Cognitive and behavioural comorbidities are prevalent in childhood and adult epilepsies and impose a substantial human and economic burden. Over the past century, the classic approach to ...understanding the aetiology and course of these comorbidities has been through the prism of the medical taxonomy of epilepsy, including its causes, course, characteristics and syndromes. Although this 'lesion model' has long served as the organizing paradigm for the field, substantial challenges to this model have accumulated from diverse sources, including neuroimaging, neuropathology, neuropsychology and network science. Advances in patient stratification and phenotyping point towards a new taxonomy for the cognitive and behavioural comorbidities of epilepsy, which reflects the heterogeneity of their clinical presentation and raises the possibility of a precision medicine approach. As we discuss in this Review, these advances are informing the development of a revised aetiological paradigm that incorporates sophisticated neurobiological measures, genomics, comorbid disease, diversity and adversity, and resilience factors. We describe modifiable risk factors that could guide early identification, treatment and, ultimately, prevention of cognitive and broader neurobehavioural comorbidities in epilepsy and propose a road map to guide future research.
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.
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).
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).
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.
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.
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.
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.
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.
•Subjective cognitive impairment (CI) is most strongly related to depression.•Subjective CI is also related to polytherapy and seizure frequency.•In presence of depression, rates of CI are high for all AEDs used in monotherapy.•Subjective CI does not correlate with most objective neuropsychological metrics.
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.
Abstract
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.
López-Rivera et al. discover differences in genetic architecture across major epileptic brain lesion types. They describe novel somatic chromosomal alterations, identify novel genes and genotype–phenotype associations, and provide support for the role of genetics in the histopathological diagnosis of epileptic lesions.
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.
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.
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.
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.
A new frontier in diagnostic radiology is the inclusion of machine-assisted support tools that facilitate the identification of subtle lesions often not visible to the human eye. Structural ...neuroimaging plays an essential role in the identification of lesions in patients with epilepsy, which often coincide with the seizure focus. In this study, we explored the potential for a convolutional neural network (CNN) to determine lateralization of seizure onset in patients with epilepsy using T1-weighted structural MRI scans as input.
Using a dataset of 359 patients with temporal lobe epilepsy (TLE) from 7 surgical centers, we tested whether a CNN based on T1-weighted images could classify seizure laterality concordant with clinical team consensus. This CNN was compared with a randomized model (comparison with chance) and a hippocampal volume logistic regression (comparison with current clinically available measures). Furthermore, we leveraged a CNN feature visualization technique to identify regions used to classify patients.
Across 100 runs, the CNN model was concordant with clinician lateralization on average 78% (SD = 5.1%) of runs with the best-performing model achieving 89% concordance. The CNN outperformed the randomized model (average concordance of 51.7%) on 100% of runs with an average improvement of 26.2% and outperformed the hippocampal volume model (average concordance of 71.7%) on 85% of runs with an average improvement of 6.25%. Feature visualization maps revealed that in addition to the medial temporal lobe, regions in the lateral temporal lobe, cingulate, and precentral gyrus aided in classification.
These extratemporal lobe features underscore the importance of whole-brain models to highlight areas worthy of clinician scrutiny during temporal lobe epilepsy lateralization. This proof-of-concept study illustrates that a CNN applied to structural MRI data can visually aid clinician-led localization of epileptogenic zone and identify extrahippocampal regions that may require additional radiologic attention.
This study provides Class II evidence that in patients with drug-resistant unilateral temporal lobe epilepsy, a convolutional neural network algorithm derived from T1-weighted MRI can correctly classify seizure laterality.
Objective
Cognitive impairment is now recognized as an impending public health crisis. About one-third of adults are concerned about their cognition, and the prevalence of objective cognitive ...impairment is much higher among those with neurological disorders. Existing screening tools are narrowly focused on detecting dementia in older adults and must be clinician-administered and scored, making them impractical for many neurology practices. This study examined the utility of a brief, self-administered, computerized cognitive screening tool, the Brief Assessment of Cognitive Health (BACH), in identifying cognitive impairment in adults.
Methods
912 adults (ages 18–84) completed BACH and a neuropsychological battery. Multivariable models were developed to provide a BACH index score reflecting the probability of cognitive impairment for individual patients. Predictive accuracy was compared to that of the Montreal Cognitive Assessment (MoCA) in a subset of 160 older adults from a Memory Disorders clinic.
Results
The final multivariable model showed good accuracy in identifying cognitively impaired individuals (
c
= 0·77). Compared to MoCA, BACH had superior predictive accuracy in identifying older patients with cognitive impairment (
c
= 0·79 vs. 0·67) as well as differentiating those with MCI or dementia from those without cognitive impairment (
c
= 0·86 vs.
c
= 0·67).
Conclusions
Results suggest that cognitive impairment can be identified in adults using a brief, self-administered, automated cognitive screening tool, and BACH provides several advantages over existing screeners: self-administered; automatic scoring; immediate results in health record; easily interpretable score; utility in wide range of patients; and flags for treatable factors that may contribute to cognitive complaints (i.e., depression, sleep problems, and stress).
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.
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