Long-term neuropsychological outcomes in children with febrile infection-related epilepsy syndrome (FIRES) treated with anakinra.

Background: Febrile-infection related epilepsy syndrome (FIRES) is a rare epilepsy syndrome in which a previously healthy individual develops refractory status epilepticus in the setting of a preceding febrile illness. There are limited data regarding detailed long-term outcomes. This study aims to describe the long-term neuropsychological outcomes in a series of pediatric patients with FIRES. Methods: This is a retrospective multi-center case series of pediatric patients with a diagnosis of FIRES treated acutely with anakinra who had neuropsychological testing at least 12 months after status epilepticus onset. Each patient underwent comprehensive neuropsychological evaluation as part of routine clinical care. Additional data collection included the acute seizure presentation, medication exposures, and outcomes. Results: There were six patients identified with a median age of 11.08 years (IQR: 8.19-11.23) at status epilepticus onset. Anakinra initiation was a median of 11 days (IQR: 9.25-13.50) after hospital admission. All patients had ongoing seizures and none of the patients returned to baseline cognitive function with a median follow-up of 40 months (IQR 35-51). Of the five patients with serial full-scale IQ testing, three demonstrated a decline in scores over time. Testing results revealed a diffuse pattern of deficits across domains and all patients required special education and/or accommodations for academic learning. Conclusions: Despite treatment with anakinra, neuropsychological outcomes in this series of pediatric patients with FIRES demonstrated ongoing diffuse neurocognitive impairment. Future research will need to explore the predictors of long-term neurocognitive outcomes in patients with FIRES and to evaluate if acute treatment interventions improve these outcomes.

Leveraging expertise and optimizing clinical research: Initial success of a pediatric epilepsy surgery collaborative.

OBJECTIVE: Improve data-driven research to inform clinical decision-making with pediatric epilepsy surgery patients by expanding the Pediatric Epilepsy Research Consortium Epilepsy Surgery (PERC-Surgery) Workgroup to include neuropsychological data. This article reports on the process and initial success of this effort and characterizes the cognitive functioning of the largest multi-site pediatric epilepsy surgery cohort in the United States. METHODS: Pediatric neuropsychologists from 18 institutions completed surveys regarding neuropsychological practice and the impact of involvement in the collaborative. Neuropsychological data were entered through an online database. Descriptive analyses examined the survey responses and cognitive functioning of the cohort. Statistical analyses examined which patients were evaluated and if composite scores differed by domain, demographics, measures used, or epilepsy characteristics. RESULTS: Positive impact of participation was evident by attendance, survey responses, and the neuropsychological data entry of 534 presurgical epilepsy patients. This cohort, ages 6 months to 21 years, were majority White and non-Hispanic, and more likely to have private insurance. Mean intelligence quotient (IQ) scores were below to low average, with weaknesses in working memory and processing speed. Full-scale IQ (FSIQ) was lowest for patients with younger age at seizure onset, daily seizures, and magnetic resonance imaging (MRI) abnormalities. SIGNIFICANCE: We established a collaborative network and fundamental infrastructure to address questions outlined by the Epilepsy Research Benchmarks. There is a wide range in the age and IQ of patients considered for pediatric epilepsy surgery, yet it appears that social determinants of health impact access to care. Consistent with other national cohorts, this US cohort has a downward shift in IQ associated with seizure severity.

When Epilepsy Grows Up .

Neurocognition in Childhood Epilepsy: Impact on Mortality and Complete Seizure Remission 50 Years Later Sillanpää M, Saarinen MM, Karrasch M, Schmidt D, Hermann BP. Epilepsia. 2019;60(1):131-138. doi:10.1111/epi.14606. Epub 2018 Nov 22. OBJECTIVE: To study associations of the severity of impairment in childhood neurocognition (NC) with long-term mortality and complete seizure remission. METHODS: A population-based cohort of 245 subjects with childhood-onset epilepsy was followed up for 50 years (median = 45, range = 2-50). Childhood NC before age 18 years was assessed as a combination of formal intelligence quotient scores and functional criteria (school achievement, working history, and psychoneurological development). Impaired NC was categorized with respect to definitions of intellectual functioning in International Classification of Diseases, Tenth Revision (R41.83, F70-F73). The outcome variables, defined as all-cause mortality and 10-year terminal remission with the 5 past years off medication (10YTR), were analyzed with Cox regression models. RESULTS: Of the 245 subjects, 119 (49%) had normal childhood NC, whereas 126 (51%) had various degrees of neurocognitive impairment. During the 50-year observation period, 71 (29%) of the subjects died, 13% of those with normal and 44% of those with impaired NC. The hazard of death increased gradually in line with more impaired cognition, reaching significance in moderate, severe, and profound impairment versus normal NC (hazard ratio [Bonferroni corrected 95% confidence interval] = 3.3 [1.2-9.2], 4.2 [1.2-14.2], and 5.5 [2.4-12.3], respectively). The chance for 10YTR was highest among subjects with normal NC (61%), whereas none of those with profound impairment reached 10YTR. In the intermediate categories, the chance was, however, not directly related to the increasing severity of impairment. SIGNIFICANCE: The severity of neurocognitive impairment during childhood shows a parallel increase in the risk of death. In comparison with normal NC, subjects with lower childhood NC are less likely to enter seizure remission. However, normal NC does not guarantee complete remission or prevent premature death in some individuals with childhood-onset epilepsy.

Lexical retrieval pre- and posttemporal lobe epilepsy surgery in a pediatric sample.

PURPOSE: This study aimed to evaluate lexical retrieval, presurgery and postsurgery, among children and adolescents who had undergone temporal lobe resection for intractable epilepsy and to compare outcomes in patients whose surgery involved the left temporal lobe or the right temporal lobe. MATERIALS AND METHODS: A retrospective chart review identified 36 patients from a major pediatric epilepsy treatment center who had undergone temporal lobe resection (21 underwent left temporal lobe resection; 15 underwent right temporal lobe resection) for intractable epilepsy and who had completed neuropsychological testing that included a measure of confrontation naming (Boston Naming Test, BNT) and verbal fluency (Delis-Kaplan Executive Function System (D-KEFS) Fluency) prior to and after surgery. Linear mixed effects regression models were used to evaluate presurgery and postsurgery changes and to compare the left temporal lobe resection group with the right temporal lobe resection group. PRINCIPAL RESULTS: Confrontation naming performance declined after left, but not right, temporal lobe resection (p<0.05). This effect was not documented for verbal fluency. MAJOR CONCLUSIONS: Left temporal lobe resection for intractable epilepsy is associated with a decline in lexical retrieval. The risk of decline in specific language functions following surgery involving the left temporal lobe should be incorporated in the counseling of patients and families in decision-making with regard to surgery.

Passive fMRI mapping of language function for pediatric epilepsy surgical planning: validation using Wada, ECS, and FMAER.

In this study we validate passive language fMRI protocols designed for clinical application in pediatric epilepsy surgical planning as they do not require overt participation from patients. We introduced a set of quality checks that assess reliability of noninvasive fMRI mappings utilized for clinical purposes. We initially compared two fMRI language mapping paradigms, one active in nature (requiring participation from the patient) and the other passive in nature (requiring no participation from the patient). Group-level analysis in a healthy control cohort demonstrated similar activation of the putative language centers of the brain in the inferior frontal (IFG) and temporoparietal (TPG) regions. Additionally, we showed that passive language fMRI produced more left-lateralized activation in TPG (LI=+0.45) compared to the active task; with similarly robust left-lateralized IFG (LI=+0.24) activations using the passive task. We validated our recommended fMRI mapping protocols in a cohort of 15 pediatric epilepsy patients by direct comparison against the invasive clinical gold-standards. We found that language-specific TPG activation by fMRI agreed to within 9.2mm to subdural localizations by invasive functional mapping in the same patients, and language dominance by fMRI agreed with Wada test results at 80% congruency in TPG and 73% congruency in IFG. Lastly, we tested the recommended passive language fMRI protocols in a cohort of very young patients and confirmed reliable language-specific activation patterns in that challenging cohort. We concluded that language activation maps can be reliably achieved using the passive language fMRI protocols we proposed even in very young (average 7.5 years old) or sedated pediatric epilepsy patients.

Benign rolandic epileptiform discharges are associated with mood and behavior problems.

Children with benign rolandic epilepsy (BRE) experience elevated rates of cognitive, behavioral, and affective problems. Frequent epileptiform spike discharges may impair behavioral functioning. To elucidate this relationship, we evaluated associations between the EEG spike frequency index (SI) and parental ratings of psychosocial adjustment and executive functioning in school-aged children with EEGs typical of BRE. Twenty-one children (6-12 years) participated. Parents completed validated questionnaires at a median of 5 months (range: 1-8) after a routine outpatient EEG. The EEG SI was calculated for wakefulness and sleep. The strength of association between the SI and behavioral variables was evaluated by simple and multivariate correlation. Higher awake and sleep SIs were associated with more symptoms of depression (P<0.001), aggression and conduct problems (P<0.01). Higher sleep SI was associated with executive dysfunction and anxiety (P<0.05). Symptoms of hyperactivity and inattention had no correlation. Increased epileptiform activity in children with BRE may predict higher rates of mood and behavioral problems.

Longer duration of epilepsy and earlier age at epilepsy onset correlate with impaired cognitive development in infancy.

We assessed the impact of age at onset of epilepsy and duration and frequency of seizures on cognitive development in children less than 3 years old. Retrospective analysis was conducted on clinical data and neuropsychological testing of 33 infants with epilepsy. Developmental quotients were calculated and were correlated with age at epilepsy onset, duration of epilepsy, seizure frequency, brain pathology, and types of seizures (with/without spasms) as potential predictors. Infants with longer duration and earlier onset of epilepsy performed worse on developmental neuropsychological testing. Regression analyses showed that age at epilepsy onset and percentage of life with epilepsy were both strongly associated (regression model P<0.0001) with developmental quotient. There was no correlation with seizure frequency. Infants with spasms had worse developmental quotients than infants without spasms (P<0.001). These results suggest that duration of epilepsy and age at onset may be the best developmental predictors during the first years of life in patients with epilepsy. Early aggressive intervention should be considered.

A survey of parent satisfaction with pediatric neuropsychological evaluations.

Satisfaction with pediatric neuropsychological evaluations was surveyed by asking parents or guardians of children who completed pediatric neuropsychological evaluations at a large children's hospital over a 2-year period to complete a 30-item rating scale. The scale included items drawn from published measures of consumer satisfaction, and incorporated a well-validated measure of general satisfaction. A total of 338 surveys were distributed, with 117 completed, for a return rate of 35%. Respondents were generally similar to non-respondents, except that respondents had a higher average level of maternal education and were more likely to have been referred for neuropsychological evaluations by sources outside the hospital. Parents were generally satisfied with pediatric neuropsychological evaluations, although some parents indicated that the evaluations did not provide as much help as expected. A factor analysis of the survey instrument revealed four dimensions of satisfaction: General Satisfaction, Clinician Acceptance/Empathy, Provision of Help, and Facilities/Administrative Assistance. Maternal education was negatively correlated with all four factors, but no other demographic, patient, or clinician variables were significantly related to satisfaction. Future studies could survey physicians and educators to provide a more complete understanding of satisfaction with pediatric neuropsychological evaluations.

Psychiatric disorders and behavioral characteristics of pediatric patients with both epilepsy and attention-deficit hyperactivity disorder.

OBJECTIVE: Attention-deficit hyperactivity disorder (ADHD) coexisting with epilepsy is poorly understood; thus, we compared the clinical correlates and psychiatric comorbid conditions of 36 children with epilepsy and ADHD aged 6 to 17 years enrolled in an ADHD treatment trial, with those reported in the literature on children with ADHD without epilepsy. METHODS: Measures included the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children (KSADS), the Wechsler Abbreviated Scale of Intelligence (WASI), and the Scales for Independent Behavior-Revised (SIB-R). RESULTS: Mean IQ was 86+/-19, and SIB-R Standard Score was 72+/-26. The ADHD-Combined subtype, composed of both inattentive and hyperactive symptoms, was most frequent (58%). Sixty-one percent exhibited a comorbid disorder, including anxiety disorders (36%) and oppositional defiant disorder (31%). CONCLUSIONS: Comorbidity in ADHD with epilepsy is similar to that in ADHD without epilepsy reported in the literature. These preliminary data argue that the pathophysiology of ADHD has common components in both populations.

Working memory and information processing speed in children with myelomeningocele and shunted hydrocephalus: analysis of the children's paced auditory serial addition test.

Working memory and information processing speed were examined in children with myelomeningocele and shunted hydrocephalus using the Children's Paced Auditory Serial Addition Test (CHIPASAT). The CHIPASAT was administered to 31 children with myelomeningocele and shunted hydrocephalus and 27 healthy siblings, all between 8 and 15 years of age. They also completed other standardized measures of working memory and processing speed. Children with myelomeningocele made fewer correct responses than siblings, although the magnitude of group differences declined as the rate of stimulus presentation increased. Children with myelomeningocele also made fewer consecutive correct responses and were more likely to provide correct but nonconsecutive responses, suggesting that they responded in a way that circumvents the working memory demands of the task. Standardized measures of processing speed and working memory accounted for significant variance in CHIPASAT performance after controlling for age, group membership, math skill, and general intellectual functioning. The results indicate that children with myelomeningocele and shunted hydrocephalus display deficits in working memory and information processing speed, and suggest that the CHIPASAT may provide a valid measure of these skills.