In May 2005, an international, interdisciplinary group of researchers gathered in Bethesda, MD, USA, for a workshop to discuss the development of treatments for patients with nonepileptic seizures (NES). Specific subgroup topics that were covered included: pediatric NES; presenting the diagnosis of NES, outcome measures for NES trials; classification of NES subtypes; and pharmacological treatment approaches and psychotherapies. The intent was to develop specific research strategies that can be expanded to involve a large segment of the epilepsy and psychiatric treatment communities. Various projects have resulted from the workshop, including the initial development of a prospective randomized clinical trial for NES.
Nonepileptic seizures; Somatoform disorders; Conversion disorder; Treatment; Clinical trials; Pharmacotherapy; Psychotherapy
We examined the association between lifetime, current history of psychiatric disorders, suicidal thoughts and behaviors with childhood-onset epilepsies in a community-based cohort of young adults.
Cases were neurotypical (normal neurological, cognitive, and imaging exams and no evidence of a brain insult responsible for the epilepsy) young adults with childhood-onset epilepsy followed since the onset of their epilepsy approximately 15 years earlier and recruited as part of a community-based study. They were compared to two different control groups, siblings and external controls from the National Comorbidity Survey-Replication (NCS-R). The Diagnostic Interview Survey assessed lifetime and current DSM-IV-TR diagnoses of mood disorders and anxiety disorders. Suicidal thoughts and suicide attempt were assessed using the Diagnostic Interview Survey for Children-IV and the Diagnostic Interview Survey.
Two hundred fifty-seven cases and 134 sibling controls participated in the DIS portion of the young adult assessment. Comparing cases both to their sibling controls and to the controls drawn from the NCS-R, we did not find any evidence to suggest a higher prevalence of lifetime and current mood or anxiety disorders, suicidal thoughts and suicide attempt in young adults with childhood-onset epilepsies.
Our findings, from a community-based sample of neurotypical young adults, do not suggest a substantial or lasting association between childhood epilepsy and psychiatric disorders and suicidal behavior.
Epilepsy; psychiatric disorders; case-control study
The relationship between cortical thickness (CThick) and sulcal depth (SDepth) changes across brain regions during development. Epilepsy youth have CThick and SDepth abnormalities and prevalent psychiatric disorders.
This study compared the CThick–SDepth relationship in children with focal epilepsy with typically developing children (TDC) and the role played by seizure and psychopathology variables.
A surface-based, computational high-resolution three-dimesional (3D) magnetic resonance image analytic technique compared regional CThick–SDepth relationships in 42 participants with focal epilepsy and 46 TDC (6–16 years) imaged in a 1.5 Tesla scanner. Psychiatric interviews administered to each participant yielded psychiatric diagnoses. Parents provided seizure-related information.
The TDC group alone demonstrated a significant negative medial fronto-orbital CThick–SDepth correlation. Focal epilepsy participants with but not without psychiatric diagnoses showed significant positive pre-central and post-central CThick–SDepth associations not found in TDC. Although the history of prolonged seizures was significantly associated with the post-central CThick–SDepth correlation, it was unrelated to the presence/absence of psychiatric diagnoses.
Abnormal CThick–SDepth pre-central and post-central associations might be a psychopathology biomarker in paediatric focal epilepsy.
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© 2015 The Royal College of Psychiatrists. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.
To date only a very narrow window of ethical dilemmas in psychogenic non-epileptic seizures (PNES) have been explored. Numerous distinct ethical dilemmas arise in diagnosing and treating pediatric and adolescent patients with PNES. Important ethical values at stake include trust, transparency, confidentiality, professionalism, autonomy of all stakeholders and justice. In order to further elucidate the ethical challenges in caring for this population, an ethical analysis of the special challenges faced in four specific domains is undertaken: (1) conducting and communicating a diagnosis of PNES; (2) advising patients about full transparency and disclosure to community including patients’ peers; (3) responding to requests to continue anti-epileptic drugs; and (4) managing challenges arising from school policy and procedure. An analysis of these ethical issues is essential for the advancement of best care practices that promote the overall well-being of patients and their families.
Diagnosis; Communication; Doctor Shopping; Disclosure; School; Anti-epileptic drugs
Neurobehavioral comorbidities are common in pediatric epilepsy with enduring adverse effects on functioning, but their neuroanatomical underpinning is unclear. Striatal and thalamic abnormalities have been associated with childhood-onset epilepsies, suggesting that epilepsy-related changes in the subcortical circuit might be associated with the combordities of children with epilepsy. We aimed to compare subcortical volumes and their relationship with age in children with complex partial seizures (CPS), childhood absence epilepsy (CAE), and healthy controls (HC). We examined the shared versus unique structural-functional relationships of these volumes with behavior problems, intelligence, language, peer interaction, and epilepsy variables in these two epilepsy syndromes.
We investigated volumetric differences of caudate, putamen, pallidum, and thalamus in children with CPS (N= 21), CAE (N=20), and HC (N=27). Study subjects underwent structural MRI, intelligence, and language testing. Parent-completed Child Behavior Checklists provided behavior problem and peer interaction scores. We examined the association of age, IQ, language, behavioral problems, and epilepsy variables with subcortical volumes that were significantly different between the children with epilepsy and HC.
Both children with CPS and CAE exhibited significantly smaller left thalamic volume compared to HC. In terms of developmental trajectory, greater thalamic volume was significantly correlated with increasing age in children with CPS and CAE but not in HC. With regard to the comorbidities, reduced left thalamic volumes were related to more social problems in children with CPS and CAE. Smaller left thalamic volumes in children with CPS were also associated with poor attention, lower IQ and language scores, and impaired peer interaction.
Our study is the first to directly compare and detect shared thalamic structural abnormalities in children with CPS and CAE. These findings highlight the vulnerability of the thalamus and provide important new insights on its possible role in the neurobehavioral comorbidities of childhood-onset epilepsy.
Given the FDA’s warning regarding the potential connection between suicidal behavior and antiepileptic drugs, this study examined methods by which to detect suicidal ideation in children with epilepsy. It compared the sensitivity, specificity, and area under the curve for identifying children with suicidal behavior using the Child Behavior Checklist (CBCL) and a structured psychiatric interview. Parent completed CBCLs provided behavior problem scores on 177 children with epilepsy, aged 5–16 years. Psychiatric diagnoses were made based on separate child and parent structured psychiatric interviews about the child. Children answered questions on suicidal behaviors during the interview. The clinically elevated CBCL Total Problems scale and having more than one psychiatric diagnosis, irrespective of type of diagnosis, were significant predictors and correctly classified children with suicidal ideation in 79% of the cases based on the CBCL and 80% of the cases with more than one psychiatric diagnosis. These findings indicate that elevated CBCL Total Problems scores, a commonly used instrument, can screen and identify risk for suicidal behavior in children with epilepsy. Additionally, irrespective of diagnosis, if a child with epilepsy has more than one psychiatric diagnosis, further assessment of suicidal behavior is warranted. Importantly, the results underscore the utility of having parents complete a questionnaire in the waiting room in order to identify children with epilepsy at risk for suicidal behavior.
pediatric epilepsy; suicide; psychiatric disorders; behavior problems
Autism spectrum disorder (ASD) is a heterogeneous disorder of brain development with wide-ranging cognitive deficits. Typically diagnosed before age 3, ASD is behaviorally defined but patients are thought to have protracted alterations in brain maturation. With longitudinal magnetic resonance imaging (MRI), we mapped an anomalous developmental trajectory of the brains of autistic compared to those of typically developing children and adolescents. Using tensor-based morphometry (TBM), we created 3D maps visualizing regional tissue growth rates based on longitudinal brain MRI scans of 13 autistic and 7 typically developing boys (mean age/inter-scan interval: autism 12.0 ± 2.3 years/2.9 ± 0.9 years; control 12.3 ± 2.4/2.8 ± 0.8). The typically developing boys demonstrated strong whole-brain white matter growth during this period, but the autistic boys showed abnormally slowed white matter development (p = 0.03, corrected), especially in the parietal (p = 0.008), temporal (p = 0.03) and occipital lobes (p =0.02). We also visualized abnormal overgrowth in autism in some gray matter structures, such as the putamen and anterior cingulate cortex. Our findings reveal aberrant growth rates in brain regions implicated in social impairment, communication deficits and repetitive behaviors in autism, suggesting that growth rate abnormalities persist into adolescence. TBM revealed persisting growth rate anomalies long after diagnosis, which has implications for evaluation of therapeutic effects.
Autism spectrum disorder; longitudinal; MRI; tensor-based morphometry; development; white matter
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 pre-school years.
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 nine 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.
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).
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.
This paper presents translational aspects of imaging and genetic studies of language and cognition in children with epilepsy of average intelligence. It also discusses current unanswered translational questions in each of these research areas. A brief review of multimodal imaging and language study findings shows that abnormal structure and function, as well as plasticity and reorganization in language-related cortical regions are found both in children with epilepsy with normal language skills and in those with linguistic deficits. The review on cognition highlights that multiple domains of impaired cognition and abnormalities in brain structure and/or connectivity are evident early on in childhood epilepsy and might be specific for epilepsy syndrome. The description of state of the art genetic analyses that can be used to explain the convergence of language impairment and Rolandic epilepsy includes a discussion of the methodological difficulties involved in these analyses. Two junior researchers describe how their current and planned studies address some of the unanswered translational questions regarding cognition and imaging and the genetic analysis of speech sound disorder, reading, and centrotemporal spikes in Rolandic epilepsy.
language; cognition; imaging; genetics; pediatric epilepsy
The heterogeneity of symptoms and cognitive deficits in schizophrenia can be explained by abnormal connectivity between brain regions. Childhood-onset schizophrenia (COS) is a particularly severe form of schizophrenia, with an onset during a key time period for both cerebral pruning and myelination.
Diffusion tensor images were acquired from 18 children and adolescents with COS and 25 controls. The COS group was divided into two sub-groups--one with linguistic impairment (LI) and the other without (NLI). The fractional anisotropy (FA), axial (AD), and radial diffusivity (RD) data from the two COS sub-groups were compared to each other and to the controls using tract-based spatial statistics (TBSS) analyses, which is a voxel-based method used to identify regions of white matter abnormalities.
TBSS identified several regions in the left hemisphere where the LI group had increased AD and RD relative to the NLI and the control groups. These areas primarily localized to linguistic tracts: left superior longitudinal fasciculus and left inferior longitudinal fasciculus/inferior fronto-occipital fasciculus. Regions of increased RD overlapped regions of increased AD, with the former showing more pronounced effects.
Studies of adult-onset schizophrenia typically identify areas of higher RD but unchanged AD; however, normal development studies have shown that while RD decreases are pronounced over this age range, smaller decreases in AD can also be detected. The observed increases in both RD and AD suggest that developmental disturbances affecting the structural connectivity of these pathways are more severe in COS accompanied by severe linguistic impairments.
Diffusion tensor imaging; Axial diffusivity; Radial diffusivity; Linguistic impairments; Neurodevelopment
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 cut-offs for CBCL problem and 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, 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 cut-offs for Total Problems and Internalizing Disorders. Among Internalizing Disorders, clinical cut-offs for Withdrawn/Depressed, and DSM-Oriented scales for Affective Disorder and Anxiety Disorder were significantly associated with family history of unprovoked seizures. Clinical cut-offs 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 Agressive 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.
epilepsy; psychiatric disorders; family history; epidemiology
Children with epilepsy are usually treated with antiepileptic drugs (AEDS). Some AEDs adversely affect behavior in susceptible children. Since psychiatric comorbidity is prevalent in pediatric epilepsy, this paper attempts to disentangle these AED side effects from the psychopathology associated with this illness. It first outlines the clinical and methodological problems involved in determining if AEDs contribute to the behavior and emotional problems of children with epilepsy. It then presents research evidence for and against the role AEDs play in the psychopathology of children with epilepsy, and outlines how future studies might investigate this problem. A brief description of how to clinically separate out AED effects from the complex illness-related and psychosocial factors that contribute to the behavior difficulties of children with epilepsy concludes the paper.
antiepileptic drugs; epilepsy; psychopathology; children
Although magnetic resonance spectroscopy has identified metabolic abnormalities in adult and childhood schizophrenia, no prior studies have investigated the relationship between neurometabolites and thought disorder. This study examined this association in language-related brain regions using proton magnetic resonance spectroscopic imaging (1H MRSI).
MRSI was acquired bilaterally from 28 youth with childhood-onset schizophrenia and 34 healthy control subjects in inferior frontal, middle frontal, and superior temporal gyri at 1.5 T and short echo time (TR/TE=1500/30 ms). CSF-corrected “total NAA” (tNAA; N-acetyl-aspartate+N-acetyl-aspartyl-glutamate), glutamate+glutamine (Glx), creatine+phosphocreatine (Cr+PCr), choline compounds (Cho), and myo-inositol (mI) were assayed in manually drawn regions-of-interest partitioned into gray matter, white matter, and CSF and then coregistered with MRSI. Speech samples of all subjects were coded for thought disorder.
In the schizophrenia group, the severity of formal thought disorder correlated significantly with tNAA in the left inferior frontal and superior temporal gyri and with Cr+PCr in left superior temporal gyrus.
Neurometabolite concentrations in language-related brain regions are associated with thought disorder in childhood-onset schizophrenia.
Childhood-onset schizophrenia; Thought Disorder; Magnetic Resonance Spectroscopy; N-acetyl aspartate; Choline compounds
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.
epilepsy; psychiatric comorbidity; quality of life; Child Health Questionnaire; child and adolescent health