Publications by authors named "Hadassa Goldberg-Stern"

49 Publications

Epilepsy and electroencephalogram evolution in YWHAG gene mutation: A new phenotype and review of the literature.

Am J Med Genet A 2021 03 4;185(3):901-908. Epub 2021 Jan 4.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

A male patient with a de novo mutation in the YWHAG gene and mild phenotype is presented. He had normal delivery and normal development, with normal speech and social milestones. At the age of 9 months, myoclonic seizures started, with generalized epileptiform discharges. The child responded well to levetiracetam monotherapy with complete seizure resolution. Levetiracetam was stopped and he remained seizure-free for 10 months. His development was appropriate for age according to psychological evaluation and he attended a regular kindergarten. At the age of approximately 4 years, the seizures reappeared with different semiology of staring with eye blinking. Electroencephalogram (EEG) showed multifocal spikes. Brain magnetic resonance imaging did not reveal any structural abnormality. Genetic analysis revealed a de novo likely pathogenic missense variant in the YWHAG gene (c.619G>A p.Glu207Lys). We compared our case to the other cases published in the literature. Our case is unique in its seizure semiology and evolution of EEG. Moreover, in contrast to our case, the majority of cases described in the literature have dysmorphism and intellectual disability or autistic spectrum disorder. This report emphasizes the phenotypic heterogeneity of YWHAG mutation as is the case in other developmental encephalopathies.
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http://dx.doi.org/10.1002/ajmg.a.62026DOI Listing
March 2021

Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability.

J Clin Invest 2020 03;130(3):1431-1445

Department of Clinical Genetics, Amsterdam University Medical Center, Amsterdam, Netherlands.

Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and influence disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis, and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in 9 patients with intellectual disability, seizures, autism, dysmorphisms, and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least 2 of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies.
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http://dx.doi.org/10.1172/JCI131145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269600PMC
March 2020

A de novo GABRA2 missense mutation in severe early-onset epileptic encephalopathy with a choreiform movement disorder.

Eur J Paediatr Neurol 2018 May 30;22(3):516-524. Epub 2017 Dec 30.

Pediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Raphael Recanati Genetics Institute, Rabin Medical Center- Beilinson Hospital, Petach Tikva 4941492, Israel; Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva 4941492, Israel. Electronic address:

Background: Early-onset epileptic encephalopathy (EOEE) is a severe convulsive disorder with a poor developmental prognosis. Although it has been associated with mutations in a number of genes, the fact that there is a large proportion of patients who remain undiagnosed suggests that there are many more still-unknown genetic causes of EOEE. Achieving a genetic diagnosis is important for understanding the biological basis of the disease, with its implications for treatment and family planning.

Methods: Whole-exome sequencing was performed in a family of Ashkenazi Jewish origin in which a male infant was diagnosed with EOEE. There was no family history of a similar neurologic disease. The patient had extreme hypotonia, neonatal hypothermia, choreiform movements, and vision impairment in addition to the convulsive disorder.

Results: A de novo heterozygous missense mutation, c.1003A > C, p.Asn335His, was identified in a conserved domain of GABRA2. GABRA2 encodes the α2 subunit of the GABA receptor.

Conclusions: In the context of previous reports of an association of de novo mutations in genes encoding different subunits of the GABA receptor (GABRB1, GABRA1, GABRG2, GABRB3) with autosomal dominant epileptic disorders, we conclude that a de novo mutation in GABRA2 is likely to cause autosomal dominant EOEE accompanied by a movement disorder and vision impairment.
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http://dx.doi.org/10.1016/j.ejpn.2017.12.017DOI Listing
May 2018

Genetic epilepsy with febrile seizures plus: Refining the spectrum.

Neurology 2017 Sep 25;89(12):1210-1219. Epub 2017 Aug 25.

From the Epilepsy Research Centre, Department of Medicine (Y.-H.Z., R.B., J.P.M., G.C.G., K.L.H., L.V., B.E.G., S.T.B., D.F.V., J.A.D., M.S.H., S.F.B., I.E.S.), The University of Melbourne, Austin Health, Australia; Department of Pediatrics (Y.-H.Z.), Peking University First Hospital, Beijing, China; Department of Neurology (L.V.), The University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, Australia; Schneider Children's Medical Center of Israel (S.K., H.G.-S.), Petach Tikvah; Department of Neurology (Z.A.), Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Westmead Hospital (A.B.), New South Wales, Australia; Department of Neurology (P.G.-S.), Sydney Children's Hospital, Australia; Department of Neurology (A.D.K.), Tel Aviv University, Israel; Women's and Children's Hospital (L.M.D.), University of Adelaide, South Australia; Center for Neurobehavioral Genetics (E.K.R.), Semel Institute, David Geffen School of Medicine, University of California, Los Angeles; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital, Victoria; and The Florey Institute of Neurosciences and Mental Health (I.E.S.), Melbourne, Australia.

Objective: Following our original description of generalized epilepsy with febrile seizures plus (GEFS+) in 1997, we analyze the phenotypic spectrum in 409 affected individuals in 60 families (31 new families) and expand the GEFS+ spectrum.

Methods: We performed detailed electroclinical phenotyping on all available affected family members. Genetic analysis of known GEFS+ genes was carried out where possible. We compared our phenotypic and genetic data to those published in the literature over the last 19 years.

Results: We identified new phenotypes within the GEFS+ spectrum: focal seizures without preceding febrile seizures (16/409 [4%]), classic genetic generalized epilepsies (22/409 [5%]), and afebrile generalized tonic-clonic seizures (9/409 [2%]). Febrile seizures remains the most frequent phenotype in GEFS+ (178/409 [44%]), followed by febrile seizures plus (111/409 [27%]). One third (50/163 [31%]) of GEFS+ families tested have a pathogenic variant in a known GEFS+ gene.

Conclusion: As 37/409 (9%) affected individuals have focal epilepsies, we suggest that GEFS+ be renamed genetic epilepsy with febrile seizures plus rather than generalized epilepsy with febrile seizures plus. The phenotypic overlap between GEFS+ and the classic generalized epilepsies is considerably greater than first thought. The clinical and molecular data suggest that the 2 major groups of generalized epilepsies share genetic determinants.
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http://dx.doi.org/10.1212/WNL.0000000000004384DOI Listing
September 2017

Polymicrogyria and myoclonic epilepsy in autosomal recessive cutis laxa type 2A.

Neurogenetics 2016 10 8;17(4):251-257. Epub 2016 Sep 8.

Department of Pediatric Neurology and Epilepsy Center, Schneider Children's Medical Center of Israel, Petach Tikva, 4920235, Israel.

Cutis laxa syndromes are rare inherited disorders of skin and connective tissue metabolism associated with variable systemic involvement. The main clinical manifestation is loose, wrinkled, redundant, inelastic skin, hypotonia, typical facies including short nose and down-slanting palpebral fissures, and varying degrees of developmental delay. The aim of this report is to describe two siblings diagnosed with a moderate form of ATP6V0A2-related cutis laxa with polymicrogyria (cobblestone-like brain dysgenesis). One of the patients has myoclonic epilepsy which may have contributed to his more severe clinical presentation. The literature on cutis laxa syndromes is reviewed.
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http://dx.doi.org/10.1007/s10048-016-0491-3DOI Listing
October 2016

RARS2 mutations cause early onset epileptic encephalopathy without ponto-cerebellar hypoplasia.

Eur J Paediatr Neurol 2016 May 2;20(3):412-7. Epub 2016 Mar 2.

Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address:

Introduction: Early onset epileptic encephalopathies (EOEEs) are a group of devastating diseases, manifesting in the first year of life with frequent seizures and/or prominent interictal epileptiform discharges on the electroencephalogram, developmental delay or regression and usually a poor prognosis. There are numerous causes for EOEEs making the diagnostic workup time consuming and costly.

Methods: We describe two siblings with fatal EOEE, profound global developmental delay and post-natal microcephaly that underwent extensive biochemical and metabolic workup in vain. Neuro-imaging disclosed non-specific progressive cerebral atrophy.

Results: Whole-exome sequencing (WES) disclosed compound heterozygous mutations in the gene encoding for mitochondrial arginyl-transfer RNA synthetase, RARS2. This gene has been previously described as the cause of pontocerebellar hypoplasia type 6.

Conclusion: We suggest that RARS2 gene mutations can cause a metabolic neurodegenerative disease manifesting primarily as EOEE with post-natal microcephaly, without the distinctive radiological features of pontocerebellar hypoplasia.
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http://dx.doi.org/10.1016/j.ejpn.2016.02.012DOI Listing
May 2016

Multiplex families with epilepsy: Success of clinical and molecular genetic characterization.

Neurology 2016 Feb 22;86(8):713-22. Epub 2016 Jan 22.

From the Sackler School of Medicine (Z.A., I.B., M.Y.N., T.L.-S., A.D.K.), Tel Aviv University, Ramat Aviv, Israel; Epilepsy Research Centre (K.L.O., K.L.H., I.E.S., S.F.B.), University of Melbourne, Austin Health, Heidelberg, Australia; Epilepsy Unit (S.K., H.G.-S., R.S.), Schneider Children's Medical Center of Israel, Petach Tikvah; Department of Neurology (A.M., M.Y.N.), Tel Aviv Sourasky Medical Center; Department of Neurology (I.B.), The Chaim Sheba Medical Center, Tel Hashomer; Shaare Zedek Medical Center (A.J.M.), Jerusalem; Department of Neurology (S.W.), Western Galilee Hospital, Nahariya; Pediatric Neurology and Child Development Center (M. Mahajnah), Hillel Yaffe Medical Center, Hadera; Ruth and Bruce Rappaport Faculty of Medicine (M. Mahajnah), Technion, Haifa; Pediatric Neurology Unit (T.L.-S.), Wolfson Medical Center, Holon; The Edmond and Lily Safra Children's Hospital (B.B.-Z.), Sheba Medical Center, Ramat Gan; Department of Neurology (E.K.), Barzilai Medical Center, Ashkelon; Faculty of Health Sciences (E.K., R.M., Z.S.), Ben-Gurion University of the Negev, Beer-Sheva; Department of Neurology (R.M.) and Pediatric Neurology Unit (Z.S.), Soroka University Medical Center, Beer-Sheva; Pediatric Neurology Unit (U.K.), Dana Children's Hospital, Tel Aviv; Department of Neurology (D.E.), Agnes Ginges Center of Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; School of Biomedical Sciences (R.H.W.), Charles Sturt University, NSW; Queensland Brain Institute (M. Mangelsdorf), University of Queensland, Brisbane, Australia; Wessex Regional Genetics Laboratory (J.N.M.), Salisbury NHS Foundation Trust, Salisbury, UK; Division of Genetic Medicine (G.L.C., H.C.M.), Department of Pediatrics, University of Washington, Seattle; Florey Institute (G.D.J., I.E.S.), Melbourne; Department of Pediatrics (I.E.S.), University of Melbourne, Royal Children's Hospital; Population Health and Immunity Division (M.B.), The Walter and Eliza Hall Institute o

Objective: To analyze the clinical syndromes and inheritance patterns of multiplex families with epilepsy toward the ultimate aim of uncovering the underlying molecular genetic basis.

Methods: Following the referral of families with 2 or more relatives with epilepsy, individuals were classified into epilepsy syndromes. Families were classified into syndromes where at least 2 family members had a specific diagnosis. Pedigrees were analyzed and molecular genetic studies were performed as appropriate.

Results: A total of 211 families were ascertained over an 11-year period in Israel. A total of 169 were classified into broad familial epilepsy syndrome groups: 61 generalized, 22 focal, 24 febrile seizure syndromes, 33 special syndromes, and 29 mixed. A total of 42 families remained unclassified. Pathogenic variants were identified in 49/211 families (23%). The majority were found in established epilepsy genes (e.g., SCN1A, KCNQ2, CSTB), but in 11 families, this cohort contributed to the initial discovery (e.g., KCNT1, PCDH19, TBC1D24). We expand the phenotypic spectrum of established epilepsy genes by reporting a familial LAMC3 homozygous variant, where the predominant phenotype was epilepsy with myoclonic-atonic seizures, and a pathogenic SCN1A variant in a family where in 5 siblings the phenotype was broadly consistent with Dravet syndrome, a disorder that usually occurs sporadically.

Conclusion: A total of 80% of families were successfully classified, with pathogenic variants identified in 23%. The successful characterization of familial electroclinical and inheritance patterns has highlighted the value of studying multiplex families and their contribution towards uncovering the genetic basis of the epilepsies.
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http://dx.doi.org/10.1212/WNL.0000000000002404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763801PMC
February 2016

De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing.

Sci Rep 2015 Oct 19;5:15199. Epub 2015 Oct 19.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

The voltage-gated Kv2.1 potassium channel encoded by KCNB1 produces the major delayed rectifier potassium current in pyramidal neurons. Recently, de novo heterozygous missense KCNB1 mutations have been identified in three patients with epileptic encephalopathy and a patient with neurodevelopmental disorder. However, the frequency of KCNB1 mutations in infantile epileptic patients and their effects on neuronal activity are yet unknown. We searched whole exome sequencing data of a total of 437 patients with infantile epilepsy, and found novel de novo heterozygous missense KCNB1 mutations in two patients showing psychomotor developmental delay and severe infantile generalized seizures with high-amplitude spike-and-wave electroencephalogram discharges. The mutation located in the channel voltage sensor (p.R306C) disrupted sensitivity and cooperativity of the sensor, while the mutation in the channel pore domain (p.G401R) selectively abolished endogenous Kv2 currents in transfected pyramidal neurons, indicating a dominant-negative effect. Both mutants inhibited repetitive neuronal firing through preventing production of deep interspike voltages. Thus KCNB1 mutations can be a rare genetic cause of infantile epilepsy, and insufficient firing of pyramidal neurons would disturb both development and stability of neuronal circuits, leading to the disease phenotypes.
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http://dx.doi.org/10.1038/srep15199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609934PMC
October 2015

Familial neonatal seizures in 36 families: Clinical and genetic features correlate with outcome.

Epilepsia 2015 Jul 15;56(7):1071-80. Epub 2015 May 15.

Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.

Objective: We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions.

Methods: Detailed clinical data were collected from 36 families comprising two or more individuals with neonatal seizures. The seizure course and occurrence of seizures later in life were analyzed. Families were screened for KCNQ2, KCNQ3, SCN2A, and PRRT2 mutations, and linkage studies were performed in mutation-negative families to exclude known loci.

Results: Thirty-three families fulfilled clinical criteria for benign familial neonatal epilepsy (BFNE); 27 of these families had KCNQ2 mutations, one had a KCNQ3 mutation, and two had SCN2A mutations. Seizures persisting after age 6 months were reported in 31% of individuals with KCNQ2 mutations; later seizures were associated with frequent neonatal seizures. Linkage mapping in two mutation-negative BFNE families excluded linkage to KCNQ2, KCNQ3, and SCN2A, but linkage to KCNQ2 could not be excluded in the third mutation-negative BFNE family. The three remaining families did not fulfill criteria of BFNE due to developmental delay or intellectual disability; a molecular lesion was identified in two; the other family remains unsolved.

Significance: Most families in our cohort of familial neonatal seizures fulfill criteria for BFNE; the molecular cause was identified in 91%. Most had KCNQ2 mutations, but two families had SCN2A mutations, which are normally associated with a mixed picture of neonatal and infantile onset seizures. Seizures later in life are more common in BFNE than previously reported and are associated with a greater number of seizures in the neonatal period. Linkage studies in two families excluded known loci, suggesting a further gene is involved in BFNE.
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http://dx.doi.org/10.1111/epi.13020DOI Listing
July 2015

Endocrine Effects of Valproate versus Carbamazepine in Males with Epilepsy: A Prospective Study.

Horm Res Paediatr 2015 14;83(5):332-9. Epub 2015 Mar 14.

Epilepsy Service, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.

Background/aims: To prospectively evaluate the long-term impact of valproate (VPA) versus carbamazepine (CBZ) on anthropometric, hormonal, and metabolic parameters in young male patients treated for epilepsy.

Methods: Of 61 boys with newly diagnosed epilepsy followed up, 24 were excluded from analysis (17 were lost to follow-up and 7 changed therapy within <1 year). Findings were compared by time, treatment (VPA or CBZ), and epilepsy type (generalized or partial) as well as against a matched control group with adequately treated hypothyroidism.

Results: Twenty-four boys were treated with VPA and 13 with CBZ. The weight-standard deviation score (SDS) significantly increased during the first 6 months of treatment (p < 0.001), irrespective of the drug type, but decreased between the first and the last visit (p = 0.01). In patients with generalized epilepsy, there was a slight decrease in height- and weight-SDS between the first and the last visit (p = 0.04 and p = 0.01, respectively). The height-SDS at the last visit was comparable to the parental height-SDS. The mean age at puberty onset was 11.2 and 11.4 years in the study and the control group, respectively (p = 0.08). There were no significant differences in the other parameters by treatment or epilepsy type.

Conclusions: Long-term therapy with VPA or CBZ has no significant endocrinological or metabolic adverse effect on male children and adolescents with epilepsy.
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http://dx.doi.org/10.1159/000375374DOI Listing
March 2016

Interictal regional delta slowing in cerebral sinus vein thrombosis.

Neurologist 2015 Feb;19(3):85-8

Departments of *Neurology ‡Imaging, Schneider Children's Medical Center of Israel, Petach Tikva †Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

The electroencephalographic finding of regional delta activity should alert to the possibility of an underlying structural abnormality of the brain as a cause. A 5-year-old boy, who presented with severe headache and focal seizures, had normal neurological examination and brain CT findings. The initial electroencephalograph showed focal delta activity. An emergent brain MRI disclosed a thrombosis of the left sigmoid sinus and jugular vein, but no parenchymal lesions. The regional delta activity can presumably serve as a marker for brain tissue damage in cerebral sinus vein thrombosis, and sometimes, even to add information to that gained from imaging studies.
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http://dx.doi.org/10.1097/NRL.0000000000000009DOI Listing
February 2015

Thiamine deficiency in infancy: long-term follow-up.

Pediatr Neurol 2014 Sep 15;51(3):311-6. Epub 2014 May 15.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Neurology Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Background: In 2003, several hundred Israeli infants risked thiamine deficiency after being fed a soy-based formula deficient in thiamine. Approximately 20 patients were seriously affected, and three of them died. We report the clinical presentation of acute encephalopathy in 11 children and the long-term sequelae of eight children who initially survived.

Patients: In the acute phase, six had bulbar signs, five had ophthalmologic signs and two had phrenic neuropathy. Three of the five patients with cardiac involvement had cardiomyopathy and died in the acute phase. One patient presented with a complete atrioventricular block.

Results: In the long-term, one patient, who was in a chronic vegetative state, died after 6 years. Seven children exhibited mental retardation and motor abnormalities, six developed severe epilepsy, two early kyphoscoliosis, and one patient remained with a complete atrioventricular block.

Conclusions: Infants who survive severe infantile thiamine deficiency have serious residual motor and cognitive sequelae as well as epilepsy.
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http://dx.doi.org/10.1016/j.pediatrneurol.2014.05.010DOI Listing
September 2014

Endocrine effects of valproic acid therapy in girls with epilepsy: a prospective study.

Eur J Paediatr Neurol 2014 Nov 29;18(6):759-65. Epub 2014 Jul 29.

Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background/aim: It is controversial whether the endocrine dysfunction in epilepsy patients is caused by the epilepsy itself, the antiepileptic therapy, or both. We prospectively evaluated the long-term impact of valproic acid monotherapy compared to other anti-epileptic drugs on anthropometric, metabolic, hormonal, and ultrasonographic parameters in girls with epilepsy.

Methods: Fifty-seven female patients with epilepsy who had started therapy at mean age of 11.5 ± 3.3 years, 42 with valproic acid (mean dose 13.1 ± 7.0 mg/kg/day and 15 with other anti-epileptic agents were followed for a mean of 3.2 years (range 1.0-8.5 years) in our center. Clinical, hormonal and transabdominal pelvic ultrasound data were collected at 3 time points: before and 6-12 months after onset of anti-epileptic drug treatment; and at the last visit while patients were still taking anti-epileptic drugs.

Results: There were no significant between-group differences regarding changes in height, body mass index standard deviation score, levels of glucose and insulin, or lipid and endocrine profile from first to last visits. Mean thyroid-stimulating hormone level increased significantly between first and last visit only in the valproic acid group (p < 0.001), with no significant difference in free T4 level over time or between groups. The rate of clinical polycystic ovary syndrome for the valproic acid group (11%) was comparable to that reported in healthy controls (5-10%).

Conclusions: Administration of valproic acid had no adverse effect on body weight, metabolic status or endocrine function over an average follow-up of 3.2 years. Valproic acid appears to be safe for use in girls with epilepsy.
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http://dx.doi.org/10.1016/j.ejpn.2014.07.004DOI Listing
November 2014

Early onset epileptic encephalopathy caused by de novo SCN8A mutations.

Epilepsia 2014 Jul 2;55(7):994-1000. Epub 2014 Jun 2.

Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan; Department of Clinical Neurology and Stroke Medicine, Yokohama City University, Yokohama, Japan.

Objective: De novo SCN8A mutations have been reported in patients with epileptic encephalopathy. Herein we report seven patients with de novo heterozygous SCN8A mutations, which were found in our comprehensive genetic analysis (target capture or whole-exome sequencing) for early onset epileptic encephalopathies (EOEEs).

Methods: A total of 163 patients with EOEEs without mutations in known genes, including 6 with malignant migrating partial seizures in infancy (MMPSI), and 60 with unclassified EOEEs, were analyzed by target capture (28 samples) or whole-exome sequencing (135 samples).

Results: We identified de novo SCN8A mutations in 7 patients: 6 of 60 unclassified EOEEs (10.0%), and one of 6 MMPSI cases (16.7%). The mutations were scattered through the entire gene: four mutations were located in linker regions, two in the fourth transmembrane segments, and one in the C-terminal domain. The type of the initial seizures was variable including generalized tonic-clonic, atypical absence, partial, apneic attack, febrile convulsion, and loss of tone and consciousness. Onset of seizures was during the neonatal period in two patients, and between 3 and 7 months of age in five patients. Brain magnetic resonance imaging (MRI) showed cerebellar and cerebral atrophy in one and six patients, respectively. All patients with SCN8A missense mutations showed initially uncontrollable seizures by any drugs, but eventually one was seizure-free and three were controlled at the last examination. All patients showed developmental delay or regression in infancy, resulting in severe intellectual disability.

Significance: Our data reveal that SCN8A mutations can cause variable phenotypes, most of which can be diagnosed as unclassified EOEEs, and rarely as MMPSI. Together with previous reports, our study further indicates that genetic testing of SCN8A should be considered in children with unclassified severe epilepsy.
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http://dx.doi.org/10.1111/epi.12668DOI Listing
July 2014

Paternal germline mosaicism of a SCN2A mutation results in Ohtahara syndrome in half siblings.

Eur J Paediatr Neurol 2014 Sep 18;18(5):567-71. Epub 2014 Apr 18.

Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel; Metabolic Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address:

Ohtahara syndrome is a devastating early infantile epileptic encephalopathy caused by mutations in different genes. We describe a patient with Ohtahara syndrome who presented on the first day of life with refractory tonic seizures and a suppression-burst pattern on EEG. The patient developed severe microcephaly, and never achieved any developmental milestones. He died at the age of 5 years. A de novo missense mutation (c. 4007C>A, p.S1336Y) in SCN2A was found. Interestingly, the father has another son with Ohtahara syndrome from a different mother. The half brother carries the same SCN2A mutation, strongly suggesting paternal gonadal mosaicism of the mutation. The broad clinical spectrum of SCN2A mutations now includes Ohtahara syndrome. This is the first report of familial Ohtahara syndrome due to a germline mosaic SCN2A mutation. Somatic mosaicism, including germline, has been described in several epileptic encephalopathies such as Dravet syndrome, KCNQ2 neonatal epileptic encephalopathy, SCN8A epileptic encephalopathy and STXBP1 related Ohtahara syndrome. Mosaicism should be considered as one of the important inheritance patterns when counseling parents with a child with these devastating diseases.
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http://dx.doi.org/10.1016/j.ejpn.2014.04.008DOI Listing
September 2014

Glutamate receptor antibodies directed against AMPA receptors subunit 3 peptide B (GluR3B) can be produced in DBA/2J mice, lower seizure threshold and induce abnormal behavior.

Psychoneuroendocrinology 2014 Apr 22;42:106-17. Epub 2014 Jan 22.

School of Behavioral Sciences, Academic College of TLV Yaffo, Israel. Electronic address:

Objective: Anti-GluR3B antibodies (GluR3B Ab's), directed against peptide B/aa372-395 of GluR3 subunit of glutamate/AMPA receptors, are found in ∼35% of epilepsy patients, activate glutamate/AMPA receptors, evoke ion currents, kill neurons and damage the brain. We recently found that GluR3B Ab's also associate with neurological/psychiatric/behavioral abnormalities in epilepsy patients. Here we asked if GluR3B Ab's could be produced in DBA/2J mice, and also modulate seizure threshold and/or cause behavioral/motor impairments in these mice.

Methods: DBA/2J mice were immunized with the GluR3B peptide in Complete Freund's Adjuvant (CFA), or with controls: ovalbumin (OVA), CFA, or phosphate-buffer saline (PBS). GluR3B Ab's and OVA Ab's were tested. Seizures were induced in all mice by the chemoconvulsant pentylenetetrazole (PTZ) at three time points, each time with less PTZ to avoid non-specific death. Behavior was examined in Open-Field, RotaRod and Grip tests.

Results: GluR3B Ab's were produced only in GluR3B-immunized mice, while OVA Ab's were produced only in OVA-immunized mice, showing high Ab's specificity. In GluR3B Ab's negative mice, seizure severity scores and percentages of animals developing generalized seizures declined in response to decreasing PTZ doses. In contrast, both parameters remained unchanged/high in the GluR3B Ab's positive mice, showing that these mice were more susceptible to seizures. The seizure scores associated significantly with the GluR3B Ab's levels. GluR3B Ab's positive mice were also more anxious in Open-Field test, fell faster in RotaRod test, and fell more in Grip test, compared to all the control mice.

Conclusions: GluR3B Ab's are produced in DBA/2J mice, facilitate seizures and induce behavioral/motor impairments. This animal model can therefore serve for studying autoimmune epilepsy and abnormal behavior mediated by pathogenic anti-GluR3B Ab's.
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http://dx.doi.org/10.1016/j.psyneuen.2014.01.005DOI Listing
April 2014

Glutamate receptor antibodies directed against AMPA receptors subunit 3 peptide B (GluR3B) associate with some cognitive/psychiatric/behavioral abnormalities in epilepsy patients.

Psychoneuroendocrinology 2014 Feb 15;40:221-31. Epub 2013 Nov 15.

School of Behavioral Sciences, Academic College of Tel Aviv-Yaffo, Tel Aviv, Israel. Electronic address:

Antibodies (Ab's) to glutamate receptors, directed specifically against AMPA receptors subunit 3 peptide B (i.e. GluR3 amino acids 372-395), named GluR3B Ab's, can by themselves activate GluR3-containing glutamate/AMPA receptors, evoke ion currents via the receptor's ion channel, kill neurons and damage the brain. Herein we first tested 14 consecutive epilepsy patients and 10 healthy controls, and found that 7 (50%) patients had GluR3B Ab's. Second, in 71 other consecutive epilepsy patients (20 generalized epilepsy, 51 partial epilepsy) and 49 controls, we found that 17 (24%) patients had GluR3B Ab's, of which 8 had generalized and 9 partial epilepsy. We then studied 41 epilepsy patients: 21 patients with GluR3B Ab's and 20 without such Ab's (pooled of both tests without biased selection), for possible association of GluR3B Ab's with disease severity and/or neurobehavioral/cognitive comorbidities. Of the 21 patients with GluR3B Ab's, 6 had symptomatic, 7 cryptogenic, and 8 idiopathic epilepsy. Of the 20 patients without GluR3B Ab's, 16 had idiopathic etiology, and 4 nonidiopathic epilepsy. We found that among the 21 patients with GluR3B Ab's, 19 patients (90%) had learning problems, 16 (76%) attention problems, and 15 (71%) psychiatric problems. In contrast, among the 20 patients without GluR3B Ab's, only 6 (30%) had learning problems (p<0.0001), 5 (25%) attention problems (p=0.0017), and 2 (10%) psychiatric problems (p<0.0001). These findings suggest either that neurobehavioral abnormalities occur more frequently in epilepsy patients already having GluR3B Ab's, and may be due to them, or that GluR3B Ab's are more frequent in patients already having neurobehavioral abnormalities.
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http://dx.doi.org/10.1016/j.psyneuen.2013.11.007DOI Listing
February 2014

Broad phenotypic heterogeneity due to a novel SCN1A mutation in a family with genetic epilepsy with febrile seizures plus.

J Child Neurol 2014 Feb 20;29(2):221-6. Epub 2013 Nov 20.

1Department of Pediatric and Adolescent Neurology, Epilepsy Center, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.

Genetic (generalized) epilepsy with febrile seizures plus is a familial epilepsy syndrome with marked phenotypic heterogeneity ranging from simple febrile seizure to severe phenotypes. Here we report on a large Israeli family with genetic (generalized) epilepsy with febrile seizures plus and 14 affected individuals. A novel SCN1A missense mutation in exon 21 (p.K1372E) was identified in all affected individuals and 3 unaffected carriers. The proband had Dravet syndrome, whereas febrile seizure plus phenotypes were present in all other affected family members. Simple febrile seizures were not observed. Phenotypes were found at both extremes of the genetic (generalized) epilepsy with febrile seizures plus spectrum and distribution of phenotypes suggested modifying familial, possibly genetic factors. We suggest that families with extreme phenotype distributions can represent prime candidates for the identification of genetic or environmental modifiers.
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http://dx.doi.org/10.1177/0883073813509016DOI Listing
February 2014

Idiopathic photosensitive occipital epilepsy: clinical and electroencephalographic (EEG) features.

J Child Neurol 2014 Mar 17;29(3):307-11. Epub 2013 Jan 17.

1Department of Pediatric and Adolescent Neurology, Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel.

Idiopathic photosensitive occipital lobe epilepsy is a reflex, age- and localization-related syndrome. We describe the clinical and electroencephalographic features, therapy, and outcome of 16 children/adolescents with this syndrome. The cohort included 2 sets of siblings and 7 patients with other first- or second-degree relatives with a seizure history. All patients had occipital onset seizures and 15 had secondarily generalized tonic-clonic seizures. Seizure frequency was relatively low in all patients but one. Myoclonic seizures later developed in 2 patients with juvenile myoclonic epilepsy. Eight patients achieved full seizure control with monotherapy, and 5 required a second drug; 3 patients had rare seizures and were not treated with antiepileptics. Seven patients required special education or developmental assistance. This interesting syndrome sheds light on the pathophysiology and genetic etiology of common phenomena such as photosensitivity and headache. Further large prospective studies are required to better define this unique syndrome and its implications.
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http://dx.doi.org/10.1177/0883073812473366DOI Listing
March 2014

Glucose transporter 1 deficiency in the idiopathic generalized epilepsies.

Ann Neurol 2012 Nov;72(5):807-15

Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.

Objective: We examined whether glucose transporter 1 (GLUT1) deficiency causes common idiopathic generalized epilepsies (IGEs).

Methods: The IGEs are common, heritable epilepsies that usually follow complex inheritance; currently little is known about their genetic architecture. Previously considered rare, GLUT1 deficiency, due to mutations in SLC2A1, leads to failure of glucose transport across the blood-brain barrier and inadequate glucose for brain metabolism. GLUT1 deficiency was first associated with an encephalopathy and more recently found in rare dominant families with epilepsy and paroxysmal exertional dyskinesia (PED). Five hundred four probands with IGEs and 470 controls underwent SLC2A1 sequencing. Glucose transport was assayed following expression of SLC2A1 variants in Xenopus oocytes. All available relatives were phenotyped, and SLC2A1 was sequenced.

Results: Functionally validated mutations in SLC2A1 were present in 7 of 504 (1.4%) probands and 0 of 470 controls. PED, undiagnosed prior to study, occurred in 1 proband and 3 of 13 relatives with mutations. The IGEs in probands and relatives were indistinguishable from typical IGE. Three cases (0.6%) had mutations of large functional effect and showed autosomal dominant inheritance or were de novo. Four (0.8%) cases had a subtle functional effect; 2 showed possible dominant inheritance, and 2 did not. These alleles leading to subtle functional impairment may contribute to complex, polygenic inheritance of IGE.

Interpretation: SLC2A1 mutations contribute to approximately 1% of IGE both as a dominant gene and as a susceptibility allele in complex inheritance. Diagnosis of GLUT1 deficiency has important treatment (ketogenic diet) and genetic counseling implications. The mechanism of restricted glucose delivery differs from the current focus on IGEs as ion channel disorders.
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http://dx.doi.org/10.1002/ana.23702DOI Listing
November 2012

Levetiracetam in children, adolescents and young adults with intractable epilepsy: efficacy, tolerability and effect on electroencephalogram--a pilot study.

Eur J Paediatr Neurol 2013 May 16;17(3):248-53. Epub 2012 Nov 16.

Epilepsy Center, Department of Child Neurology, Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Levetiracetam has been authorized for use in Israel as an add-on therapy for intractable epilepsy since May 2006. The aim of the present study was to document its effectiveness for this indication in children, adolescents, and young adults. The medical files of 78 patients aged 0.5-39 years (mean, 14.2 years) treated at our center for intractable epilepsy were reviewed. All received levetiracetam as add-on therapy following a failure to respond to at least 3 anti-epileptic drugs. Fifty-two patients (67%) had partial epilepsy and the remainder had primary generalized epilepsy. The epilepsy was symptomatic in 57%, cryptogenic in 27%, and idiopathic in 15%. Average age at first seizure was 4.1 years. In 45% of patients, the number of seizures was reduced by half with levetiracetam treatment; 11.5% of the cohort achieved complete remission. There was a statistically significant correlation between clinical seizure control and improvement in the electroencephalography findings (p = 0.0012). The drug was well tolerated, with a retention rate of 69% after one year. The most common adverse effects were irritability and impulsiveness, in 26.9% of patients. Severe behavioral side effects (psychosis, confusion) were experienced by 6.4%. In conclusion, levetiracetam is an effective and tolerable add-on agent for use in most epileptic children, adolescents, and young adults who fail to respond to at least 3 antiepileptic drugs and should be the treatment of choice in this setting. Despite the relatively high rate of behavioral side effects in this study, the retention rate at one year was high.
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http://dx.doi.org/10.1016/j.ejpn.2012.10.008DOI Listing
May 2013

PRRT2 phenotypic spectrum includes sporadic and fever-related infantile seizures.

Neurology 2012 Nov 17;79(21):2104-8. Epub 2012 Oct 17.

Florey Neuroscience Institutes, Melbourne, Australia.

Objective: Benign familial infantile epilepsy (BFIE) is an autosomal dominant epilepsy syndrome characterized by afebrile seizures beginning at about 6 months of age. Mutations in PRRT2, encoding the proline-rich transmembrane protein 2 gene, have recently been identified in the majority of families with BFIE and the associated syndrome of infantile convulsions and choreoathetosis (ICCA). We asked whether the phenotypic spectrum of PRRT2 was broader than initially recognized by studying patients with sporadic benign infantile seizures and non-BFIE familial infantile seizures for PRRT2 mutations.

Methods: Forty-four probands with infantile-onset seizures, infantile convulsions with mild gastroenteritis, and benign neonatal seizures underwent detailed phenotyping and PRRT2 sequencing. The familial segregation of mutations identified in probands was studied.

Results: The PRRT2 mutation c.649-650insC (p.R217fsX224) was identified in 11 probands. Nine probands had a family history of BFIE or ICCA. Two probands had no family history of infantile seizures or paroxysmal kinesigenic dyskinesia and had de novo PRRT2 mutations. Febrile seizures with or without afebrile seizures were observed in 2 families with PRRT2 mutations.

Conclusions: PRRT2 mutations are present in >80% of BFIE and >90% ICCA families, but are not a common cause of other forms of infantile epilepsy. De novo mutations of PRRT2 can cause sporadic benign infantile seizures. Seizures with fever may occur in BFIE such that it may be difficult to distinguish BFIE from febrile seizures and febrile seizures plus in small families.
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http://dx.doi.org/10.1212/WNL.0b013e3182752c6cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511925PMC
November 2012

Does a normalizing electroencephalogram in benign childhood epilepsy with centrotemporal spikes abort attention deficit hyperactivity disorder?

Pediatr Neurol 2012 Oct;47(4):279-83

Pediatric Neurology Unit, Dana Children's Hospital, Tel Aviv, Israel.

This retrospective study delineated the efficacy of antiepileptic drugs in preventing the need for methylphenidate in patients with benign childhood epilepsy with centrotemporal spikes and attention deficit hyperactivity disorder. Seventeen patients were identified. A reduction of electroencephalogram pathologic activity by more than 50% was achieved in some patients with the antiepileptic drugs levetiracetam, sulthiame, lamotrigine, clobazam, and valproic acid. Complete normalization was achieved in two patients with sulthiame. Improvement in attention along with the reduction of pathologic electroencephalogram activity was observed in four patients, two with sulthiame, and one each with lamotrigine and levetiracetam (which was ceased because of suicidal tendencies). However, this improvement in attention was either temporary or not significant enough to discontinue methylphenidate. Methylphenidate was eventually prescribed to all patients.
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http://dx.doi.org/10.1016/j.pediatrneurol.2012.06.009DOI Listing
October 2012

Nonpharmacologic treatment of migraine with low-dose propranolol or amitriptyline.

Pediatr Neurol 2012 Jun;46(6):345-9

Ambulatory Day Hospitalization Center, Schneider Children's Medical Center of Israel, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

This study evaluated the effectiveness of nonpharmacologic measures combined with low-dose propranolol or amitriptyline for treating severe pediatric migraine. Data were collected from the medical files of 118 patients (mean age, 12.54 ± 3.14 years S.D.). All were treated with nonpharmacologic measures. In addition, 93 children received propranolol (mean initial dose, 0.4 ± 0.17 mg/kg/day S.D.), and 25 received amitriptyline (mean initial dose, 0.26 ± 0.1 mg/kg/day S.D.). Twenty patients were switched from propranolol to amitriptyline during treatment. In both groups, headache frequency was reduced by >50% per month in ~80% of patients. Patients without aura responded significantly better to propranolol than patients with aura (P = 0.02). No significant difference was evident in response to pharmacologic treatment by migraine frequency or type (episodic chronic). No significant difference was evident in response to amitriptyline between patients with or without aura. The response rate was higher than previously reported for placebo. Low-dose propranolol and low-dose amitriptyline, when combined with nonpharmacologic measures, are equally effective in reducing the frequency of migraine in children. Propranolol is preferred because of its lower risk of side effects. An additive effect of nonpharmacologic measures may allow for a reduction in drug dose.
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http://dx.doi.org/10.1016/j.pediatrneurol.2012.03.017DOI Listing
June 2012

Effect of melatonin on seizure frequency in intractable epilepsy: a pilot study.

J Child Neurol 2012 Dec 28;27(12):1524-8. Epub 2012 Feb 28.

Department of Child Neurology, Epilepsy Center, Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel.

Melatonin is effective for treating sleep-wake cycle disturbances and has been reported occasionally to decrease epileptic seizure frequency, with no long-term side effects. In this pilot study, the investigators examined the effect of melatonin on seizures, sleep quality, and behavior in 10 patients aged 9 to 32 years with intractable epilepsy. Patients were randomized to receive melatonin (10 mg daily at bedtime) followed by placebo or placebo followed by melatonin for 3 weeks each, with a 1-week washout period in between. Seizure frequency was monitored by daily diaries and actigraphy recordings; behavioral and sleep parameters were rated by caregivers. Diurnal seizures decreased significantly with melatonin compared with placebo (P = .034, Wilcoxon test). Maximal number of seizures, seizure duration, sleep efficiency or latency, and behavioral parameters remained unchanged. No major side effects or seizure aggravation were documented. It is concluded that melatonin could be effective and safe for decreasing daytime seizure frequency in patients with intractable epilepsy.
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http://dx.doi.org/10.1177/0883073811435916DOI Listing
December 2012

PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome.

Am J Hum Genet 2012 Jan;90(1):152-60

Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.

Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, which encodes proline-rich transmembrane protein 2, in 14 of 17 families (82%) affected by BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families affected by infantile convulsions and choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 cause both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy in terms of both age of expression (infancy versus later childhood) and anatomical substrate (cortex versus basal ganglia).
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http://dx.doi.org/10.1016/j.ajhg.2011.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257886PMC
January 2012

[Infantile spasms and modified hypsarrhythmia].

Harefuah 2011 Apr;150(4):373-7, 418, 417

Pediatric Neurology Department, Schneider Children Medical Center, Israel.

The West syndrome was described by the physician West in his own son in 1841 and is defined as a triad of myoclonic seizures called "infantile spasms", electrographic abnormalities called "hypsarrhythmia" and arrest of psychomotor development and mental retardation. These symptoms are so pathognomonic that the impression is that the syndrome is caused by a single mechanism, but actually there is heterogeneity of etiologies, different recommendations of treatment and prognosis. The West syndrome was established as an infantiLe epileptic syndrome (ILAE Task Force, 1989). Infantile spasm is the most common epileptic syndrome during infancy and entails 50% of all epilepsies between ages one month to one year. Its incidence is 1:3200-3500 live births. Despite its absolute definition, the variability of etiologies, clinical presentation and electrographic make it difficult to set rigid, clear treatment guidelines and research methodology. This review aims to present modified hypsarrhythmia, the etiologies and prognosis of symptomatic infantile spasms, and emphasize the importance of early recognition of modified hypsarrhythmia by surveillance of electroencephalograms.
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April 2011

Long-term follow-up for ophthalmologic sequelae in children treated with corticosteroids for infantile spasms.

J Child Neurol 2012 Mar 22;27(3):332-6. Epub 2011 Nov 22.

Department of Pediatrics E/Ambulatory Day Hospitalization Center, Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel.

The aim of the study was to determine if early steroid treatment of infantile spasms is associated with ocular complications years after its termination. Twenty-five patients with infantile spasms who underwent prolonged treatment with intramuscular synthetic adrenocorticotropic hormone (ACTH) and oral prednisone were evaluated for ocular complications 2 to 33 years after treatment cessation. Patients were followed by an ophthalmic examination that included anterior and posterior segments and measurement of intraocular pressure. Intraocular pressure was normal bilaterally in all patients. Findings on anterior segment examination were unremarkable. On posterior segment examination, 3 patients had an increased cup/disc ratio with normal intraocular pressure. In 2 patients, the increased ratio was considered an anatomical variant. Posterior segment findings in 2 patients were attributed to their background disease. In conclusion, early treatment with high-dose synthetic adrenocorticotropic hormone and oral prednisone for infantile spasm is apparently not associated with a risk of occular complications on long-term follow-up.
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http://dx.doi.org/10.1177/0883073811420494DOI Listing
March 2012

Effect of high-dose glucocorticosteroid treatment for infantile spasms on quantitative bone parameters later in life.

J Child Neurol 2012 Jan 21;27(1):74-9. Epub 2011 Jul 21.

Department of Pediatrics E/Ambulatory Day Care Center, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.

This study evaluated possible long-term effects of prolonged high-dose glucocorticosteroid administration in infancy. Thirty patients (16 male, 14 female; age 4.8-33 years) who had completed treatment with adrenocorticotropic hormone (ACTH) followed by glucocorticoids for infantile spasms at a tertiary pediatric hospital at least 2 years previously were invited to undergo quantitative bone ultrasound. The mean speed of soundZ score was -1.085 ± 1.079 for the radius and -0.22 ± 1.19 for the tibia on the nondominant side (P = .0022). The difference from the reference mean (0) was statistically significant for the radius (P < .001). There were no significant differences in radial or tibial mean speed of soundZ scores by age (prepubertal versus pubertal/postpubertal). In conclusion, a high percentage of patients treated with glucocorticoids for infantile spasms have a low radial speed of soundZ score later in life. Long-term follow-up can help to prevent and treat impairments in bone density, especially in non-weight-bearing organs.
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http://dx.doi.org/10.1177/0883073811413583DOI Listing
January 2012

The prevalence of atypical presentations and comorbidities of benign childhood epilepsy with centrotemporal spikes.

Epilepsia 2011 Aug 21;52(8):1483-8. Epub 2011 Jun 21.

Pediatric Neurology Unit, Tel Aviv, Sourasky, Medical Center, Tel Aviv, Israel.

Purpose: Benign childhood epilepsy with centrotemporal spikes (BCECTS) is the most common epileptic syndrome in childhood. The outcome is usually excellent, but there are some atypical forms of BCECTS with less favorable outcomes. The aim of this study was to delineate the frequency of these atypical features among patients with BCECTS.

Methods: We conducted a retrospective chart study by retrieving the medical records of all consecutive patients with BCECTS who were evaluated in four pediatric neurology outpatient clinics in Israel between the years 1991 and 2008.

Key Findings: A total of 196 patients with BCECTS were identified (78 female and 118 male; mean age at time of diagnosis 7.64 years, range 1.5-14). The mean duration of follow-up was 4.43 years (range 2-11). Nine patients (4.6%) developed electrical status epilepticus in slow waves sleep (ESES) during follow-up, four (2%) had Landau-Kleffner syndrome, three (1.5%) had BCECTS with frequent refractory seizures, two (1%) had BCECTS with falls at presentation, one (0.5%) had a "classic" atypical variant, and one (0.5%) had oromotor dysfunction. None had rolandic status epilepticus. Sixty-one patients (31%) had attention deficit hyperactivity disorder (ADHD), 43 (21.9%) had specific cognitive deficits, and 23 (11.7%) had behavioral abnormalities, including aggressiveness, anxiety disorders, depression, and pervasive developmental disorder (PDD).

Significance: The prevalence of most atypical forms of BCECTS other than ESES is low. There is, however, a high prevalence of ADHD and specific cognitive deficits among patients with BCECTS.
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http://dx.doi.org/10.1111/j.1528-1167.2011.03136.xDOI Listing
August 2011