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Language and social skills are essential for intrapersonal and interpersonal functioning and quality of life. Since epilepsy impacts these important domains of individuals' functioning, understanding the psychosocial and biological factors involved in the relationship among epilepsy, language, and social skills has important theoretical and clinical implications. This review first describes the psychosocial and biological factors involved in the association between language and social behavior in children and in adults and their relevance for epilepsy. It reviews the findings of studies of social skills and the few studies conducted on the inter-relationship of language and social skills in pediatric and adult epilepsy. The paper concludes with suggested future research and clinical directions that will enhance early identification and treatment of epilepsy patients at risk for impaired language and social skills., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: We aimed to compare long-term social outcomes in young adults with childhood-onset epilepsy (cases) with neurologically normal sibling controls., Methods: Long-term social outcomes were assessed at the 15-year follow-up of the Connecticut Study of Epilepsy, a community-based prospective cohort study of children with newly diagnosed epilepsy. Young adults with childhood-onset epilepsy with complicated (abnormal neurologic exam findings, abnormal brain imaging with lesion referable to epilepsy, intellectual disability (ID; IQ < 60) or informative history of neurologic insults to which the occurrence of epilepsy might be attributed), and uncomplicated epilepsy presentations were compared to healthy sibling controls. Age, gender, and matched-pair adjusted generalized linear models stratified by complicated epilepsy and 5-year seizure-free status estimated adjusted odds ratios (aORs) and 95% confidence intervals [CIs] for each outcome., Results: The 15-year follow-up included 361 individuals with epilepsy (59% of initial cases; N = 291 uncomplicated and N = 70 complicated epilepsy; mean age 22 years [standard deviation, SD 3.5]; mean epilepsy onset 6.2 years [SD 3.9]) and 173 controls. Social outcomes for cases with uncomplicated epilepsy with ≥5 years terminal remission were comparable to controls; cases with uncomplicated epilepsy <5 years seizure-free were more likely to be less productive (school/employment < 20 h/week) (aOR 3.63, 95% CI 1.83-7.20) and not to have a driver's license (aOR 6.25, 95% CI 2.85-13.72). Complicated cases with epilepsy <5 years seizure-free had worse outcomes across multiple domains; including not graduating high school (aOR 24.97, 95% CI 7.49-83.30), being un- or underemployed (<20 h/week) (aOR 11.06, 95% CI 4.44-27.57), being less productively engaged (aOR 15.71, 95% CI 6.88-35.88), and not living independently (aOR 10.24, 95% CI 3.98-26.36). Complicated cases without ID (N = 36) had worse outcomes with respect to productive engagement (aOR 6.02; 95% CI 2.48-14.58) compared to controls. Cases with complicated epilepsy were less likely to be driving compared to controls, irrespective of remission status or ID., Significance: In individuals with uncomplicated childhood-onset epilepsy presentations and 5-year terminal remission, young adult social outcomes are comparable to those of sibling controls. Complicated epilepsy, notable for intellectual disability, and seizure remission status are important prognostic indicators for long-term young adult social outcomes in childhood-onset epilepsy., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Objective: To test whether the reported association between pediatric epilepsy and behavioral problems may be distorted by the use of parental proxy report instruments., Study Design: Children in the Connecticut Study of Epilepsy were assessed 8-9 years after their epilepsy diagnosis (time-1) with the parent-proxy Child Behavior Check List (CBCL) (ages 6-18 years) or the Young Adult Self-Report (≥18 years of age). For children <18 years of age, parents also completed the Child Health Questionnaire, which contains scales for impact of child's illness on the parents. The same study subjects completed the Adult Self-Report 6-8 years later (time-2). Sibling controls were also tested. Case-control differences were examined for evidence suggesting more behavioral problems in cases with epilepsy than in controls based on proxy- vs self-report measures., Results: At time-1, parent-proxy CBCL scores were significantly higher (worse) for cases than controls (n = 140 matched pairs). After adjustment for Child Health Questionnaire scales reflecting parent emotional and time impact, only 1 case-control difference on the CBCL remained significant. Self-reported Young Adult Self-Report scores did not differ between cases and controls (n = 42 pairs). At time-2, there were no significant self-reported case-control differences on the Adult Self-Report (n = 105 pairs)., Conclusions: Parent-proxy behavior measures appear to be influenced by the emotional impact of epilepsy on parents. This may contribute to apparent associations between behavioral problems and childhood epilepsy. Self-report measures in older adolescents (>18 years of age) and young adults do not confirm parental perceptions. Evidence suggesting more behavioral problems in children with epilepsy should be interpreted in light of the source of information., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: This study identified items on the Child Behavior Checklist (CBCL) that predict those children and adolescents with epilepsy at highest risk for multiple psychiatric diagnoses., Methods: Three hundred twenty-eight children, ages 5-18 years, and their parents participated in separate structured psychiatric interviews about the children, which yielded Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR) diagnoses. Parents completed the CBCL. The sample was divided into a younger (≤12 years, n = 214) group and an older (>12-18 years, n = 114) group. This study identified a reduced set of parent-reported CBCL items associated with Multiple Diagnoses versus Single Diagnosis versus No Diagnosis using chi-square tests and stepwise logistic regression. We then performed a generalized logistic regression with Multiple Diagnoses versus Single Diagnosis versus No Diagnosis as the dependent variable and the reduced CBCL set of items as predictors. We calculated the area under the ROC (receiver operating characteristic) curve (AUC) as a measure of diagnostic accuracy for pairwise comparisons., Results: For the younger group, seven items (clingy, cruelty/bullying, perfectionist, nervous, poor school work, inattentive, and sulks) had high diagnostic accuracy (AUC = 0.88), and for the older group, three items (disobedient at school, loner, and lies/cheats) had high accuracy (AUC = 0.91) when comparing children with multiple psychiatric diagnoses to children with no diagnosis. For both age groups, there was less diagnostic accuracy in identifying children with a single versus no diagnosis (AUC = 0.75 [young]; 0.70 [older])., Significance: These findings suggest that responses to these two subsets of parent-reported CBCL items should alert clinicians to children and adolescents with epilepsy at risk for multiple psychiatric diagnoses and in need of a psychiatric referral., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Background: Adults with childhood-onset epilepsy experience poorer adult social outcomes than their peers. The relative roles of seizures over time versus learning and psychiatric problems are unclear., Methods: We examined independent influences of psychiatric and learning disorders and of seizure course in 241 young adults (22-35 years old) with uncomplicated epilepsy in a longitudinal community-based cohort study. Social outcomes were ascertained throughout the study. A history of psychiatric and learning problems was ascertained ∼9 years after study entry. Seizure course was: "Excellent," no seizures after the first year, in complete remission at last contact (N = 95, 39%); "Good," seizures occurred 1 to 5 years after diagnosis, in complete remission at last contact (N = 56, 23%); "Fluctuating," more complicated trajectories, but never pharmacoresistant (N = 70, 29%); "Pharmacoresistant," long-term pharmacoresistant (N = 20, 8%). Multiple logistic regression was used to identify contributors to each social outcome., Results: Better seizure course predicted college completion, being either employed or pursuing a degree, and driving, but was not substantially associated with other social outcomes. Poorer seizure course was associated with a greater likelihood of having offspring, particularly in women without partners. Learning problems, psychiatric disorders, or both negatively influenced all but 2 of the social outcomes., Conclusions: In young adults with uncomplicated epilepsy, the course of seizures contributed primarily to education, employment, and driving. A history of learning problems and psychiatric disorders adversely influenced most adult outcomes. These findings identify potential reasons for vocational and social difficulties encountered by young adults with childhood epilepsy and areas to target for counseling and transition planning., (Copyright © 2016 by the American Academy of Pediatrics.)

Objectives: We examined the associations of lifetime and current histories of psychiatric disorders and of suicidal thoughts and behaviors with childhood-onset epilepsies in a community-based cohort of young adults., Methods: Cases were neurotypical (normal neurologic, cognitive, and imaging examinations 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 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (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 (DIS-IV)., Results: Two hundred fifty-seven cases and 134 sibling controls participated in the DIS-IV 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., Significance: 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., (Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.)

Discontinuation of antiepileptic drugs should be a first step in treatment of nonepileptic seizures without comorbid epilepsy. However, clinical practices vary and standardized guidelines are not available. The aim of this study was to survey members of the American Epilepsy and Child Neurology Societies about factors that influence their decision about antiepileptic drug management in patients with nonepileptic seizures. A total of 236 respondents completed this survey, of whom 84% were academic pediatric neurologists and 96.2% were very willing to discontinue antiepileptic drugs in these patients. Clinicians with sufficient knowledge about nonepileptic seizures had fewer concerns about the potential for medical errors, were less influenced by requests made by patients or parents to continue antiepileptic drugs, and were comfortable making this decision if patients receive ongoing psychiatric care. Results of this survey highlight the need to examine if the same factors are involved in a large sample of community clinicians., (© The Author(s) 2013.)

We evaluated several commonly used screening instruments for the detection of mood disorders, anxiety disorders, and attention-deficit hyperactivity disorder (ADHD). These were compared to a criterion-based standardized questionnaire, the Diagnostic Interview Survey (DIS)-IV, designed to make DSM-IV-TR diagnoses in the community-based study of childhood-onset epilepsy. The DIS-IV was administered to young adult cases with epilepsy at a 15-year follow-up assessment and compared to symptom screens administered at the same visit, and at a previous 9-year assessment. Among cases, the specificity of the DIS-IV ranged from 0.77 to 0.99 and the predictive value of a negative psychiatric diagnosis was similarly high. Sensitivity was lower, ranging from 0 to 0.77, with correspondingly low predictive value of a positive diagnosis. Symptom-based instruments assess current symptom burden and are useful for determining associations with ongoing seizures or quality of life. Criterion-based standardized interviews, such as the DIS-IV, provide psychiatric diagnoses over the lifetime, which is most useful in studies of epilepsy genetics and studies of comorbidities and prognosis of epilepsy., (© 2013.)

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 behavioral problem scores on 177 children with epilepsy, aged 5-16years. Psychiatric diagnoses were made based on separate child and parent structured psychiatric interviews about the child. The children answered questions on suicidal behaviors during the interview. A clinically elevated score in the CBCL Total Problems scale and having more than one psychiatric diagnosis, irrespective of the 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., (© 2013.)

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 11 y 11 mo, SD 2 y) 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., (© 2013 Mac Keith Press.)

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The clinical manifestations of depression in people with epilepsy (PWE) are pleomorphic, often associated with anxiety symptoms and anxiety disorders. The ongoing debate of whether the clinical presentation of depression in PWE is unique to this neurologic disorder is reviewed. Comorbid depression can impact the recruitment of PWE for pharmacologic trials with antiepileptic drugs (AEDs). Yet, the impact of depression on the response of the seizure disorder to pharmacotherapy with AEDs and its impact on worse adverse events may bias the interpretation of the trial findings, particularly when depressed patients are included in the AED trials. PWE have a greater suicidal risk than the general population. This risk is mediated by multiple factors, and recent data from the FDA have imputed a potential pathogenic role to all AEDs. The recognition of patients at risk is reviewed. Yet, the validity of the FDA data has been questioned, and the status of this controversial question is analyzed. As in the case of epilepsy, depression and pain syndromes have a relatively high comorbidity. The negative impact of depression on pain is reminiscent of that of depression in PWE; furthermore, the high comorbidity may be also associated with the existence of common pathogenic mechanisms. Neurologists and in particular, epileptologists establish the diagnosis of psychogenic non-epileptic seizures (PNES) in whom a comorbid depressive disorder is very often identified. The role of depression in the course of PNES and its treatment are discussed. Scarce data are available on the treatment of depression in PWE. Thus, clinicians have had to adopt data from patients with primary depressive disorders. We outline a consensus strategy on the identification and treatment of depressive disorders in adult and pediatric patients with epilepsy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Depression is the most frequent psychiatric comorbidity in people with epilepsy (PWE) with lifetime prevalence rates ranging between 30 and 35%. Multifactorial variables play a pathogenic role in the high comorbid occurrence of these two disorders. These variables were critically examined during an international symposium held in Chicago in September 2010, the results of which are presented in two companion manuscripts. The first manuscript summarizes new epidemiologic data highlighting the bidirectional relation between depression and epilepsy and related methodological issues in studying this relationship. An examination of the neurobiologic aspects of primary mood disorders, mood disorders in PWE and pathogenic mechanisms of epilepsy derived from studies in animal models and humans is allowing a better understanding of the complex relation between the two conditions. In the first manuscript, we review data from animal models of epilepsy in which equivalent symptoms of depression and anxiety disorders develop and, conversely, animal models of depression in which the kindling process is facilitated. Data from structural and functional neuroimaging studies in humans provide a further understanding of potential common pathogenic mechanisms operant in depression and epilepsy that may explain their high comorbidity. The negative impact of depression on the control of seizure disorders has been documented in various studies. In this manuscript, these data are reviewed and potential mechanisms explaining this phenomenon are proposed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: 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., Methods: 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., Key Findings: 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., Significance: 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., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Objective: 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., Methods: 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., Results: 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)., Conclusions: 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.

This paper first summarizes the main findings of clinical studies conducted over the past two and a half decades on psychopathology (i.e., psychiatric diagnoses, behavior and emotional problems) in children with new onset and chronic epilepsy both with and without intellectual disability who are treated medically and surgically. Although impaired social relationships are core features of the psychiatric disorders found in pediatric epilepsy, few studies have examined social competence (i.e., social behavior, social adjustment, and social cognition) in these children. There also is a dearth of treatment studies on the frequent psychiatric comorbidities of pediatric epilepsy, attention deficit hyperactivity disorder, anxiety disorders, and depression. Drs. Hamiwka and Jones then describe their current and planned studies on social competence and cognitive behavioral treatment of anxiety disorders, respectively, in these children and how they might mitigate the poor long-term psychiatric and social outcome of pediatric epilepsy., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Epilepsy is a prevalent childhood neurological disorder, but there are few prospective quantitative magnetic resonance imaging studies examining patterns of brain development compared to healthy controls. Controlled prospective investigations initiated at or near epilepsy onset would best characterize the nature, timing and course of neuroimaging abnormalities in paediatric epilepsy. In this study, we report the results of a deformation-based morphometry technique to examine baseline and 2-year prospective neurodevelopmental brain changes in children with new and recent onset localization-related epilepsies (n = 24) and idiopathic generalized epilepsies (n = 20) compared to healthy controls (n = 36). Children with epilepsy demonstrated differences from controls in baseline grey and white matter volumes suggesting antecedent anomalies in brain development, as well as abnormal patterns of prospective brain development that involved not only slowed white matter expansion, but also abnormalities of cortical grey matter development involving both greater and lesser volume changes compared to controls. Furthermore, abnormal neurodevelopmental changes extended outside the cortex affecting several subcortical structures including thalamus, cerebellum, brainstem and pons. Finally, there were significant differences between the epilepsy syndromes (localization-related epilepsies and idiopathic generalized epilepsies) with the idiopathic generalized epilepsies group showing a more disrupted pattern of brain structure both at baseline and over the 2-year interval.

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., (Copyright © 2010 Elsevier Inc. All rights reserved.)

This study examined the relationship between suicidal ideation and frontotemporal volumes, particularly orbital frontal gyrus volume, in 51 subjects with epilepsy with a mean age of 9.8 (2.1) years. Structured psychiatric interviews of the children and parents provided information on suicidal behavior and DSM-IV diagnoses. Tissue of 1.5-T MRI scans was segmented, and total brain, frontal lobe, frontal parcellations, and temporal lobe volumes were computed. The 11 subjects with epilepsy with suicidal ideation had significantly smaller right orbital frontal gyrus white matter volumes and larger left temporal lobe gray matter volumes than the 40 children without suicidal thoughts. Given the role of the orbital frontal gyrus in both emotional regulation and epilepsy, these findings highlight the biological underpinnings of suicidal ideation in pediatric epilepsy., (Copyright 2010. Published by Elsevier Inc.)

Children with epilepsy and control children were followed over a 2-year interval. Comorbidities of epilepsy, often defined as problems related to IQ, academic achievement, language, and psychopathology, were evaluated prospectively. It was hypothesized that over time (1) the presence of comorbidities would predict worse outcomes, and (2) epilepsy variables would negatively impact comorbidities. The study included 39 children with complex partial seizures (CPS), 25 children with childhood absence epilepsy (CAE), and 27 healthy children, aged 7.6-16.1years. The findings were notable for stability over the interval in all three groups. Additionally, baseline seizure variables and change over the interval appear to play a role in IQ and math achievement scores of children with epilepsy with average IQ and in the reading achievement scores of those with below-average IQ. However, seizure variables at baseline and follow-up were not predictors of DSM-IV diagnoses, depression, anxiety, or behavioral problems., (Copyright 2010 Elsevier Inc. All rights reserved.)

In this study the relationship between language skill and frontotemporal volumes was compared in 69 medically treated subjects with epilepsy and 34 healthy children, aged 6.1-16.6 years. Also, whether patients with linguistic deficits had abnormal volumes and atypical associations between volumes and language skills in these brain regions was determined. The children underwent language testing and MRI scans at 1.5 T. Brain tissue was segmented and frontotemporal volumes were computed. Higher mean language scores were significantly associated with larger inferior frontal gyrus, temporal lobe, and posterior superior temporal gyrus gray matter volumes in the epilepsy group and in the children with epilepsy with average language scores. Increased total brain and dorsolateral prefrontal gray and white matter volumes, however, were associated with higher language scores in the healthy controls. Within the epilepsy group, linguistic deficits were related to smaller anterior superior temporal gyrus gray matter volumes and there was a negative association between language scores and dorsolateral prefrontal gray matter volumes. These findings demonstrate abnormal development of language-related brain regions, and imply differential reorganization of brain regions subserving language in children with epilepsy with normal linguistic skills and in those with impaired language., ((c) 2010 Elsevier Inc. All rights reserved.)

Purpose: This study examined the severity and range of linguistic impairments in young, intermediate, and adolescent youth with epilepsy and how these deficits were associated with illness effects, nonverbal intelligence, psychopathology, and reading., Methods: Tests of language, intelligence, achievement, and structured psychiatric interviews were administered to 182 epilepsy youth, aged 6.3-8.1, 9.1-11.7, and 13.0-15.2 years, as well as to 102 age- and gender-matched normal children. Parents provided demographic, seizure-related, and behavioral information on their children., Results: Significantly more epilepsy subjects had language scores 1 standard deviation (SD) below average than the age-matched control groups did. The intermediate and adolescent epilepsy groups also had significantly lower mean language scores compared to their matched controls. The older compared to the younger epilepsy groups had more language impairment and a wider range of linguistic deficits. Longer duration of illness, childhood absence epilepsy, psychiatric diagnosis, and socioeconomic status were associated with linguistic deficits in the young group. Prolonged seizures, lower Performance IQ, and minority status predicted low language scores in the intermediate epilepsy group. In the adolescent group, language impairment was associated with poor seizure control, decreased Performance IQ, and lower socioeconomic status. Linguistic and reading deficits were significantly related in each epilepsy group., Conclusions: The age-related increase in linguistic impairment, different profiles of predictors in each age group, and the relationship of linguistic deficits with poor reading skills have important clinical, developmental, theoretical, and academic implications.

This exploratory study compared the responses of 20 Caucasian and 20 Hispanic mothers of children with epilepsy about possible obstacles to mental health care (MHC) for their children before and after they read a brochure on the neurobehavioral comorbidities of epilepsy. The intervention significantly increased the mothers' knowledge of the behavior and cognitive comorbidities of pediatric epilepsy and their treatment. Baseline differences in the attitude toward MHC and the stigma of epilepsy between Hispanic and Caucasian mothers were no longer apparent after the intervention. Irrespective of ethnicity, the mothers also became significantly more aware that their children did not want to have epilepsy-related behavior and learning difficulties. Efficient use of time spent in doctors' waiting rooms to educate parents about the neurobehavioral comorbidities of epilepsy can address the lack-of-knowledge barrier to MHC. However, the study's findings suggested a need to determine if there are specific obstacles to MHC in pediatric epilepsy.

The aim of this study was to determine if volumes of frontotemporal regions associated with language were related to thought disorder in 42 children, aged 5-16 years, with cryptogenic epilepsy, all of whom had complex partial seizures (CPS). The children with CPS and 41 age- and gender-matched healthy children underwent brain MRI scans at 1.5 T. Tissue was segmented, and total brain, frontal lobe, and temporal lobe volumes were computed. Thought disorder measures, IQ, and seizure information were collected for each patient. The subjects with CPS had more thought disorder, smaller total gray matter and orbital frontal gray matter volumes, as well as larger temporal lobe white matter volumes than the control group. In the CPS group, thought disorder was significantly related to smaller orbital frontal and inferior frontal gray matter volumes, increased Heschl's gyrus gray matter volumes, and smaller superior temporal gyrus white matter volumes. However, significantly larger orbital frontal gyrus, superior temporal gyrus, and temporal lobe gray matter volumes and decreased Heschl's gyrus white matter volumes were associated with thought disorder in the control group. These findings suggest that thought disorder might represent a developmental disability involving frontotemporal regions associated with language in pediatric CPS.

In this study, focus groups were used to examine parents' attitudes toward mental health services, use of mental health and other services, as well as service-related and other challenges encountered by parents of children with epilepsy. Both quantitative and qualitative analytic approaches were used to analyze the transcripts of 36 parents grouped into six focus groups by socioeconomic status (SES) (high, low) and ethnicity (African-American, Caucasian, Hispanic). The quantitative analyses demonstrated that, irrespective of SES and ethnicity, the parents were highly aware of their children's behavioral, emotional, and cognitive difficulties and the lack of knowledge about epilepsy among medical, educational, and mental health professionals. The higher-SES parents were significantly more concerned about inadequate educational services and the need for medical services, but less concerned about mental health and medical service use than the lower-SES parents. Insufficient knowledge about epilepsy and about services, parent emotional difficulties, and use of educational services differed significantly by ethnicity. The qualitative analyses highlighted the parents' concerns regarding misconceptions about epilepsy and the stigma toward mental health care among the African-American and Hispanic parents. These findings suggest the need for accessible and better-quality mental health, educational, and medical services for children with epilepsy irrespective of SES and ethnicity. They also underscore the importance of educating parents, service providers, and the general public about epilepsy.

Affective disorders in people with epilepsy (PWE) have become increasingly recognized as a primary factor in the morbidity and mortality of epilepsy. To improve the recognition and treatment of affective disorders in PWE, an expert panel comprising members from the Epilepsy Foundation's Mood Disorders Initiative have composed a Consensus Statement. This document focuses on depressive disorders in particular and reviews the appearance and treatment of the disorder in children, adolescents, and adults. Idiosyncratic aspects of the appearance of depression in this population, along with physiological and cognitive issues and barriers to treatment, are reviewed. Finally, a suggested approach to the diagnosis of affective disorders in PWE is presented in detail. This includes the use of psychometric tools for diagnosis and a stepwise algorithmic approach to treatment. Recommendations are based on the general depression literature as well as epilepsy-specific studies. It is hoped that this document will improve the overall detection and subsequent treatment of affective illnesses in PWE.

Eighteen pediatric neurologists and 18 pediatricians completed a 5-point Likert scale questionnaire on their knowledge of, attitudes toward, and management of the behavioral, cognitive, and psychosocial aspects of pediatric epilepsy, before and after a lecture on this topic. They also responded to questions about possible barriers to mental health care of children with epilepsy. The brief educational intervention modified the knowledge/attitudes of pediatricians compared with pediatric neurologists on the impact of epilepsy on behavior and cognition in children with epilepsy. However, there were no between-group differences in how providers perceived their competence to assess behavioral and cognitive comorbid conditions in pediatric epilepsy. Responses to open-ended questions suggested insufficient mental health coverage for and expertise on pediatric epilepsy, resistance of mental health clinicians to treat children with epilepsy, and the stigma of mental health as possible barriers to mental health care in children with epilepsy. In addition to the need for provider education about the behavioral and cognitive comorbid conditions of pediatric epilepsy, these findings emphasize the importance of examining alternative routes to increasing mental health care for children with epilepsy.

Objective: To critically review literature published from 1996 to 2007 on psychopathology in children with epilepsy (CWE)., Method: Using Ovid, we searched Medline and PsychInfo databases for original studies on epidemiology, risk factors, clinical characteristics, treatment, and outcome of psychopathology in CWE, ages 0 to 18 years, using the terms "psychopathology," "emotional and behavioral problems," and "mental health problems." We selectively present the findings of studies that are clinically relevant to mental health professionals., Results: Psychopathology occurs in 37% to 77% of CWE, and attention, internalizing, and thought problems may be specific to epilepsy. Cognitive and linguistic deficits, as well as family factors, have moderating effects on psychopathology in CWE. The association of epilepsy-related variables, including antiepileptic drugs, with psychopathology is inconsistent in cognitively normal CWE. Children with symptomatic epilepsy and devastating epilepsy syndromes have high rates of global developmental delay, hyperactivity, and autistic symptoms. The treatment of psychopathology in CWE integrates standard psychiatric practices., Conclusions: Epilepsy is a neuropsychiatric disorder characterized by seizures, psychopathology, cognitive, and linguistic problems. Improved early identification of CWE at risk for psychopathology, evidence-based psychiatric treatment, and multidisciplinary management strategies would advance clinical practice in this highly complex field of pediatric neuropsychiatry.

It is well recognized that children with epilepsy are at heightened risk for developing behavior problems and psychiatric disorders. Studies identifying factors associated with child behavior were reviewed and findings were placed into two broad categories for review and critique: illness-related variables and psychosocial variables. Illness-related variables were seizure frequency and seizure control, type of epilepsy, age of onset, duration of illness, and antiepileptic drugs. Psychosocial variables were reviewed using a family stress framework: stressors, perceptions, adaptive resources, coping, and family adjustment. After the literature on each category is reviewed, an integrated heuristic model that includes key illness-related and psychosocial variables is presented.

The aim of this study was to characterize the distribution, timing, and risk factors for psychiatric comorbidity in children with recent onset epilepsy. Children aged 8 to 18 years with recent onset epilepsy (<1 year in duration) of idiopathic etiology (n=53) and a healthy comparison group (n=50) underwent a structured psychiatric diagnostic interview to characterize the spectrum of lifetime-to-date history of comorbid psychiatric disorder. There was no significant difference between the children with recent onset epilepsy and healthy comparison children in sex (31 males, 22 females vs 23 males, 27 females) or mean age 12.7y [SD 3.3] vs 12.7y [SD 3.2]). Children with recent onset epilepsy exhibited an elevated rate of lifetime-to-date Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) Axis I disorders compared with the comparison group. They showed significantly higher rates of depressive disorders (22.6 vs. 4%, p=0.01), anxiety disorders (35.8 vs 22%, p<0.05), and attention-deficit-hyperactivity disorder (26.4 vs 10%, p=0.01) with elevated but less prevalent rates of oppositional defiant and tic disorders. A subset of children with epilepsy (45%) exhibited DSM-IV Axis I disorders before the first recognized seizure, suggesting the potential influence of antecedent neurobiological factors that remain to be identified. The increased prevalence of psychiatric comorbidity antedating epilepsy onset may be consistent with the presence of underlying neurobiological influences independent of seizures, epilepsy syndrome, and medication treatment.

Children with epilepsy are at increased risk for social difficulties compared with other children. This review investigated the types of social difficulties that children with epilepsy experience, the risk factors for their social difficulties and possible interventions for treating their social difficulties, such as social skills training, educational and speech and language interventions, and psychopharmacotherapy. Recommendations for future research on social difficulties in children with epilepsy are discussed.

Depression is a frequent comorbidity in epilepsy patients. A variety of biological factors may underlie epilepsy-associated depression. We examined whether kindling-induced chronic increase in seizure susceptibility is accompanied by behavioral symptoms of depression. Three-week-old Wistar rats underwent rapid kindling: 84 initially subconvulsant electrical stimulations of ventral hippocampus delivered every 5 minutes, followed by depression-specific behavioral tests performed 2 and 4 weeks later. Kindled animals exhibited a sustained increase in immobility time in the forced swim test and the loss of taste preference toward calorie-free saccharin, as compared with controls. Initial loss of preference toward the intake of calorie-containing sucrose was followed by the increased consumption at 4 weeks. At both time points, animals exhibited enhanced seizure susceptibility on test stimulations of the hippocampus. We conclude that neuronal plastic changes associated with the kindling state are accompanied by the development of depressive behavior.

This study examined if children with cryptogenic epilepsy and complex partial seizures (CPS) have smaller total brain, frontal, and temporal lobe volumes than normal children and how this is related to seizure, cognitive, psychiatric, and demographic variables. Forty-four children with CPS and 38 normal children, aged 5-16 years, underwent brain MRI scans at 1.5 T. Tissue was segmented, and total brain, frontal lobe, frontal parcellation, and temporal lobe volumes were computed. Other than significantly larger temporal lobe white matter volumes in the CPS group, there were no significant differences in brain volumes between the CPS and normal groups. Earlier onset, longer duration of illness, younger chronological age, and presence of a psychiatric diagnosis were significantly related to smaller frontotemporal volumes in subjects with CPS. Although these findings suggest that CPS might affect development of the temporal and frontal regions, we are unable to rule out the possibility that smaller frontotemporal volumes might predispose children to CPS. These findings highlight the need to control for seizure, cognitive, psychiatric, and demographic variables in studies of frontotemporal volumes in pediatric CPS.

BackgroundThe 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.AimsThis 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.MethodA 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.ResultsThe 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.ConclusionsAbnormal CThick-SDepth pre-central and post-central associations might be a psychopathology biomarker in paediatric focal epilepsy.Declaration interestNone.Copyright and usage© 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.

PurposeNeurobehavioral comorbidities are common in pediatric epilepsy with enduring adverse effects on functioning, but their neuroanatomic 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 comorbidities 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.MethodsWe 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 magnetic resonance imaging (MRI), intelligence, and language testing. Parent-completed Child Behavior Checklists provided behavior problem and peer interaction scores. We examined the association of age, intelligence quotient (IQ), language, behavioral problems, and epilepsy variables with subcortical volumes that were significantly different between the children with epilepsy and HC.Key findingsBoth 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.SignificanceOur 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.

Objectives This study examined the risk factors for learning problems (LP) in pediatric psychogenic non-epileptic seizures (PNES) and their specificity by comparing psychopathology, medical, cognitive/linguistic/achievement, bullying history, and parent education variables between subjects with PNES with and without LP and between subjects with PNES and siblings with LP. Methods 55 subjects with PNES and 35 siblings, aged 8–18 years, underwent cognitive, linguistic, and achievement testing, and completed somatization and anxiety sensitivity questionnaires. A semi-structured psychiatric interview about the child was administered to each subject and parent. Child self-report and/or parent report provided information on the presence/absence of LP. Parents also provided each subject's medical, psychiatric, family, and bullying history information. Results Sixty percent (33/55) of the PNES and 49% (17/35) of the sibling subjects had LP. A multivariable logistic regression demonstrated that bullying and impaired formulation of a sentence using a stimulus picture and stimulus word were significantly associated with increased likelihood of LP in the PNES youth. In terms of the specificity of the LP risk factors, a similar analysis comparing LP in the youth with PNES and sibling groups identified anxiety disorder diagnoses and bullying as the significant risk factors associated with LP in the PNES youth. Conclusions These findings emphasize the need to assess youth with PNES for LP, particularly if they have experienced bullying, have linguistic deficits, and meet criteria for anxiety disorder diagnoses. [ABSTRACT FROM AUTHOR]

Objective Psychogenic nonepileptic seizures ( PNES) in youth are symptoms of a difficult to diagnose and treat conversion disorder. PNES is associated with high medical and psychiatric morbidity, but specific PNES risk factors in the pediatric population are not known. We examined if youth with PNES have a distinct biopsychosocial risk factor profile compared to their siblings and if the interrelationships between these risk factors differentiate the PNES probands from the sibling group. Methods This multisite study included 55 youth with a confirmed diagnosis of PNES (age range 8.6-18.4 years) and their 35 sibling controls (age range 8.6-18.1 years). A video EEG and psychiatric assessment confirmed the PNES diagnosis. Parents reported on each child's past and present medical/epilepsy, psychiatric, family, and educational history. Each child underwent a structured psychiatric interview, standardized cognitive and academic achievement testing, and completed self-report coping, daily stress, adversities, and parental bonding questionnaires. Results Compared to their siblings, the PNES probands had significantly more lifetime comorbid medical, neurological (including epilepsy), and psychiatric problems; used more medications and intensive medical services; had more higher anxiety sensitivity, practiced solitary emotional coping, and experienced more lifetime adversities. A principal components analysis of these variables identified a somatopsychiatric, adversity, epilepsy, and cognitive component. The somatopsychiatric and adversity components differentiated the probands from the siblings, and were highly significant predictors of PNES with odds ratios of 15.1 (95% CI [3.4, 67.3], and 9.5 (95% CI [2.0, 45.7]), respectively. The epilepsy and cognitive components did not differentiate between the PNES and sibling groups. Significance These findings highlight the complex biopsychosocial and distinct vulnerability profile of pediatric PNES. They also underscore the need for screening the interrelated risk factors included in the somatopsychiatric and adversity components and subsequent mental health referral for confirmation of the diagnosis and treatment of youth with PNES. [ABSTRACT FROM AUTHOR]

Abstract: Though posttraumatic epilepsy (PTE) is a prominent sequela of traumatic brain injury (TBI), other nonepileptic phenomena also warrant consideration. Within two UCLA pediatric TBI cohorts, we categorized five spell types: 1) PTE; 2) Epilepsy with other potential etiologies (cortical dysplasia, primary generalized); 3) Psychopathology; 4) Behavior misinterpreted as seizures; and 5) Other neurologic events. The two cohort subsets differed slightly in injury severity, but they were otherwise similar. Overall, PTE occurred in 40%, other epilepsy etiologies in 14%, and nonepileptic spells collectively in 46%. Among children with spells, PTE was associated with severe TBI (p=0.001), whereas psychopathology (p=0.014) and epilepsy with other etiologies (p=0.006) were associated with milder TBI severity. Posttraumatic epilepsy (p=0.002) and misinterpreted behavior (p=0.049) occurred with younger injury age. Psychopathology (p=0.020) and other neurologic events (p=0.002) occurred with older injury age. In evaluating possible PTE, clinicians should maintain a broad differential diagnosis to prevent misdiagnosis and inappropriate treatment. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

The article presents a study that examined the effects of childhood absence epilepsy (CAE) on age-related cortical morphometry and cognitive abilities. Results showed CAE diagnosed children did not show normal regional age-related changes like sucal depth. Seizure variables such as age of onset and frequency in CAE subjects did not have a significant impact on the association between age and cortical morphometry measures. Findings suggest CAE patients use different brain regions in performing cognitive functions.

This study compared frontotemporal brain volumes in children with childhood absence epilepsy (CAE) to age- and gender-matched children without epilepsy. It also examined the association of these volumes with seizure, demographic, perinatal, intelligence quotient (IQ), and psychopathology variables. Twenty-six children with CAE, aged 7.5–11.8 years, and 37 children without epilepsy underwent brain magnetic resonance imaging (MRI) scans at 1.5 Tesla. Tissue was segmented, and total brain, frontal lobe, frontal parcellations, and temporal lobe volumes were computed. All children had IQ testing and structured psychiatric interviews. Parents provided seizure, perinatal, and behavioral information on each child. The CAE group had significantly smaller gray matter volumes of the left orbital frontal gyrus as well as both left and right temporal lobes compared to the age- and gender-matched children without epilepsy. In the CAE group these volumes were related to age, gender, ethnicity, and pregnancy complications but not to seizure, IQ, and psychopathology variables. In the group of children without epilepsy, however, the volumes were related to IQ. These findings suggest that CAE impacts brain development in regions implicated in behavior, cognition, and language. In addition to supporting the cortical focus theory of CAE, these findings also imply that CAE is not a benign disorder. [ABSTRACT FROM AUTHOR]

Abstract: This study compared thought disorder (i.e., impaired use of language to formulate and organize thoughts) in 93 children with complex partial seizures (CPSs) and 56 children with primary generalized epilepsy with absence (PGE) and its relationship to age, seizure, cognitive, and linguistic variables. By the use of psychopathology, social competence, academic achievement, and school problem measures, the functional implications of thought disorder in these two groups were compared. When demographic variables were controlled for, there were no significant differences in thought disorder scores between the CPS and PGE groups. However, the profile of age, gender, seizure, and cognitive variables related to thought disorder differed in the CPS and PGE groups. Within each group, different aspects of thought disorder were associated with different seizure variables. Thought disorder was related to psychopathology, school problems, decreased academic achievement, and poor peer interaction in the CPS group, but with school problems in the PGE group. These findings suggest that CPS and PGE affect the normal maturation of children’s discourse skills, albeit through different mechanisms. The relationship of thought disorder to behavioral, academic, and social problems implies that these discourse deficits are one component of the developmental disabilities or comorbidities associated with pediatric CPS and PGE. [Copyright &y& Elsevier]