Publications by authors named "Cigdem Akman"

44 Publications

Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group.

Authors:
Joerg Klepper Cigdem Akman Marisa Armeno Stéphane Auvin Mackenzie Cervenka Helen J Cross Valentina De Giorgis Adela Della Marina Kristin Engelstad Nicole Heussinger Eric H Kossoff Wilhelmina G Leen Baerbel Leiendecker Umrao R Monani Hirokazu Oguni Elizabeth Neal Juan M Pascual Toni S Pearson Roser Pons Ingrid E Scheffer Pierangelo Veggiotti Michél Willemsen Sameer M Zuberi Darryl C De Vivo

Epilepsia Open 2020 Sep 13;5(3):354-365. Epub 2020 Aug 13.

Department of Neurology and Pediatrics Vagelos College of Physicians and Surgeons at Columbia University New York NY USA.

Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide-ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye-head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic variants. KDT represent standard choices with Glut1DS-specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. linical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long-term disease burden. Impaired development of the brain microvasculature is one such complication of delayed Glut1DS treatment in the postnatal period. This international consensus statement should facilitate prompt diagnosis and guide best standard of care for Glut1DS throughout the life cycle.
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http://dx.doi.org/10.1002/epi4.12414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469861PMC
September 2020

De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder.

Authors:
Ghayda M Mirzaa Jessica X Chong Amélie Piton Bernt Popp Kimberly Foss Hui Guo Ricardo Harripaul Kun Xia Joshua Scheck Kimberly A Aldinger Samin A Sajan Sha Tang Dominique Bonneau Anita Beck Janson White Sonal Mahida Jacqueline Harris Constance Smith-Hicks Juliane Hoyer Christiane Zweier André Reis Christian T Thiel Rami Abou Jamra Natasha Zeid Amy Yang Laura S Farach Laurence Walsh Katelyn Payne Luis Rohena Milen Velinov Alban Ziegler Elise Schaefer Vincent Gatinois David Geneviève Marleen E H Simon Jennefer Kohler Joshua Rotenberg Patricia Wheeler Austin Larson Michelle E Ernst Cigdem I Akman Rachel Westman Patricia Blanchet Lori-Anne Schillaci Catherine Vincent-Delorme Karen W Gripp Francesca Mattioli Gwenaël Le Guyader Bénédicte Gerard Michèle Mathieu-Dramard Gilles Morin Roksana Sasanfar Muhammad Ayub Nasim Vasli Sandra Yang Rick Person Kristin G Monaghan Deborah A Nickerson Ellen van Binsbergen Gregory M Enns Annika M Dries Leah J Rowe Anne C H Tsai Shayna Svihovec Jennifer Friedman Zehra Agha Raheel Qamar Lance H Rodan Julian Martinez-Agosto Charlotte W Ockeloen Marie Vincent William James Sunderland Jonathan A Bernstein Evan E Eichler John B Vincent Michael J Bamshad

Genet Med 2020 03 14;22(3):538-546. Epub 2019 Nov 14.

Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.

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.
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http://dx.doi.org/10.1038/s41436-019-0693-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060121PMC
March 2020

Ictal onset patterns of subdural intracranial electroencephalogram in children: How helpful for predicting epilepsy surgery outcome?

Authors:
Aliza S Alter Ravi Dhamija Tiffani L McDonough Stephie Shen Danielle K McBrian Arthur M Mandel Guy M McKhann Neil A Feldstein Cigdem I Akman

Epilepsy Res 2019 01 28;149:44-52. Epub 2018 Oct 28.

Department of Neurology, Division of Child Neurology, New York-Presbyterian Hospital/ Columbia University College of Physicians and Surgeons, 180 Fort Washington Avenue, New York, New York, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.eplepsyres.2018.10.008DOI Listing
January 2019

Safety and efficacy of stereoelectroencephalography in pediatric focal epilepsy: a single-center experience.

Authors:
Hannah E Goldstein Brett E Youngerman Belinda Shao Cigdem I Akman Arthur M Mandel Danielle K McBrian James J Riviello Sameer A Sheth Guy M McKhann Neil A Feldstein

J Neurosurg Pediatr 2018 Oct 20;22(4):444-452. Epub 2018 Jul 20.

2Division of Pediatric Neurosurgery, Department of Neurological Surgery, Children's Hospital of New York, Columbia-Presbyterian, New York.

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.
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http://dx.doi.org/10.3171/2018.5.PEDS1856DOI Listing
October 2018

Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses.

Authors:
Laura Addis William Sproviero Sanjeev V Thomas Roberto H Caraballo Stephen J Newhouse Kumudini Gomez Elaine Hughes Maria Kinali David McCormick Siobhan Hannan Silvia Cossu Jacqueline Taylor Cigdem I Akman Steven M Wolf David E Mandelbaum Rajesh Gupta Rick A van der Spek Dario Pruna Deb K Pal

J Med Genet 2018 09 22;55(9):607-616. Epub 2018 May 22.

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.

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 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 (, , and ), 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.
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http://dx.doi.org/10.1136/jmedgenet-2018-105319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119347PMC
September 2018

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.

Authors:
Melodie R Winawer Nicole G Griffin Jorge Samanamud Evan H Baugh Dinesh Rathakrishnan Senthilmurugan Ramalingam David Zagzag Catherine A Schevon Patricia Dugan Manu Hegde Sameer A Sheth Guy M McKhann Werner K Doyle Gerald A Grant Brenda E Porter Mohamad A Mikati Carrie R Muh Colin D Malone Ann Marie R Bergin Jurriaan M Peters Danielle K McBrian Alison M Pack Cigdem I Akman Christopher M LaCoursiere Katherine M Keever Joseph R Madsen Edward Yang Hart G W Lidov Catherine Shain Andrew S Allen Peter D Canoll Peter B Crino Annapurna H Poduri Erin L Heinzen

Ann Neurol 2018 06 16;83(6):1133-1146. Epub 2018 May 16.

Institute for Genomic Medicine, Columbia University, New York, NY.

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.
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http://dx.doi.org/10.1002/ana.25243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105543PMC
June 2018

Early Recurrence of First Unprovoked Seizures in Children.

Authors:
Leah R Goldberg Catherine G Kernie Kathleen Lillis Jonathan Bennett Gregory Conners Charles G Macias James Callahan Cigdem Akman W Allen Hauser Nathan Kuppermann Peter S Dayan

Acad Emerg Med 2018 03 28;25(3):275-282. Epub 2017 Nov 28.

Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY.

Objectives: The risk of early seizure recurrences after first unprovoked seizures in children is largely unknown. We aimed to determine the rate of seizure recurrence within 14 days of first unprovoked seizures in children and identify associated risk factors. Secondarily, we aimed to determine the risk of recurrence at 48 hours and 4 months.

Methods: We conducted a secondary analysis of a multicenter cohort study of children 29 days to 18 years with first unprovoked seizures. Emergency department (ED) clinicians completed standardized histories and physical examinations. The primary outcome, recurrent seizure at 14 days, and the secondary outcomes, recurrence at 48 hours and 4 months, were assessed by telephone follow-up and medical record review. For each recurrence time point, we excluded those patients for whom no seizure had recurred but chronic antiepileptic drugs had been initiated.

Results: A total of 475 patients were enrolled in the parent study. Of evaluable patients for this secondary analysis, 26 of 392 (6.6%, 95% confidence interval [CI] = 4.4%-9.6%) had recurrences within 48 hours of the incident seizures, 58 of 366 (15.8%, 95% CI = 12.3%-20.0%) had recurrences within 14 days, and 107 of 340 (31.5%, 95% CI = 26.6%-36.7%) had recurrences within 4 months. On logistic regression analysis, age younger than 3 years was independently associated with a higher risk of 14-day recurrence (adjusted odds ratio [OR] = 2.1, 95% CI = 1.2-3.7; p = 0.01). Having had more than one seizure within the 24 hours prior to ED presentation was independently associated with a higher risk of seizure recurrence at 48 hours (adjusted OR = 4.3, 95% CI = 1.9-9.8; p < 0.001).

Conclusions: Risk of seizure recurrence 14 days after first unprovoked seizures in children is substantial, with younger children at higher risk. Prompt completion of an electroencephalogram and evaluation by a neurologist is appropriate for these children.
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http://dx.doi.org/10.1111/acem.13341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842104PMC
March 2018

Epilepsy surgery for epileptic encephalopathy as a sequela of herpes simplex encephalitis: case report.

Authors:
Birce Dilge Taskin Kurenai Tanji Neil A Feldstein Maureen McSwiggan-Hardin Cigdem I Akman

J Neurosurg Pediatr 2017 Jul 28;20(1):56-63. Epub 2017 Apr 28.

Department of Neurology, Division of Child Neurology, Columbia University Medical Center, New York.

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.
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http://dx.doi.org/10.3171/2017.3.PEDS16632DOI Listing
July 2017

A microRNA-328 binding site in PAX6 is associated with centrotemporal spikes of rolandic epilepsy.

Authors:
Naim Panjwani Michael D Wilson Laura Addis Jennifer Crosbie Elaine Wirrell Stéphane Auvin Roberto H Caraballo Maria Kinali David McCormick Caroline Oren Jacqueline Taylor John Trounce Tara Clarke Cigdem I Akman Steven L Kugler David E Mandelbaum Patricia McGoldrick Steven M Wolf Paul Arnold Russell Schachar Deb K Pal Lisa J Strug

Ann Clin Transl Neurol 2016 07 2;3(7):512-22. Epub 2016 Jun 2.

Program in Genetics and Genome Biology The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada; Division of Biostatistics Dalla Lana School of Public Health University of Toronto Toronto Ontario M5T 3M7 Canada; The Centre for Applied Genomics The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada.

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.
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http://dx.doi.org/10.1002/acn3.320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931716PMC
July 2016

Staged laser interstitial thermal therapy and topectomy for complete obliteration of complex focal cortical dysplasias.

Authors:
Jason A Ellis Juan C Mejia Munne Shih-Hsiu Wang Danielle K McBrian Cigdem I Akman Neil A Feldstein Guy M McKhann

J Clin Neurosci 2016 Sep 24;31:224-8. Epub 2016 May 24.

Department of Neurological Surgery, Columbia University Medical Center, Neurological Institute of New York, 710 West 168th Street, New York, NY 10032, USA.

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.
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http://dx.doi.org/10.1016/j.jocn.2016.02.016DOI Listing
September 2016

Diagnosing Glucose Transporter 1 Deficiency at Initial Presentation Facilitates Early Treatment.

Authors:
Cigdem Inan Akman Julia Yu Aliza Alter Kristin Engelstad Darryl C De Vivo

J Pediatr 2016 Apr 22;171:220-6. Epub 2016 Jan 22.

Division of Pediatric Neurology, Department of Neurology, Colleen Giblin Research Laboratory, Columbia University College of Physician and Surgeons, New York, NY. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jpeds.2015.12.030DOI Listing
April 2016

Risk factors for reading disability in families with rolandic epilepsy.

Authors:
Yaiza Hernández Vega Anna Smith Hannah Cockerill Shan Tang Zaloa Agirre-Arrizubieta Sushma Goyal Marisa Pina Cigdem I Akman Nicola Jolleff Colm McGinnity Kumudini Gomez Rajesh Gupta Elaine Hughes John Jackman David McCormick Caroline Oren David Scott Jacqueline Taylor John Trounce Tara Clarke Steven Kugler David E Mandelbaum Patricia McGoldrick Steven Wolf Lisa J Strug Deb K Pal

Epilepsy Behav 2015 Dec 12;53:174-9. Epub 2015 Nov 12.

King's College London, UK; King's Health Partners, London, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.yebeh.2015.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719157PMC
December 2015

Prevalence of and Risk Factors for Intracranial Abnormalities in Unprovoked Seizures.

Authors:
Peter S Dayan Kathleen Lillis Jonathan Bennett Gregory Conners Pam Bailey James Callahan Cigdem Akman Neil Feldstein Joshua Kriger W Allen Hauser Nathan Kuppermann

Pediatrics 2015 Aug 20;136(2):e351-60. Epub 2015 Jul 20.

Departments of Emergency Medicine and Pediatrics, Davis School of Medicine, University of California, Sacramento, California.

Background And Objectives: Prospective data are lacking to determine which children might benefit from prompt neuroimaging after unprovoked seizures. We aimed to determine the prevalence of, and risk factors for, relevant intracranial abnormalities in children with first, unprovoked seizures.

Methods: We conducted a 6-center prospective study in children aged >28 days to 18 years with seemingly unprovoked seizures. Emergency department (ED) clinicians documented clinical findings on a standardized form. Our main outcome was the presence of a clinically relevant intracranial abnormality on computed tomography (CT) or MRI, defined as those that might change management, either emergently, urgently, or nonurgently.

Results: We enrolled 475 of 625 (76%) eligible patients. Of 354 patients for whom cranial MRI or CT scans were obtained in the ED or within 4 months of the ED visit, 40 (11.3%; 95% confidence interval [CI]: 8.0-14.6%) had clinically relevant intracranial abnormalities, with 3 (0.8%; 95% CI: 0.1-1.8%) having emergent/urgent abnormalities. On logistic regression analysis, a high-risk past medical history (adjusted odds ratio: 9.2; 95% CI: 2.4-35.7) and any focal aspect to the seizure (odds ratio: 2.5; 95% CI: 1.2-5.3) were independently associated with clinically relevant abnormalities.

Conclusions: Clinically relevant intracranial abnormalities occur in 11% of children with first, unprovoked seizures. Emergent/urgent abnormalities, however, occur in <1%, suggesting that most children do not require neuroimaging in the ED. Findings on patient history and physical examination identify patients at higher risk of relevant abnormalities.
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http://dx.doi.org/10.1542/peds.2014-3550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516940PMC
August 2015

Topography of brain glucose hypometabolism and epileptic network in glucose transporter 1 deficiency.

Authors:
Cigdem Inan Akman Frank Provenzano Dong Wang Kristin Engelstad Veronica Hinton Julia Yu Ronald Tikofsky Masonari Ichese Darryl C De Vivo

Epilepsy Res 2015 Feb 11;110:206-15. Epub 2014 Dec 11.

Department of Neurology, Division of Pediatric Neurology, Colleen Giblin Research Laboratory, Columbia University College of Physician & Surgeons, United States.

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.
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http://dx.doi.org/10.1016/j.eplepsyres.2014.11.007DOI Listing
February 2015

Application of envelope trend to analyze early EEG changes in the frontal regions during intracarotid amobarbital procedure in children.

Authors:
Cigdem I Akman Vesna Micic Michael Quach Angus A Wilfong Rebecca Schultz James J Riviello Mary L Chapieski

Epilepsy Behav 2015 Feb 2;43:66-73. Epub 2015 Jan 2.

Division of Pediatric Neurology, Texas Children's Hospital, Houston, TX, USA.

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.
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http://dx.doi.org/10.1016/j.yebeh.2014.08.011DOI Listing
February 2015

Long-term clinical course of Glut1 deficiency syndrome.

Authors:
Aliza S Alter Kristin Engelstad Veronica J Hinton Jacqueline Montes Toni S Pearson Cigdem I Akman Darryl C De Vivo

J Child Neurol 2015 Feb 30;30(2):160-9. Epub 2014 Apr 30.

Department of Neurology, Columbia University, New York, NY, USA

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.
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http://dx.doi.org/10.1177/0883073814531822DOI Listing
February 2015

Generalized periodic epileptiform discharges in critically ill children: clinical features, and outcome.

Authors:
Cigdem I Akman Karine J Abou Khaled Eric Segal Vesna Micic James J Riviello

Epilepsy Res 2013 Oct 21;106(3):378-85. Epub 2013 Aug 21.

Department of Neurology, Division of Pediatric Neurology, Columbia University College of Physician & Surgeons, United States; Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, United States; Department of Neurology, Kellaway Section of Neurophysiology, Baylor College of Medicine, United States. Electronic address:

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.
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http://dx.doi.org/10.1016/j.eplepsyres.2013.06.019DOI Listing
October 2013

Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS).

Authors:
Toni S Pearson Cigdem Akman Veronica J Hinton Kristin Engelstad Darryl C De Vivo

Curr Neurol Neurosci Rep 2013 Apr;13(4):342

Department of Neurology, Columbia University, 710 west 168th Street, New York, NY 10032, USA.

Glut1 deficiency syndrome (Glut1 DS) was originally described in 1991 as a developmental encephalopathy characterized by infantile onset refractory epilepsy, cognitive impairment, and mixed motor abnormalities including spasticity, ataxia, and dystonia. The clinical condition is caused by impaired glucose transport across the blood brain barrier. The past 5 years have seen a dramatic expansion in the range of clinical syndromes that are recognized to occur with Glut1 DS. In particular, there has been greater recognition of milder phenotypes. Absence epilepsy and other idiopathic generalized epilepsy syndromes may occur with seizure onset in childhood or adulthood. A number of patients present predominantly with movement disorders, sometimes without any accompanying seizures. In particular, paroxysmal exertional dyskinesia is now a well-documented clinical feature that occurs in individuals with Glut1 DS. A clue to the diagnosis in patients with paroxysmal symptoms may be the triggering of episodes during fasting or exercise. Intellectual impairment may range from severe to very mild. Awareness of the broad range of potential clinical phenotypes associated with Glut1 DS will facilitate earlier diagnosis of this treatable neurologic condition. The ketogenic diet is the mainstay of treatment and nourishes the starving symptomatic brain during development.
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http://dx.doi.org/10.1007/s11910-013-0342-7DOI Listing
April 2013

Refractory status epilepticus associated with anti-SSA (anti-Ro) antibodies.

Authors:
Jeremy J Moeller Daniel Friedman Patricia Dugan Cigdem I Akman

Can J Neurol Sci 2012 Sep;39(5):660-3

Department of Medicine, Dalhousie University, Halifax, NS, Canada.

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http://dx.doi.org/10.1017/s0317167100015444DOI Listing
September 2012

Generalized periodic epileptiform discharges in critically ill children: a continuum of status epilepticus or an epiphenomenon?

Authors:
Cigdem I Akman James J Riviello

J Clin Neurophysiol 2011 Aug;28(4):366-72

Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

Purpose: Generalized periodic epileptiform discharges (GPEDs) are a specific periodic EEG pattern, reported with status epilepticus (SE) or a metabolic or an anoxic encephalopathy in critically ill patients. In this study, we examined the clinical course and evolution of EEG findings associated with GPEDs in children with refractory convulsive SE.

Methods: The EEG reports of 279 children with SE diagnosed between 2002 and 2010 were reviewed to detect GPEDs. Ten children were identified with GPEDs on continuous EEG recording. The entire EEG recording was available for review in only six children. In the clinical course, seizure characteristics and evolution of EEG findings were analyzed.

Results: Six children (age, 5 to 17 years) were admitted to the intensive care unit with refractory convulsive SE. All had acute symptomatic SE except for one child with a history of epilepsy and developmental delay. Intravenous anesthetic agents were used to treat convulsive SE in five children. After tapering the intravenous anesthetic agents, GPEDs were seen on the continuous EEG recording, nonconvulsive seizures occurred in five, and nonconvulsive SE in four children. None of the children returned to baseline, and three children died.

Conclusions: Generalized periodic epileptiform discharges are seen during the treatment course of convulsive SE in children and heralded seizure recurrence. We found a sequential evolution of the EEG patterns after the control of convulsive SE, with GPEDs occurring in a dynamic fashion in a continuum along with burst suppression and electrographic seizures. Recognizing that GPEDs represent a still active epileptic state after the control of convulsive SE with intravenous anesthetic agents and modifying the treatment regimen to control GPEDs may prevent immediate seizure recurrence.
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http://dx.doi.org/10.1097/WNP.0b013e3182273486DOI Listing
August 2011

Seizure detection using digital trend analysis: Factors affecting utility.

Authors:
Cigdem I Akman Vesna Micic Anita Thompson James J Riviello

Epilepsy Res 2011 Jan 10;93(1):66-72. Epub 2010 Dec 10.

Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, United States.

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.
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http://dx.doi.org/10.1016/j.eplepsyres.2010.10.018DOI Listing
January 2011

Recurrent distal 7q11.23 deletion including HIP1 and YWHAG identified in patients with intellectual disabilities, epilepsy, and neurobehavioral problems.

Authors:
Melissa B Ramocki Magdalena Bartnik Przemyslaw Szafranski Katarzyna E Kołodziejska Zhilian Xia Jaclyn Bravo G Steve Miller Diana L Rodriguez Charles A Williams Patricia I Bader Elżbieta Szczepanik Tomasz Mazurczak Dorota Antczak-Marach James G Coldwell Cigdem I Akman Karen McAlmon Melinda P Cohen James McGrath Elizabeth Roeder Jennifer Mueller Sung-Hae L Kang Carlos A Bacino Ankita Patel Ewa Bocian Chad A Shaw Sau Wai Cheung Tadeusz Mazurczak Paweł Stankiewicz

Am J Hum Genet 2010 Dec 25;87(6):857-65. Epub 2010 Nov 25.

Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.

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.
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http://dx.doi.org/10.1016/j.ajhg.2010.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997378PMC
December 2010

Recurrent seizure-related injuries in people with epilepsy at a tertiary epilepsy center: a 2-year longitudinal study.

Authors:
David E Friedman Ronnie S Tobias Cigdem I Akman E O'Brian Smith Harvey S Levin

Epilepsy Behav 2010 Nov 18;19(3):400-4. Epub 2010 Sep 18.

Department of Neurology, Baylor College of Medicine, Houston, TX, USA.

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.
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http://dx.doi.org/10.1016/j.yebeh.2010.07.029DOI Listing
November 2010

Nonconvulsive status epilepticus and continuous spike and slow wave of sleep in children.

Authors:
Cigdem Inan Akman

Semin Pediatr Neurol 2010 Sep;17(3):155-62

Department of Pediatrics, Division of Pediatric Neurology, Columbia University School of Physicians & Surgeons, Morgan Children's Hospital at New York Presbyterian, New York, NY, USA.

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.
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http://dx.doi.org/10.1016/j.spen.2010.06.009DOI Listing
September 2010

Acute hyperglycemia produces transient improvement in glucose transporter type 1 deficiency.

Authors:
Cigdem I Akman Kristin Engelstad Veronica J Hinton Paivi Ullner Dorcas Koenigsberger Linda Leary Dong Wang Darryl C De Vivo

Ann Neurol 2010 Jan;67(1):31-40

Department of Neurology, Baylor College of Medicine, Houston, TX, USA.

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.
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http://dx.doi.org/10.1002/ana.21797DOI Listing
January 2010

Epilepsy duration impacts on brain glucose metabolism in temporal lobe epilepsy: results of voxel-based mapping.

Authors:
Cigdem I Akman Masonori Ichise Aviva Olsavsky Ronald S Tikofsky Ronald L Van Heertum Frank Gilliam

Epilepsy Behav 2010 Mar 10;17(3):373-80. Epub 2010 Feb 10.

Comprehensive Epilepsy Center, Department of Neurology, Columbia University College of Physicians & Surgeons, New York, NY, USA.

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.
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http://dx.doi.org/10.1016/j.yebeh.2009.12.007DOI Listing
March 2010

Subclinical seizures in children diagnosed with localization-related epilepsy: clinical and EEG characteristics.

Authors:
Cigdem I Akman Maria A Montenegro Susan Jacob Karen Eck Danielle McBrian Claudia A Chiriboga Marc C Patterson

Epilepsy Behav 2009 Sep 25;16(1):86-98. Epub 2009 Jul 25.

Comprehensive Epilepsy Center, Department of Neurology, Columbia University College of Physician and Surgeons, New York, NY, USA.

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.
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http://dx.doi.org/10.1016/j.yebeh.2009.06.026DOI Listing
September 2009

Seizure frequency in children with epilepsy: factors influencing accuracy and parental awareness.

Authors:
Cigdem Inan Akman Maria A Montenegro Susan Jacob Karen Eck Claudia Chiriboga Frank Gilliam

Seizure 2009 Sep 9;18(7):524-9. Epub 2009 Jul 9.

Division of Pediatric Neurology, Department of Neurology, Columbia University College of Physician & Surgeons, New York, NY, USA.

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.
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http://dx.doi.org/10.1016/j.seizure.2009.05.009DOI Listing
September 2009

Limbic encephalitis associated with anti-GAD antibody and common variable immune deficiency.

Authors:
Cigdem I Akman Marc C Patterson Arye Rubinstein Ronit Herzog

Dev Med Child Neurol 2009 Jul 3;51(7):563-7. Epub 2009 Feb 3.

Comprehensive Epilepsy Center, Department of Neurology, Division of Pediatric Neurology and Epilepsy, Columbia University College of Physicians and Surgeons, New York, NY, USA.

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.
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http://dx.doi.org/10.1111/j.1469-8749.2008.03217.xDOI Listing
July 2009

Long-term outcome of symptomatic infantile spasms established by video-electroencephalography (EEG) monitoring.

Authors:
Maria A Montenegro Karen Eck Susan Jacob Joshua Cappell Claudia Chriboga Ronald Emerson Marc C Patterson Cigdem I Akman

J Child Neurol 2008 Nov;23(11):1288-92

Comprehensive Epilepsy Center, Department of Neurology, Columbia University College of Physician & Surgeons, New York, New York, USA.

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.
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http://dx.doi.org/10.1177/0883073808318540DOI Listing
November 2008