Cross-cultural application of the international classification of cognitive disorders in epilepsy cognitive phenotypes in people with temporal lobe epilepsy in India.

OBJECTIVE: Efforts to understand the global variability in cognitive profiles in patients with epilepsy have been stymied by the lack of a standardized diagnostic system. This study examined the cross-cultural applicability of the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) in a cohort of patients with temporal lobe epilepsy (TLE) in India that was diverse in language, education, and cultural background. METHODS: A cohort of 548 adults with TLE from Mumbai completed a presurgical comprehensive neuropsychological evaluation. The IC-CoDE taxonomy was applied to derive cognitive phenotypes in the sample. Analyses of variance were conducted to examine differences in demographic and clinical characteristics across the phenotypes, and chi-squared tests were used to determine whether the phenotype distribution differed between the Mumbai sample and published data from a multicenter US sample. RESULTS: Using the IC-CoDE criteria, 47% of our cohort showed an intact cognitive profile, 31% a single-domain impairment, 16% a bidomain impairment, and 6% a generalized impairment profile. The distribution of cognitive phenotypes was similar between the Indian and US cohorts for the intact and bidomain phenotypes, but differed for the single and generalized domains. There was a larger proportion of patients with single-domain impairment in the Indian cohort and a larger proportion with generalized impairment in the US cohort. Among patients with single-domain impairment, a greater proportion exhibited memory impairment in the Indian cohort, whereas a greater proportion showed language impairment in the US sample, likely reflecting differences in language administration procedures and sample characteristics including a higher rate of mesial temporal sclerosis in the Indian sample. SIGNIFICANCE: Our results demonstrate the applicability of IC-CoDE in a group of culturally and linguistically diverse patients from India. This approach enhances our understanding of cognitive variability across cultures and enables harmonized and inclusive research into the neuropsychological aspects of epilepsy.

The genomic landscape across 474 surgically accessible epileptogenic human brain lesions.

Understanding the exact molecular mechanisms involved in the aetiology of epileptogenic pathologies with or without tumour activity is essential for improving treatment of drug-resistant focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (>350×) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants in low-grade epilepsy-associated tumours (7.92 ± 5.65 single-nucleotide variants) than in brain tissue from malformations of cortical development (6.11 ± 4 single-nucleotide variants) or hippocampal sclerosis (5.1 ± 3.04 single-nucleotide variants). Tumour tissues also had the largest number of likely pathogenic variant carrying cells. low-grade epilepsy-associated tumours had the highest proportion of samples with one or more somatic copy-number variants (24.7%), followed by malformations of cortical development (5.4%) and hippocampal sclerosis (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among low-grade epilepsy-associated tumours. For germline variant-associated malformations of cortical development genes such as TSC2, DEPDC5 and PTEN, germline single-nucleotide variants were frequently identified within large loss of heterozygosity regions, supporting the recently proposed 'second hit' disease mechanism in these genes. We detect somatic variants in 12 established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the aetiology of low-grade epilepsy-associated tumours (e.g. BRAF) and malformations of cortical development (e.g. SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with low-grade epilepsy-associated tumours and NRAS Q61 mutated protein with a complex malformation of cortical development characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21-q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical-genetic analyses showed that the numbers of somatic single-nucleotide variant across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with low-grade epilepsy-associated tumours. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening and guides future directions for clinical implementation of epilepsy surgery genetics.

Influence of psychological factors on the relationship between subjective and objective memory in adults with pharmacoresistant temporal lobe epilepsy.

PURPOSE: Many adults with temporal lobe epilepsy (TLE) report subjective cognitive impairment; however, prior studies have shown a discrepancy between these subjective complaints and objective cognitive deficits on neuropsychological measures. Mood disorders/symptoms are also common in TLE and have been linked to greater subjective cognitive difficulties. To further understand these relationships, this retrospective study sought to determine if symptoms of depression and anxiety moderate or mediate the relationship between subjective cognitive impairment and objective cognitive performance in adults with TLE. METHOD: Participants were 345 adults (mean age = 40.7; 55 % female) with pharmacoresistant TLE who completed self-report screening measures of depression, anxiety, and subjective cognitive function along with objective memory measures as part of a pre-surgical clinical neuropsychological evaluation. A series of linear regression analyses was conducted to examine the potential moderating and mediating effects of mood on the relationship between subjective and objective memory function after adjusting for relevant covariates. RESULTS: Consistent with existing literature, self-reported depression and anxiety symptoms were significantly correlated with subjective memory difficulties across all scales (all p < .001). Subjective memory impairment was also significantly correlated with objective memory performance on neuropsychological measures, albeit with small effect sizes (estimate range 0.04-0.20). Contrary to our hypothesis, depression and anxiety did not moderate or mediate the relationship between subjective memory complaints and objective memory performance. CONCLUSIONS: While symptoms of depression and anxiety were associated with subjective memory ability in this cohort of adults with TLE, this study suggests that mood symptoms do not fully explain the relationship between subjective and objective memory function, likely reflecting the complex and multifactorial relationships among these variables. Nevertheless, our results highlight the importance of screening for depression and anxiety symptoms and assessing patients' subjective memory complaints as part of a neuropsychological evaluation as each of these factors tap into a different aspect of the patient functioning.

Utility of automated memory measures in identifying cognitive impairment in adults with epilepsy.

OBJECTIVE: Cognitive impairment is prevalent in epilepsy and often presents at the time of initial diagnosis. This study sought to validate brief, self-administered, iPad-based recognition memory tasks in a sample of patients with epilepsy and to examine their screening utility in identifying patients with cognitive impairment. METHODS: The Words and Faces tests were administered to 145 adult patients with epilepsy along with a neuropsychological battery. Correlation analyses examined the convergent and divergent validity of the Words and Faces tests, and a series of logistic regression analyses examined discriminative ability in identifying patients with and without cognitive impairments on neuropsychological measures. Patient performance was compared to that of a healthy control group (n = 223), and the relationship between the Words and Faces test performance and disease-related variables (i.e., antiepileptic medication burden, seizure lateralization/localization) was examined. RESULTS: The Words and Faces tests were positively correlated with traditional paper-and-pencil neuropsychological measures of episodic memory, with generally moderate to large effect sizes (r > .40), while correlations between the Words and Faces tests and non-memory measures were generally small in magnitude (r < .30). Patients with epilepsy had significantly lower scores on Words and Faces tests compared to healthy controls, and performance was associated with antiepileptic medication burden and seizure localization. The Words and Faces tests demonstrated good predictive accuracy in identifying any cognitive impairment (concordance (c) statistic = .77) and excellent predictive accuracy (c = .85) in identifying patients with impairments on traditional memory measures. The Words and Faces tests also demonstrated reasonable discrimination for impairments in non-memory domains including executive function, language, attention, processing speed, and visuospatial ability (c = .62 -.70). Importantly, the Words and Faces Immediate Index performed just as well as the Total Score (which included delayed memory performance), suggesting a short version of this measure is sufficient for identifying patients with cognitive impairment. CONCLUSIONS: The Words and Faces tests are valid, computerized tools that can be used to screen for memory and other cognitive impairment in adults with epilepsy.

Polygenic burden and its association with baseline cognitive function and postoperative cognitive outcome in temporal lobe epilepsy.

OBJECTIVE: Demographic and disease factors are associated with cognitive deficits and postoperative cognitive declines in adults with pharmacoresistant temporal lobe epilepsy (TLE), but the role of genetic factors in cognition in TLE is not well understood. Polygenic scores (PGS) for neurological and neuropsychiatric disorders and IQ have been associated with cognition in patient and healthy populations. In this exploratory study, we examined the relationship between PGS for Alzheimer's disease (AD), depression, and IQ and cognitive outcomes in adults with TLE. METHODS: 202 adults with pharmacoresistant TLE had genotyping and completed neuropsychological evaluations as part of a presurgical work-up. A subset (n = 116) underwent temporal lobe resection and returned for postoperative cognitive testing. Logistic regression was used to determine if PGS for AD, depression, and IQ predicted baseline domain-specific cognitive function and cognitive phenotypes as well as postoperative language and memory decline. RESULTS: No significant findings survived correction for multiple comparisons. Prior to correction, higher PGS for AD and depression (i.e., increased genetic risk for the disorder), but lower PGS for IQ (i.e., decreased genetic likelihood of high IQ) appeared possibly associated with baseline cognitive impairment in TLE. In comparison, higher PGS for AD and IQ appeared as possible risk factors for cognitive decline following temporal lobectomy, while the possible relationship between PGS for depression and post-operative cognitive outcome was mixed. SIGNIFICANCE: We did not observe any relationships of large effect between PGS and cognitive function or postsurgical outcome; however, results highlight several promising trends in the data that warrant future investigation in larger samples better powered to detect small genetic effects.

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.

A proposed new taxonomy of cognitive phenotypes in multiple sclerosis: The International Classification of Cognitive Disorders in MS (IC-CoDiMS).

BACKGROUND: Characterization of cognitive impairment (CI) in multiple sclerosis into distinct phenotypes holds promise for individualized treatments and biomarker exploration. OBJECTIVE: Apply a previously validated, neuropsychologically driven diagnostic algorithm to identify a taxonomy of the type of cognitive phenotypes in multiple sclerosis. METHODS: An algorithm developed and validated in other neurological diseases was applied to a cohort of 1281 people with multiple sclerosis who underwent clinical neuropsychological evaluation across three multiple sclerosis centers. A domain was marked impaired if scores on two tests within the domain fell below one of the two thresholds of interest (compared to controls; -1.0 SD and -1.5 SD below the mean). Results were then tabulated for each participant to determine the type of impairments across the sample. RESULTS: At -1 SD threshold, 48.7% were intact, 21.6% had single-domain, 14.3% bi-domain, and 15.4% multi-domain impairment. At -1.5 SD threshold, 72.9% were intact, 14.0% had single-domain, 8.2% bi-domain, and 5.0% multi-domain impairment. Processing speed was the most frequent single-domain impairment, followed by executive function and memory. CONCLUSIONS: These findings advance the taxonomy of cognitive phenotypes in multiple sclerosis and clarify the type and distribution of possible cognitive diagnoses, pave the way for further investigation of associated biomarkers, and provide clinically meaningful information to guide individualized treatment and rehabilitation.

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.

Establishing the cross-cultural applicability of a harmonized approach to cognitive diagnostics in epilepsy: Initial results of the International Classification of Cognitive Disorders in Epilepsy in a Spanish-speaking sample.

OBJECTIVE: This study was undertaken to evaluate the cross-cultural application of the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) to a cohort of Spanish-speaking patients with temporal lobe epilepsy (TLE) living in the United States. METHODS: Eighty-four Spanish-speaking patients with TLE completed neuropsychological measures of memory, language, executive function, visuospatial functioning, and attention/processing speed as part of the Neuropsychological Screening Battery for Hispanics. The contribution of demographic and clinical variables to cognitive performance was evaluated. A sensitivity analysis was conducted by examining the base rates of impairment across several impairment thresholds. The IC-CoDE taxonomy was then applied, and the base rate of cognitive phenotypes for each cutoff was calculated. The distribution of phenotypes was compared to the published IC-CoDE taxonomy data, which utilized a large, multicenter cohort of English-speaking patients with TLE. RESULTS: Across the different impairment cutoffs, memory was the most impaired cognitive domain, with impairments in list learning ranging from 50% to 78%. Application of the IC-CoDE taxonomy utilizing a -1.5-SD cutoff revealed an intact cognitive profile in 47.6% of patients, single-domain impairment in 23.8% of patients, bidomain impairment in 14.3% of patients, and generalized impairment in 14.3% of the sample. This distribution was comparable to the phenotype distribution observed in the IC-CoDE validation sample. SIGNIFICANCE: We demonstrate a similar pattern and distribution of cognitive phenotypes in a Spanish-speaking epilepsy cohort compared to an English-speaking sample. This suggests stability in the underlying phenotypes associated with TLE and applicability of the IC-CoDE for guiding cognitive diagnostics in epilepsy research that can be applied to culturally and linguistically diverse samples.

The relationship between mood and anxiety and cognitive phenotypes in adults with pharmacoresistant temporal lobe epilepsy.

OBJECTIVE: Patients with temporal lobe epilepsy (TLE) are often at a high risk for cognitive and psychiatric comorbidities. Several cognitive phenotypes have been identified in TLE, but it is unclear how phenotypes relate to psychiatric comorbidities, such as anxiety and depression. This observational study investigated the relationship between cognitive phenotypes and psychiatric symptomatology in TLE. METHODS: A total of 826 adults (age = 40.3, 55% female) with pharmacoresistant TLE completed a neuropsychological evaluation that included at least two measures from five cognitive domains to derive International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) cognitive phenotypes (i.e., intact, single-domain impairment, bi-domain impairment, generalized impairment). Participants also completed screening measures for depression and anxiety. Psychiatric history and medication data were extracted from electronic health records. Multivariable proportional odds logistic regression models examined the relationship between IC-CoDE phenotypes and psychiatric variables after controlling for relevant covariates. RESULTS: Patients with elevated depressive symptoms had a greater odds of demonstrating increasingly worse cognitive phenotypes than patients without significant depressive symptomatology (odds ratio [OR] = 1.123-1.993, all corrected p's < .05). Number of psychotropic (OR = 1.584, p < .05) and anti-seizure medications (OR = 1.507, p < .001), use of anti-seizure medications with mood-worsening effects (OR = 1.748, p = .005), and history of a psychiatric diagnosis (OR = 1.928, p < .05) also increased the odds of a more severe cognitive phenotype, while anxiety symptoms were unrelated. SIGNIFICANCE: This study demonstrates that psychiatric factors are not only associated with function in specific cognitive domains but also with the pattern and extent of deficits across cognitive domains. Results suggest that depressive symptoms and medications are strongly related to cognitive phenotype in adults with TLE and support the inclusion of these factors as diagnostic modifiers for cognitive phenotypes in future work. Longitudinal studies that incorporate neuroimaging findings are warranted to further our understanding of the complex relationships between cognition, mood, and seizures and to determine whether non-pharmacologic treatment of mood symptoms alters cognitive phenotype.

Application of the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) to frontal lobe epilepsy using multicenter data.

RATIONALE: The International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) was recently introduced as a consensus-based, empirically-driven taxonomy of cognitive disorders in epilepsy and has been effectively applied to patients with temporal lobe epilepsy (TLE). The purpose of this study was to apply the IC-CoDE to patients with frontal lobe epilepsy (FLE) using national multicenter data. METHODS: Neuropsychological data of 455 patients with FLE aged 16 years or older were available across four US-based sites. First, we examined test-specific impairment rates across sites using two impairment thresholds (1.0 and 1.5 standard deviations below the normative mean). Following the proposed IC-CoDE guidelines, patterns of domain impairment were determined based on commonly used tests within five cognitive domains (language, memory, executive functioning, attention/processing speed, and visuospatial ability) to construct phenotypes. Impairment rates and distributions across phenotypes were then compared with those found in patients with TLE for which the IC-CoDE classification was initially validated. RESULTS: The highest rates of impairment were found among tests of naming, verbal fluency, speeded sequencing and set-shifting, and complex figure copy. The following IC-CoDE phenotype distributions were observed using the two different threshold cutoffs: 23-40% cognitively intact, 24-29% single domain impairment, 13-20% bi-domain impairment, and 18-33% generalized impairment. Language was the most common single domain impairment (68% for both thresholds) followed by attention and processing speed (15-18%). Overall, patients with FLE reported higher rates of cognitive impairment compared with patients with TLE. CONCLUSIONS: These results demonstrate the applicability of the IC-CoDE to epilepsy syndromes outside of TLE. Findings indicated generally stable and reproducible phenotypes across multiple epilepsy centers in the U.S. with diverse sample characteristics and varied neuropsychological test batteries. Findings also highlight opportunities for further refinement of the IC-CoDE guidelines as the application expands.

Comparative Effectiveness of Stereotactic Electroencephalography Versus Subdural Grids in Epilepsy Surgery.

OBJECTIVE: The aim was to compare the outcomes of subdural electrode (SDE) implantations versus stereotactic electroencephalography (SEEG), the 2 predominant methods of intracranial electroencephalography (iEEG) performed in difficult-to-localize drug-resistant focal epilepsy. METHODS: The Surgical Therapies Commission of the International League Against Epilepsy created an international registry of iEEG patients implanted between 2005 and 2019 with ≥1 year of follow-up. We used propensity score matching to control exposure selection bias and generate comparable cohorts. Study endpoints were: (1) likelihood of resection after iEEG; (2) seizure freedom at last follow-up; and (3) complications (composite of postoperative infection, symptomatic intracranial hemorrhage, or permanent neurological deficit). RESULTS: Ten study sites from 7 countries and 3 continents contributed 2,012 patients, including 1,468 (73%) eligible for analysis (526 SDE and 942 SEEG), of whom 988 (67%) underwent subsequent resection. Propensity score matching improved covariate balance between exposure groups for all analyses. Propensity-matched patients who underwent SDE had higher odds of subsequent resective surgery (odds ratio [OR] = 1.4, 95% confidence interval [CI] 1.05, 1.84) and higher odds of complications (OR = 2.24, 95% CI 1.34, 3.74; unadjusted: 9.6% after SDE vs 3.3% after SEEG). Odds of seizure freedom in propensity-matched resected patients were 1.66 times higher (95% CI 1.21, 2.26) for SEEG compared with SDE (unadjusted: 55% seizure free after SEEG-guided resections vs 41% after SDE). INTERPRETATION: In comparison to SEEG, SDE evaluations are more likely to lead to brain surgery in patients with drug-resistant epilepsy but have more surgical complications and lower probability of seizure freedom. This comparative-effectiveness study provides the highest feasible evidence level to guide decisions on iEEG. ANN NEUROL 2021;90:927-939.

Cognitive phenotypes in frontal lobe epilepsy.

OBJECTIVE: Neuropsychological profiles are heterogeneous both across and within epilepsy syndromes, but especially in frontal lobe epilepsy (FLE), which has complex semiology and epileptogenicity. This study aimed to characterize the cognitive heterogeneity within FLE by identifying cognitive phenotypes and determining their demographic and clinical characteristics. METHOD: One hundred and six patients (age 16-66; 44% female) with FLE completed comprehensive neuropsychological testing, including measures within five cognitive domains: language, attention, executive function, processing speed, and verbal/visual learning. Patients were categorized into one of four phenotypes based on the number of impaired domains. Patterns of domain impairment and clinical and demographic characteristics were examined across phenotypes. RESULTS: Twenty-five percent of patients met criteria for the Generalized Phenotype (impairment in at least four domains), 20% met criteria for the Tri-Domain Phenotype (impairment in three domains), 36% met criteria for the Domain-Specific Phenotype (impairment in one or two domains), and 19% met criteria for the Intact Phenotype (no impairment). Language was the most common domain-specific impairment, followed by attention, executive function, and processing speed. In contrast, learning was the least impacted cognitive domain. The Generalized Phenotype had fewer years of education compared to the Intact Phenotype, but otherwise, there was no differentiation between phenotypes in demographic and clinical variables. However, qualitative analysis suggested that the Generalized and Tri-Domain Phenotypes had a more widespread area of epileptogenicity, whereas the Intact Phenotype most frequently had seizures limited to the lateral frontal region. SIGNIFICANCE: This study identified four cognitive phenotypes in FLE that were largely indistinguishable in clinical and demographic features, aside from education and extent of epileptogenic zone. These findings enhance our appreciation of the cognitive heterogeneity within FLE and provide additional support for the development and use of cognitive taxonomies in epilepsy.

Timing of referral to evaluate for epilepsy surgery: Expert Consensus Recommendations from the Surgical Therapies Commission of the International League Against Epilepsy.

Epilepsy surgery is the treatment of choice for patients with drug-resistant seizures. A timely evaluation for surgical candidacy can be life-saving for patients who are identified as appropriate surgical candidates, and may also enhance the care of nonsurgical candidates through improvement in diagnosis, optimization of therapy, and treatment of comorbidities. Yet, referral for surgical evaluations is often delayed while palliative options are pursued, with significant adverse consequences due to increased morbidity and mortality associated with intractable epilepsy. The Surgical Therapies Commission of the International League Against Epilepsy (ILAE) sought to address these clinical gaps and clarify when to initiate a surgical evaluation. We conducted a Delphi consensus process with 61 epileptologists, epilepsy neurosurgeons, neurologists, neuropsychiatrists, and neuropsychologists with a median of 22 years in practice, from 28 countries in all six ILAE world regions. After three rounds of Delphi surveys, evaluating 51 unique scenarios, we reached the following Expert Consensus Recommendations: (1) Referral for a surgical evaluation should be offered to every patient with drug-resistant epilepsy (up to 70 years of age), as soon as drug resistance is ascertained, regardless of epilepsy duration, sex, socioeconomic status, seizure type, epilepsy type (including epileptic encephalopathies), localization, and comorbidities (including severe psychiatric comorbidity like psychogenic nonepileptic seizures [PNES] or substance abuse) if patients are cooperative with management; (2) A surgical referral should be considered for older patients with drug-resistant epilepsy who have no surgical contraindication, and for patients (adults and children) who are seizure-free on 1-2 antiseizure medications (ASMs) but have a brain lesion in noneloquent cortex; and (3) referral for surgery should not be offered to patients with active substance abuse who are noncooperative with management. We present the Delphi consensus results leading up to these Expert Consensus Recommendations and discuss the data supporting our conclusions. High level evidence will be required to permit creation of clinical practice guidelines.

Atrophy and cognitive profiles in older adults with temporal lobe epilepsy are similar to mild cognitive impairment.

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.

Quality of life after epilepsy surgery: How domain-specific cognitive changes impact QOL within the context of seizure outcome.

PURPOSE: Neurosurgery is an effective treatment option for pharmacoresistant epilepsy. Although post-surgical seizure freedom is considered the primary goal of epilepsy surgery, other factors that impact Quality of Life (QOL) are also important to consider, including post-surgical cognitive changes. This study aimed to examine the impact of post-surgical cognitive changes on QOL in the context of seizure outcomes. METHODS: Participants were 196 adults with focal epilepsy who underwent either frontal (n = 27) or temporal (n = 169) lobe resection. Each participant completed pre- and post-surgical neuropsychological evaluations, and cognitive composites were constructed for the following domains: language, attention/processing speed, memory, executive function, and visuospatial skill. The Quality of Life in Epilepsy (QOLIE-10) questionnaire was used to assess QOL. Seizure outcome was determined by seizure status six months post-surgery. RESULTS: Eighty-one percent of patients were seizure-free post-surgery and generally reported improved QOL. While a significant portion of patient's demonstrated declines in language and verbal memory following surgery, only a decline in verbal memory was associated with worse QOL; however, this relationship was no longer significant after controlling for seizure outcome. Instead, reduced post-surgical QOL was primarily observed in those who experienced both seizure recurrence and a decline in executive function. Notably, depression was a significant covariate in all of the models. CONCLUSIONS: The findings from this study improve our ability to counsel patients about the trade-off between cognitive decline and seizure remittance in the greater context of overall QOL. Reassuringly, it appears that QOL is improved regardless of cognitive changes when patients have good seizure outcomes. However, for those that experience a "double hit" (i.e., cognitive decline without seizure remission), post-surgical QOL may be reduced. Changes in depression also appear to play a crucial role in QOL outcomes.

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.

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.

Predicting mood decline following temporal lobe epilepsy surgery in adults.

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.

Diagnosing cognitive disorders in older adults with epilepsy.

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.