Exploring the neurological features of individuals with germline PTEN variants: A multicenter study.

OBJECTIVE: PTEN, a known tumor suppressor gene, is a mediator of neurodevelopment. Individuals with germline pathogenic variants in the PTEN gene, molecularly defined as PTEN hamartoma tumor syndrome (PHTS), experience a variety of neurological and neuropsychiatric challenges during childhood, including autism spectrum disorder (ASD). However, the frequency and nature of seizures and the utilization of allied health services have not been described. METHODS: Young patients with PHTS and sibling controls were recruited across five centers in the United States and followed every 6-12 months for a mean of 2.1 years. In addition to the history obtained from caregivers, neurodevelopmental evaluations and structured dysmorphology examinations were conducted, and brain MRI findings, received therapies, and epilepsy characteristics were reported. RESULTS: One hundred and seven patients with PHTS (median age 8.7 years; range 3-21 years) and 38 controls were enrolled. ASD and epilepsy were frequent among patients with PHTS (51% and 15%, respectively), with generalized epilepsy strongly associated with ASD. Patients with epilepsy often required two antiseizure medications. Neuroimaging revealed prominent perivascular spaces and decreased peritrigonal myelination in individuals with PHTS-ASD. Allied therapy use was frequent and involved physical, occupational, speech, and social skills therapies, with 89% of all patients with PHTS, regardless of ASD diagnosis, utilizing at least one service. INTERPRETATION: This prospective, longitudinal study highlights the wide neurological spectrum seen in young individuals with PHTS. ASD is common in PHTS, comorbid with epilepsy, and allied health services are used universally. Our findings inform care discussions with families about neurological outcomes in PHTS.

Intelligence quotient testing in children with hearing loss: A systematic review.

OBJECTIVE: The objective of the current study is to perform a systematic review of the research literature to evaluate the impact of hearing loss on intelligence quotient (IQ) scores in pediatric patients. DATA SOURCES: Ovid MEDLINE, EMBASE, CINAHL, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched from their inception up to December 21st, 2021. REVIEW METHODS: Studies evaluating neurocognitive testing and hearing loss in children aged 21 years old or younger who had not undergone auditory rehabilitation were included in the study. Two independent reviewers evaluated titles, abstracts, and full texts for all included studies. RESULTS: The literature search yielded 3199 studies of which 431 studies underwent full-text screening. 21 studies were ultimately selected for inclusion and contained a total of 1716 pediatric patients assessed through 13 different validated tests of intelligence. Six studies included both hearing impaired (HI) and normal hearing (NH) patients, and IQ testing results. CONCLUSION: The results of this large systematic review demonstrate that hearing impaired children may perform lower than their age-matched normal hearing peers on IQ testing across a battery of IQ testing modalities.

Development of webcam-collected and artificial-intelligence-derived social and cognitive performance measures for neurodevelopmental genetic syndromes.

This study focused on the development and initial psychometric evaluation of a set of online, webcam-collected, and artificial intelligence-derived patient performance measures for neurodevelopmental genetic syndromes (NDGS). Initial testing and qualitative input was used to develop four stimulus paradigms capturing social and cognitive processes, including social attention, receptive vocabulary, processing speed, and single-word reading. The paradigms were administered to a sample of 375 participants, including 163 with NDGS, 56 with idiopathic neurodevelopmental disability (NDD), and 156 neurotypical controls. Twelve measures were created from the four stimulus paradigms. Valid completion rates varied from 87 to 100% across measures, with lower but adequate completion rates in participants with intellectual disability. Adequate to excellent internal consistency reliability (α = 0.67 to 0.95) was observed across measures. Test-retest reproducibility at 1-month follow-up and stability at 4-month follow-up was fair to good (r = 0.40-0.73) for 8 of the 12 measures. All gaze-based measures showed evidence of convergent and discriminant validity with parent-report measures of other cognitive and behavioral constructs. Comparisons across NDGS groups revealed distinct patterns of social and cognitive functioning, including people with PTEN mutations showing a less impaired overall pattern and people with SYNGAP1 mutations showing more attentional, processing speed, and social processing difficulties relative to people with NFIX mutations. Webcam-collected performance measures appear to be a reliable and potentially useful method for objective characterization and monitoring of social and cognitive processes in NDGS and idiopathic NDD. Additional validation work, including more detailed convergent and discriminant validity analyses and examination of sensitivity to change, is needed to replicate and extend these observations.

Attention-deficit/hyperactivity disorder in children with hearing loss.

OBJECTIVE: To evaluate rates of Attention-Deficit/Hyperactivity Disorder (AD/HD) diagnosis among pediatric patients with normal hearing (NH) and hearing loss (HL) with and without comorbidities. STUDY DESIGN: Retrospective cohort study of NH and HL patients following chart review of all pediatric patients with a history of tympanostomy tube placement treated at the Cleveland Clinic Foundation between 2019 and 2022. METHODS: Patient demographic information, hearing status (type of HL, laterality, severity), and comorbidities including prematurity, genetic syndromes, disorders with neurological impairment, and autism spectrum disorder (ASD) were collected. Rate of AD/HD amongst HL and NH cohorts with and without comorbidities were compared using Fisher's exact test. Covariate-adjusted analysis was also completed (sex, current age, age at tube placement, and OSA). The primary outcome of interest was rates of AD/HD among children with NH and HL, and the secondary outcome of interest was the impact of comorbidities on rates of AD/HD diagnosis in these cohorts. RESULTS: Of the 919 screened patients between 2019 and 2022, there were 778 NH patients and 141 HL patients (80 bilateral, 61 unilateral). HL ranged from mild (n = 110) to moderate (n = 21) to severe/profound (n = 9). Overall, the rate of AD/HD was significantly higher in HL children (12.1% HL vs 3.6% NH, p < 0.001). Of the 919 patients, 157 had comorbidities. In children without comorbidities, HL children still had significantly higher rates of AD/HD compared to NH children (8.0% vs 1.9%, p = 0.02), but there was loss of significance after covariate adjustment (p = 0.72). CONCLUSION: The rate of AD/HD among children with HL (12.1%) is higher than the rate of AD/HD in NH children (3.6%), consistent with previous findings. After excluding patients with comorbidities and adjusting for covariates, there are similar rates of AD/HD between HL and NH patients. Given high rates of comorbidities and AD/HD in HL patients and potential for augmented developmental challenges, clinicians should have a low threshold to refer children with HL for neurocognitive testing, particularly those with any of the comorbidities or covariates described in this study.

Development of informant-report neurobehavioral survey scales for PTEN hamartoma tumor syndrome and related neurodevelopmental genetic syndromes.

There are few well-validated measures that are appropriate for assessing the full range of neurobehavioral presentations in PTEN hamartoma tumor syndrome (PHTS) and other neurodevelopmental genetic syndromes (NDGS). As potential therapeutics are developed, having reliable, valid, free, and easily accessible measures to track a range of neurobehavioral domains will be crucial for future clinical trials. This study focused on the development and initial psychometric evaluation of a set of freely available informant-report survey scales for PHTS-the Neurobehavioral Evaluation Tool (NET). Concept elicitation, quantitative ratings, and cognitive interviewing processes were conducted with stakeholders and clinician-scientist experts, used to identify the most important neurobehavioral domains for this population, and to ensure items were appropriate for the full range of individuals with PHTS. Results of this process identified a PHTS neurobehavioral impact model with 11 domains. The final NET scales assessing these domains were administered to a sample of 384 participants (median completion time = 20.6 min), including 32 people with PHTS, 141 with other NDGS, 47 with idiopathic neurodevelopmental disorder (NDD), and 164 neurotypical controls. Initial psychometric results for the total scores of each scale indicated very good model (ω = 0.83-0.99) and internal consistency reliability (α = 0.82-0.98) as well as excellent test-retest reproducibility at 1-month follow-up (r = 0.78-0.98) and stability at 4-month follow-up (r = 0.76-0.96). Conditional reliability estimates indicated very strong measurement precision in key score ranges for assessing PHTS and other people with NDGS and/or idiopathic NDD. Comparisons across domains between PHTS and the other groups revealed specific patterns of symptoms and functioning, including lower levels of challenging behavior and more developed daily living and executive functioning skills relative to other NDGS. The NET appears to be a reliable and potentially useful tool for clinical characterization and monitoring of neurobehavioral symptoms in PHTS and may also have utility in the assessment of other NDGS and idiopathic NDD. Additional validation work, including convergent and discriminant validity analyses, are needed to replicate and extend these observations.

Characterization and Prediction of Short-term Outcomes in Memory After Temporal Lobe Resection in Children With Epilepsy.

BACKGROUND AND OBJECTIVES: The aim of this study was to characterize short-term outcomes in episodic memory, as assessed by the Children's Memory Scale (CMS), after temporal lobe resection in children with epilepsy using empirical methods for assessing cognitive change (i.e., reliable change indices [RCI] and standardized regression-based change scores [SRB]) and develop and internally validate clinically applicable models to predict postoperative memory decline. METHODS: This retrospective cohort study included children aged 6-16 years who underwent resective epilepsy surgery that included the temporal lobe (temporal only: "temporal" and multilobar: "temporal plus") and who completed preoperative and postoperative neuropsychological assessments including the CMS. Change scores on the CMS delayed memory subtests (Faces, Stories, and Word Pairs) were classified as decline, no change, or improvement using epilepsy-specific RCI and SRB. Logistic regression models for predicting postoperative memory decline were developed and internally validated with bootstrapping. RESULTS: Of the 126 children included, most of them demonstrated either no significant change (54%-69%) or improvement (8%-14%) in memory performance using RCI on individual measures at a median of 7 months after surgery. A subset of children (23%-33%) showed postoperative declines. Change distributions obtained using RCI and SRB were not statistically significantly different from each other. Preoperative memory test score, surgery side, surgery extent, and preoperative full-scale IQ were predictors of memory decline. Prediction models for memory decline included subsets of these variables with bias-corrected concordance statistics ranging from 0.70 to 0.75. The models were well calibrated although slightly overestimated the probability of verbal memory decline in high-risk patients. DISCUSSION: This study used empiric methodology to characterize memory outcome in children after temporal lobe resection. Provided online calculator and nomograms may be used by clinicians to estimate the risk of postoperative memory decline for individual patients before surgery.

Longitudinal neurobehavioral profiles in children and young adults with PTEN hamartoma tumor syndrome and reliable methods for assessing neurobehavioral change.

BACKGROUND: Individuals with PTEN hamartoma tumor syndrome (PHTS) demonstrate a distinct neurobehavioral profile suggesting primary disruption of frontal lobe symptoms, with more severe cognitive deficits in those with associated autism spectrum disorder (ASD) that extend to other areas of neurobehavioral function as well (e.g., adaptive behavior, sensory deficits). The current study sought to characterize longitudinal neurobehavioral profiles in individuals with PHTS who completed serial assessments (2-3 evaluations) over a 2-year time period. METHODS: Comprehensive neurobehavioral evaluations were conducted on 92 participants (age range 6-21) with PHTS and/or ASD. Spaghetti plots and linear mixed effects models were used to visualize the individual patient profiles and group trends and examine the group differences in cognitive/behavioral test scores over time. Practice-adjusted reliable change indices (RCIs) and standardized regression-based change scores (SRBs) were calculated for those measures in the battery with adequate sample sizes and test-retest reliabilities for future use in assessing neurobehavioral change in children and young adults with PHTS. RESULTS: Wide individual differences were observed at baseline across all measures. Encouragingly, baseline differences between patient groups persisted at the same magnitude over a 2-year time period with no differences in longitudinal neurobehavioral profiles within any one group. Test-retest reliabilities were generally high, ranging from 0.62 to 0.97, and group mean change from baseline to 12 months was small (range - 3.8 to 3.7). A Microsoft Excel calculator was created that clinicians and researchers can use to automatically calculate RCI and SRB thresholds at both 80% and 90% confidence intervals using test scores from a given child or young adult with PHTS. CONCLUSIONS: Our results suggest that the neurobehavioral phenotypes observed in individuals with PHTS remain relatively stable over time, even in those with ASD. The RCIs and SRBs provided can be used in future research to examine patient outcomes at the individual level as well as to detect negative deviations from the expected trajectory that can be used to inform intervention strategies.

Mother knows best or does she? Perceptions of the memory abilities of pediatric patients with epilepsy as reported by patients and their parents across time.

PURPOSE: This study compared the self-reported and parent-reported memory of children with epilepsy across time and explored the relationships between these measures of subjective memory and the children's actual performance on objective neuropsychological tests. METHOD: One-hundred and nineteen children with epilepsy who were surgical candidates underwent comprehensive neuropsychological testing that included the Everyday Verbal Memory Questionnaire (EVMQ). Each child's parent and 82 of the children themselves completed the appropriate version of this subjective memory measure. After 9 months, the children returned for a second neuropsychological evaluation with 71 parents and 39 children completing the same questionnaire. Approximately one-third of the children in the study underwent surgery between the two evaluations. Standardized regression-based norms were used to quantify change in cognitive abilities across assessments. RESULTS: Results revealed significant relationships between parent reports and child reports of the children's memory abilities. Parent reports, but not child reports, correlated with the children's objective test scores at baseline. In contrast, children were more attuned to changes in their memory across time. CONCLUSIONS: These findings demonstrate the importance of considering both parent and child perceptions of everyday cognitive functioning when evaluating cognition and cognitive changes over time in pediatric patients with epilepsy.

Cognitive outcomes following pediatric epilepsy surgery.

OBJECTIVES: To characterize outcomes following pediatric epilepsy surgery across a broad range of cognitive domains using empirical methods (i.e., reliable change indices: RCIs), compare these outcomes with those based on traditional methods (i.e., standard deviation: SD), and identify factors associated with postoperative cognitive declines and/or improvements. METHODS: This retrospective cohort study included 186 children who underwent surgical resection for treatment of pharmacoresistant epilepsy and who completed pre- and postoperative neuropsychological assessments. Postoperative testing occurred approximately 6.5 months after surgery and included measures of intelligence, attention/working memory, processing speed, language, executive functioning, visuospatial skills, memory, and academic achievement. Change scores for each patient were classified as decline, no change, or improvement using epilepsy-specific RCIs. Chi-square goodness of fit tests were used to compare the distribution of outcomes as classified with RCIs to those obtained using a traditional one SD cutoff. Multinomial regression analyses were conducted to identify factors associated with cognitive decline and/or improvement. RESULTS: While 18% of children demonstrated no postoperative declines or improvements in any cognitive domain, the majority demonstrated relatively focal changes (declines and/or improvements in 1-2 cognitive domains). Rates of postoperative decline and improvement across individual cognitive domains were variable and ranged from 4-35% and 2-31%, respectively. Compared to RCIs, SD methodology often overestimated postoperative improvements and varied with respect to declines. Factors associated with RCI decline or improvement included preoperative performance, age at surgery, surgery site, and postoperative seizures. SIGNIFICANCE: Results suggest substantial variability in individual cognitive outcomes approximately 6.5 months following pediatric epilepsy surgery. The differences in change distributions obtained using epilepsy-specific RCIs versus SDs highlight the need for studies using empiric methodology to study postoperative cognitive change. Variables associated with postoperative cognitive change may be used to develop multivariable prediction models in future studies to aid clinical decision-making and patient counseling.

Brief Report: Role of Parent-Reported Executive Functioning and Anxiety in Insistence on Sameness in Individuals with Germline PTEN Mutations.

This study aimed to characterize the relationship between insistence on sameness (IS), executive functioning (EF) and anxiety among individuals with PTEN mutations and individuals with macrocephalic ASD. The sample included 38 individuals with PTEN mutation and ASD diagnosis (PTEN-ASD; Mage = 8.93 years, SDage = 4.75), 23 with PTEN mutation without ASD (PTEN-no ASD; Mage = 8.94 years; SDage = 4.85) and 25 with ASD and macrocephaly but with no PTEN mutation (Macro-ASD; Mage = 11.99 years; SDage = 5.15). The final model accounted for 45.7% of variance in IS, with Set-Shifting EF subdomain as a unique independent predictor (t = 4.12, p < 0.001). This investigation provides the first preliminary evidence for the EF-anxiety-IS interrelationship in individuals with PTEN mutations and with macrocephalic ASD.

Psychiatric Characteristics Across Individuals With PTEN Mutations.

Germline heterozygous PTEN mutations have been associated with high prevalence of autism spectrum disorder (ASD) and elevated rates and severity of broadly defined behavioral problems. However, limited progress has been made toward understanding whether PTEN mutation is associated with specific psychiatric co-morbidity profiles when compared to idiopathic ASD. The current study aimed to utilize a cross-measure approach to compare concurrent psychiatric characteristics across children and adolescents with PTEN mutation with (PTEN-ASD; n = 38) and without ASD (PTEN-No ASD; n = 23), and ASD with macrocephaly but no PTEN mutation (macro-ASD; n = 25) using the Child Behavior Checklist (CBCL) and the Aberrant Behavior Checklist (ABC). There were significant group effects for the CBCL Internalizing and Externalizing broad symptom score, the majority of specific CBCL syndrome scores, and all ABC subscale scores. Post-hoc comparisons revealed greater behavioral symptoms in the ASD groups (PTEN-ASD and macro-ASD) compared to the PTEN-no ASD group on nearly all subtest scores examined. There were no statistically significant differences between the PTEN-ASD and macro-ASD groups; however, there was a trend for the macro-ASD group showing higher levels of aggressive behaviors. Our findings provide evidence of specific behavior profiles across PTEN-No ASD, PTEN-ASD, and macro-ASD groups and highlight the importance of early identification of behavioral vulnerabilities in individuals with PTEN mutations in order to provide access to appropriate evidence-based interventions.

Cognitive outcomes following frontal lobe resection for treatment of epilepsy in children and adolescents.

OBJECTIVE: To use reliable change indices (RCIs) developed specifically for pediatric patients with epilepsy to examine cognitive outcomes after frontal lobe resection for pharmacoresistant epilepsy. METHODS: Forty-one pediatric patients (25 male, Mage = 10 years) completed comprehensive neuropsychological evaluations before and an average of 6.5 months after frontal lobe resections for treatment of epilepsy. Evaluations included tests of intelligence, attention/working memory, processing speed, language, visuospatial skills, executive function, and episodic memory. Practice effect-adjusted RCIs were used to determine clinically significant postoperative cognitive change. Demographic, disease, and surgical variables were examined to identify factors associated with postoperative cognitive decline or improvement. RESULTS: Within each cognitive domain, there was a large proportion of patients (51-84%) who did not exhibit significant cognitive change. In terms of overall cognitive profile, 44% demonstrated improvement in at least one domain and 69% declined in at least one domain. Postoperative cognitive improvement occurred most commonly in the domain of processing speed, whereas postoperative cognitive decline occurred most frequently in the domain of visuospatial skills. Younger age at surgery was associated with cognitive improvement. Older age at seizure onset and higher baseline cognitive performance were associated with cognitive decline. SIGNIFICANCE: Approximately 6.5 months after frontal lobe resection, only 15% of our sample showed stable performance across all cognitive domains. Seventeen percent of patients showed improvements without declines, 42% showed declines without improvements, and 27% showed a mix of improvements and declines across different cognitive domains. Age and baseline abilities were associated with postoperative cognitive change on multiple measures. With 1 in 8 children demonstrating postoperative decline across three or more domains, further research is needed to identify factors associated with cognitive decline in order to inform clinical decision-making and patient/family counseling.

Toward better characterization of restricted and repetitive behaviors in individuals with germline heterozygous PTEN mutations.

This study aimed to further our understanding of restricted and repetitive behaviors (RRB) among individuals with germline pathogenic mutations in PTEN by providing multimethod characterization and comparison of key RRB subdomains across individuals with PTEN mutations with autism spectrum disorder (ASD) (PTEN-ASD), with PTEN mutations without ASD (PTEN-No ASD) and with ASD and macrocephaly but without PTEN mutations (Macro-ASD). Of 86 total research participants, 38 had PTEN-ASD (Mage  = 8.93 years, SDage  = 4.75), 25 Macro-ASD (Mage  = 11.99 years; SDage  = 5.15), and 23 PTEN-No ASD (Mage  = 8.94 years; SDage  = 4.85). The Repetitive Behavior Scale-Revised (RBS-R) and the Autism Diagnostic Interview-Revised (ADI-R) were used as measures of distinct RRB domains. There were significant group differences in the RBS-R repetitive motor behaviors (RMB; F = 4.52, p = 0.014, ω2  = 0.08), insistence on sameness (IS; F = 4.11, p = 0.02, ω2  = 0.05), and circumscribed interests (CI; F = 7.80, p = 0.001, ω2  = 0.14) scales. Post hoc comparisons showed that the PTEN-No ASD group had significantly lower RMB, IS, and CI scores compared to both PTEN-ASD and Macro-ASD groups. Importantly, PTEN-No ASD group still showed elevated RRB levels. Furthermore, there was a portion of individuals in PTEN-No ASD group whose Full-Scale Intelligence Quotient (FSIQ) was >70 that did not show floor level scores in the RMB domain. After adjusting for age and FSIQ scores, group differences were no longer statistically significant. RMB, IS, and CI domains showed distinct association patterns with sex, age, and FSIQ. This investigation provides the largest and most comprehensive characterization of distinct RRB domains in individuals with PTEN mutations to date. Despite the limitations, our findings have important assessment and treatment implications.

A randomized double-blind controlled trial of everolimus in individuals with PTEN mutations: Study design and statistical considerations.

This randomized, double-blind controlled trial of everolimus in individuals with germline phosphatase and tensin homolog mutations (PTEN) was designed to evaluate the safety of everolimus compared with placebo and to evaluate the efficacy of everolimus on neurocognition and behavior compared to placebo as measured by standardized neurocognitive and motor measures as well as behavioral questionnaires. The safety profile of everolimus is characterized by manageable adverse events that are generally reversible and non-cumulative. The primary safety endpoint of this study was drop-out rate due to side effects, comparing everolimus versus placebo. We also sought to determine the frequency of adverse events by type and severity. The main efficacy endpoint was a neurocognitive composite computed in two ways: 1) an average for working memory, processing speed, and fine motor subtests; and 2) the same average as above except weighted 2/3, and an additional average based on all other available neurocognitive testing measures assessing the additional domains of nonverbal ability, visuomotor skills, verbal learning, and receptive and expressive language, weighted 1/3. Secondary efficacy endpoints examined the effect of everolimus on overall global clinical improvement, autism symptoms, behavioral problems, and adaptive abilities as measured by validated, standardized instruments. We predicted that the rate of adverse events would be no more than 10% higher in the everolimus group compared to placebo, and overall severity of side effects would be minimal. We also expected that individuals receiving everolimus would show more improvement, relative to those taking placebo, on the composite neurocognitive index.

Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism.

BACKGROUND: PTEN is a well-established risk gene for autism spectrum disorder (ASD). Yet, little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). The primary aim of the present study was to examine group differences in peripheral blood-derived PTEN pathway protein levels between PTEN-ASD, PTEN no-ASD, and idiopathic macrocephalic ASD patients (macro-ASD). Secondarily, associations between protein levels and neurobehavioral functions were examined in the full cohort. METHODS: Patients were recruited at four tertiary medical centers. Peripheral blood-derived protein levels from canonical PTEN pathways (PI3K/AKT and MAPK/ERK) were analyzed using Western blot analyses blinded to genotype and ASD status. Neurobehavioral measures included standardized assessments of global cognitive ability and multiple neurobehavioral domains. Analysis of variance models examined group differences in demographic, neurobehavioral, and protein measures. Bivariate correlations, structural models, and statistical learning procedures estimated associations between molecular and neurobehavioral variables. To complement patient data, Western blots for downstream proteins were generated to evaluate canonical PTEN pathways in the PTEN-m3m4 mouse model. RESULTS: Participants included 61 patients (25 PTEN-ASD, 16 PTEN no-ASD, and 20 macro-ASD). Decreased PTEN and S6 were observed in both PTEN mutation groups. Reductions in MnSOD and increases in P-S6 were observed in ASD groups. Elevated neural P-AKT/AKT and P-S6/S6 from PTEN murine models parallel our patient observations. Patient PTEN and AKT levels were independently associated with global cognitive ability, and p27 expression was associated with frontal sub-cortical functions. As a group, molecular measures added significant predictive value to several neurobehavioral domains over and above PTEN mutation status. LIMITATIONS: Sample sizes were small, precluding within-group analyses. Protein and neurobehavioral data were limited to a single evaluation. A small number of patients were excluded with invalid protein data, and cognitively impaired patients had missing data on some assessments. CONCLUSIONS: Several canonical PTEN pathway molecules appear to influence the presence of ASD and modify neurobehavioral function in PTEN mutation patients. Protein assays of the PTEN pathway may be useful for predicting neurobehavioral outcomes in PTEN patients. Future longitudinal analyses are needed to replicate these findings and evaluate within-group relationships between protein and neurobehavioral measures. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02461446.

Neurobehavioral phenotype of autism spectrum disorder associated with germline heterozygous mutations in PTEN.

Germline mutations in PTEN, the gene that encodes phosphatase and tensin homolog, have been identified in up to 20% of children with autism spectrum disorder (ASD) and macrocephaly and are associated with marked abnormalities in the white matter of the brain. This study sought to characterize the neurobehavioral phenotype of PTEN-ASD. Comprehensive neurobehavioral evaluations were conducted in 36 participants (ages 3-21 years) with PTEN-ASD and compared to two groups of controls: non-syndromic ASD with macrocephaly (Macro-ASD, n = 25) and those with PTEN mutations without ASD (PTEN-no ASD, n = 23). Linear regression analysis or Kruskal-Wallis tests were used to examine group differences on neurobehavioral measures (cognitive, behavioral, sensory, and adaptive functioning) and, for select measures, one-sample t-tests were used to compare group performance to healthy control norms. These analyses revealed a distinct neuropsychological profile associated with mutations in PTEN suggesting primary disruption of frontal lobe systems (i.e., attention, impulsivity, reaction time, processing speed, and motor coordination). Cognitive deficits in PTEN-ASD are more severe than those in PTEN-no ASD and extend to other areas of neurobehavioral function, specifically, adaptive behavior and sensory deficits. While core ASD symptoms are similar in PTEN-ASD and Macro-ASD, PTEN-ASD had lower clinical ratings of autism severity and showed more sensory abnormalities suggestive of less sensory responsiveness. Together, these results suggest that PTEN-ASD has a distinct neurobehavioral phenotype compared to idiopathic ASD that is likely to warrant special consideration for overall assessment and treatment.

Noninvasive identification of seizure lateralization in children: Name that thing.

OBJECTIVE: With this prospective, observational study, we aimed to determine whether noninvasive language tasks, developed specifically for children, could reliably identify the hemisphere of seizure onset in pediatric epilepsy. METHODS: Seventy-eight children with unilateral epilepsy (44 left), aged 6-15 years (mean age = 11.8, SD = 2.6), completed the Children's Auditory Naming and Visual Naming Tests, the Boston Naming Test, and other verbal and nonverbal tasks. Multivariate analysis of variance was used to compare test performance between left and right hemisphere epilepsy groups, and χ2 analyses and odds ratios were used to examine classification of left vs right hemisphere epilepsy for individual patients based on test performance. RESULTS: Group comparisons revealed poorer auditory naming in children with left hemisphere epilepsy (p = 0.02), yet no significant differences on measures of visual naming, general intelligence, or other cognitive functions. Moreover, χ2 analyses using auditory naming cutoff scores to define intact vs impaired performance correctly classified seizure laterality in a significant proportion of children (p = 0.004). The odds of left hemisphere epilepsy were 4.2 times higher (95% confidence interval 1.4-11.7) than the odds of right hemisphere epilepsy with poor auditory naming performance. In the subset of patients with temporal lobe epilepsy (TLE), the odds of left TLE were 11.3 times higher (95% confidence interval 2.00-63.17) than the odds of right TLE with poor auditory naming performance. CONCLUSION: Contrary to previous findings, naming performance can lateralize hemisphere of seizure onset in children with epilepsy, thereby assisting in the preoperative workup for pediatric epilepsy surgery.

Effects of surgical side and site on mood and behavior outcome in children with pharmacoresistant epilepsy.

Children with epilepsy have a high rate of mood and behavior problems; yet few studies consider the emotional and behavioral impact of surgery. No study to date has been sufficiently powered to investigate effects of both side (left/right) and site (temporal/frontal) of surgery. One hundred patients (aged 6-16) and their families completed measures of depression, anxiety, and behavioral function as part of neuropsychological evaluations before and after surgery for pharmacoresistant epilepsy. Among children who had left-sided surgeries (frontal = 16; temporal = 38), there were significant interactions between time (pre to post-operative neuropsychological assessment) and resection site (frontal/temporal) on anhedonia, social anxiety, and withdrawn/depressed scales. Patients with frontal lobe epilepsy (FLE) endorsed greater pre-surgical anhedonia and social anxiety than patients with temporal lobe epilepsy (TLE) with scores normalizing following surgery. While scores on the withdrawn/depressed scale were similar between groups before surgery, the FLE group showed greater symptom improvement after surgery. In children who underwent right-sided surgeries (FLE = 20; TLE = 26), main effects of time (patients in both groups improved) and resection site (caregivers of FLE patients endorsed greater symptoms than those with TLE) were observed primarily on behavior scales. Individual data revealed that a greater proportion of children with left FLE demonstrated clinically significant improvements in anhedonia, social anxiety, and aggressive behavior than children with TLE. This is the first study to demonstrate differential effects of both side and site of surgery in children with epilepsy at group and individual levels. Results suggest that children with FLE have greater emotional and behavioral dysfunction before surgery, but show marked improvement after surgery. Overall, most children had good emotional and behavioral outcomes, with most scores remaining stable or improving.

Seizure-free and neuropsychological outcomes after temporal lobectomy with amygdalohippocampectomy in pediatric patients with hippocampal sclerosis.

OBJECT: Temporal lobe epilepsy is an uncommon clinical syndrome in the pediatric population. The most common underlying pathologies include low-grade gliomas, cortical dysplasia, and, less commonly, hippocampal sclerosis (HS). There is a paucity of data on neuropsychological and seizure-free outcomes in these patients after temporal lobectomy. In this study, the authors reviewed their seizure-free and neuropsychological outcomes after temporal lobectomy for pediatric HS. METHODS: The authors retrospectively reviewed the medical records of pediatric patients with HS who underwent anterior temporal lobectomy and amygdalohippocampectomy between 1998 and 2011 at the Cleveland Clinic. Results of neuropsychological assessment before and after surgery and seizure-free outcome at last follow-up were obtained. RESULTS: Forty-five patients met the inclusion criteria. Thirty-four (76%) patients had pathology of HS alone and 10 (22%) had HS and cortical dysplasia. The mean duration of follow-up was 60.2 months. Eighty-four percent of patients had postoperative Engel Class I or II outcomes. Neuropsychological outcomes remained unchanged or minimally improved postoperatively. CONCLUSIONS: Seizure-free outcomes in pediatric HS are similar to historical rates in adult HS. Neuropsychological assessments remain stable after temporal lobectomy. Standard temporal lobectomy should be considered in pediatric patients with medically intractable epilepsy secondary to HS.

Epilepsy surgery in children with electrical status epilepticus in sleep.

OBJECTIVE: Pediatric epilepsy surgery candidates with unilateral congenital or early-acquired brain lesions may present with refractory seizures and generalized electroencephalographic features such as electrical status epilepticus in sleep (ESES). The purpose of our study was to review the clinical presentation, neuroimaging findings, and outcome in a series of children with unilateral brain lesions and ESES undergoing resective surgery for refractory epilepsy. METHODS: A total of 415 consecutive patients younger than 18 years of age undergoing video electroencephalographic evaluation and epilepsy surgery at Cleveland Clinic were reviewed for ESES, an underlying pathological lesion, and outcome after surgery. RESULTS: Eight patients were included. All patients presented with medically refractory epilepsy, hemiparesis, and developmental delay. The pathogenesis was perinatal infarction in 7 patients and malformation of cortical development in 1 patient. Preoperative electroencephalography demonstrated generalized interictal spikes, electroencephalographic seizures, and ESES in all cases. Age at the time of surgery ranged from 3 to 14 years. Six patients underwent hemispherectomy, and 2 patients underwent focal resection. Six patients became seizure-free after resection. Two patients with functional hemispherectomy continued to have rare seizures, but were much improved. These patients also had perinatal infarctions in the hemisphere contralateral to the resection, possibly indicating a less beneficial outcome. Postoperative electroencephalography demonstrated resolution of generalized interictal discharges and ESES in all. Formal pre- and postoperative neuropsychological testing showed overall improvement of age-equivalent scores. CONCLUSION: Children with unilateral brain lesions and seizures may become seizure-free after epilepsy surgery, even if the preoperative electroencephalogram shows generalized ESES. The lesion occurring early in life and the location of the lesion may play a role in the development of ESES. Cognitive impairment may be aggravated by the persistence of ESES. Preliminary developmental data in this small sample suggest that termination of seizures and possibly of ESES by epilepsy surgery may have developmental benefits.