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Tracy A Glauser - One of the best experts on this subject based on the ideXlab platform.
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ictal connectivity in Childhood Absence Epilepsy associations with outcome
Epilepsia, 2018Co-Authors: Jeffrey R Tenney, Jing Xiang, Darren S Kadis, William Agler, Leonid Rozhkov, Mekibib Altaye, Jennifer Vannest, Tracy A GlauserAbstract:OBJECTIVE The understanding of Childhood Absence Epilepsy (CAE) has been revolutionized over the past decade, but the biological mechanisms responsible for variable treatment outcomes are unknown. Our purpose in this prospective observational study was to determine how pretreatment ictal network pathways, defined using a combined electroencephalography (EEG)-functional magnetic resonance imaging (EEG-fMRI) and magnetoencephalography (MEG) effective connectivity analysis, were related to treatment response. METHODS Sixteen children with newly diagnosed and drug-naive CAE had 31 typical Absence seizures during EEG-fMRI and 74 during MEG. The spatial extent of the pretreatment ictal network was defined using fMRI hemodynamic response with an event-related independent component analysis (eICA). This spatially defined pretreatment ictal network supplied prior information for MEG-effective connectivity analysis calculated using phase slope index (PSI). Treatment outcome was assessed 2 years following diagnosis and dichotomized to ethosuximide (ETX)-treatment responders (N = 11) or nonresponders (N = 5). Effective connectivity of the pretreatment ictal network was compared to the treatment response. RESULTS Patterns of pretreatment connectivity demonstrated strongest connections in the thalamus and posterior brain regions (parietal, posterior cingulate, angular gyrus, precuneus, and occipital) at delta frequencies and the frontal cortices at gamma frequencies (P < .05). ETX treatment nonresponders had pretreatment connectivity, which was decreased in the precuneus region and increased in the frontal cortex compared to ETX responders (P < .05). SIGNIFICANCE Pretreatment ictal connectivity differences in children with CAE were associated with response to antiepileptic treatment. This is a possible mechanism for the variable treatment response seen in patients sharing the same Epilepsy syndrome.
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modeling pathogenesis and treatment response in Childhood Absence Epilepsy
Epilepsia, 2018Co-Authors: Andrew T Knox, Tracy A Glauser, Jeffrey R Tenney, William W Lytton, Katherine D HollandAbstract:Objective Childhood Absence Epilepsy (CAE) is a genetic generalized Epilepsy syndrome with polygenic inheritance, with genes for γ-aminobutyric acid (GABA) receptors and T-type calcium channels implicated in the disorder. Previous studies of T-type calcium channel electrophysiology have shown genetic changes and medications have multiple effects. The aim of this study was to use an established thalamocortical computer model to determine how T-type calcium channels work in concert with cortical excitability to contribute to pathogenesis and treatment response in CAE. Methods The model is comprised of cortical pyramidal, cortical inhibitory, thalamocortical relay, and thalamic reticular single-compartment neurons, implemented with Hodgkin-Huxley model ion channels and connected by AMPA, GABAA , and GABAB synapses. Network behavior was simulated for different combinations of T-type calcium channel conductance, inactivation time, steady state activation/inactivation shift, and cortical GABAA conductance. Results Decreasing cortical GABAA conductance and increasing T-type calcium channel conductance converted spindle to spike and wave oscillations; smaller changes were required if both were changed in concert. In contrast, left shift of steady state voltage activation/inactivation did not lead to spike and wave oscillations, whereas right shift reduced network propensity for oscillations of any type. Significance These results provide a window into mechanisms underlying polygenic inheritance in CAE, as well as a mechanism for treatment effects and failures mediated by these channels. Although the model is a simplification of the human thalamocortical network, it serves as a useful starting point for predicting the implications of ion channel electrophysiology in polygenic Epilepsy such as CAE.
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pretreatment behavior and subsequent medication effects in Childhood Absence Epilepsy
Neurology, 2017Co-Authors: Ruth C Shinnar, Avital Cnaan, Peggy Clark, Shlomo Shinnar, Dennis J. Dlugos, David Masur, Deborah G Hirtz, Chunyan Liu, Erica F Weiss, Tracy A GlauserAbstract:Objective: To characterize pretreatment behavioral problems and differential effects of initial therapy in children with Childhood Absence Epilepsy (CAE). Methods: The Child Behavior Checklist (CBCL) was administered at baseline, week 16–20, and month 12 visits of a randomized double-blind trial of ethosuximide, lamotrigine, and valproate. Total problems score was the primary outcome measure. Results: A total of 382 participants at baseline, 310 participants at the week 16–20 visit, and 168 participants at the month 12 visit had CBCL data. At baseline, 8% (95% confidence interval [CI] 6%–11%) of children with CAE had elevated total problems scores (mean 52.9 ± 10.91). At week 16–20, participants taking valproic acid had significantly higher total problems (51.7 [98.3% CI 48.6–54.7]), externalizing problems (51.4 [98.3% CI 48.5–54.3]), attention problems (57.8 [98.3% CI 55.6–60.0]), and attention-deficit/hyperactivity problems (55.8 [98.3% CI 54.1–57.6]) scores compared to participants taking ethosuximide (46.5 [98.3% CI 43.4–49.6]; 45.8 [98.3% CI 42.9–48.7]; 54.6 [98.3% CI 52.4–56.9]; 53.0 [98.3% CI 51.3–54.8]). Lack of seizure freedom and elevated week 16–20 Conner Continuous Performance Test confidence index were associated with worse total problems scores. At month 12, participants taking valproic acid had significantly higher attention problems scores (57.9 [98.3% CI 55.6–60.3]) compared to participants taking ethosuximide (54.5 [95% CI 52.1–56.9]). Conclusions: Pretreatment and ongoing behavioral problems exist in CAE. Valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine, further reinforcing ethosuximide as the preferred initial therapy for CAE. Clinicaltrials.gov identifier: NCT00088452. Classification of evidence: This study provides Class II evidence that for children with CAE, valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine.
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pharmacogenetics of antiepileptic drug efficacy in Childhood Absence Epilepsy
Annals of Neurology, 2017Co-Authors: Tracy A Glauser, Katherine D Holland, Valerie P Obrien, Mehdi Keddache, Lisa J MartinAbstract:Objective To determine whether common polymorphisms in CACNA1G, CACNA1H, CACNA1I, and ABCB1 are associated with differential short-term seizure outcome in Childhood Absence Epilepsy (CAE). Methods Four hundred forty-six CAE children in a randomized double-blind trial of ethosuximide, lamotrigine, and valproate had short-term seizure outcome determined. Associations between polymorphisms (minor allele frequency ≥ 15%) in 4 genes and seizure outcomes were assessed. In vitro electrophysiology on transfected CACNA1H channels determined impact of 1 variant on T-type calcium channel responsiveness to ethosuximide. Results Eighty percent (357 of 446) of subjects had informative short-term seizure status (242 seizure free, 115 not seizure free). In ethosuximide subjects, 2 polymorphisms (CACNA1H rs61734410/P640L, CACNA1I rs3747178) appeared more commonly among not–seizure-free participants (p = 0.011, odds ratio [OR] = 2.63, 95% confidence limits [CL] = 1.25–5.56; p = 0.026, OR = 2.38, 95% CL = 1.11–5.00). In lamotrigine subjects, 1 ABCB1 missense polymorphism (rs2032582/S893A; p = 0.015, OR = 2.22, 95% CL = 1.16–4.17) was more common in not–seizure-free participants, and 2 CACNA1H polymorphisms (rs2753326, rs2753325) were more common in seizure-free participants (p = 0.038, OR = 0.52, 95% CL = 0.28–0.96). In valproate subjects, no common polymorphisms were associated with seizure status. In vitro electrophysiological studies showed no effect of the P640L polymorphism on channel physiology in the Absence of ethosuximide. Ethosuximide's effect on rate of decay of CaV3.2 was significantly less for P640L channel compared to wild-type channel. Interpretation Four T-type calcium channel variants and 1 ABCB1 transporter variant were associated with differential drug response in CAE. The in vivo P640L variant's ethosuximide effect was confirmed by in vitro electrophysiological studies. This suggests that genetic variation plays a role in differential CAE drug response. Ann Neurol 2017;81:444–453
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second monotherapy in Childhood Absence Epilepsy
Neurology, 2017Co-Authors: Avital Cnaan, Deborah Hirtz, Peggy Clark, Shlomo Shinnar, Dennis J. Dlugos, David Masur, Peter C Adamson, Ravindra Arya, Tracy A GlauserAbstract:Objective: To determine optimal second monotherapy for children with Childhood Absence Epilepsy (CAE) experiencing initial treatment failure. Methods: Children with CAE experiencing treatment failure during the double-blind phase of a randomized controlled trial comparing ethosuximide, valproic acid, and lamotrigine were randomized to open-label second monotherapy with one of the 2 other study therapies. Primary study outcome was freedom from failure proportion at week 16–20 and month 12 visits after randomization. Secondary study outcome was percentage of participants experiencing attentional dysfunction at these visits. Results: A total of 208 children were enrolled, randomized, and received second therapy. At both week 16–20 visit and month 12 visit, ethosuximide9s (63%, 57%) and valproic acid9s (65%, 49%) freedom from failure proportions were similar to each other and higher than lamotrigine9s (45%, 36%, p = 0.051 and p = 0.062). At both time points, ethosuximide and valproic acid had superior seizure control compared to lamotrigine ( p Conclusions: As second monotherapy, ethosuximide and valproic acid, demonstrated higher freedom from failure proportions and greater efficacy than lamotrigine; valproic acid was associated with more attentional dysfunction. Ethosuximide is the optimal second monotherapy for children with CAE not responding to initial therapy with other medications. ClinicalTrials.gov identifier: NCT00088452. Classification of evidence: This study provides Class III evidence that for children with CAE experiencing initial treatment failure, second monotherapy with ethosuximide or valproic acid is superior to lamotrigine.
Hal Blumenfeld - One of the best experts on this subject based on the ideXlab platform.
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historical trend toward improved long term outcome in Childhood Absence Epilepsy
Epilepsy Research, 2019Co-Authors: Elliot Morse, Anne T Berg, Kathryn Giblin, Mi Hae Chung, Carolin I Dohle, Hal BlumenfeldAbstract:Abstract We retrospectively analyzed published studies to investigate historical trends in outcome of Childhood Absence Epilepsy (CAE). We included patients based on onset of Absence seizures in Childhood, 3 Hz bilateral spike-wave discharges on EEG, and availability of seizure-free outcome data. The primary endpoint was seizure-freedom off medications by study publication year. We also analyzed relationships between seizure-freedom and 1. treatment medication, and 2. CAE diagnostic criteria. We included 29 studies published 1945–2013, encompassing 2416 patients. Seizure-freedom off medications was higher for studies after 1985 versus before 1975 (82% versus 35%; p 10; p
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long term seizure remission in Childhood Absence Epilepsy might initial treatment matter
Epilepsia, 2014Co-Authors: Anne T Berg, Susan R Levy, Francine M Testa, Hal BlumenfeldAbstract:Objectives: Examine the possible association between long-term seizure outcome in Childhood Absence Epilepsy (CAE) and the initial treatment choice.
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symptoms of anxiety and depression in Childhood Absence Epilepsy
Epilepsia, 2011Co-Authors: Clemente Vega, Hal Blumenfeld, Matthew Vestal, Rachel Berman, Jennifer N Guo, Brendan Killory, Nathan Danielson, Leisel Martin, J Gonzalez, Marisa N SpannAbstract:Childhood Absence Epilepsy (CAE) has been recently linked to a number of cognitive, behavioral, and emotional disorders. Identification of affective disorders (anxiety and depression) presents unique challenges in pediatric populations, and successful early intervention may significantly improve long-term developmental outcomes. The current study examined the specific anxiety and depression symptoms children with CAE experience, and explored the role of disease factors in the severity of their presentation. Forty-five subjects with CAE and 41 healthy matched controls, ages 6-16 years, participated in the study. The Behavior Assessment System for Children (BASC) was completed by parents, and the Anxiety and Depression subscales were used to characterize problems. Item analysis within the subscales revealed that children with CAE demonstrated higher rates of symptoms of anxiety (nervousness and thought rumination) and depression (sadness and crying), as well as more general psychosocial problems including isolation and low self-esteem. Disease duration, intractability, and medication effects were not associated with higher rates of affective problems in this limited patient sample. Screening of patients with CAE for comorbid psychiatric disorders early by focusing on specific symptom profiles unique to this population may enhance overall treatment and developmental outcomes.
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resting functional connectivity between the hemispheres in Childhood Absence Epilepsy
Neurology, 2011Co-Authors: Xiaoxiao Bai, Matthew Vestal, Rachel Berman, Brendan Killory, Nathan Danielson, Michiro Negishi, J Guo, Edward J Novotny, R T Constable, Hal BlumenfeldAbstract:Objective: The fundamental mechanisms by which Childhood Absence Epilepsy (CAE) changes neural networks even between seizures remain poorly understood. During seizures, cortical and subcortical networks exhibit bihemspheric synchronous activity based on prior EEG-fMRI studies. Our aim was to investigate whether this abnormal bisynchrony may extend to the interictal period, using a blood oxygen level–dependent (BOLD) resting functional connectivity approach. Methods: EEG-fMRI data were recorded from 16 patients with CAE and 16 age- and gender-matched controls. Three analyses were performed. 1) Using 16 pairs of seizure-related regions of interest (ROI), we compared the between-hemisphere interictal resting functional connectivity of patients and controls. 2) For regions showing significantly increased interhemispheric connectivity in CAE, we then calculated connectivity to the entire brain. 3) A paired-voxel approach was performed to calculate resting functional connectivity between hemispheres without the constraint of predefined ROIs. Results: We found significantly increased resting functional connectivity between hemispheres in the lateral orbitofrontal cortex of patients with CAE compared to normal controls. Enhanced between-hemisphere connectivity localized to the lateral orbitofrontal cortex was confirmed by all 3 analysis methods. Conclusions: Our results demonstrate abnormal increased connectivity between the hemispheres in patients with CAE in seizure-related regions, even when seizures were not occurring. These findings suggest that the lateral orbitofrontal cortex may play an important role in CAE pathophysiology, warranting further investigation. In addition, resting functional connectivity analysis may provide a promising biomarker to improve our understanding of altered brain function in CAE during the interictal period.
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differentiation of attention related problems in Childhood Absence Epilepsy
Epilepsy & Behavior, 2010Co-Authors: Clemente Vega, Hal Blumenfeld, Mi Hae Chung, Matthew Vestal, Matthew N Desalvo, Rachel Berman, Marisa N SpannAbstract:The current study examined the specific types of attention-related problems children with Childhood Absence Epilepsy (CAE) experience and the role of disease factors in the development of attention-related problems. Thirty-eight subjects with CAE and 46 healthy controls, aged 6 to 16, participated in the study. The Behavior Assessment System for Children (BASC) was completed by parents, and the Attention Problems and Hyperactivity subscales were used to characterize the problems of children with CAE. Item analysis within the subscales revealed that children with CAE demonstrate higher rates of hyperactive (overactivity and fidgetiness) and inattentive (forgetfulness and distractibility) problems, and require more supervision. Within-CAE-group analyses revealed that those who were actively having seizures were more impatient and those with a longer duration of illness were less proficient in completing homework. Children with CAE are at risk for certain inattentive and hyperactive problems, which can differ depending on duration of illness and active seizure status.
Peggy Clark - One of the best experts on this subject based on the ideXlab platform.
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pretreatment behavior and subsequent medication effects in Childhood Absence Epilepsy
Neurology, 2017Co-Authors: Ruth C Shinnar, Avital Cnaan, Peggy Clark, Shlomo Shinnar, Dennis J. Dlugos, David Masur, Deborah G Hirtz, Chunyan Liu, Erica F Weiss, Tracy A GlauserAbstract:Objective: To characterize pretreatment behavioral problems and differential effects of initial therapy in children with Childhood Absence Epilepsy (CAE). Methods: The Child Behavior Checklist (CBCL) was administered at baseline, week 16–20, and month 12 visits of a randomized double-blind trial of ethosuximide, lamotrigine, and valproate. Total problems score was the primary outcome measure. Results: A total of 382 participants at baseline, 310 participants at the week 16–20 visit, and 168 participants at the month 12 visit had CBCL data. At baseline, 8% (95% confidence interval [CI] 6%–11%) of children with CAE had elevated total problems scores (mean 52.9 ± 10.91). At week 16–20, participants taking valproic acid had significantly higher total problems (51.7 [98.3% CI 48.6–54.7]), externalizing problems (51.4 [98.3% CI 48.5–54.3]), attention problems (57.8 [98.3% CI 55.6–60.0]), and attention-deficit/hyperactivity problems (55.8 [98.3% CI 54.1–57.6]) scores compared to participants taking ethosuximide (46.5 [98.3% CI 43.4–49.6]; 45.8 [98.3% CI 42.9–48.7]; 54.6 [98.3% CI 52.4–56.9]; 53.0 [98.3% CI 51.3–54.8]). Lack of seizure freedom and elevated week 16–20 Conner Continuous Performance Test confidence index were associated with worse total problems scores. At month 12, participants taking valproic acid had significantly higher attention problems scores (57.9 [98.3% CI 55.6–60.3]) compared to participants taking ethosuximide (54.5 [95% CI 52.1–56.9]). Conclusions: Pretreatment and ongoing behavioral problems exist in CAE. Valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine, further reinforcing ethosuximide as the preferred initial therapy for CAE. Clinicaltrials.gov identifier: NCT00088452. Classification of evidence: This study provides Class II evidence that for children with CAE, valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine.
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pretreatment seizure semiology in Childhood Absence Epilepsy
Neurology, 2017Co-Authors: Sudha Kilaru Kessler, Avital Cnaan, Joan A Conry, Deborah Hirtz, Solomon L Moshe, Shlomo Shinnar, Eli M Mizrahi, F. Hu, Dennis J. Dlugos, Peggy ClarkAbstract:Objective: To determine seizure semiology in children with newly diagnosed Childhood Absence Epilepsy and to evaluate associations with short-term treatment outcomes. Methods: For participants enrolled in a multicenter, randomized, double-blind, comparative-effectiveness trial, semiologic features of pretreatment seizures were analyzed as predictors of treatment outcome at the week 16 to 20 visit. Results: Video of 1,932 electrographic Absence seizures from 416 participants was evaluated. Median seizure duration was 10.2 seconds; median time between electrographic seizure onset and clinical manifestation onset was 1.5 seconds. For individual seizures and by participant, the most common semiology features were pause/stare (seizure 95.5%, participant 99.3%), motor automatisms (60.6%, 86.1%), and eye involvement (54.9%, 76.5%). The interrater agreement for motor automatisms and eye involvement was good (72%–84%). Variability of semiology features between seizures even within participants was high. Clustering analyses revealed 4 patterns (involving the presence/Absence of eye involvement and motor automatisms superimposed on the nearly ubiquitous pause/stare). Most participants experienced more than one seizure cluster pattern. No individual semiologic feature was individually predictive of short-term outcome. Seizure freedom was half as likely in participants with one or more seizure having the pattern of eye involvement without motor automatisms than in participants without this pattern. Conclusions: Almost all Absence seizures are characterized by a pause in activity or staring, but rarely is this the only feature. Semiologic features tend to cluster, resulting in identifiable Absence seizure subtypes with significant intraparticipant seizure phenomenologic heterogeneity. One seizure subtype, pause/stare and eye involvement but no motor automatisms, is specifically associated with a worse treatment outcome.
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second monotherapy in Childhood Absence Epilepsy
Neurology, 2017Co-Authors: Avital Cnaan, Deborah Hirtz, Peggy Clark, Shlomo Shinnar, Dennis J. Dlugos, David Masur, Peter C Adamson, Ravindra Arya, Tracy A GlauserAbstract:Objective: To determine optimal second monotherapy for children with Childhood Absence Epilepsy (CAE) experiencing initial treatment failure. Methods: Children with CAE experiencing treatment failure during the double-blind phase of a randomized controlled trial comparing ethosuximide, valproic acid, and lamotrigine were randomized to open-label second monotherapy with one of the 2 other study therapies. Primary study outcome was freedom from failure proportion at week 16–20 and month 12 visits after randomization. Secondary study outcome was percentage of participants experiencing attentional dysfunction at these visits. Results: A total of 208 children were enrolled, randomized, and received second therapy. At both week 16–20 visit and month 12 visit, ethosuximide9s (63%, 57%) and valproic acid9s (65%, 49%) freedom from failure proportions were similar to each other and higher than lamotrigine9s (45%, 36%, p = 0.051 and p = 0.062). At both time points, ethosuximide and valproic acid had superior seizure control compared to lamotrigine ( p Conclusions: As second monotherapy, ethosuximide and valproic acid, demonstrated higher freedom from failure proportions and greater efficacy than lamotrigine; valproic acid was associated with more attentional dysfunction. Ethosuximide is the optimal second monotherapy for children with CAE not responding to initial therapy with other medications. ClinicalTrials.gov identifier: NCT00088452. Classification of evidence: This study provides Class III evidence that for children with CAE experiencing initial treatment failure, second monotherapy with ethosuximide or valproic acid is superior to lamotrigine.
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long term outcomes of generalized tonic clonic seizures in a Childhood Absence Epilepsy trial
Neurology, 2015Co-Authors: Shlomo Shinnar, Avital Cnaan, Deborah Hirtz, Peggy Clark, Solomon L Moshe, Eli M Mizrahi, Dennis J. Dlugos, David Masur, Tracy A GlauserAbstract:Objective: To determine incidence and early predictors of generalized tonic-clonic seizures (GTCs) in children with Childhood Absence Epilepsy (CAE). Methods: Occurrence of GTCs was determined in 446 children with CAE who participated in a randomized clinical trial comparing ethosuximide, lamotrigine, and valproate as initial therapy for CAE. Results: As of June 2014, the cohort had been followed for a median of 7.0 years since enrollment and 12% (53) have experienced at least one GTC. The median time to develop GTCs from initial therapy was 4.7 years. The median age at first GTC was 13.1 years. Fifteen (28%) were not on medications at the time of their first GTC. On univariate analysis, older age at enrollment was associated with a higher risk of GTCs ( p = −0.0009), as was the duration of the shortest burst on the baseline EEG ( p = 0.037). Failure to respond to initial treatment ( p p p = 0.017) and not seen in those initially treated with lamotrigine. Conclusions: The occurrence of GTCs in a well-characterized cohort of children with CAE appears lower than previously reported. GTCs tend to occur late in the course of the disorder. Children initially treated with ethosuximide who are responders have a particularly low risk of developing subsequent GTCs.
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pretreatment cognitive deficits and treatment effects on attention in Childhood Absence Epilepsy
Neurology, 2013Co-Authors: David Masur, Avital Cnaan, Deborah Hirtz, Peggy Clark, Shlomo Shinnar, Ruth C Shinnar, Erica F Weiss, Jichuan Wang, Tracy A GlauserAbstract:Objective: To determine the neurocognitive deficits associated with newly diagnosed untreated Childhood Absence Epilepsy (CAE), develop a model describing the factorial structure of items measuring academic achievement and 3 neuropsychological constructs, and determine short-term differential neuropsychological effects on attention among ethosuximide, valproic acid, and lamotrigine. Methods: Subjects with newly diagnosed CAE entering a double-blind, randomized controlled clinical trial had neuropsychological testing including assessments of general intellectual functioning, attention, memory, executive function, and achievement. Attention was reassessed at the week 16–20 visit. Results: At study entry, 36% of the cohort exhibited attention deficits despite otherwise intact neurocognitive functioning. Structural equation modeling of baseline neuropsychological data revealed a direct sequential effect among attention, memory, executive function, and academic achievement. At the week 16–20 visit, attention deficits persisted even if seizure freedom was attained. More subjects receiving valproic acid (49%) had attention deficits than subjects receiving ethosuximide (32%) or lamotrigine (24%) ( p = 0.0006). Parental assessment did not reliably detect attention deficits before or after treatment ( p Conclusions: Children with CAE have a high rate of pretreatment attentional deficits that persist despite seizure freedom. Rates are disproportionately higher for valproic acid treatment compared with ethosuximide or lamotrigine. Parents do not recognize these attentional deficits. These deficits present a threat to academic achievement. Vigilant cognitive and behavioral assessment of these children is warranted. Classification of evidence: This study provides Class I evidence that valproic acid is associated with more significant attentional dysfunction than ethosuximide or lamotrigine in children with newly diagnosed CAE.
Gerhard S Drenthen - One of the best experts on this subject based on the ideXlab platform.
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functional brain network characteristics are associated with Epilepsy severity in Childhood Absence Epilepsy
NeuroImage: Clinical, 2020Co-Authors: Gerhard S Drenthen, Eric Fonseca L A Wald, Walter H Backes, Jos G M Hendriksen, Albert P Aldenkamp, Jeroen R Vermeulen, Sylvia Klinkenberg, Floor Fasen, Mariette Debeijvan H J A Hall, Jacobus F A JansenAbstract:Abstract While cognitive impairments are not generally considered to be part of the Childhood Absence Epilepsy (CAE) syndrome, some recent studies report cognitive, mainly attentional, deficits. Here we set out to investigate the whole brain functional network of children with CAE and controls. Furthermore, the possible relation of the functional network abnormalities with Epilepsy and neurocognitive characteristics is studied. Seventeen children with Childhood CAE (aged 9.2 ± 2.1 years) and 15 controls (aged 9.8 ± 1.8 years) were included. Resting state functional MRI was acquired to study the functional network. Using graph theoretical analysis, three global metrics of the functional network were investigated: the characteristic path length, the clustering coefficient, and the small-worldness. A multivariable linear regression model including age, sex, and subject motion as covariates was used to investigate group differences in the graph metrics. Subsequently, relations of the graph metrics with Epilepsy and neurocognitive characteristics were assessed. Longer path lengths, weaker clustering and a lower small-world network topology were observed in children with CAE compared to controls. Moreover, longer path lengths were related to a longer duration of CAE and a higher number of Absence seizure per hour. Clustering and small-worldness were not significantly related to Epilepsy or neurocognitive characteristics. The organization of the functional network of children with CAE is less efficient compared to controls, and is related to disease duration. These preliminary findings suggest that CAE is associated with alterations in the functional network.
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lower myelin water content of the frontal lobe in Childhood Absence Epilepsy
Epilepsia, 2019Co-Authors: Gerhard S Drenthen, Eric Fonseca L A Wald, Walter H Backes, Mariette H J A Van Hall, Jos G M Hendriksen, Albert P Aldenkamp, Jeroen R Vermeulen, Sylvia KlinkenbergAbstract:Objective The frontal lobe in Childhood Absence Epilepsy (CAE) might be affected due to the suggested involvement of the frontal lobe during Absence seizures and reports on attentional deficits. Previously, subtle white matter abnormalities have been reported in CAE. However, the impact of one of the most characteristic components of the white matter, the myelin content, remains underdetermined. Therefore, this study investigated whether the myelin content in frontal areas is adversely affected in CAE compared to controls. Methods Seventeen children with Childhood Absence Epilepsy (mean age ± standard deviation [SD], 9.2 ± 2.1 years) and 15 age- and sex-matched controls (mean age ± SD, 9.8 ± 1.8 years) underwent neuropsychological assessment and a magnetic resonance imaging (MRI) examination. T2 relaxometry scans were used to distinguish myelin-water from tissue water and to determine the myelin-water fraction (MWF) in the frontal, temporal, parietal, occipital, and insular lobes. A linear regression model including age and sex as covariates was used to investigate group differences. Furthermore, the relationship of MWF with cognitive performance and Epilepsy characteristics was determined. Results The frontal lobe revealed a significantly lower myelin-water content in children with CAE compared to controls over the developmental age range of 6-12 years (5.7 ± 1.0% vs 6.6 ± 1.1%, P = 0.02). This association was not found for any of the other four lobes (P > 0.10). No significant relation was found between myelin-water content and cognitive performance or Epilepsy characteristics. Significance The lower frontal myelin-water content of children with CAE in comparison with healthy controls probably reflects an altered neurodevelopmental aspect in CAE, of which the underlying mechanisms still need to be unraveled.
Shlomo Shinnar - One of the best experts on this subject based on the ideXlab platform.
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pretreatment behavior and subsequent medication effects in Childhood Absence Epilepsy
Neurology, 2017Co-Authors: Ruth C Shinnar, Avital Cnaan, Peggy Clark, Shlomo Shinnar, Dennis J. Dlugos, David Masur, Deborah G Hirtz, Chunyan Liu, Erica F Weiss, Tracy A GlauserAbstract:Objective: To characterize pretreatment behavioral problems and differential effects of initial therapy in children with Childhood Absence Epilepsy (CAE). Methods: The Child Behavior Checklist (CBCL) was administered at baseline, week 16–20, and month 12 visits of a randomized double-blind trial of ethosuximide, lamotrigine, and valproate. Total problems score was the primary outcome measure. Results: A total of 382 participants at baseline, 310 participants at the week 16–20 visit, and 168 participants at the month 12 visit had CBCL data. At baseline, 8% (95% confidence interval [CI] 6%–11%) of children with CAE had elevated total problems scores (mean 52.9 ± 10.91). At week 16–20, participants taking valproic acid had significantly higher total problems (51.7 [98.3% CI 48.6–54.7]), externalizing problems (51.4 [98.3% CI 48.5–54.3]), attention problems (57.8 [98.3% CI 55.6–60.0]), and attention-deficit/hyperactivity problems (55.8 [98.3% CI 54.1–57.6]) scores compared to participants taking ethosuximide (46.5 [98.3% CI 43.4–49.6]; 45.8 [98.3% CI 42.9–48.7]; 54.6 [98.3% CI 52.4–56.9]; 53.0 [98.3% CI 51.3–54.8]). Lack of seizure freedom and elevated week 16–20 Conner Continuous Performance Test confidence index were associated with worse total problems scores. At month 12, participants taking valproic acid had significantly higher attention problems scores (57.9 [98.3% CI 55.6–60.3]) compared to participants taking ethosuximide (54.5 [95% CI 52.1–56.9]). Conclusions: Pretreatment and ongoing behavioral problems exist in CAE. Valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine, further reinforcing ethosuximide as the preferred initial therapy for CAE. Clinicaltrials.gov identifier: NCT00088452. Classification of evidence: This study provides Class II evidence that for children with CAE, valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine.
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pretreatment seizure semiology in Childhood Absence Epilepsy
Neurology, 2017Co-Authors: Sudha Kilaru Kessler, Avital Cnaan, Joan A Conry, Deborah Hirtz, Solomon L Moshe, Shlomo Shinnar, Eli M Mizrahi, F. Hu, Dennis J. Dlugos, Peggy ClarkAbstract:Objective: To determine seizure semiology in children with newly diagnosed Childhood Absence Epilepsy and to evaluate associations with short-term treatment outcomes. Methods: For participants enrolled in a multicenter, randomized, double-blind, comparative-effectiveness trial, semiologic features of pretreatment seizures were analyzed as predictors of treatment outcome at the week 16 to 20 visit. Results: Video of 1,932 electrographic Absence seizures from 416 participants was evaluated. Median seizure duration was 10.2 seconds; median time between electrographic seizure onset and clinical manifestation onset was 1.5 seconds. For individual seizures and by participant, the most common semiology features were pause/stare (seizure 95.5%, participant 99.3%), motor automatisms (60.6%, 86.1%), and eye involvement (54.9%, 76.5%). The interrater agreement for motor automatisms and eye involvement was good (72%–84%). Variability of semiology features between seizures even within participants was high. Clustering analyses revealed 4 patterns (involving the presence/Absence of eye involvement and motor automatisms superimposed on the nearly ubiquitous pause/stare). Most participants experienced more than one seizure cluster pattern. No individual semiologic feature was individually predictive of short-term outcome. Seizure freedom was half as likely in participants with one or more seizure having the pattern of eye involvement without motor automatisms than in participants without this pattern. Conclusions: Almost all Absence seizures are characterized by a pause in activity or staring, but rarely is this the only feature. Semiologic features tend to cluster, resulting in identifiable Absence seizure subtypes with significant intraparticipant seizure phenomenologic heterogeneity. One seizure subtype, pause/stare and eye involvement but no motor automatisms, is specifically associated with a worse treatment outcome.
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second monotherapy in Childhood Absence Epilepsy
Neurology, 2017Co-Authors: Avital Cnaan, Deborah Hirtz, Peggy Clark, Shlomo Shinnar, Dennis J. Dlugos, David Masur, Peter C Adamson, Ravindra Arya, Tracy A GlauserAbstract:Objective: To determine optimal second monotherapy for children with Childhood Absence Epilepsy (CAE) experiencing initial treatment failure. Methods: Children with CAE experiencing treatment failure during the double-blind phase of a randomized controlled trial comparing ethosuximide, valproic acid, and lamotrigine were randomized to open-label second monotherapy with one of the 2 other study therapies. Primary study outcome was freedom from failure proportion at week 16–20 and month 12 visits after randomization. Secondary study outcome was percentage of participants experiencing attentional dysfunction at these visits. Results: A total of 208 children were enrolled, randomized, and received second therapy. At both week 16–20 visit and month 12 visit, ethosuximide9s (63%, 57%) and valproic acid9s (65%, 49%) freedom from failure proportions were similar to each other and higher than lamotrigine9s (45%, 36%, p = 0.051 and p = 0.062). At both time points, ethosuximide and valproic acid had superior seizure control compared to lamotrigine ( p Conclusions: As second monotherapy, ethosuximide and valproic acid, demonstrated higher freedom from failure proportions and greater efficacy than lamotrigine; valproic acid was associated with more attentional dysfunction. Ethosuximide is the optimal second monotherapy for children with CAE not responding to initial therapy with other medications. ClinicalTrials.gov identifier: NCT00088452. Classification of evidence: This study provides Class III evidence that for children with CAE experiencing initial treatment failure, second monotherapy with ethosuximide or valproic acid is superior to lamotrigine.
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long term outcomes of generalized tonic clonic seizures in a Childhood Absence Epilepsy trial
Neurology, 2015Co-Authors: Shlomo Shinnar, Avital Cnaan, Deborah Hirtz, Peggy Clark, Solomon L Moshe, Eli M Mizrahi, Dennis J. Dlugos, David Masur, Tracy A GlauserAbstract:Objective: To determine incidence and early predictors of generalized tonic-clonic seizures (GTCs) in children with Childhood Absence Epilepsy (CAE). Methods: Occurrence of GTCs was determined in 446 children with CAE who participated in a randomized clinical trial comparing ethosuximide, lamotrigine, and valproate as initial therapy for CAE. Results: As of June 2014, the cohort had been followed for a median of 7.0 years since enrollment and 12% (53) have experienced at least one GTC. The median time to develop GTCs from initial therapy was 4.7 years. The median age at first GTC was 13.1 years. Fifteen (28%) were not on medications at the time of their first GTC. On univariate analysis, older age at enrollment was associated with a higher risk of GTCs ( p = −0.0009), as was the duration of the shortest burst on the baseline EEG ( p = 0.037). Failure to respond to initial treatment ( p p p = 0.017) and not seen in those initially treated with lamotrigine. Conclusions: The occurrence of GTCs in a well-characterized cohort of children with CAE appears lower than previously reported. GTCs tend to occur late in the course of the disorder. Children initially treated with ethosuximide who are responders have a particularly low risk of developing subsequent GTCs.
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pretreatment cognitive deficits and treatment effects on attention in Childhood Absence Epilepsy
Neurology, 2013Co-Authors: David Masur, Avital Cnaan, Deborah Hirtz, Peggy Clark, Shlomo Shinnar, Ruth C Shinnar, Erica F Weiss, Jichuan Wang, Tracy A GlauserAbstract:Objective: To determine the neurocognitive deficits associated with newly diagnosed untreated Childhood Absence Epilepsy (CAE), develop a model describing the factorial structure of items measuring academic achievement and 3 neuropsychological constructs, and determine short-term differential neuropsychological effects on attention among ethosuximide, valproic acid, and lamotrigine. Methods: Subjects with newly diagnosed CAE entering a double-blind, randomized controlled clinical trial had neuropsychological testing including assessments of general intellectual functioning, attention, memory, executive function, and achievement. Attention was reassessed at the week 16–20 visit. Results: At study entry, 36% of the cohort exhibited attention deficits despite otherwise intact neurocognitive functioning. Structural equation modeling of baseline neuropsychological data revealed a direct sequential effect among attention, memory, executive function, and academic achievement. At the week 16–20 visit, attention deficits persisted even if seizure freedom was attained. More subjects receiving valproic acid (49%) had attention deficits than subjects receiving ethosuximide (32%) or lamotrigine (24%) ( p = 0.0006). Parental assessment did not reliably detect attention deficits before or after treatment ( p Conclusions: Children with CAE have a high rate of pretreatment attentional deficits that persist despite seizure freedom. Rates are disproportionately higher for valproic acid treatment compared with ethosuximide or lamotrigine. Parents do not recognize these attentional deficits. These deficits present a threat to academic achievement. Vigilant cognitive and behavioral assessment of these children is warranted. Classification of evidence: This study provides Class I evidence that valproic acid is associated with more significant attentional dysfunction than ethosuximide or lamotrigine in children with newly diagnosed CAE.