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Epilepsy incidence and prevalence peaks in older adults yet systematic studies of brain ageing and cognition in older adults with epilepsy remain limited. Here, we characterize patterns of cortical atrophy and cognitive impairment in 73 older adults with temporal lobe epilepsy (>55 years) and compare these patterns to those observed in 70 healthy controls and 79 patients with amnestic mild cognitive impairment, the prodromal stage of Alzheimer's disease. Patients with temporal lobe epilepsy were recruited from four tertiary epilepsy surgical centres; amnestic mild cognitive impairment and control subjects were obtained from the Alzheimer's Disease Neuroimaging Initiative database. Whole brain and region of interest analyses were conducted between patient groups and controls, as well as between temporal lobe epilepsy patients with early-onset (age of onset <50 years) and late-onset (>50 years) seizures. Older adults with temporal lobe epilepsy demonstrated a similar pattern and magnitude of medial temporal lobe atrophy to amnestic mild cognitive impairment. Region of interest analyses revealed pronounced medial temporal lobe thinning in both patient groups in bilateral entorhinal, temporal pole, and fusiform regions (all P < 0.05). Patients with temporal lobe epilepsy demonstrated thinner left entorhinal cortex compared to amnestic mild cognitive impairment (P = 0.02). Patients with late-onset temporal lobe epilepsy had a more consistent pattern of cortical thinning than patients with early-onset epilepsy, demonstrating decreased cortical thickness extending into the bilateral fusiform (both P < 0.01). Both temporal lobe epilepsy and amnestic mild cognitive impairment groups showed significant memory and language impairment relative to healthy control subjects. However, despite similar performances in language and memory encoding, patients with amnestic mild cognitive impairment demonstrated poorer delayed memory performances relative to both early and late-onset temporal lobe epilepsy. Medial temporal lobe atrophy and cognitive impairment overlap between older adults with temporal lobe epilepsy and amnestic mild cognitive impairment highlights the risks of growing old with epilepsy. Concerns regarding accelerated ageing and Alzheimer's disease co-morbidity in older adults with temporal lobe epilepsy suggests an urgent need for translational research aimed at identifying common mechanisms and/or targeting symptoms shared across a broad neurological disease spectrum., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., Competing Interests: Authors declare no conflict of interest., (© 2021 The Author(s).)

Objective: To characterize the nature and prevalence of cognitive disorders in older adults with temporal lobe epilepsy (TLE) and compare their cognitive profiles to patients with amnestic mild cognitive impairment (ie, aMCI)., Methods: Seventy-one older patients with TLE, 77 aMCI, and 69 normal aging controls (NACs), all 55-80 years of age, completed neuropsychological measures of memory, language, executive function, and processing speed. An actuarial neuropsychological method designed to diagnose MCI was applied to individual patients to identify older adults with TLE who met diagnostic criteria for MCI (TLE-MCI). A linear classifier was performed to evaluate how well the diagnostic criteria differentiated patients with TLE-MCI from aMCI. In TLE, the contribution of epilepsy-related and vascular risk factors to cognitive impairment was evaluated using multiple regression., Results: Forty-three TLE patients (60%) met criteria for TLE-MCI, demonstrating marked deficits in both memory and language. When patients were analyzed according to age at seizure onset, 63% of those with an early onset (<50 years) versus 56% of those with late onset (≥ 50 years) met criteria for TLE-MCI. A classification model between TLE-MCI and aMCI correctly classified 81.1% (90.6% specificity, 61.3% sensitivity) of the cohort based on neuropsychological scores. Whereas TLE-MCI showed greater deficits in language relative to aMCI, patients with aMCI showed greater rapid forgetting on memory measures. Both epilepsy-related risk factors and the presence of leukoaraiosis on MRI contributed to impairment profiles in TLE-MCI., Significance: Cognitive impairment is a common comorbidity in epilepsy and it presents in a substantial number of older adults with TLE. Although the underlying etiologies are unknown in many patients, the TLE-MCI phenotype may be secondary to an accumulation of epilepsy and vascular risk factors, signal the onset of a neurodegenerative disease, or represent a combination of factors., (© 2020 International League Against Epilepsy.)

Objective: To develop a model to predict the probability of mood decline in adults following temporal lobe resection for the treatment of pharmacoresistant epilepsy., Methods: Variable selection was performed on 492 patients from the Cleveland Clinic using best subsets regression. After completing variable selection, a subset of variables was requested from four epilepsy surgery centers across North America (n = 100). All data were combined to develop a final model to predict postoperative mood decline (N = 592). Internal validation with bootstrap resampling was performed. A clinically significant increase in depressive symptoms was defined as a 15% increase in Beck Depression Inventory-Second Edition score and a postoperative raw score > 11., Results: Fourteen percent of patients in the Cleveland Clinic cohort and 22% of patients in the external cohort experienced clinically significant increases in depressive symptoms following surgery. The final prediction model included six predictor variables: psychiatric history, resection side, relationship status, verbal fluency score, age at preoperative testing, and presence/absence of malformation of cortical development on magnetic resonance imaging. The model had an optimism-adjusted c-statistic of .70 and good calibration, with slight probability overestimation in higher risk patients., Significance: Clinicians can utilize our nomogram via a paper tool or online calculator to estimate the risk of postoperative mood decline for individual patients prior to temporal lobe epilepsy surgery., (© 2021 International League Against Epilepsy.)

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.

Focal epilepsy (FE) is clinically highly heterogeneous. It has been shown recently that not only rare but also a subset of common genetic variants confer risk for FE. The relatively modest power of genetic studies in FE suggests a high genetic heterogeneity of FE when grouped as one disorder. We hypothesize that the clinical heterogeneity of FE is correlated with genetic heterogeneity on a common risk variant level. To test the hypothesis, we used an FE polygenic risk score "FE-PRS" that combines small effect sizes of thousands of common variants from the largest FE-GWAS (genome-wide association study) into a single measure. We grouped 414 individuals with FE according to common clinical features into subgroups, either by one feature at a time or by all features combined in a cluster analysis. We examined their association with FE-PRS compared to 20 435 matched population controls and observed heterogeneous FE-PRS burden among the subgroups. The highest phenotypic variance explained by FE-PRS was identified in a cluster analysis-defined FE subgroup where all individuals had unknown etiologies and psychiatric comorbidities, and the majority had early onset seizures. Our results indicate that genetic factors associated with FE have differential burden among FE subtypes. Future studies using better-powered FE-PRS might have clinical utility., (© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To characterize seizure and cognitive outcomes of sparing vs removing an magnetic resonance imaging (MRI)-normal hippocampus in patients with temporal lobe epilepsy., Methods: In this retrospective cohort study, we reviewed clinical, imaging, surgical, and histopathological data on 152 individuals with temporal lobe epilepsy and nonlesional hippocampi categorized into hippocampus-spared (n = 74) or hippocampus-resected (n = 78). Extra-hippocampal lesions were allowed. Pre- and postoperative cognitive data were available on 86 patients. Predictors of seizure and cognitive outcomes were identified using Cox-proportional hazard modeling followed by treatment-specific model reduction according to Akaike information criterion, and built into an online risk calculator., Results: Seizures recurred in 40% within one postoperative year, and in 63% within six postoperative years. Male gender (P = .03), longer epilepsy duration (P < .01), normal MRI (P = .04), invasive evaluation (P = .02), and acute postoperative seizures (P < .01) were associated with a higher risk of recurrence. We found no significant difference in postoperative seizure freedom rates at 5 years between those whose hippocampus was spared and those whose hippocampus was resected (P = .17). Seizure outcome models built with pre- and postoperative data had bootstrap validated concordance indices of 0.65 and 0.72. The dominant hippocampus-spared group had lower rates of decline in verbal memory (39% vs 70%; P = .03) and naming (41% vs 79%; P = .01) compared to the hippocampus-resected group. Partial hippocampus sparing had the same risk of verbal memory decline as for complete removal., Significance: Sparing or removing an MRI-normal hippocampus yielded similar long-term seizure outcome. A more conservative approach, sparing the hippocampus, only partially shields patients from postoperative cognitive deficits. Risk calculators are provided to facilitate clinical counseling., (© 2020 International League Against Epilepsy.)

Epilepsy incidence and prevalence peaks in older adults, yet systematic studies of brain aging and epilepsy remain limited. We investigated topological network disruption in older adults with temporal lobe epilepsy (TLE; age > 55 years). Additionally, we examined the potential network disruption overlap between TLE and amnestic mild cognitive impairment (aMCI), the prodromal stage of Alzheimer disease. Measures of network integration ("global path efficiency") and segregation ("transitivity" and "modularity") were calculated from cortical thickness covariance from 73 TLE subjects, 79 aMCI subjects, and 70 healthy controls. Compared to controls, TLE patients demonstrated abnormal measures of segregation (increased transitivity and decreased modularity) and integration (decreased global path efficiency). aMCI patients also displayed increased transitivity and decreased global path efficiency, but these differences were less pronounced than in TLE. At the local level, TLE patients demonstrated decreased local path efficiency focused in the bilateral temporal lobes, whereas aMCI patients had a more frontal-parietal distribution. These results suggest that network disruption at the global and local level is present in both disorders, but global disruption may be a particularly salient feature in older adults with TLE. These findings motivate further research into whether these network changes have distinct cognitive correlates or are progressive in older adults with epilepsy., (© 2020 International League Against Epilepsy.)

Objective: Memory dysfunction is prevalent in many neurological disorders and can have a significant negative impact on quality of life. The genetic contributions to memory impairment in epilepsy, particularly temporal lobe epilepsy (TLE), remain poorly understood. Here, we compare the brain transcriptome between TLE patients with and without verbal memory impairments to identify genes and signaling networks important for episodic memory., Methods: Brain tissues were resected from 23 adults who underwent dominant temporal lobectomy for treatment of pharmacoresistant epilepsy. To control for potential effects of APOE on memory, only those homozygous for the APOE ε3 allele were included. A battery of memory tests was performed, and patients were stratified into two groups based on preoperative memory performance. The groups were well matched on demographic and disease-related variables. Total RNA-Seq and small RNA-Seq were performed on RNA extracted from the brain tissues. Pathway and integrative analyses were subsequently performed., Results: We identified 1092 differentially expressed transcripts (DETs), with the majority (71%) being underexpressed in brain tissues from patients with impaired memory compared to those from patients with intact memory. Enrichment analysis revealed overrepresentation of genes in pathways pertaining to brain-related neurological dysfunction, including a subset associated with neurodegenerative diseases, memory, and cognition (APP, MAPT, PINK1). Despite including patients with identical APOE genotypes, we identify APOE as a differentially expressed gene associated with memory status. Small RNA-Seq identified four differentially expressed microRNAs (miRNAs) that were predicted to target a subset (22%) of all DETs. Integrative analysis showed that these miRNA-predicted DET targets impact brain-related pathways and biological processes also pertinent to memory and cognition., Significance: TLE-associated memory status may be influenced by differences in gene expression profiles within the temporal lobe. Upstream processes influencing differential expression signatures, such as miRNAs, could serve as biomarkers and potential treatment targets for memory impairment in TLE., (© 2020 International League Against Epilepsy.)

Psychogenic nonepileptic seizures (PNES) are diagnosed in approximately 30% of patients referred to tertiary care epilepsy centers. Little is known about the molecular pathology of PNES, much less about possible underlying genetic factors. We generated whole-exome sequencing and whole-genome genotyping data to identify rare, pathogenic (P) or likely pathogenic (LP) variants in 102 individuals with PNES and 448 individuals with focal (FE) or generalized (GE) epilepsy. Variants were classified for all individuals based on the ACMG-AMP 2015 guidelines. For research purposes only, we considered genes associated with neurological or psychiatric disorders as candidate genes for PNES. We observe in this first genetic investigation of PNES that six (5.88%) individuals with PNES without coexistent epilepsy carry P/LP variants (deletions at 10q11.22-q11.23, 10q23.1-q23.2, distal 16p11.2, and 17p13.3, and nonsynonymous variants in NSD1 and GABRA5). Notably, the burden of P/LP variants among the individuals with PNES was similar and not significantly different to the burden observed in the individuals with FE (3.05%) or GE (1.82%) (PNES vs. FE vs. GE (3 × 2 χ 2 ), P = 0.30; PNES vs. epilepsy (2 × 2 χ 2 ), P = 0.14). The presence of variants in genes associated with monogenic forms of neurological and psychiatric disorders in individuals with PNES shows that genetic factors are likely to play a role in PNES or its comorbidities in a subset of individuals. Future large-scale genetic research studies are needed to further corroborate these interesting findings in PNES.

Objective: To define left temporal lobe regions where surgical resection produces a persistent postoperative decline in naming visual objects., Methods: Pre- and postoperative brain magnetic resonance imaging data and picture naming (Boston Naming Test) scores were obtained prospectively from 59 people with drug-resistant left temporal lobe epilepsy. All patients had left hemisphere language dominance at baseline and underwent surgical resection or ablation in the left temporal lobe. Postoperative naming assessment occurred approximately 7 months after surgery. Surgical lesions were mapped to a standard template, and the relationship between presence or absence of a lesion and the degree of naming decline was tested at each template voxel while controlling for effects of overall lesion size., Results: Patients declined by an average of 15% in their naming score, with wide variation across individuals. Decline was significantly related to damage in a cluster of voxels in the ventral temporal lobe, located mainly in the fusiform gyrus approximately 4-6 cm posterior to the temporal tip. Extent of damage to this region explained roughly 50% of the variance in outcome. Picture naming decline was not related to hippocampal or temporal pole damage., Significance: The results provide the first statistical map relating lesion location in left temporal lobe epilepsy surgery to picture naming decline, and they support previous observations of transient naming deficits from electrical stimulation in the basal temporal cortex. The critical lesion is relatively posterior and could be avoided in many patients undergoing left temporal lobe surgery for intractable epilepsy., (© 2020 International League Against Epilepsy.)

Objective: To identify cognitive phenotypes in temporal lobe epilepsy (TLE) and test their reproducibility in a large, multi-site cohort of patients using both data-driven and clinically driven approaches., Method: Four-hundred seven patients with TLE who underwent a comprehensive neuropsychological evaluation at one of four epilepsy centers were included. Scores on tests of verbal memory, naming, fluency, executive function, and psychomotor speed were converted into z-scores based on 151 healthy controls (HCs). For the data-driven method, cluster analysis (k-means) was used to determine the optimal number of clusters. For the clinically driven method, impairment was defined as >1.5 standard deviations below the mean of the HC, and patients were classified into groups based on the pattern of impairment., Results: Cluster analysis revealed a three-cluster solution characterized by (a) generalized impairment (29%), (b) language and memory impairment (28%), and (c) no impairment (43%). Based on the clinical criteria, the same broad categories were identified, but with a different distribution: (a) generalized impairment (37%), (b) language and memory impairment (30%), and (c) no impairment (33%). There was a 82.6% concordance rate with good agreement (κ = .716) between the methods. Forty-eight patients classified as having a normal profile based on cluster analysis were classified as having generalized impairment (n = 16) or an isolated language/memory impairment (n = 32) based on the clinical criteria. Patients with generalized impairment had a longer disease duration and patients with no impairment had more years of education. However, patients demonstrating the classic TLE profile (ie, language and memory impairment) were not more likely to have an earlier age at onset or mesial temporal sclerosis., Significance: We validate previous findings from single-site studies that have identified three unique cognitive phenotypes in TLE and offer a means of translating the patterns into a clinical diagnostic criteria, representing a novel taxonomy of neuropsychological status in TLE., (© 2020 International League Against Epilepsy.)

Numerous studies have shown that surgical resection of the left anterior temporal lobe (ATL) is associated with a decline in object naming ability (Hermann et al., 1999). In contrast, few studies have examined the effects of left ATL surgery on auditory description naming (ADN) or category-specific naming. Compared with object naming, which loads heavily on visual recognition processes, ADN provides a more specific measure of concept retrieval. The present study examined ADN declines in a large group of patients who were tested before and after left ATL surgery, using a 2 × 2 × 2 factorial manipulation of uniqueness (common vs. proper nouns), taxonomic category (living vs. nonliving things), and time (pre- vs. postsurgery). Significant declines occurred across all categories but were substantially larger for proper living (PL) concepts, i.e., famous individuals. The disproportionate decline in PL noun naming relative to other conditions is consistent with the notion that the left ATL is specialized not only for retrieval of unique entity concepts, but also plays a role in processing social concepts and person-specific features., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Epilepsy is clinically heterogeneous, and neurological or psychiatric comorbidities are frequently observed in patients. It has not been tested whether common risk variants for generalized or focal epilepsy are enriched in people with other disorders or traits related to brain or cognitive function. Here, we perform two brain-focused phenome association studies of polygenic risk scores (PRS) for generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) with all binary brain or cognitive function-related traits available for 334,310 European-ancestry individuals of the UK Biobank. Higher GE-PRS were associated with not having a college or university degree (P = 3.00x10-4), five neuroticism-related personality traits (P<2.51x10-4), and having ever smoked (P = 1.27x10-6). Higher FE-PRS were associated with several measures of low educational attainment (P<4.87x10-5), one neuroticism-related personality trait (P = 2.33x10-4), having ever smoked (P = 1.71x10-4), and having experienced events of anxiety or depression (P = 2.83x10-4). GE- and FE-PRS had the same direction of effect for each of the associated traits. Genetic factors associated with GE or FE showed similar patterns of correlation with genetic factors associated with cortical morphology in a subset of the UKB with 16,612 individuals and T1 magnetic resonance imaging data. In summary, our results suggest that genetic factors associated with epilepsies may confer risk for other neurological and psychiatric disorders in a population sample not enriched for epilepsy., Competing Interests: The authors have declared that no competing interests exist.

Pharmacoresistance is a major clinical challenge for approximately 30% of patients with epilepsy. Previous studies indicate nuclear receptors (NRs), drug efflux transporters, and cytochrome P450 enzymes (CYPs) control drug passage across the blood-brain barrier (BBB) in drug-resistant epilepsy. Here, we (1) evaluate BBB changes, neurovascular nuclear receptors, and drug transporters in lesional/epileptic (EPI) and non-lesional/non-epileptic (NON-EPI) regions of the same brain, (2) examine regional CYP expression and activity, and (3) investigate the association among CYP brain expression, seizure frequency, duration of epilepsy, and antiepileptic drug (AED) combination. We used surgically resected brain specimens from patients with medically intractable epilepsy (n = 22) where the epileptogenic loci were well-characterized by invasive and non-invasive methods; histology confirmed distinction of small NON-EPI regions from EPI tissues. NRs, transporters, CYPs, and tight-junction proteins were assessed by western blots/immunohistochemistry, and CYP metabolic activity was determined and compared. The relationship of CYP expression with seizure frequency, duration of epilepsy, and prescribed AEDs was evaluated. Decreased BBB tight-junction proteins accompanied IgG leakage in EPI regions and correlated with upregulated NR and efflux transporter levels. CYP expression and activity significantly increased in EPI compared to NON-EPI tissues. Change in EPI and NON-EPI CYP3A4 expression increased in patients taking AEDs that were CYP substrates, was downregulated when CYP- and non-CYP-substrate AEDs were given together, and correlated with seizure frequency. Our studies suggest focal neurovascular CYP-NR-transporter alterations, as demonstrated by the relationship of seizure frequency and AED combination to brain CYP3A4, might together impact biotransformation machinery of human pharmacoresistant epilepsy.

Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10-15; Cleveland: P = 2.85×10-4; Finnish-ancestry Epi25: P = 1.80×10-4) or population controls (Epi25: P = 2.35×10-70; Cleveland: P = 1.43×10-7; Finnish-ancestry Epi25: P = 3.11×10-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10-19; Cleveland: P = 1.69×10-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10-15; Cleveland: P = 1.39×10-2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

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.

Objective: This retrospective, observational study investigated the relationship between objective naming decline and patient report of subjective decline in language functioning following epilepsy surgery. The role of depression in this relationship was also examined., Methods: A total of 429 adults with pharmacoresistant epilepsy completed the Boston Naming Test (BNT) and Memory Assessment Clinics Self-Rating Scale (MAC-S) before and after resective surgery. Multiple regression analyses were used to examine the relationship between objective naming decline and subjective language functioning, while controlling for the confounding effect of depression., Results: Individuals who experienced moderate to severe naming decline (≥11 raw points on BNT) following surgery reported a decline in subjective language functioning (p < .001) and endorsed problems with word-retrieval as well as more general semantic abilities. Those who experienced mild naming decline (5-10 raw points) also reported an increase in subjective language problems (p = .006). Complaints in this group were less severe than in those with more marked naming declines and were primarily related to word-retrieval. Both of these relationships remained significant after controlling for the confounding effect of depression (p < .005-.014)., Conclusions: Individuals with epilepsy who experience naming decline following surgery perceive these declines in their daily life, regardless of whether or not they are depressed. Findings support the utilization of risk models to predict naming outcome and the importance of counseling patients regarding the risk for naming decline following surgery., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: A subgroup of patients with Parkinson disease (PD) develops impulse control disorders (ICD) associated with their dopamine replacement therapy. Patients and their families may be reluctant to report ICD symptoms or unaware these symptoms are related to PD medication, which can make detecting an ICD difficult for clinicians. Ideally, a behavioral measure that is sensitive to ICD could be employed to ensure that patients with these behaviors are identified and treated. The Iowa Gambling Task (IGT), a standardized decision-making task, has proven sensitive in other populations with impulse control problems. We hypothesized that the IGT would differentiate between PD patients with and without ICD., Methods: We compared IGT performance and disease variables in 24 PD patients with ICD and 24 PD patients without ICD. Patient groups were matched in terms of age, sex, and duration of PD., Results: There were no significant differences in IGT scores between PD groups. IGT performance declined with increasing age, but the majority of patients performed within normal limits based on published age- and education-corrected normative data., Conclusions: The IGT did not distinguish between PD patients with and without ICD. Increasing age negatively impacted performance in both groups. Other studies have found that IGT performance may decline in normal aging. Our results suggest that the IGT lacks the sensitivity and specificity needed to differentiate between age-related deficits and disruption in frontal-subcortical circuits underlying ICD associated with PD medications. Therefore, the IGT is not an appropriate behavioral measure for ICD in PD patients., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The objective of this study was to determine whether three common genetic polymorphisms [apolipoprotein (APOE) ε4 (rs42938 and rs7412), brain derived neurotrophic factor (BDNF) Met (rs6265), and catechol-O-methyltransferase (COMT) Val (rs4680)] are associated with increased psychiatric symptomatology in individuals with pharmacoresistant epilepsy., Methods: One hundred forty-eight adults (M age  = 38 years; 53% female) with refractory epilepsy completed self-report measures of mood, anxiety, and/or personality/psychopathology. Mann-Whitney U, t-tests, and Fisher's exact tests were used to determine if APOE4, BDNF Val66Met, or COMT Val158Met are associated with increased psychiatric symptomatology in people with epilepsy., Results: As a group, BDNF Met carriers reported greater symptoms of depression on the Personality Assessment Inventory (PAI) than those without a Met allele (p = 0.004); COMT Val carriers reported greater symptoms on the PAI Schizophrenia (p = 0.007), Antisocial Features (p = 0.04), and Alcohol Problems (p = 0.03) scales than noncarriers. On the individual level, a significantly greater proportion of BDNF Met carriers demonstrated elevated PAI Depression scores compared to those without a Met allele (p = 0.046). There was also a larger proportion of COMT Val carriers with elevated PAI Anxiety scores as compared to those without a Val allele (p = 0.036)., Significance: This retrospective cross-sectional study provides preliminary evidence for a genetic basis of psychiatric comorbidities in epilepsy and suggests that BDNF and COMT may play an important role in the pathophysiology of mental health problems in this vulnerable population., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To examine the convergent and discriminant validity of two brief computerized episodic memory measures in a large, diverse clinical sample of adults undergoing neuropsychological assessment., Method: Computerized measures of word and face memory were administered to 233 adults (age 30 and over) who also completed comprehensive neuropsychological testing., Results: Moderate correlations were observed between the computerized memory tests and a wide range of traditional neuropsychological measures of episodic memory (e.g. word-list learning, story recall, face recognition, design recall). Select measures of visuomotor processing speed and language were also related to performance on the computerized tasks. In contrast, the computerized memory tests showed weak correlations with tests in other cognitive domains (i.e. visuospatial skills, attention/working memory, executive function, motor dexterity, academic skills) and self-report screening measures of mood and anxiety. Similar to traditional measures of episodic memory, the computerized memory measures were sensitive to effects of age and gender., Conclusions: Computerized measures of word and face memory showed good convergent and discriminant validity in this diverse clinical sample supporting the construct validity of these measures. This indicates that it may be feasible to measure memory function in clinical settings using brief, well-designed computerized memory measures.

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 χ 2 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, χ 2 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., (© 2018 American Academy of Neurology.)

Objective: To develop and externally validate models to predict the probability of postoperative naming decline in adults following temporal lobe epilepsy surgery using easily accessible preoperative clinical predictors., Methods: In this retrospective, prediction model development study, multivariable models were developed in a cohort of 719 patients who underwent temporal lobe epilepsy surgery at Cleveland Clinic and externally validated in a cohort of 138 patients who underwent temporal lobe surgery at one of 3 epilepsy surgery centers in the United States (Columbia University Medical Center, Emory University School of Medicine, University of Washington School of Medicine)., Results: The development cohort was 54% female with an average age at surgery of 36 years (SD 12). Twenty-six percent of this cohort experienced clinically relevant postoperative naming decline. The model included 5 variables: side of surgery, age at epilepsy onset, age at surgery, sex, and education. When applied to the external validation cohort, the model performed very well, with excellent calibration and a c statistic (reflecting discriminatory ability) of 0.81. A second model predicting moderate to severe postoperative naming decline included 3 variables: side of surgery, age at epilepsy onset, and preoperative naming score. This model generated a c statistic of 0.84 in the external validation cohort and showed good calibration., Conclusion: Externally validated nomograms are provided in 2 easy-to-use formats (paper version and online calculator) clinicians can use to estimate the probability of naming decline in patients considering epilepsy surgery for treatment of pharmacoresistant temporal lobe epilepsy., (© 2018 American Academy of Neurology.)

Objectives: Depression is common in epilepsy, with rates ranging from 20 to 55% in most samples and reports as high as 70% in patients with intractable epilepsy. However, some contend that depression may be over- and/or under-reported and treated in this population. This may be due to the use of common self-report depression measures that fail to take into account the overlap of disease and depressive symptoms and also the host of side effects associated with antiepileptic medication, which may also be construed as depression., Methods: The present study examined the utility of common self-report depression measures and those designed specifically for the medically ill, including a proposed new measure, to determine which may be more appropriate for use among people with epilepsy., Results: We found that common self-report depression measures are useful for screening depression in epilepsy, particularly with a raised cutoff for one, with sensitivities ranging from .91 to .96. A measure designed for the medically ill obtained the greatest specificity of .91, suggesting its use as a diagnostic tool with a slightly raised cutoff. The positive likelihood ratio of this latter measure was 8.76 with an overall classification accuracy of 88%., Conclusions: Assessment of depression in epilepsy can be improved when utilizing self-report measures that better differentiate disease symptoms from neurovegetative symptoms of depression (e.g. fatigue, sleep disturbance). This was demonstrated in the present study. Clinical implications are discussed.

Objective: Subjective cognitive complaints are a frequent concern of patients with epilepsy. The Aldenkamp-Baker Neuropsychological Assessment Schedule (ABNAS) is a patient-reported scale validated to measure adverse cognitive effects of antiepileptic drugs (AEDs). The goals of this study were to identify predictors of patient-reported cognitive dysfunction and to assess the relationship between subjective and objective cognitive impairment., Methods: The Cleveland Clinic Knowledge Program Data Registry was used to identify adult patients seen in outpatient epilepsy clinic from January to May 2015 and who completed the following scales: ABNAS for subjective cognitive impairment, Patient Health Questionnaire (PHQ-9) for depression, Generalized Anxiety Disorder 7-item (GAD-7) scale, Quality of Life in Epilepsy (QOLIE-10), and EuroQOL five dimensions questionnaire (EQ-5D) for health-related quality of life. Topiramate (TPM) was considered a high-risk medication for cognitive impairment. Patients were categorized into groups based on total ABNAS score: subjective cognitive impairment (ABNAS>15; N=270) and no subjective cognitive impairment (ABNAS≤15; N=400). Multivariable logistic regression models were constructed to identify independent predictors of subjective cognitive impairment. In a subset of patients who had neuropsychological testing within 6months of completing the ABNAS (N=60), Pearson correlations and multivariable logistic regression models, controlling for number of AEDs, depression, and anxiety, assessed the relationship between subjective cognitive impairment and objective cognitive performance on measures of intelligence, attention/working memory, verbal fluency, naming, processing speed, manual dexterity, visuomotor processing, and verbal memory., Results: Forty percent of patients in the overall sample (N=270/670) reported cognitive impairment. The variables most strongly associated with subjective cognitive impairment were PHQ-9 score, number of AEDs, and seizure frequency. In the subset of patients with neuropsychological testing, ABNAS score was correlated with anxiety (r=0.44), depression (r=0.38), and attention/working memory (r=-0.31). After adjusting for depression and anxiety, patients who endorsed subjective cognitive impairment scored significantly lower on measures of nonverbal intelligence and attention/working memory, but not on other cognitive measures., Conclusions: Subjective cognitive impairment as reported on the ABNAS is most strongly associated with depressive symptomatology, number of AEDs, and seizure frequency, but not with most objective cognitive measures. Identifying these three predictors provides a clear framework to understand and address subjective cognitive complaints in adult patients with epilepsy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: The International League Against Epilepsy (ILAE) proposed a classification system for hippocampal sclerosis (HS) based on location and extent of hippocampal neuron loss. The literature debates the usefulness of this classification system when studying memory in people with temporal lobe epilepsy (TLE) and determining memory outcome after temporal lobe resection (TLR). This study further explores the relationship between HS ILAE subtypes and episodic memory performance in patients with TLE and examines memory outcomes after TLR., Methods: This retrospective study identified 213 patients with TLE who underwent TLR and had histopathological evidence of HS (HS ILAE type 1a = 92; type 1b = 103; type 2 = 18). Patients completed the Wechsler Memory Scale-3rd Edition prior to surgery, and 78% of patients had postoperative scores available. Linear regressions examined differences in preoperative memory scores as a function of pathology classification, controlling for potential confounders. Fisher's exact tests were used to compare pathology subtypes on the magnitude of preoperative memory impairment and the proportion of patients who experienced clinically meaningful postoperative memory decline., Results: Individuals with HS ILAE type 2 demonstrated better preoperative verbal memory performance than patients with HS ILAE type 1; however, individual data revealed verbal and visual episodic memory impairments in many patients with HS ILAE type 2. The base rate of postoperative memory decline was similar among all 3 pathology groups., Significance: This is the largest reported overall sample and the largest subset of patients with HS ILAE type 2. Group data suggest that patients with HS ILAE type 2 perform better on preoperative memory measures, but individually there were no differences in the magnitude of memory impairment. Following surgery, there were no statistically significant differences between groups in the proportion of patients who declined. Future research should focus on quantitative measurements of hippocampal neuronal loss, and multicenter collaboration is encouraged., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Objective: To summarize the existing literature on resective epilepsy surgery (RES) in older adults (≥60 years old) and examine seizure and neuropsychological outcomes in a single-center large cohort of older adults undergoing RES and their comparison to a consecutive, younger (25- to45-year-old) adult population who underwent RES in routine clinical practice., Methods: First, a comprehensive literature review was performed. Then, we identified older adults who underwent RES at our center (2000-2015). Outcome analysis was performed on patients who had ≥1 year of clinical follow-up. A younger cohort of patients who underwent RES during the same period was selected for comparison. The 2 groups were compared with respect to demographic and disease variables as well as key clinical outcomes., Results: Seizure outcomes on 58 older patients were reported in existing literature; 72% achieved Engel class I outcome ≥1 year postoperatively. Sixty-four older adults underwent RES at our center, accounting for 2.8% of all RES during the study period. A total of 51 older adults (M age  = 65) among them had ≥1-year clinical follow-up; 80% achieved Engel I outcome after a mean follow-up of 3.2 years. This was comparable to the 68% Engel class I outcome among 50 consecutive younger adults, despite later age of onset, longer epilepsy duration, and more comorbidities (all p < 0.001) among older adults. The majority (86%) of older adults were referred to our center after years of suffering from drug-resistant epilepsy. There were no group differences in surgical complications. However, 1 older adult passed away post-RES. There was no difference in post-RES neuropsychological outcomes compared to younger adults, except significantly higher number of older adults showed a decline in confrontational naming., Significance: RES in well-selected older adults is a safe and effective therapy, and advanced age should not preclude consideration of surgical therapy in older adults with pharmacoresistant epilepsy.

This retrospective study examined the potential role of side and site of surgery in psychological symptom change after epilepsy surgery and determined the base rate of psychological change at the individual level. Two-hundred twenty-eight adults completed the Personality Assessment Inventory (PAI) before and after temporal (TLR; n=190) or frontal lobe resection (FLR; n=38). Repeated measures ANOVAs with bootstrapping examined differences in psychological outcome as a function of surgical site separately in patients who underwent left- versus right-sided resections. Individual's PAI score changes were then used to determine the prevalence of clinically meaningful postoperative symptom change. Following left-sided resections, there were significant group-by-time interactions on Somatic Complaints, Anxiety, and Anxiety Related Disorders. There was also a trend in this direction on the Depression scale. TLR patients endorsed greater preoperative symptoms than FLR patients on all of these scales, except the Somatic Complaints scale. After surgery, TLR patients reported symptom improvement on all four scales, while scores of FLR patients remained relatively stable over time. Endorsement of Mania-related symptoms increased in both TLR and FLR groups from pre-to post-surgical testing. Following right-sided resections, both groups endorsed symptom improvements on Somatic Complaints, Anxiety, and Depression scales following surgery. In addition, the TLR group endorsed more Mania-related symptoms than the FLR group regardless of time. Patterns of meaningful change in individual patients were generally consistent with group findings, with the most frequent improvements observed following TLR. However, there were a small subset of patients who reported symptom exacerbation after surgery. Our results suggest that surgical lateralization and localization are important factors in postoperative psychological outcome and highlight the importance of considering psychological change at the individual patient level. Further research is needed to identify potential risk factors for symptom exacerbation to aid in preoperative counseling and identify those patients most in need of postoperative psychological surveillance., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: This retrospective cohort study characterized cognitive and motor outcomes in a large sample of adults who underwent frontal lobe resections for treatment of pharmacoresistant epilepsy., Methods: Ninety patients who underwent unilateral frontal lobe resection for epilepsy (42 language-dominant hemisphere/48 nondominant hemisphere) between 1989 and 2014 completed comprehensive preoperative and postoperative neuropsychological evaluations that included measures of verbal and nonverbal intellectual functioning, attention/working memory, processing speed, language, executive functioning, verbal and visual memory, and motor functioning. Objective methods were used to assess meaningful change across a wide range of abilities and to identify factors associated with neuropsychological decline following frontal lobectomy. Detailed postoperative neuroimaging analysis was conducted to characterize region, extent, and volume of resection., Results: Forty-eight percent of patients did not demonstrate meaningful postoperative declines in cognition and an additional 42% demonstrated decline in 1 or 2 cognitive domains. When cognitive decline was observed, it usually occurred on measures of intelligence, visuomotor processing speed, or executive functioning. Side and site of resection were unrelated to cognitive outcome, but played a role in decline of contralateral manual dexterity following supplementary motor area resection. Higher preoperative ability, older age at surgery, absence of a malformation of cortical development on MRI, and poor seizure outcome were related to cognitive decline on some measures, but had poor sensitivity in identifying at-risk patients., Conclusions: The vast majority of patients who undergo frontal lobectomy for treatment of pharmacoresistant epilepsy demonstrate good cognitive and motor outcomes., (© 2017 American Academy of Neurology.)

Objective: This retrospective, observational study examined the frequency and magnitude of change in naming ability as a function of side/site of epilepsy surgery and identified predictive factors to assist clinicians in identifying patients at low, moderate, or high risk of postoperative naming decline., Methods: A total of 875 adults with pharmacoresistant epilepsy (454 left/421 right; 763 temporal/87 frontal/25 posterior quadrant) met inclusion criteria and completed the Boston Naming Test before and after surgery. Clinically meaningful change in naming ability was assessed using reliable change indices for epilepsy. Demographic, cognitive, and seizure variables were examined to determine factors most predictive of naming decline and to develop a decision tree to assist with clinical decision-making., Results: Naming decline was rare in right-sided resections and did not exceed the level expected by chance (5% overall; 90% confidence interval [CI] ± 2%). Naming decline occurred in 41% (CI ± 5%) of patients after left temporal resection (TLR) compared to 10%-12% (CI ± 10%-19%) in other left-sided surgical groups. A sizable proportion of left TLR patients (17%; CI ± 4%) showed substantial declines in naming (>11 points). Decline following left TLR was related to later age at seizure onset, older age at surgery, and higher preoperative naming ability. These factors correctly predicted naming decline in 68% of patients and were associated with degree of decline following left TLR. A decision tree is provided to assist clinicians in identifying patients at low, moderate, or high risk for postoperative naming declines., Conclusions: In addition to discussions regarding risk for memory decline following left TLR, patients should be counseled about potential decline in word-finding ability., (© 2016 American Academy of Neurology.)

Objectives: The objective of this cohort study was to compare neuropsychological outcomes following left temporal lobe resection (TLR) in patients with epilepsy who had or had not undergone prior invasive monitoring., Methods: Data were obtained from an institutional review board-approved, neuropsychology registry for patients who underwent epilepsy surgery at Cleveland Clinic between 1997 and 2013. A total of 176 patients (45 with and 131 without invasive EEG) met inclusion criteria. Primary outcome measures were verbal memory and language scores. Other cognitive outcomes were also examined. Outcomes were assessed using difference in scores from before to after surgery and by presence/absence of clinically meaningful decline using reliable change indices (RCIs). Effect of invasive EEG on cognitive outcomes was estimated using weighting and propensity score adjustment to account for differences in baseline characteristics. Linear and logistic regression models compared surgical groups on all cognitive outcomes., Results: Patients with invasive monitoring showed greater declines in confrontation naming; however, when RCIs were used to assess clinically meaningful change, there was no significant treatment effect on naming performance. No difference in verbal memory was observed, regardless of how the outcome was measured. In secondary outcomes, patients with invasive monitoring showed greater declines in working memory, which were no longer apparent using RCIs to define change. There were no outcome differences on other cognitive measures., Conclusions: Results suggest that invasive EEG monitoring conducted prior to left TLR is not associated with greater cognitive morbidity than left TLR alone. This information is important when counseling patients regarding cognitive risks associated with this elective surgery., (© 2015 American Academy of Neurology.)

Background: Presence of dementia is a contraindication for DBS treatment of Parkinson's disease. Recent evidence suggests that borderline cognitive function, as measured with a common screening measure, the Mattis Dementia Rating Scale, has a negative impact on quality of life (QoL) after DBS of the STN., Methods: We attempted to replicate and extend this finding in a larger group of patients with a wider range of preoperative global cognitive performance., Results: Our data indicate that performance on the screening measure is not associated with QoL or medical outcomes, even with scores well below the cutoff for identifying dementia., Conclusions: This cognitive screening measure lacks sufficient sensitivity to warrant its use in predicting which patients will show QoL benefit from DBS., (© 2015 International Parkinson and Movement Disorder Society.)

Reliable change indices (RCIs) and standardized regression-based (SRB) change score norms permit evaluation of meaningful changes in test scores following treatment interventions, like epilepsy surgery, while accounting for test-retest reliability, practice effects, score fluctuations due to error, and relevant clinical and demographic factors. Although these methods are frequently used to assess cognitive change after epilepsy surgery in adults, they have not been widely applied to examine cognitive change in children with epilepsy. The goal of the current study was to develop RCIs and SRB change score norms for use in children with epilepsy. Sixty-three children with epilepsy (age range: 6-16; M=10.19, SD=2.58) underwent comprehensive neuropsychological evaluations at two time points an average of 12 months apart. Practice effect-adjusted RCIs and SRB change score norms were calculated for all cognitive measures in the battery. Practice effects were quite variable across the neuropsychological measures, with the greatest differences observed among older children, particularly on the Children's Memory Scale and Wisconsin Card Sorting Test. There was also notable variability in test-retest reliabilities across measures in the battery, with coefficients ranging from 0.14 to 0.92. Reliable change indices and SRB change score norms for use in assessing meaningful cognitive change in children following epilepsy surgery are provided for measures with reliability coefficients above 0.50. This is the first study to provide RCIs and SRB change score norms for a comprehensive neuropsychological battery based on a large sample of children with epilepsy. Tables to aid in evaluating cognitive changes in children who have undergone epilepsy surgery are provided for clinical use. An Excel sheet to perform all relevant calculations is also available to interested clinicians or researchers., (Copyright © 2015 Elsevier Inc. All rights reserved.)

With the completion of the Human Genome Project and the advent of more advanced sequencing platforms capable of high throughput genotyping at reduced cost, research on the genetics/genomics of cognition has expanded rapidly over the past several decades. This has been facilitated even further by global consortia including HapMap, 1000 Genomes Project, ENCODE, and others, which have made information regarding genetic variation and genomic functional elements readily available to all researchers. Thus, the goal of this Targeted Review is not to provide an exhaustive review of the existing literature on the role of genetic factors in cognition. Rather, we will highlight some of the most consistent findings in this field, review the research in epilepsy to date, and provide a background within which to set forth unique opportunities epilepsy may provide to further elucidate the role of genetics in cognition., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: This study aimed to assess the accuracy and operating characteristics of the Patient Health Questionnaire-9 (PHQ-9) for depression screening in adults with epilepsy., Methods: Tertiary epilepsy center patients served as the study population, with 237 agreeing to structured interview using the Mini-International Neuropsychiatric Interview (MINI), a "gold standard" instrument developed for rapid diagnosis of neuropsychiatric disorders, including major depressive disorder (MDD); 172 also completed the PHQ-9, and 127 completed both the PHQ-9 and the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) within two days of the MINI. Sensitivity, specificity, positive and negative predictive values, and areas under the ROC curves for each instrument were determined. Cut-points of 10 for the PHQ-9 and 15 for the NDDI-E were used, and ratings at or above the cut-points were considered screen-positive. The PHQ-9 was divided into cognitive/affective (PHQ-9/CA) and somatic (PHQ-9/S) subscales to determine comparative depression screening accuracy., Results: The calculated areas under the ROC curves for the PHQ-9 (n=172) and the PHQ-9/CA and PHQ-9/S subscales were 0.914, 0.924, and 0.846, respectively, with the PHQ-9 more accurate than the PHQ-9/S (p=0.002) but not different from the PHQ-9/CA (p=0.378). At cut-points of 10 and 15, respectively, the PHQ-9 had higher sensitivity (0.92 vs 0.87) but lower specificity (0.74 vs 0.89) compared with the NDDI-E. The areas under the ROC curves of the PHQ-9 and the NDDI-E showed similar accuracy (n=127; 0.930 vs 0.934; p=0.864)., Significance: The PHQ-9 is an efficient and nonproprietary depression screening instrument with excellent accuracy validated for use in adult patients with epilepsy as well as multiple other medical populations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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.

Objective: Misleading manifestations of common epilepsy syndromes might account for some epilepsy surgery failures, thus we sought to characterize patients with difficult to diagnose (atypical) mesial temporal lobe epilepsy (mTLE)., Methods: We retrospectively reviewed our surgical database over 12 years to identify patients who underwent a standard anterior temporal lobectomy after undergoing intracranial EEG (ICEEG) evaluation with a combination of depth and subdural electrodes. We carefully studied electroclinical manifestations, neuroimaging data, neuropsychological findings, and indications for ICEEG., Results: Of 835 patients who underwent anterior temporal lobectomy, 55 were investigated with ICEEG. Ten of these had atypical mTLE features and were not considered to have mTLE preoperatively. All of them had Engel class I outcome for 3 to 7 years (median 3.85). Five reported uncommon auras, and 3 had no auras. Scalp-EEG and nuclear imaging studies failed to provide adequate localization. None had MRI evidence of hippocampal sclerosis. However, ICEEG demonstrated exclusive mesial temporal seizure onset in all patients. Clues suggesting the possibility of mTLE were typical auras when present, anterior temporal epileptiform discharges or ictal patterns, small hippocampi, asymmetrical or ipsilateral temporal hypometabolism on PET, anterior temporal hyperperfusion on ictal SPECT, and asymmetry of memory scores. Histopathology revealed hippocampal sclerosis in 6 patients and gliosis in 2., Conclusions: Atypical electroclinical presentation may be deceptive in some patients with mTLE. We emphasize the importance of searching for typical mTLE features to guide ICEEG study of mesial temporal structures in such patients, who may otherwise mistakenly undergo extramesial temporal resections or be denied surgery.

Candidates for epilepsy surgery often use the word "hope" to express their attitudes and beliefs about surgery. However, studies suggest that hope has a multiplicity of meanings that are not well understood. The goal of this analysis was to evaluate whether Candidates for epilepsy surgery use hope language to express a traditional, expected optimism during presurgery interviews. We examined patients' uses of the word "hope" and its derivatives (hoping, hopeful, hopefully) through a secondary analysis of 37 interviews of adult patients prior to epilepsy surgery. Approximately 1/3 of all hope statements were coded as expressions of optimism, while 1/3 were not optimistic, and 1/3 had unclear meanings. In addition to traditionally optimistic uses of the term, other themes surrounding use of this word included ideas of dread, worry, uncertainty, and temporizing language. This information may help clinicians communicate more effectively with patients, enhancing the informed consent process for epilepsy surgery., (© 2013.)

The objective of this retrospective study was to determine if dual pathology [DUAL - focal cortical dysplasia (FCD) and mesial temporal sclerosis (MTS)] in patients with left temporal lobe epilepsy is associated with greater risk for cognitive decline following temporal lobectomy than single pathology (MTS only). Sixty-three adults (Mage=36.5years, female: 52.4%) who underwent left anterior temporal lobectomy for treatment of epilepsy (MTS=28; DUAL=35) completed preoperative and postoperative neuropsychological evaluations. The base rate of dual pathology was 55.5%. Repeated measures ANOVAs yielded significant 2-way interactions (group×time) on most measures of language and memory with generally moderate effect sizes. Specifically, patients with MTS only demonstrated postoperative declines, while those with dual pathology remained unchanged or improved. Results suggest that dual pathology may be associated with better cognitive outcome following epilepsy surgery than MTS alone, possibly reflecting limited functionality of the resected tissue or intrahemispheric reorganization of function in the context of a developmental lesion., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: We sought to characterize cognition in individuals with germline PTEN mutations (n = 23) as well as in PTEN mutation-negative individuals with classic Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (n = 2)., Methods: Twenty-five individuals completed a comprehensive neuropsychological evaluation. One sample t-tests and effect sizes were used to examine differences in participant test scores compared with normal controls. Composite scores were created for each patient within each of the cognitive domains assessed and classified as above average, average, or below average according to normative standards. χ(2) analyses compared these classifications to expected proportions in normal control samples., Results: The mean intelligence quotient was in the average range, and the range of intellectual functioning was very wide (from extremely low to very superior). However, in a large subset of patients, scores were lower than expected on measures of motor functioning, executive functioning, and memory recall, suggesting disruption of frontal circuits in these participants., Conclusion: This is the first study to characterize cognition in individuals with PTEN mutations and associated syndromes using a comprehensive neuropsychological battery. Contrary to previous reports suggesting an association with intellectual disability, the mean intelligence quotient was average, and there was a broad range of intellectual abilities. Specific evidence of disruption of frontal circuits may have implications for treatment compliance and cancer surveillance, and further investigation is warranted.

Executive dysfunction occurs in a variety of patients who have sustained damage to the frontal lobes. In individuals with frontal lobe epilepsy (FLE) or after unilateral frontal lobe resection (FLR), a unique neuropsychological profile linking executive functions (EF) with the frontal lobe has been elusive, with conflicting findings in the literature. Some studies show greater risk of executive impairment with left-sided FLE or FLR, while others report greater risk for right-sided patients. Some studies report no relationship between FLE and EF impairment, while others show EF impairment regardless of side of seizure foci or surgery. In patients with temporal lobe epilepsy, executive dysfunction is associated with depressed mood possibly reflecting disruption of cortical-limbic pathways and/or frontal-striatal circuitry. Although not previously examined, depression level may affect executive functioning in those with FLE or FLR. We hypothesized that FLE patients with poor mood state would show greater executive dysfunction than FLE patients without poor mood state. The relationship among EF, side of surgery and depressed mood before and 8 months after unilateral FLR was evaluated in 64 patients using validated measures of EF and mood state (Beck Depression Inventory-II). Results indicated that individuals with depressed mood before surgery had greater difficulty on a task of mental flexibility compared to patients without preoperative depressed mood. Further, individuals with depressed mood before surgery had significant increases in perseverative responding and completed fewer categories on a card-sorting task after surgery compared to patients without preoperative depressed mood. Regression analyses showed that among side of surgery, seizure freedom status after surgery and depression status, only pre-surgical depression status explained a significant amount of variance in executive functioning performance after surgery. Results suggest that clinically elevated depressive symptoms before surgery are a risk factor for moderate declines in EF after surgery. Results may be attributable to reduced cognitive reserve in patients with depressive symptoms, or may reflect a common cause attributable to damage to unilateral dorsal and ventral lateral frontal lobe., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Few studies have focused on language changes following frontal lobe epilepsy (FLE) surgery. The aim of the current study is to quantify the role of resection location and size in verbal fluency decline after FLE surgery and to examine its predictors. A retrospective chart review identified 36 adult patients who underwent FLE surgery. Verbal fluency was assessed using the Controlled Oral Word Association Test (COWAT). Nine (25%) of the patients had significant decline. Binary logistic regression incorporating side of resection and preoperative COWAT score significantly predicted decline and accounted for 25% of the variance. A trend was also noted for decliners to have higher postoperative seizure recurrence (p=0.067). There was no effect of size of resection. Patients undergoing FLE surgery are at risk of verbal fluency decline, especially if they have a high presurgical verbal fluency score, undergo a frontal lobe resection in the language dominant hemisphere, and have poor seizure outcome., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Loring et al. (Journal of clinical and experimental neuropsychology, 2005:27;610–617) observed relationships between VSVT hard item performance and IQ and memory indices in epilepsy surgical candidates, with a potential confound of low FSIQ on VSVT performance. The present study replicated the Loring et al. study in a larger sample and extended their findings by examining the relationships among VSVT performance, FSIQ, and working memory. A total of 404 patients with medically intractable epilepsy completed a comprehensive neuropsychological assessment. Differences in WAIS-III and WMS-III performance were examined as a function of VSVT hard score categories as determined by Grote et al. (2000)--that is, valid, > 20/24; questionable, 18–20; or invalid, < 18. Quantile regression models were constructed to compare the strength of the relationship between FSIQ and VSVT at various points of the FSIQ distribution. Linear regression analyses examined working memory as a potential mediator between FSIQ and VSVT performance. The invalid group performed more poorly than the valid and questionable groups on multiple measures of intelligence and memory. The strength of the relationship between FSIQ and VSVT hard item performance decreased as FSIQ increased, and working memory mediated this relationship. Results suggest VSVT hard item scores may be impacted by working memory difficulties and/or low intellectual functioning.

This study sought to determine if word-finding difficulties (WFDs), which are common in adults with dominant temporal lobe epilepsy (TLE), are related to performance on verbal cognitive measures, including memory. One hundred six individuals with left TLE and pathologically confirmed mesial temporal sclerosis completed comprehensive preoperative neuropsychological evaluations. Patients were divided into two groups based on the degree of benefit received from phonemic cueing on a confrontation naming task. Cognitive performance was then compared between patients with greater and fewer WFDs. Patients with greater WFDs demonstrated poorer performance on many verbal cognitive measures compared to those with fewer WFDs. In contrast, there were no significant differences between groups on any of the nonverbal cognitive measures. Chi-square analyses indicated that below average verbal memory performance occurred at a significantly higher rate for patients with greater WFDs (42-46%) as compared to patients with fewer WFDs (18-24%). Results showed that WFDs confound performance on verbal cognitive measures in adult patients with left TLE, particularly on measures with high demands for lexical retrieval. This suggests that when patients have word-retrieval difficulties, measures of verbal memory and verbal intelligence may be underestimated and potentially lead to misinterpretation of test performance and misinformation regarding risk of declines after surgical resection., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Little is known about the effects of epilepsy surgery on memory in older adults. The purpose of this study was to determine if older adults exhibit greater memory decline than younger adults after anterior temporal lobectomy (ATL). Patients 55 years and older at time of surgery (23 left, 14 right ATL, range 55-66 years) were compared to patients age 25-35 years (44 left, 33 right ATL) to assess differences in preoperative to postoperative change in WMS-III index scores. Repeated-measures ANOVAs and ANCOVAs revealed that older patients did not demonstrate greater decline than younger patients across any of the memory indices. Rather, in the left ATL group, older patients showed less decline than younger patients on the Auditory Delayed Memory Index. Similarly, in the right ATL group, older patients showed less decline than younger patients on the Visual Delayed Memory Index. These patterns were also apparent in frequency of individual change. Results provide preliminary evidence that older adults who are good candidates for ATL are not at greater risk for memory decline when measured at 7 months postoperatively.

Resection of seizure foci is an effective treatment for the control of medically intractable epilepsy. However, cognitive morbidity can occur as a result of surgical intervention. This morbidity is dependent on several factors, including location and extent of resection, disease characteristics, patient demographic characteristics, and functional status of the tissue to be resected. In this review article, the authors provide a summary of the neurocognitive outcomes of epilepsy surgery with an emphasis on presurgical predictors of postsurgical cognitive decline.

This study examined pre-surgical depressed mood as a predictor of post-surgical memory change in adults who underwent temporal lobe resections (TLRs; n = 211). Patients completed the Wechsler Memory Scale-III and Beck Depression Inventory-Second Edition (BDI-II) before and after TLR (left = 110, right = 101) and were divided into two groups (clinically elevated depressive symptoms or not depressed) based on BDI-II score. Left-TLR patients with poorer pre-surgical mood had greater verbal memory declines after surgery compared with nondepressed left- or right-TLR patients and right-TLR patients with poor mood. Further, pre-surgical BDI-II score demonstrated incremental validity in predicting post-surgical memory change in left-TLR patients beyond pre-surgical memory scores. Differences in seizure outcome and post-surgical mood change could not account for memory decline. Results suggest that elevated pre-surgical depressive symptomatology is a risk factor for post-surgical memory decline and indicate that mood should be considered when advising patients about cognitive risks associated with temporal lobectomy. Results are discussed in terms of poor pre-surgical mood as an indicator of reduced cognitive reserve.

This study investigated the relationship between the apolipoprotein (APOE) ε4 allele and brain volumes in patients with medically intractable temporal lobe epilepsy (TLE). MRI-based volumetric analyses of the hippocampi, cerebral hemispheres, and whole brain were conducted in 59 patients with TLE (31 with left TLE, 28 with right TLE) with hippocampal sclerosis (HS). There were no differences in hippocampal, hemispheric, or whole brain volumes as a function of ε4 status even after correcting for hemispheric and total brain volumes. However, APOE ε4 carriers showed a trend toward having a smaller discrepancy between ipsilateral and contralateral hippocampal volumes than patients without this allele, and post hoc analyses suggest there may be an increased incidence of bilateral HS in ε4 carriers. In summary, APOE ε4 is not associated with significant hippocampal, hemispheric, or whole brain atrophy in patients with medically intractable TLE. However, ε4 carriers may be more likely to have bilateral HS, with an apparent dose-dependent effect., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To characterize the interaction between language dominance and lateralization of the epileptic focus for pre- and postoperative Boston Naming Test (BNT) performance in patients undergoing anterior temporal lobectomy (ATL)., Methods: Analysis of pre- and postoperative BNT scores depending on lateralization of language as measured by the intracarotid amobarbital procedure (IAP) versus lateralization of the temporal lobe epileptic focus., Results: Changes between pre- and postoperative BNT performance depended on epilepsy lateralization (effect size=0.189) with significant decrease in patients undergoing left ATL. Subgroup analysis in these showed that postoperative decline in BNT scores was significant in patients with atypical (n=14; p<0.05), but did not reach statistical significance in patients with left language dominance (n=36; p=0.09). Chi-square test revealed a trend of higher proportions of patients experiencing significant postsurgical deterioration in naming performance in atypical (57.1%) as compared to left language dominance (30.6%; p=0.082). Surgical failure was also associated with greater decline of BNT scores and was more common in atypical than in left language dominant patients (chi(2) (1, n=98)=4.62, p=0.032). Age of onset, duration of epilepsy, and seizure frequency had no impact on changes in BNT performance., Conclusion: Atypical language dominance is a predictor of change in visual naming performance after left ATL and may also impact postsurgical seizure control. This should be considered when counseling surgical candidates., (Copyright 2010 Elsevier Ltd. All rights reserved.)