures recorded by stereotactic depth electrodes, using previously validated methods. Distinct spatial clusters of channels with the ictal high-gamma signature were identified, and seizure hubs were defined as stereotypically recruited nonoverlapping clusters. Clusters correlated with asynchronous seizure terminations to provide supportive evidence for independent seizure activity at these sites. The spatial overlap between seizure hubs and interictal ripples was compared., Results: Ictal HGA was detected in 71% of seizures and 10% of implanted contacts, enabling tracking of contiguous and noncontiguous seizure recruitment. Multiple seizure hubs were identified in 54% of cases, including 43% of patients thought preoperatively to have unifocal epilepsy. Noncontiguous recruitment was associated with asynchronous seizure termination (odds ratio = 19.7; p = 0.029). Interictal ripples demonstrated greater spatial overlap with ictal HGA in cases with single seizure hubs compared with those with multiple hubs (100% vs. 66% per patient; p = 0.03)., Conclusions: Ictal HGA may serve as a useful adjunctive biomarker to distinguish contiguous seizure spread from propagation to remote seizure sites. High-gamma sites were found to cluster in stereotyped seizure hubs rather than being broadly distributed. Multiple hubs were common even in cases that were considered unifocal., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 by the American Clinical Neurophysiology Society.)

Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n = 16), focal cortical dysplasia type I and related phenotypes (n = 48), focal cortical dysplasia type II (n = 44), or focal cortical dysplasia type III (n = 15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1 and NIPBL, genes previously associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that focal cortical dysplasia types I, II and III are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: This study aimed to assess the clinical outcome and outcome predictive factors in pediatric epilepsy patients evaluated with stereo-electroencephalography (SEEG)., Methods: Thirty-eight patients who underwent SEEG implantation at the Pediatric Epilepsy Center in New York Presbyterian Hospital between June 2014 and December 2019 were enrolled for retrospective chart review. Postoperative seizure outcomes were evaluated in patients with at least 12-months follow up. Meta-analysis was conducted via electronic literature search of data reported from 2000 to 2020 to evaluate significant surgical outcome predictors for SEEG evaluation in the pediatric population., Results: In the current case series of 25 postsurgical patients with long-term follow up, 16 patients (64.0%) were seizure free. An additional 7 patients (28.0%) showed significant seizure improvement and 2 patients (8.0%) showed no change in seizure activity. Patients with nonlesional magnetic resonance imaging (MRI) achieved seizure freedom in 50% (5/10) of cases. By comparison, 73% (11/15) of patients with lesional MRI achieved seizure freedom. Out of 12 studies, 158 pediatric patients were identified for inclusion in a meta-analysis of the effectiveness of SEEG. Seizure freedom was reported 54.4% (n = 86/158) of patients at last follow up. Among patients with nonlesional MRI, 45% (n = 24) achieved seizure freedom compared with patients with lesional MRI findings (61.2%, n:= 60) (p = 0.02). The risk for seizure recurrence was 2.15 times higher [95% confidence interval [CI] 1.06-4.37, p = 0.033] in patients diagnosed with nonlesional focal epilepsy compared to those with lesional epilepsy [ 1.49 (95% CI 1.06-2.114, p = 0.021]., Conclusion: Evaluation by SEEG implantation in pediatric epilepsy is effective in localizing the epileptogenic zone with favorable outcome. Presence of a non-lesional brain MRI was associated with lower chances of seizure freedom. Further research is warranted to improve the efficacy of SEEG in localizing the epileptogenic zone in pediatric patients with non-lesional brain MRI., (Copyright © 2021. Published by Elsevier B.V.)

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures., (© 2021 International League Against Epilepsy.)

Purpose: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292)., Methods: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships., Results: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment., Conclusion: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

Aims: We aimed to classify ictal onset patterns (IOPs) in pediatric patients undergoing intracranial electroencephalography (IEEG) to guide surgery for refractory epilepsy. We aimed to determine if morphology of IOPs can predict surgical outcome., Materials and Methods: We performed a retrospective review of pediatric patients who underwent epilepsy surgery guided by subdural IEEG from 2007 to 2016. IEEG seizures were reviewed by a blinded epileptologist. Data was collected on outcomes., Results: Twenty-three patients with 784 seizures were included. Age at seizure onset was 0.2-11 (mean 4.3, standard deviation 3.2) years. Age at time of IEEG was 4-20 (mean 13.5, standard deviation 4.4) years. Five distinct IOPs were seen at seizure onset: A) Low voltage fast activity (LVFA) with spread to adjacent electrodes (n = 7 patients, 30%), B) Burst of LVFA followed by electrodecrement (n = 12 patients, 52%), C) Burst of rhythmic spike waves (RSW) followed by electrodecrement (n = 9 patients, 39%), D) RSW followed by LVFA (n = 7 patients, 30%), E) Rhythmic spikes alone (n = 10 patients, 43%). Twelve patients (52%) had the same IOP type with all seizures. When the area of the IOP was resected, 14 patients (61%) had Engel I outcomes. Patients who had LVFA seen within their predominant IOP type were more likely to have good surgical outcomes (odds ratio 7.50, 95% confidence interval 1.02-55.0, p = 0.05). Patients who had only one IOP type were more likely to have good outcomes than patients who had multiple IOP types (odds ratio 12.6, 95% confidence interval 1.19-134, p = 0.04). Patients who had LVFA in their predominant IOP type were older than patients who did not have LVFA (mean age 15.0 vs. 9.9 years, p = 0.02)., Conclusions: LVFA at ictal onset and all seizures having the same IOP morphology are associated with increased likelihood of surgical success in children, but LVFA is less common in children who are younger at the time of IEEG., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Patients with medically refractory localization-related epilepsy (LRE) may be candidates for surgical intervention if the seizure onset zone (SOZ) can be well localized. Stereoelectroencephalography (SEEG) offers an attractive alternative to subdural grid and strip electrode implantation for seizure lateralization and localization; yet there are few series reporting the safety and efficacy of SEEG in pediatric patients., Methods: The authors review their initial 3-year consecutive experience with SEEG in pediatric patients with LRE. SEEG coverage, SOZ localization, complications, and preliminary seizure outcomes following subsequent surgical treatments are assessed., Results: Twenty-five pediatric patients underwent 30 SEEG implantations, with a total of 342 electrodes placed. Ten had prior resections or ablations. Seven had no MRI abnormalities, and 8 had multiple lesions on MRI. Based on preimplantation hypotheses, 7 investigations were extratemporal (ET), 1 was only temporal-limbic (TL), and 22 were combined ET/TL investigations. Fourteen patients underwent bilateral investigations. On average, patients were monitored for 8 days postimplant (range 3-19 days). Nearly all patients were discharged home on the day following electrode explantation. There were no major complications. Minor complications included 1 electrode deflection into the subdural space, resulting in a minor asymptomatic extraaxial hemorrhage; and 1 in-house and 1 delayed electrode superficial scalp infection, both treated with local wound care and oral antibiotics. SEEG localized the hypothetical SOZ in 23 of 25 patients (92%). To date, 18 patients have undergone definitive surgical intervention. In 2 patients, SEEG localized the SOZ near eloquent cortex and subdural grids were used to further delineate the seizure focus relative to mapped motor function just prior to resection. At last follow-up (average 21 months), 8 of 15 patients with at least 6 months of follow-up (53%) were Engel class I, and an additional 6 patients (40%) were Engel class II or III. Only 1 patient was Engel class IV., Conclusions: SEEG is a safe and effective technique for invasive SOZ localization in medically refractory LRE in the pediatric population. SEEG permits bilateral and multilobar investigations while avoiding large craniotomies. It is conducive to deep, 3D, and perilesional investigations, particularly in cases of prior resections. Patients who are not found to have focally localizable seizures are spared craniotomies.

Background: Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases., Objective: To identify rare, causal CNV in patients with RE., Methods: We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India., Results: We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5%) with recurrent risk factor CNVs and 15 (8.0%) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies ( KCTD7 , ARHGEF15 , CACNA2D1, GRIN2A and ARHGEF4 ), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin., Conclusion: Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation., Competing Interests: Competing interests: LA is a contractor for Eli Lilly and Company. SVT has received research grants from the Scientific bodies under the Government of India. DM consults for Cyberonics., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD., Methods: We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD., Results: We observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53%; Evidence for FCD was not observed in either brain tissue specimen., Interpretation: We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018., (© 2018 American Neurological Association.)

Herpes simplex virus (HSV) encephalitis can manifest with different clinical presentations, including acute monophasic illness and biphasic chronic granulomatous HSV encephalitis. Chronic encephalitis is much less common, and very rare late relapses are associated with intractable epilepsy and progressive neurological deficits with or without evidence of HSV in the cerebrospinal fluid. The authors report on an 8-year-old girl with a history of treated HSV-1 encephalitis when she was 13 months of age and focal epilepsy when she was 2 years old. Although free of clinical seizures, when she was 5, she experienced behavioral and academic dysfunction, which was later attributed to electrographic focal seizures and worsening electroencephalography (EEG) findings with electrical status epilepticus during slow-wave sleep (ESES). Following a right temporal lobectomy, chronic granulomatous encephalitis was diagnosed. The patient's clinical course improved with the resolution of seizures and EEG abnormalities.

Anatomically complex focal cortical dysplasias may present significant challenges to safe and complete surgical resection via standard operative corridors. Laser interstitial thermal therapy (LITT) is an emerging minimally invasive technique that may address some of these challenges, enabling stereotactic ablation of deep and/or surgically inaccessible regions. However, complete ablation may not be feasible in all cases. To address this dilemma, we have designed a protocol utilizing staged LITT followed by topectomy to effect complete obliteration of a complex focal cortical dysplasia. The approach presented demonstrates the feasibility, safety, and clinical utility of combining laser ablation and open surgery for the definitive management of this lesion., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: Rolandic epilepsy is a common genetic focal epilepsy of childhood characterized by centrotemporal sharp waves on electroencephalogram. In previous genome-wide analysis, we had reported linkage of centrotemporal sharp waves to chromosome 11p13, and fine mapping with 44 SNPs identified the ELP4-PAX6 locus in two independent US and Canadian case-control samples. Here, we aimed to find a causative variant for centrotemporal sharp waves using a larger sample and higher resolution genotyping array., Methods: We fine-mapped the ELP4-PAX6 locus in 186 individuals from rolandic epilepsy families and 1000 population controls of European origin using the Illumina HumanCoreExome-12 v1.0 BeadChip. Controls were matched to cases on ethnicity using principal component analysis. We used generalized estimating equations to assess association, followed up with a bioinformatics survey and literature search to evaluate functional significance., Results: Homozygosity at the T allele of SNP rs662702 in the 3' untranslated region of PAX6 conferred increased risk of CTS: Odds ratio = 12.29 (95% CI: 3.20-47.22), P = 2.6 × 10(-4) and is seen in 3.9% of cases but only 0.3% of controls., Interpretation: The minor T allele of SNP rs662702 disrupts regulation by microRNA-328, which is known to result in increased PAX6 expression in vitro. This study provides, for the first time, evidence of a noncoding genomic variant contributing to the etiology of a common human epilepsy via a posttranscriptional regulatory mechanism.

Objective: To profile the initial clinical events of glucose transporter 1 deficiency syndrome (Glut1 DS) in order to facilitate the earliest possible diagnosis., Study Design: We retrospectively reviewed 133 patients with Glut1 DS from a single institution. Family interviews and medical record reviews identified the first clinical event(s) reported by the caregivers., Results: Average age of the first event was 8.15 ± 11.9 months (range: 0.01-81). Ninety-one patients experienced the first symptom before age 6 months (68%). Thirty-three additional patients (25%) presented before age 2 years. Only 9 patients (7%), reported the first event after age 2 years. Seizures were the most common first event (n = 81, 61%), followed by eye movement abnormalities (n = 51, 38%) and changes in muscle strength and tone (n = 30, 22%). Eye movement abnormalities, lower cerebrospinal fluid glucose values, and lower Columbia Neurological Scores correlated with earlier onset of the first event (r: -0.17, 0.22, and 0.25 respectively, P < .05). There was no correlation with age of first event and red blood cell glucose uptake or mutation type., Conclusions: Glut1 DS is a treatable cause of infantile onset encephalopathy. Health care providers should recognize the wide spectrum of paroxysmal events that herald the clinical onset of Glut1 DS in early infancy to facilitate prompt diagnosis, immediate treatment, and improved long-term outcome., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The high prevalence and impact of neurodevelopmental comorbidities in childhood epilepsy are now well known, as are the increased risks and familial aggregation of reading disability (RD) and speech sound disorder (SSD) in rolandic epilepsy (RE). The risk factors for RD in the general population include male sex, SSD, and ADHD, but it is not known if these are the same in RE or whether there is a contributory role of seizure and treatment-related variables., Methods: An observational study of 108 probands with RE (age range: 3.6-22 years) and their 159 siblings (age range: 1-29 years; 83 with EEG data) were singly ascertained in the US or UK through a proband affected by RE. We used a nested case-control design, multiple logistic regression, and generalized estimating equations to test the hypothesis of an association between RD and seizure variables or antiepileptic drug treatment in RE; we also assessed an association between EEG focal sharp waves and RD in siblings., Results: Reading disability was reported in 42% of probands and 22% of siblings. Among probands, RD was strongly associated with a history of SSD (OR: 9.64, 95% CI: 2.45-37.21), ADHD symptoms (OR: 10.31, 95% CI: 2.15-49.44), and male sex (OR: 3.62, 95% CI: 1.11-11.75) but not with seizure or treatment variables. Among siblings, RD was independently associated only with SSD (OR: 4.30, 95% CI: 1.42-13.0) and not with the presence of interictal EEG focal sharp waves., Significance: The principal risk factors for RD in RE are SSD, ADHD, and male sex, the same risk factors as for RD without epilepsy. Seizure or treatment variables do not appear to be important risk factors for RD in probands with RE, and there was no evidence to support interictal EEG focal sharp waves as a risk factor for RD in siblings. Future studies should focus on the precise neuropsychological characterization of RD in families with RE and on the effectiveness of standard oral-language and reading interventions., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Rationale: (18)F fluorodeoxyglucose positron emission tomography ((18)F FDG-PET) facilitates examination of glucose metabolism. Previously, we described regional cerebral glucose hypometabolism using (18)F FDG-PET in patients with Glucose transporter 1 Deficiency Syndrome (Glut1 DS). We now expand this observation in Glut1 DS using quantitative image analysis to identify the epileptic network based on the regional distribution of glucose hypometabolism., Methods: (18)F FDG-PET scans of 16 Glut1 DS patients and 7 healthy participants were examined using Statistical parametric Mapping (SPM). Summed images were preprocessed for statistical analysis using MATLAB 7.1 and SPM 2 software. Region of interest (ROI) analysis was performed to validate SPM results., Results: Visual analysis of the (18)F FDG-PET images demonstrated prominent regional glucose hypometabolism in the thalamus, neocortical regions and cerebellum bilaterally. Group comparison using SPM analysis confirmed that the regional distribution of glucose hypo-metabolism was present in thalamus, cerebellum, temporal cortex and central lobule. Two mildly affected patients without epilepsy had hypometabolism in cerebellum, inferior frontal cortex, and temporal lobe, but not thalamus. Glucose hypometabolism did not correlate with age at the time of PET imaging, head circumference, CSF glucose concentration at the time of diagnosis, RBC glucose uptake, or CNS score., Conclusion: Quantitative analysis of (18)F FDG-PET imaging in Glut1 DS patients confirmed that hypometabolism was present symmetrically in thalamus, cerebellum, frontal and temporal cortex. The hypometabolism in thalamus correlated with the clinical history of epilepsy., (Copyright © 2014. Published by Elsevier B.V.)

Background: Intracarotid amobarbital procedure (IAP) is acknowledged as the gold standard test for language lateralization. EEG is performed routinely during IAP to monitor the anesthetization of a brain hemisphere. Here, we studied the correlation between the early EEG changes using envelope trend and the clinical outcome of IAP., Method: Fifty consecutive patients underwent IAP at Texas Children's Hospital (2004-2009). Intracarotid amobarbital procedure was considered "complete" or "incomplete" based on the outcome if the procedure was completed or aborted due to behavior changes. Envelope trend was used to calculate the median EEG amplitude changes within the first 60s of IAP. Statistical analysis was performed to determine the role of EEG changes and clinical features on the procedure outcome., Results: Only 30 IAP-EEG files were available for review. Amobarbital was administered at the dose of 60-150mg (mean: 110±20). The intracarotid amobarbital procedure was recorded as complete in 23 patients and incomplete in 7 patients. EEG changes occurred within the first few seconds following amobarbital injection. Following amobarbital injection, focal slowing was present in the ipsilateral frontal region or both ipsilateral and contralateral frontal regions. Elapsed time to the first EEG change or duration and change in median EEG amplitude in the ipsilateral frontal regions were indifferent between the complete and incomplete groups (p>0.05). However, the median amplitude changes between the ipsilateral and contralateral frontal regions within each group were found significant only in the complete group (p<0.05), suggesting ipsilateral without contralateral frontal slowing. Other than age at the time of IAP (p=0.03), none of the other clinical features correlated with the clinical outcome of IAP (p>0.05)., Conclusion: Early EEG changes during IAP using envelope trend may predict successful completion of the IAP test. Younger children are at risk of behavioral changes during IAP., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Our objective is to characterize the long-term course of Glut1 deficiency syndrome. Longitudinal outcome measures, including Columbia Neurological Scores, neuropsychological tests, and adaptive behavior reports, were collected for 13 participants with Glut1 deficiency syndrome who had been followed for an average of 14.2 (range = 8.9-23.6) years. A parent questionnaire assessed manifestations throughout development. The 6-Minute Walk Test captured gait disturbances and triggered paroxysmal exertional dyskinesia. All longitudinal outcomes remained stable over time. Epilepsy dominated infancy and improved during childhood. Dystonia emerged during childhood or adolescence. Earlier introduction of the ketogenic diet correlated with better long-term outcomes on some measures. Percent-predicted 6-Minute Walk Test distance correlated significantly with Columbia Neurological Scores. We conclude that Glut1 deficiency syndrome is a chronic condition, dominated by epilepsy in infancy and by movement disorders thereafter. Dietary treatment in the first postnatal months may effect improved outcomes, emphasizing the importance of early diagnosis and treatment., (© The Author(s) 2014.)

Purpose: Generalized periodic epileptiform discharges (GPDs) are a specific periodic EEG pattern, reported as having a poor clinical outcome. The incidence and clinical implications of this EEG pattern in children are not known. In this study, we examined the clinical features of children with GPDs., Methods: EEG-video monitoring reports of children with critical illness in the intensive care unit were retrospectively reviewed to detect GPDs. The clinical history, hospital course and seizure characteristics were reviewed and outcome was based on the clinical findings at hospital discharge., Results: Twenty one children (age 2-18 years) were identified with GPDs. The most common underlying etiology was encephalitis (N=11). At the time of EEG, a continuous intravenous infusion (cIV) of an anticonvulsant drug was used to treat refractory status epilepticus (RSE). Non-convulsive seizures (NCS) were identified in 15, and clinical seizures in 13 children after GPDs were detected. GPDs occurred after a dose reduction in the cIV in 43%. Neuroimaging done in 16 children showed an acute change in 13/16 (81%) and chronic changes in 2/16 (13%). Five children (23%) died. Seven (33%) children had a favorable outcome, whereas the remaining children had a moderate to severe disability at the time of hospital discharge., Conclusion: GPDs are seen during the course of RSE in critically ill children and are associated with seizure recurrence. A lower mortality rate occurs in children with GPDs compared to adult counterparts, likely related to different etiologies. Although the significance of GPDs must be determined within the context of the clinical situation, GPDs suggest a still active epileptic process., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: EEG monitoring is important for the early detection of seizures during the course of critical illness. However, the logistics of real time EEG interpretation is challenging for the neurophysiology and critical care medicine teams. This study evaluated factors affecting the utility of digital trend analysis (DTA) for rapid seizure identification in children., Methods: digital EEG files of seizures in critically ill children were retrieved for DTA. The envelop trend (ET) and compressed spectral array (CSA) were applied to the raw EEG data and presented to an experienced and inexperienced user for interpretation who were blinded to conventional EEG findings. The EEG findings with and without presence of seizures and features of seizures were analyzed., Results: we found that a number of factors affected accurate seizure detection including factors related to interpreter's experiences, display size and type of DTA methods used for analysis in addition to baseline EEG findings. ET was more dependent on user experience, furthermore, display size and multimodal DTA application (CSA and ET combined) increased the sensitivity of seizure detection for the experienced user compared to inexperience users. The artifacts were reported as seizures regardless of experience without presence of conventional EEG recording. The maximum spike amplitude, seizure duration, and seizure frequency were other important determinants for accuracy. Electrographic seizures with shorter duration were better detected by ET, and the maximum spike amplitude was important for both the ET and CSA. Repetitive seizures are readily detected by both digital trending methods. Artifacts may be reported as seizures regardless of experience if conventional EEG recording is not available for the interpretation., Conclusion: DTA applied to the raw EEG data does produce a graphic display that facilitates identification of seizures. The actual characteristics of the electrographic seizure may predict which DTA method is better and the overall accuracy of seizure detection may increase when multimodal trending is used simultaneously. Application of DTA alone with display of conventional EEG is beneficial for rapid interpretation of EEG findings regardless of experience., (2010 Elsevier B.V. All rights reserved.)

We report 26 individuals from ten unrelated families who exhibit variable expression and/or incomplete penetrance of epilepsy, learning difficulties, intellectual disabilities, and/or neurobehavioral abnormalities as a result of a heterozygous microdeletion distally adjacent to the Williams-Beuren syndrome region on chromosome 7q11.23. In six families with a common recurrent ∼1.2 Mb deletion that includes the Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG) genes and that is flanked by large complex low-copy repeats, we identified sites for nonallelic homologous recombination in two patients. There were no cases of this ∼1.2 Mb distal 7q11.23 deletion copy number variant identified in over 20,000 control samples surveyed. Three individuals with smaller, nonrecurrent deletions (∼180-500 kb) that include HIP1 but not YWHAG suggest that deletion of HIP1 is sufficient to cause neurological disease. Mice with targeted mutation in the Hip1 gene (Hip1⁻(/)⁻) develop a neurological phenotype characterized by failure to thrive, tremor, and gait ataxia. Overall, our data characterize a neurodevelopmental and epilepsy syndrome that is likely caused by recurrent and nonrecurrent deletions, including HIP1. These data do not exclude the possibility that YWHAG loss of function is also sufficient to cause neurological phenotypes. Based on the current knowledge of Hip1 protein function and its proposed role in AMPA and NMDA ionotropic glutamate receptor trafficking, we believe that HIP1 haploinsufficiency in humans will be amenable to rational drug design for improved seizure control and cognitive and behavioral function., (Copyright © 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Though seizure-related injuries (SRIs) among people with epilepsy (PWE) have recently gained much attention in the literature, most studies are retrospective and data are gathered indirectly through questionnaires or medical record documentation. We investigated SRIs and their associated risks in PWE attending a tertiary care center with direct and systematic inquiries during routine clinic follow-up visits over a 2-year period (N = 306). Past SRIs occurred in 54% of all patients, and 24% experienced recurrent SRIs during the study period. On multiple regression analyses, past SRI was associated with tonic-clonic seizures (TCSs) (3.2, 95% CI = 1.7-5.8) and cognitive handicap (4.3, 95% CI 1.5-16.1), and recurrent SRI was associated with TCSs (3.5, 95% CI = 1.6-7.9). Most recurrent SRIs (72%) involved head injury. SRIs are common when assessed systematically in a tertiary care setting, and TCSs represent a risk factor for recurrent SRIs. The potential clinical impact of recurrent SRIs on PWE requires further study., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Nonconvulsive status epilepticus (NCSE) is a special epileptic state that can be more common than previously thought in children and adult patients. Currently, there is no universally accepted definition for NCSE. Early and accurate diagnosis depends on a high index of suspicion and rapid availability of electroencephalographic recording. The clinical presentation of NCSE can vary from a mild confusional state to a coma. The underlying etiology is also quite diverse. In critically ill patients, NCSE has been reported with convulsive status epilepticus (CSE), hypoxemia, acute ischemic or hemorrhagic stroke, encephalitis, or trauma. The estimated incidence of NCSE is 15% to 40% in post-CSE, 8% in subarachnoid hemorrhage, and 8% to 10% in coma. As seen in CSE, there is a bimodal distribution with NCSE in critically ill patients; children (age <1 year) and elderly appear to be at great risk. NCSE has also been reported in a number of epilepsy syndromes, such as childhood absence epilepsy, Panayiotopoulos syndrome, Lennox-Gastaut syndrome, and Dravet syndrome. However, it is difficult to determine the incidence of NCSE in an ambulatory setting because of the great variation in clinical presentation and underlying etiology. This review examines the clinical features, outcome, and treatment approach for NCSE in 2 different clinical settings, in ambulatory and critically ill patients. NCSE is reviewed in children and adults to distinguish similarities and differences in their clinical presentation., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: [(18)F]Fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) is a valuable method for detecting focal brain dysfunction associated with epilepsy. Evidence suggests that a progressive decrease in [(18)F]FDG uptake occurs in the epileptogenic cortex with an increase in the duration of epilepsy. In this study, our aim was to use statistical parametric mapping (SPM) to test the validity of this relationship in a retrospective study of patients with temporal lobe epilepsy (TLE)., Methods: [(18)F]FDG-PET scans of 46 adult patients with pharmacoresistant unilateral TLE (25 RTLE and 21 LTLE) were subjected to SPM analysis., Results: Forty-six patients were diagnosed with nonlesional TLE, 16 of whom had hippocampal sclerosis (HS). The average duration of epilepsy was 17.4 +/- 12.3 years (3-46 years), <5 years in 10 patients and >or=10 years in 30 patients. Visual analysis of [(18)F]FDG-PET scans revealed hypometabolism in the epileptogenic temporal cortex in 31 (67%) patients. After SPM analysis of all [(18)F]FDG-PET images, hypometabolism was unilateral and reported in lateral and mesial structures of the epileptogenic temporal cortex in addition to the ipsilateral fusiform and middle occipital gyrus. Subsequent analysis revealed that temporal lobe hypometabolism was present only in patients with longer epilepsy duration (>or=10 years) in parahippocampal gyrus, uncus, and middle and superior temporal gyrus (P < 0.05 corrected). Epilepsy duration was inversely correlated with decreased glucose uptake in the inferior temporal gyrus, hippocampus, and parahippocampal gyrus of the epileptogenic temporal cortex (P < 0.05). Age at seizure onset did not affect the correlation between epilepsy duration and glucose uptake except in the inferior temporal gyrus (P < 0.05)., Conclusion: Voxel-based mapping supports the assertion that glucose hypometabolism of the epileptogenic temporal lobe cortex and other neighboring cortical regions increases with longer epilepsy duration in TLE., ((c) 2009 Elsevier Inc. All rights reserved.)

Objective: Glucose transporter type 1 deficiency syndrome (Glut1-DS) is characterized clinically by acquired microcephaly, infantile-onset seizures, psychomotor retardation, choreoathetosis, dystonia, and ataxia. The laboratory signature is hypoglycorrhachia. The 5-hour oral glucose tolerance test (OGTT) was performed to assess cerebral function and systemic carbohydrate homeostasis during acute hyperglycemia, in the knowledge that GLUT1 is constitutively expressed ubiquitously and upregulated in the brain., Methods: Thirteen Glut1-DS patients completed a 5-hour OGTT. Six patients had prolonged electroencephalographic (EEG)/video monitoring, 10 patients had plasma glucose and serum insulin measurements, and 5 patients had repeated measures of attention, memory, fine motor coordination, and well-being. All patients had a full neuropsychological battery prior to OGTT., Results: The glycemic profile and insulin response during the OGTT were normal. Following the glucose load, transient improvement of clinical seizures and EEG findings were observed, with the most significant improvement beginning within the first 30 minutes and continuing for 180 minutes. Thereafter, clinical seizures returned, and EEG findings worsened. Additionally, transient improvement in attention, fine motor coordination, and reported well-being were observed without any change in memory performance., Interpretation: This study documents transient neurological improvement in Glut1-DS patients following acute hyperglycemia, associated with improved fine motor coordination and attention. Also, systemic carbohydrate homeostasis was normal, despite GLUT1 haploinsufficiency, confirming the specific role of GLUT1 as the transporter of metabolic fuel across the blood-brain barrier. The transient improvement in brain function underscores the rate-limiting role of glucose transport and the critical minute-to-minute dependence of cerebral function on fuel availability for energy metabolism.

Objective: Subclinical seizures (SCSs) are characterized by paroxysmal rhythmic epileptiform discharges that evolve in time and space in the absence of objective clinical manifestation or report of a seizure. The aim of this study was to evaluate the frequency and characteristics of SCSs in children with localization-related epilepsy (LRE)., Methods: The results of video/EEG monitoring were reviewed to identify patients with SCS. We identified 187 children diagnosed with LRE, in 32 of whom SCSs were reported in the EEG recording., Results: SCSs were reported only in the children who had received a diagnosis of either symptomatic or cryptogenic LRE. All children had a history of clinical seizure(s). The ictal onset of SCSs was most frequent from the temporal and frontal lobes. SCSs were lateralized to the left hemispheres in 19, right hemisphere in 8, and both hemispheres independently in 5 children. SCSs were more often reported in young children, and associated with a history of developmental delay, infantile spasms, and frequent seizures. EEG abnormalities included background slowing and lack of normal sleep architecture in addition to the epileptiform activity. Seizure freedom was reported less often in children with SCSs. Six patients seizure free at the time of the admission were found to have SCSs., Conclusion: Subclinical seizures are not uncommon in children with LRE, in particular, with younger age, developmental disability, and medically refractory clinical course. Video/EEG monitoring will be informative in selected children with LRE to assess the seizure frequency more accurately.

Rationale: The objective of this study was to ascertain the accuracy of clinical reports to determine the seizure frequency in children diagnosed with epilepsy., Methods: We reviewed the clinical record of 78 children (January-May of 2006) admitted to the EEG-video monitoring with epilepsy diagnosis. Clinical reports of parents and the files of EEG-video monitoring were reviewed to determine parents' awareness for seizures., Results: During video-EEG monitoring, 1244 were recorded on 78 children. Seizures were confirmed in 1095 of which 472 were correctly reported (38%) by parents whereas 623 remained under-reported (50%). Parents' report thus had a sensitivity of 43%, positive predictive value of 76% to identify seizures. Based on the EEG-video monitoring, seizures were reported accurately in 22 (28%) and under-reported in 38 (49%) children. In the under-reported group, none of the seizures were recognized in 10 (13%), only a portion identified in 28 children. The parents' report describing seizure frequency has limited value for young children (p=0.01) and children with absence seizures (p=0.03). However, clinical reports were accurate for the children with developmental delay (p<0.06) or not being on any anticonvulsant drug (AED) therapy (p=0.02)., Conclusion: Our results indicate that a significant number of seizures remain under-reported by parents of children with epilepsy. The current study underscores that the seizure frequency should be interpreted with caution for young children and children with absence seizures. Video-EEG recording has a complimentary role to the clinical observation for the accurate assessment of seizure frequency in children.

A variety of autoantibodies have been identified with complex neurological disorders including limbic encephalitis. The underlying trigger for the immune-mediated process and the role of autoantibodies in the pathogenesis of limbic encephalitis remain to be clarified. Here, we report a 16-year-old female who was diagnosed with acute-onset non-neoplastic limbic encephalitis. The initial treatment with pulse doses of i.v. methylprednisolone improved the neurological symptoms. During the next 12 months, progressive decline was reported in her academic functioning and seizure control. Additional diagnostic evaluation revealed no evidence of malignancy or central nervous system infection but circulating anti-GAD antibodies were present in the serum and cerebrospinal fluid. Intravenous gammaglobulin infusion was initiated and continued monthly. Intravenous and oral steroids were added to the intravenous immunoglobulin treatment because of the worsening course and seizures, despite treatment with antiepileptic medications. Screening for quantitative immunoglobulins demonstrated hypogammaglobulinaemia with low immunoglobulin M and G in addition to low immunoglobulin A levels. There was a lack of protective pneumococcal antibody titers before and after immunization. Therefore, common variable immunodeficiency was suspected despite there being no history of recurrent infections. To our knowledge, this is the first report describing a possible link between immune-mediated limbic encephalitis and immune deficiency.

In this study, we examine the long-term clinical outcome of children with symptomatic infantile spasm. The children between 2 and 18 years of age diagnosed with symptomatic infantile spasms were reviewed. Sixty-eight children (age range, 2-13 years; mean, 4.5 years) met the inclusion criteria. Children who underwent epilepsy surgery were excluded. Age of onset for infantile spasms ranged from 1 to 24 months (mean, 7.1 months). Developmental delay was noted in all; there was seizure freedom in 14 children (20.5%). Infantile spasms were reported as the only seizure type in 10 (14.5%) children older than age 2 years. During the follow-up; symptomatic generalized epilepsy was diagnosed in 23 children (34%) and focal epilepsy in 21 (31%). The long-term outcome of these children remains unchanged in the majority of the children with symptomatic infantile spasms. We could not establish any risk factor that might be related to favorable or adverse outcome.

Purpose: Centrotemporal sharp (CTS) waves, the electroencephalogram (EEG) hallmark of rolandic epilepsy, are found in approximately 4% of the childhood population. The inheritance of CTS is presumed autosomal dominant but this is controversial. Previous studies have varied considerably in methodology, especially in the control of bias and confounding. We aimed to test the hypothesis of autosomal dominant inheritance of CTS in a well-designed family segregation analysis study., Methods: Probands with rolandic epilepsy were collected through unambiguous single ascertainment. Siblings in the age range 4-16 years underwent sleep-deprived EEG; observations from those who remained awake were omitted. CTS were rated as present or absent by two independent observers blinded to the study hypothesis and subject identities. We computed the segregation ratio of CTS, corrected for ascertainment. We tested the segregation ratio estimate for consistency with dominant and recessive modes of inheritance, and compared the observed sex ratio of those affected with CTS for consistency with sex linkage., Results: Thirty siblings from 23 families underwent EEG examination. Twenty-three showed evidence of sleep in their EEG recordings. Eleven of 23 recordings demonstrated CTS, yielding a corrected segregation ratio of 0.48 (95% CI: 0.27-0.69). The male to female ratio of CTS affectedness was approximately equal., Conclusions: The segregation ratio of CTS in rolandic epilepsy families is consistent with a highly penetrant autosomal dominant inheritance, with equal sex ratio. Autosomal recessive and X-linked inheritance are rejected. The CTS locus might act in combination with one or more loci to produce the phenotype of rolandic epilepsy.

Eyelid myoclonia is a type of epileptic seizure characterized by marked jerking of the eyelids, often associated with jerky upward deviation of the eyeballs. It can be triggered by eye closure. The ictal electroencephalographic pattern of eyelid myoclonia consists of generalized polyspike waves at 3 to 6 Hz. Eyelid myoclonia can be a component of the clinical seizures seen with idiopathic, symptomatic, or cryptogenic generalized epilepsy. The objective of this study was to describe the unusual focal ictal electroencephalogram features of two patients with developmental delay and eyelid myoclonia. To the best of our knowledge, this unique electroencephalogram finding was not previously described.

Background: Nonconvulsive status epilepticus (NCSE) is a highly heterogeneous clinical condition that is understudied in the pediatric population., Objective: To analyze the epidemiological, clinical, and electroencephalograpic features in pediatric patients with NCSE., Methods: We identified 19 pediatric patients with NCSE from the epilepsy database of the Comprehensive Epilepsy Center at, Columbia University between June 2000 and December 2003. Continuous electroencephalographic (EEG) monitoring was analyzed and chart review was performed., Results: The patients ranged from 1 month old to 17 years of age. Five patients developed NCSE following convulsive status epilepticus (CSE), and a further 12 patients developed NCSE after brief convulsions. Two developed NCSE as the first manifestation during a comatose state following hypoxic events. Acute hypoxic-ischemic injury was the most frequent etiology of NCSE in our population (5 of 19; 26%), followed by exacerbation of underlying neurometabolic disease (4 of 19; 21%), acute infection (3 of 19; 16%), change in antiepileptic drug regimen (3 of 19;16%), refractory epilepsy (2 of 19; 11%) and intracranial hemorrhage (2 of 19; 11%). Six patients had associated periodic lateralized epileptiform discharges (PLEDs), one had generalized periodic epileptiform discharges (GPEDs). Five (5 of 19; 26%) patients died of the underlying acute medical illness. Periodic discharges were associated with worse outcome., Conclusion: The majority of our patients with NCSE had preceding seizures in the acute setting prior to the diagnosis of NCSE, though most of these seizures were brief, isolated convulsions (12 patients) rather than CSE (five patients). Prolonged EEG monitoring to exclude NCSE may be warranted in pediatric patients even after brief convulsive seizures. Prompt recognition and treatment may be necessary to improve neurological outcome.

A 3 1/2-year-old boy presented with megaloblastic anemia and recurrent episodes of severe lactic acidosis and coma. At age 4 years, he developed sepsis and died; postmortem examination failed to show any gross abnormality in any tissue. Biochemical analysis of muscle showed decreased activities for all respiratory chain enzymes except complex II. Muscle histochemistry revealed diffuse cytochrome c oxidase deficiency. Southern blot analysis of mitochondrial DNA from muscle, liver, and blood showed a heteroplasmic single mitochindrial DNA deletion of 2.4 kb, which removed the genes for cytochrome c oxidase I and II and the transfer ribonucleic acid genes for serine and aspartic acid. Single large-scale deletions in mitochondrial DNA have been associated with Pearson's syndrome, Kearns-Sayre syndrome, and progressive external ophthalmoplegia. This patient's presentation is unusual and suggests an overlap between Pearson's syndrome and Kearns-Sayre syndrome.

Lamotrigine (LTG) is one of the newer-generation antiepileptic drugs (AEDs) with broad-spectrum efficacy against a variety of seizures and epileptic syndromes. We retrospectively evaluated the effects of LTG as add-on therapy on EEGs of children and adolescents. The EEGs of 53 patients (mean age: 12.5 years) with primarily pharmacoresistant epilepsy were reviewed prior to and after LTG add-on therapy. Multiple seizure types were seen in 25, generalized seizures in 15, and complex partial seizures in 13 of the patients. Preceding LTG therapy, the baseline EEG was abnormal because of slow background in 60.3% and localized spikes in 35.8%, generalized spikes in 28.3%, or both in 24.5%. The EEG analysis during the 2-year follow-up period showed improvement in the background in 21.9%, interictal activity in 37.8%, and ictal pattern in 41.1% of the EEG recordings. Overall, LTG resulted in improvement in electrographic features which paralleled the clinical improvement.

Status epilepticus (SE) is associated with a significant risk of cognitive impairment. While many factors likely determine cognitive outcome following SE, there is evidence that cognitive ability prior to a neurological insult may be an important determinant of outcome. Patients with greater cognitive abilities or so-called cognitive reserve may be less vulnerable to injury than patients with limited cognitive ability. Here we tested the hypothesis that cognitive abilities prior to SE would be predictive of cognitive outcome. Immature rats were tested in the water maze, a test of visual-spatial memory, and divided into fast and slow learners. Animals were then subjected to SE and retested in the water maze 23 days later. Control rats were tested in the same manner but not subjected to SE. SE resulted in marked impairment in water maze performance. However, no statistical difference was noted in performance between slow and fast learners in either the SE or control group. Likewise, no differences were seen in the histopathology of the slow and fast learners. This study demonstrates that SE adversely effects visual-spatial memory equally in both fast and slow learners and does not support the theory that cerebral reserve plays a major role in cognitive function following a cerebral insult.

Zonisamide is a broad-spectrum antiepileptic drug used to treat various types of seizures. Although visual hallucinations have not been reported as an adverse effect of this agent, we describe three patients who experienced complex visual hallucinations and altered mental status after zonisamide treatment was begun or its dosage increased. All three had been diagnosed earlier with epilepsy, and their electroencephalogram (EEG) findings were abnormal. During monitoring, visual hallucinations did not correlate with EEG readings, nor did video recording capture any of the described events. None of the patients had experienced visual hallucinations before this event. The only recent change in their treatment was the introduction or increased dosage of zonisamide. With either discontinuation or decreased dosage of the drug the symptoms disappeared and did not recur. Further observations and reports will help clarify this adverse effect. Until then, clinicians need to be aware of this possible complication associated with zonisamide.

Gelastic seizures are characterized by inappropriate, stereotyped laughter and are often first recognized when other epileptic manifestations occur. They are frequently associated with hypothalamic hamartomas. Central nervous system developmental abnormalities are rarely reported with gelastic seizures. There is only one case report of gelastic seizure caused by holoprosencephaly. We report a 2-year-old girl with multiple brain structural abnormalities including tectal tumor (possibly hamartoma), multiple subependymal nodules, and holoprosencephaly. She developed seizures during the newborn period and presented with gelastic seizure and simple partial seizure at 3 months of age.

Multifocal independent spike syndrome (MISS) is an identifiable electroclinical syndrome, which combines intractable motor seizures, mental retardation and multifocal independent spike discharges. Similarities to the Lennox Gastaut syndrome cause frequent misdiagnosis; however, MISS is a distinct electroclinical syndrome in children with a better prognosis and a different EEG pattern. We report an 8-year-old boy with MISS, whose intractable seizures were completely controlled for the first time with tiagabine as add-on therapy. Tiagabine should be studied further in the treatment of intractable multiple seizures of childhood.