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ABSTRACT: OBJECTIVE: We hypothesized that total brain volume, white matter volume, and lobar cortical thickness would be different in epilepsy patients. We studied valproate relative to nonvalproate by using patients with epilepsy and healthy controls. METHODS: Patients with focal intractable epilepsy from a tertiary epilepsy center were the primary group for analysis. A confirmatory analysis was carried out in an independent group of subjects imaged as part of a community-based study of childhood-onset epilepsy. Total brain volume; white matter volume; and frontal, parietal, occipital, and temporal lobe thickness were measured by processing whole-brain T1-weighted MRI using FreeSurfer 5.1. RESULTS: Total brain volume, white matter volume, and parietal thickness were reduced in the valproate group relative to controls and nonvalproate users (valproate, n = 9; nonvalproate, n = 27; controls, n = 45; all male). These findings were confirmed in an independent group (valproate, n = 7; nonvalproate, n = 70; controls, n = 20; all male). CONCLUSIONS: Sodium valproate use in epilepsy is associated with parietal lobe thinning, reduced total brain volume, and reduced white matter volume. LEVEL OF EVIDENCE: This study provides Class IV evidence that use of valproate in epilepsy is associated with reduced parietal lobe thickness, total brain volume, and white matter volume.
Neurology 04/2013; · 8.31 Impact Factor
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ABSTRACT: AIM: To determine whether early measures of adaptive behavior are predictive of later school difficulties and achievement in otherwise neurotypical (unimpaired) children with onset of epilepsy during the preschool years. METHOD: In a prospective cohort study, parents completed the Vineland Adaptive Behavior Scales (VABS) for children who were aged 5 years or less at epilepsy diagnosis. Eight to 9 years later, the children were assessed using the Wechsler Intelligence Scales for Children (WISC), the Wide Range Achievement Test (WRAT), and the Child Behavior Checklist (CBCL). Associations of VABS scores with later WRAT and CBCL scores were tested. RESULTS: A total of 108 neurotypical children (64 males, 44 females; mean age at testing 11y 11mo, SD 2y) were studied. After adjustment for IQ and other factors, there was an increase of 0.15 points (95% confidence interval [CI] 0.03-0.27 points; p=0.03) and 0.14 points (95% CI 0.0-0.28 points; p=0.05) in WRAT reading and spelling scores for each 1-point increment in the VABS communication score. Corresponding numbers for the VABS socialization score were 0.20 (95% CI 0.08-0.32; p=0.005) and 0.17 (95% CI 0.05-0.29; p=0.005). CONCLUSION: In neurotypical preschool children with epilepsy, early social and communication scores predict later school performance. These findings raise questions about opportunities for early identification and intervention for children at greatest risk.
Developmental Medicine & Child Neurology 03/2013; · 2.92 Impact Factor
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ABSTRACT: PURPOSE: BECTS (benign epilepsy with centro-temporal spikes) is one of the most common childhood-onset epilepsy syndromes. We investigated quantitative evidence for brain morphological variation associated with BECTS to provide insights into the neuroanatomical basis of this disorder. METHODS: Three independent BECTS groups were imaged at different stages: (a) near onset (n=16, mean age 9.3±1.6 years), (b) ∼9 years after onset (n=9, mean age 15.8±2.3 years), and (c) ∼15 years after onset (n=10, mean age 22.7±2.7 years). Age-matched controls were imaged with each group. Whole brain T1-weighted MRI was acquired. Voxel-based morphometry (groups a-c) and cortical thickness analyses (groups b and c) were undertaken within each group and for the groups combined. The relationship between cortical morphology and age was investigated. KEY FINDINGS: The voxel-based morphometry analysis indicated increased bilateral grey matter volume in the superior frontal gyrus, insula and right inferior frontal gyrus regions in BECTS. The magnitude of the increase lessened with age of the cases. Cortical thickness analysis revealed thicker cortex in BECTS along middle and inferior frontal gyri bilaterally, left insula and bilateral supramarginal gyrus in the 9-year-after-onset group, that normalised with age. The rate of cortical thickness changes with age were greater in BECTS cases than in controls. SIGNIFICANCE: Increased cortical gray matter associated with BECTS was found. The decreasing magnitude of the effect with increasing age parallels the natural history of the disorder. The areas affected are consistent with neurocognitive dysfunction in BECTS.
Epilepsy research 01/2013; · 2.48 Impact Factor
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ABSTRACT: Increasing evidence suggests that uncontrolled seizures have deleterious effects on cognition and behavior, particularly in the developing brain.
In a community-based cohort, 198 children, aged <8 years with new-onset epilepsy were followed prospectively and reassessed with the Wechsler Intelligence Scales for Children, Third Edition (WISC-III) 8-9 years later. Linear regression analyses with interactions between age at onset (age) and pharmacoresistance (PR) were used to test whether earlier onset conveyed greater vulnerability to the effects of uncontrolled seizures. Full-scale IQ (FSIQ) and the 4 subdomain scores were examined. Adjustment for adaptive behavior scores in a subset was performed. A dichotomous indicator for IQ <80 or ≥80 was used to permit inclusion of children who were not tested, particularly those who were untestable.
FSIQ was not correlated with age. PR was associated with an 11.4 point lower FSIQ (p = 0.002) and similar decrements in each WISC-III domain. There were substantial age-PR interactions for FSIQ (p = 0.003) and 3 domain scores, indicating a lessening impact of PR with increasing age. The dichotomous IQ indicator was strongly correlated with age at onset in the pharmacoresistant group (p < 0.0001) and not in the non-pharmacoresistant group (p = 0.61). Adjustment for adaptive behavior measured near onset did not alter the conclusions.
Uncontrolled seizures impair cognitive function with effects being most severe in infancy and lessening with increasing age at onset. These findings further emphasize the need for early aggressive treatment and seizure control in infants and young children.
Neurology 09/2012; 79(13):1384-91. · 8.31 Impact Factor
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ABSTRACT: Increasingly, there has been an interest in the association between epilepsy and autism. The high frequency of autism in some of the early-onset developmental encephalopathic epilepsies is frequently cited as evidence of the relationship between autism and epilepsy. While these specific forms of epilepsy carry a higher-than-expected risk of autism, most, if not all, of the association may be due to intellectual disability (ID). The high prevalence of interictal EEG discharges in children with autism is also cited as further evidence although errors in the diagnosis of epilepsy seem to account for at least part of those findings. The prevalence of ID is substantially elevated in children with either epilepsy or autism. In the absence of ID, there is little evidence of a substantial, if any, increased risk of autism in children with epilepsy. Further, although the reported prevalence of autism has increased over the last several years, much of this increase may be attributable to changes in diagnostic practices, conceptualization of autism in the presence of ID, and laws requiring provision of services for children with autism. In the context of these temporal trends, any further efforts to tease apart the relationships between epilepsy, ID, and autism will have to address head-on the accuracy of diagnosis of all three conditions before we can determine whether there is, indeed, a special relationship between autism and epilepsy.
Epilepsy & Behavior 02/2012; 23(3):193-8. · 2.34 Impact Factor
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ABSTRACT: The 1989 Classification of the Epilepsies has recently been abandoned and recommendations for new terminology, concepts, and organizational approaches have been made. Chief among the changes are: (1) generalized and focal, while retained for seizures, were abandoned as obligatory descriptors of epilepsies; (2) instead of idiopathic, symptomatic, and cryptogenic, terms such as genetic, structural-metabolic, and epilepsy of unknown cause were recommended and specifically defined; (3) no specific classification structure was proposed. Instead, epilepsies and information about them should be flexibly organized according to features that are most relevant to a specific purpose. The electroclinical diagnoses themselves remain unchanged. A simple clinically practical approach to use epilepsy syndromes in preliminary diagnosis, evaluation, and management of newly presenting epilepsy was proposed which utilizes guidelines and recommendations from various national and international organizations. For example, children under 2-3years of age should be evaluated initially by a pediatric epilepsy specialist. Magnetic resonance imaging is an integral part of the early evaluation of anyone with newly presenting seizures, unless certain common and quite specific self-limited and pharmacoresponsive diagnoses can be made (e.g., childhood absence epilepsy). Any patient who fails trials of two or more medications should be evaluated thoroughly at an epilepsy center.
Handbook of Clinical Neurology 01/2012; 107:99-111.
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ABSTRACT: To examine whether family history of unprovoked seizures is associated with behavioral disorders in epilepsy probands, thereby supporting the hypothesis of shared underlying genetic susceptibility to these disorders.
We conducted an analysis of the 308 probands with childhood onset epilepsy from the Connecticut Study of Epilepsy with information on first-degree family history of unprovoked seizures and of febrile seizures whose parents completed the Child Behavior Checklist (CBCL) at the 9-year follow-up. Clinical cutoffs for CBCL problem and Diagnostic and Statistical Manual of Mental Disorders (DSM)-Oriented scales were examined. The association between first-degree family history of unprovoked seizure and behavioral disorders was assessed separately in uncomplicated and complicated epilepsy and separately for first-degree family history of febrile seizures. A subanalysis, accounting for the tendency for behavioral disorders to run in families, was adjusted for siblings with the same disorder as the proband. Prevalence ratios were used to describe the associations.
In probands with uncomplicated epilepsy, first-degree family history of unprovoked seizure was significantly associated with clinical cutoffs for Total Problems and Internalizing Disorders. Among Internalizing Disorders, clinical cutoffs for Withdrawn/Depressed, and DSM-Oriented scales for Affective Disorder and Anxiety Disorder were significantly associated with family history of unprovoked seizures. Clinical cutoffs for Aggressive Behavior and Delinquent Behavior, and DSM-Oriented scales for Conduct Disorder and Oppositional Defiant Disorder were significantly associated with family history of unprovoked seizure. Adjustment for siblings with the same disorder revealed significant associations for the relationship between first-degree family history of unprovoked seizure and Total Problems and Aggressive Behavior in probands with uncomplicated epilepsy; marginally significant results were seen for Internalizing Disorder, Withdrawn/Depressed, and Anxiety Disorder. There was no association between family history of unprovoked seizure and behavioral problems in probands with complicated epilepsy. First-degree family history of febrile seizure was not associated with behavioral problems in probands with uncomplicated or in those with complicated epilepsy.
Increased occurrence of behavioral disorders in probands with uncomplicated epilepsy and first degree family history of unprovoked seizure suggests familial clustering of these disorders. This supports the idea that behavioral disorders may be another manifestation of the underlying pathophysiology involved in epilepsy or closely related to it.
Epilepsia 12/2011; 53(2):301-7. · 3.96 Impact Factor
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ABSTRACT: We compared associations of epilepsy remission status and severity as well as psychiatric and other comorbidities with child and parent-proxy reports of health-related quality of life (HRQoL) in adolescents previously diagnosed with epilepsy.
In a prospective, community-based study of newly diagnosed childhood epilepsy, HRQoL of 277 children was assessed 8 to 9 years after diagnosis by using child and parent-proxy versions of the Child Health Questionnaire (CHQ). Multiple linear regression models adjusted for age and gender were used to compare associations of epilepsy remission and "complicated" epilepsy (secondary to an underlying neurologic insult or epileptic encephalopathy) status and psychiatric and other comorbidities with HRQoL.
Mean age of epilepsy onset was 4.4 years (SD: 2.6). At the 9-year reassessment, children were, on average, 13.0 years old (SD: 2.6); 64% were seizure-free for 5 years, 31% were taking antiepileptic drugs, and 19% had a complicated epilepsy. Prevalence of comorbidities at follow-up were 26% psychiatric diagnosis; 39% neurodevelopmental spectrum disorder (NDSD); 24% chronic medical illness; and 15% migraine. In multivariable analysis, having a psychiatric disorder was broadly associated with child (6 of 11 scales) and parent-proxy (7 of 12 scales) HRQoL (P ≤ .0125). Five-year remission and complicated epilepsy status had few or no associations with HRQoL. Although parent-proxy HRQoL was strongly associated with NDSD (6 of 11 scales), child-reported HRQoL was not (2 of 11 scales).
Psychiatric comorbidities are strongly associated with long-term HRQoL in childhood-onset epilepsy, which suggests that comprehensive epilepsy care must include screening and treatment for these conditions, even if seizures remit.
PEDIATRICS 12/2011; 128(6):e1532-43. · 4.47 Impact Factor
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ABSTRACT: Health-related quality of life (HRQOL) is associated with seizure recency among adults with epilepsy. In a prospective, community-based study of long-term outcomes of childhood-onset epilepsy, we evaluated whether worse HRQOL is associated with more recent seizures among children and adolescents with epilepsy. We used the Child Health Questionnaire (CHQ), a generic measure with child and parent-proxy versions, to measure HRQOL. Among 277 children with epilepsy (CWE) assessed 9 years after diagnosis, parent-proxy reported but not child self-reported HRQOL was significantly worse for those having seizures in the prior year than for those who were seizure free ≥1 year across the majority of scales. There were no differences between CWE in remission for 1-5 years and those seizure free ≥5 years for child and parent-proxy reported HRQOL with the exception of the parent Emotional Impact scale, suggesting that HRQOL differences related to seizure recency level off after the initial year of remission.
Epilepsy & Behavior 11/2011; 23(1):47-51. · 2.34 Impact Factor
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Anne T Berg
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ABSTRACT: By now, most are aware that changes are afoot in the concepts and terminology used for discussing and "classifying" epilepsy (1). The changes have been met with scorn and derision by some (2, 3). In balance, they seem to be appreciated, not for being a final product but for finally moving the field from out of an archaic past in which it was stuck and into the present and, may we hope, the future. As it stands, the report, and its recommendations likely elicit feelings of dissatisfaction for not being complete, final, and carved in stone. The report did not even presume to present a new classification. The authors of the report share that frustration, with the caveat that little should ever be carved in stone in a field that is moving as rapidly as the life sciences.
Epilepsy currents / American Epilepsy Society. 09/2011; 11(5):138-40.
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ABSTRACT: Epilepsy is associated with academic and neurocognitive disorders, with the latter often assumed to explain the former. We examined utilization of special education services (SpES) in relation to neurocognitive test scores in a case-matched sibling control study. In a follow-up assessment 8-9 years after entry into a prospective study of childhood-onset epilepsy, cases and siblings participated in an interview and standardized neurocognitive testing. Analyses included 142 pairs in which both had Full Scale IQ ≥ 80 and the case had normal examination and imaging. Sixty-four (45%) cases and 25 (17.6%) controls reported SpES utilization, (matched odds ratio [mOR]=5.3, P<0.0001). Adjustment for neurocognitive test scores resulted in a mOR of 4.6 (P<0.0001). Types and duration of services were similar in cases and controls. Twenty-four percent of school-aged cases were already receiving services at the time of initial epilepsy diagnosis. Young people with epilepsy have academic difficulties that are not explained simply by cognitive test scores.
Epilepsy & Behavior 08/2011; 22(2):336-41. · 2.34 Impact Factor
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Epilepsia 06/2011; 52(6):1205-8. · 3.96 Impact Factor
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ABSTRACT: Concepts and terminology for classifying seizures and epilepsies have, until recently, rested on ideas developed nearly a century ago. In order for clinical epilepsy and practice to benefit fully from the major technological and scientific advances of the last several years, advances that are revolutionizing our understanding and treatment of the epilepsies, it is necessary to break with the older vocabulary and approaches to classifying epilepsies and seizures. The Commission on Classification and Terminology made specific recommendations to move this process along and ensure that classification will reflect the best knowledge, will not be arbitrary, and will ultimately serve the purpose of improving clinical practice as well as research on many levels. The recommendations include new terms and concepts for etiology and seizure types as well as abandoning the 1989 classification structure and replacing it instead with a flexible multidimensional approach in which the most relevant features for a specific purpose can be emphasized. This is not a finished product and will take yet more time to achieve. Waiting any longer, however, would be a disservice to patient care and will continue the longstanding frustrations with the earlier system which, at this point in time, can be viewed as both antiquated and arbitrary.
Epilepsia 06/2011; 52(6):1058-62. · 3.96 Impact Factor
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ABSTRACT: Determine the probability of attaining complete remission in children with nonsyndromic epilepsy (NSE) over the course of ≥10 years from initial diagnosis; identify early predictors of complete remission; and assess the risk of relapse after achieving complete remission.
In a prospective community-based cohort, complete remission was defined as 5 years seizure-free and medication-free. Any subsequent seizure for any reason was a relapse. Univariate and bivariate analyses were conducted with standard methods including the Kaplan-Meier approach. Proportional hazards modeling was used for multivariable analysis.
Of 613 cohort members, 347 had NSEs, of whom 294 (85%) were followed ≥10 years (maximum = 17.9). A total of 170 in 294 (58%) achieved complete remission, 10 of whom (6%) relapsed. Seizure outcome at 2 years (remission, pharmacoresistant, unclear) (p < 0.0001) and underlying cause (p < 0.0001) distinguished groups with complete remission ranging from ~20% to ~75%. Older age at onset was independently associated with a poorer chance of complete remission. Relapses occurred up to 7.5 years after attaining complete remission and were marginally associated with underlying cause (p = 0.06).
Complete remission occurs in over one-half of young people with NSE and generally persists. Meaningful but imperfect predication is possible based on underlying cause and early seizure control. The finding of age effects may play a role in meaningful identification of phenotypes, which could become fruitful targets for genetic and imaging investigations in these otherwise poorly differentiated epilepsies.
Annals of Neurology 04/2011; 70(4):566-73. · 11.09 Impact Factor
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ABSTRACT: The prevalence of autism spectrum disorders for children with epilepsy in the general population is unknown. In a prospective community-based study of newly diagnosed childhood epilepsy, autism spectrum disorder was determined from parental interviews, medical records, and expert reviews by a child psychiatrist. A total of 28 (5%) participants had autism spectrum disorders. West syndrome (prevalence ratio = 4.53, P = .002) and intellectual impairment (prevalence ratio = 4.34, P = .002) were independently associated with autism spectrum disorder. Absent West syndrome, male gender was associated with autism spectrum disorder (prevalence ratio = 3.71, P = .02). For participants with overall normal cognitive abilities, 2.2% had autism spectrum disorder, which is substantially higher than estimates from the general population (0.5%-0.9%). In addition to West syndrome, which has repeatedly been shown to have a special relationship with autism spectrum disorder, the most important determinants of autism spectrum disorder in the general population (intellectual impairment and male sex) are also important in young people with epilepsy.
Journal of child neurology 03/2011; 26(5):540-7. · 1.59 Impact Factor
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ABSTRACT: People with epilepsy have a higher risk for suicide than people without epilepsy. The relationship between seizure control and suicide is controversial. A standardized protocol to record history, diagnostic testing, and neuropsychiatric assessments was administered. The Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) were administered presurgically and yearly for up to 5 years. Among the 396 enrolled, 4 of 27 deaths were attributed to suicide. The standardized mortality ratio, compared with suicides in the U.S. population and adjusted for age and gender, was 13.3 (95% CI=3.6-34.0). Only one patient had a BDI score suggestive of severe depression (BDI=33), one had depressive symptoms that did not the meet the depressive range (BDI=7), and the other two reported no depressive symptoms. Two of the patients reported moderate to severe anxiety symptoms (BAI=17 and 21, respectively). Suicide may occur after epilepsy surgery, even when patients report excellent seizure control.
Epilepsy & Behavior 02/2011; 20(3):462-4. · 2.34 Impact Factor
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ABSTRACT: Childhood-onset epilepsy is associated with psychiatric and cognitive difficulties and with poor social outcomes in adulthood. In a prospective cohort of young people with epilepsy, we studied psychiatric and neurodevelopmental disorders and epilepsy-related characteristics, all factors that may influence long-term social outcomes. Five hundred one subjects, 159 with complicated (IQ <80 or brain lesion) and 342 with uncomplicated epilepsy, were included. Psychiatric disorders and neurodevelopmental disorders were more common in complicated epilepsy (P<0.005). In uncomplicated epilepsy, externalizing but not internalizing disorders were strongly associated with neurodevelopmental disorders. Internalizing disorders and neurodevelopmental disorders were associated with lack of 5-year remission. Type of epilepsy was not associated with neurodevelopmental disorders or psychiatric disorders. Various comorbid conditions in epilepsy cluster together and are modestly associated with imperfect seizure control. These need to be considered together in evaluating and managing young people with epilepsy and may help explain long-term social outcomes above and beyond poor seizure control.
Epilepsy & Behavior 02/2011; 20(3):550-5. · 2.34 Impact Factor
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Anne T Berg
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ABSTRACT: Consistent with previous findings, two recent studies of temporal lobectomy from Kerala, India demonstrate that early seizure recurrence bodes poorly for long-term seizure control, and that relapse following drug discontinuation affects one-third of patients. Key questions in the field now concern advanced preoperative and intraoperative techniques for improving surgical outcomes.
Nature Reviews Neurology 01/2011; 7(6):311-2. · 12.46 Impact Factor
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Anne T Berg
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ABSTRACT: Although epilepsy is defined by the occurrence of spontaneous epileptic seizures, a large body of evidence indicates that epilepsy is linked to a spectrum of behavioral, psychiatric, and cognitive disorders as well as to sudden death. Explanations for these associations include the following: (1) The effects of structural lesions that may impair the functions subserved by the regions of the brain involved in the lesion. (2) The effects of seizure activity that may begin well before a clinical seizure occurs and may persist long after it is over, raising questions about what truly constitutes "interictal." In addition, encephalopathic effects of epilepsy in infancy during critical periods in development may be particularly severe and potentially irreversible. (3) Shared mechanisms underlying seizures as well as these other disorders in the absence of structural lesions or separate diseases of the central nervous system (CNS). Epidemiologic and clinical studies demonstrate the elevated risk of cognitive, psychiatric, and behavioral disorders not just during but also prior to the onset of epilepsy (seizures) itself. These may outlast the active phase of epilepsy as well. The mounting evidence argues strongly for the recognition of epilepsy as part of a spectrum of disorders and against the notion that even uncomplicated epilepsy can a priori be considered benign.
Epilepsia 01/2011; 52 Suppl 1:7-12. · 3.96 Impact Factor
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ABSTRACT: In 2008, the Food and Drug Administration (FDA) issued a warning that any and all antiepileptic drugs (AEDs) might increase the risk of suicidal ideation, suicide attempt, and completed suicide. Considerable confusion and concern followed regarding the use of these drugs, in general, and specifically for people with epilepsy. Recently, four publications examined suicidality and AED use among several databases and illustrated how biases affect the findings. None of the studies was able to control completely for the indication for which the AEDs were prescribed or to account for the varying intensities with which different specialists monitoring patients for suicidality. Though multiple analyses were conducted for many AEDs, no study controlled for the numerous comparisons made. The result is a multitude of contradictions in the findings across studies and even within studies, with no study providing clear or convincing support for the FDA conclusions. This review attempts to clarify the methodological issues in assessing potential associations between AED use and suicidality.
Epilepsy currents / American Epilepsy Society. 11/2010; 10(6):137-45.
