Breaking the CoDE of Cognitive Disorders in Epilepsy

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. 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. 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. 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.

Studies have established that radiotherapy for childhood brain tumors (BTs) increases the risk of cerebrovascular disease (CVD); however, it is unclear how this will affect cognitive function. This study aimed to investigate the associations between radiotherapy-induced CVD, white matter hyperintensities (WMHs), and neurocognitive outcomes in adult survivors of childhood BTs. In a cross-sectional setting, we conducted a national cohort that included 68 radiotherapy-treated survivors of childhood BTs after a median follow-up of 20 years. Markers of CVD and WMHs were evaluated using brain MRI, and the sum of CVD-related findings was calculated. Additionally, the associations among CVD findings, WMHs, and neuropsychological test results were analyzed. Of the 68 childhood BT survivors, 54 (79%) were diagnosed with CVD and/or WMHs at a median age of 27 years. CVD and/or WMHs were associated with lower scores for verbal intelligence quotient, performance intelligence quotient (PIQ), executive function, memory, and visuospatial ability (P < .05). Additionally, survivors with microbleeds had greater impairments in the PIQ, processing speed, executive function, and visuospatial ability (P < .05). WMHs and CVD burden were associated with greater difficulties in memory function and visuospatial ability (P < .05). Small-vessel disease burden was associated with PIQ scores, processing speed, working memory, and visuospatial ability. The study results suggest that markers of radiotherapy-induced CVD, the additive effect of CVD markers, and risk factors of dementia are associated with cognitive impairment, which may suggest that the survivors are at a high risk of developing early-onset dementia.

Bipolar disorder (BD) and temporal lobe epilepsy (TLE) overlap in domains including epidemiology, treatment response, shared neurotransmitter involvement and temporal lobe pathology. Comparison of cognitive function in both disorders may indicate temporal lobe mediated processes relevant to BD. This systematic review examines neuropsychological test profiles in euthymic bipolar disorder type I (BD-I) and pre-surgical TLE and compares experimental designs used. A search of PubMed, PsychINFO, and Scopus using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted. Inclusion criteria were comparison group or pre- to post-surgical patients; reported neuropsychological tests; participants aged 18-60 years. Fifty six studies met criteria: 27 BD-I; 29 TLE. Deficits in BD-I compared to healthy controls (HC) were in executive function, attention span and verbal memory. Deficits in TLE compared to HC were in executive function and memory. In the pre- to post-surgical comparisons, verbal memory in left temporal lobe (LTL) and, less consistently, visuospatial memory in right temporal lobe (RTL) epilepsy declined following surgery. BD-I studies used comprehensive test batteries in well-defined euthymic patients compared to matched HC groups. TLE studies used convenience samples pre- to post-surgery, comparing LTL and RTL subgroups, few included comparisons to HC (5 studies). TLE studies typically examined a narrow range of known temporal lobe-mediated neuropsychological functions, particularly verbal and visuospatial memory. Both disorders exhibit deficits in executive function and verbal memory suggestive of both frontal and temporal lobe involvement. However, deficits in TLE are measured pre- to post-surgery and not controlled at baseline pre-surgery. Further research involving a head-to-head comparison of the two disorders on a broad range of neuropsychological tests is needed to clarify the nature and extent of cognitive deficits and potential overlaps.

Alterations in 24-hour movement patterns, or circadian rest/activity rhythms (RARs), commonly occur with aging. Using linear mixed effects (LME) modeling, we examined associations of baseline RARs with longitudinal change in cognition. Participants (N=424; 47% male, baseline age 72.8±10.1 years) were from the Baltimore Longitudinal Study of Aging and completed 5.6±0.8 nights of wrist actigraphy at baseline. Tests of memory, executive function, attention, language, and visuospatial ability were administered at baseline and subsequent visits (3.7±1.7 years of follow-up in those with >1 visit (n=295)). In unadjusted random intercept and slope LME models, greater RAR stability predicted slower memory decline, and higher activity during participants’ least active 5 hours (L5) predicted slower decline in visuospatial ability. After covariate adjustment, higher activity in participants’ most active 10 hours (M10) and higher L5 predicted slower decline in visuospatial ability (p<.05). Further research is needed on RARs as risk factors for later-life cognitive decline.

Objective: Drug-resistant temporal lobe epilepsy (TLE) is a neurological disorder characterized by cognitive deficits. This study examined whether patients with TLE and different cognitive phenotypes differ in cortisol levels and affectivity while controlling for demographic and clinical variables. Methods: In this cross-sectional study, 79 adults with TLE underwent neuropsychological evaluation in which memory, language, attention/processing speed, executive function, and affectivity were assessed. Six saliva samples were collected in the afternoon to examine the ability of the hypothalamic-pituitary-adrenal (HPA) axis to descend according to the circadian rhythm (C1 to C6). The cortisol area under the curve concerning ground (AUCg) was computed to examine global cortisol secretion. Results: Three cognitive phenotypes were identified: memory impairment, generalized impairment, and no impairment. The memory-impairment phenotype showed higher cortisol levels at C4, C5, and C6 than the other groups (p = 0.03, η2 = 0.06), higher cortisol AUCg than the generalized-impairment phenotype (p = 0.004, η2 = 0.14), and a significant reduction in positive affectivity after the evaluation (p = 0.026, η2 = 0.11). Higher cortisol AUCg and reductions in positive affectivity were significant predictors of the memory-impairment phenotype (p < 0.001; Cox and Snell R2 = 0.47). Conclusions: Patients with memory impairment had a slower decline in cortisol levels in the afternoon, which could be interpreted as an inability of the HPA axis to inhibit itself. Thus, chronic stress may influence hippocampus-dependent cognitive function more than other cognitive functions in patients with TLE.

Research has demonstrated that better value-based decision making (e.g., waiting or working for rewards) relates to greater executive function (EF) ability. However, EF is not a static ability, but is influenced by the emotional content of the task. As such, EF ability in emotional contexts may have unique associations with value-based decision making, in which costs and benefits are explicit. Participants (N = 229) completed an EF task (with both negative and neutral task conditions) and two value-based decision-making tasks. Willingness to wait and to work were evaluated in separate path models relating the waiting and working conditions to the EF conditions. Willingness to wait and willingness to work showed distinct relationships with EF ability: Greater EF ability on a negative, but not on a neutral, EF task was related to a willingness to wait for a reward, whereas greater EF ability across both EF tasks was related to a greater willingness to work for a reward. EF ability on a negative EF task showed an inverted-U relationship to willingness to wait for reward, and was most related to willingness to wait at a 6-month delay. Greater EF, regardless of whether the task was negative or neutral, was related to a greater willingness to work when reward was uncertain (50%) or was likely (88%), but not when reward was unlikely (12%). This study suggests that the emotional content of value-based decisions impacts the relationship between EF ability and willingness to wait or to work for reward.

Blood pressure variability (BPV) is associated with cognitive decline and Alzheimer's disease (AD), but relationships with AD risk gene apolipoprotein (APOE) ɛ4 remain understudied. Examined the longitudinal relationship between BPV and cognitive change in APOE ɛ4 carriers and APOE ɛ3 homozygotes. 1,194 Alzheimer's Disease Neuroimaging Initiative participants (554 APOE ɛ4 carriers) underwent 3-4 blood pressure measurements between study baseline and 12-month follow-up. Visit-to-visit BPV was calculated as variability independent of mean over these 12 months. Participants subsequently underwent ≥1 neuropsychological exam at 12-month follow-up or later (up to 156 months later). Composite scores for the domains of memory, language, executive function, and visuospatial abilities were determined. Linear mixed models examined the 3-way interaction of BPV×APOE ɛ4 carrier status x time predicting change in composite scores. Higher systolic BPV predicted greater decline in memory (+1 SD increase of BPV: β= -0.001, p < 0.001) and language (β= -0.002, p < 0.0001) among APOE ɛ4 carriers, but not APOE ɛ3 homozygotes (memory: +1 SD increase of BPV: β= 0.0001, p = 0.57; language: β= 0.0001, p = 0.72). Systolic BPV was not significantly associated with change in executive function or visuospatial abilities in APOE ɛ4 carriers (ps = 0.08-0.16) or APOE ɛ3 homozygotes (ps = 0.48-0.12). Cognitive decline associated with high BPV may be specifically accelerated among APOE ɛ4 carriers.

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessData Point to Potential New Use for Common AntidepressantJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:21 Sep 2012https://doi.org/10.1176/pn.47.18.psychnews_47_18_15-bAbstractThe SSRI antidepressant fluoxetine may hold another benefit—helping people with mesial temporal lobe epilepsy who experience learning problems.Many patients with mesial temporal lobe epilepsy complain of learning and memory problems. So William Gray, M.D., a professor of neurosurgery at Cardiff University in Wales in the United Kingdom, decided to conduct research to better understand the situation and perhaps find a way to remedy these patients’ learning deficits.First Gray and his colleagues tested 12 mesial temporal lobe epilepsy subjects and 12 healthy control subjects to see how good their learning and memory capabilities were and found that the former group had more learning problems.They then turned to a rat model for epilepsy and tested rats with this condition for learning and memory abilities. Compared with healthy rats, the rats with the epilepsy-like condition showed evidence of learning and memory deficits, just as the human subjects had.Further testing suggested that the rats’ learning and memory impairments were due to reduced and abnormal production of new nerves in the hippocampus.The scientists then gave fluoxetine to the epilepsy rats to see whether it might improve their learning and memory, since fluoxetine is known to improve memory in people with mild cognitive impairment and those with memory difficulties due to chemotherapy, or what is sometimes called “chemo brain” or “chemo fog” (Psychiatric News, March 16).Fluoxetine did improve learning and hippocampal nerve regeneration in the study rats, but did not show any effect on memory improvement.Thus fluoxetine might prove useful for improving learning in people with mesial temporal lobe epilepsy, Gray and his colleagues concluded in a report in the August Brain. “A well-tolerated pharmacological therapy that restores learning to normal could be of great clinical benefit,” they wrote.They also remain hopeful that fluoxetine might help the memories of these epilepsy patients, at least in those with less-severe hippocampal damage, even though their animal tests did not point to this possibility.The research was funded by Epilepsy Research UK.An abstract of “Fluoxetine Restores Spatial Learning but Not Accelerated Forgetting in Mesial Temporal Lobe Epilepsy” is posted at http://brain.oxfordjournals.org/content/135/8/2358.abstract. > ISSUES NewArchived

SummaryTemporal lobe epilepsy (TLE) is typically associated with long-term memory dysfunction. The frontal lobes support high-level cognition comprising executive skills and working memory that is vital for daily life functioning. Deficits in these functions have been increasingly reported in TLE. Evidence from both the neuropsychological and neuroimaging literature suggests both executive function and working memory are compromised in the presence of TLE. In relation to executive impairment, particular focus has been paid to set shifting as measured by the Wisconsin Card Sorting Task. Other discrete executive functions such as decision-making and theory of mind also appear vulnerable but have received little attention. With regard to working memory, the medial temporal lobe structures appear have a more critical role, but with emerging evidence of hippocampal dependent and independent processes. The relative role of underlying pathology and seizure spread is likely to have considerable bearing upon the cognitive phenotype and trajectory in TLE. The identification of the nature of frontal lobe dysfunction in TLE thus has important clinical implications for prognosis and surgical management. Longitudinal neuropsychological and neuroimaging studies assessing frontal lobe function in TLE patients pre- and postoperatively will improve our understanding further.

Cognitive function is an indicator for global physical and mental health, and cognitive impairment has been associated with poorer life outcomes and earlier mortality. A standard cognition test, adapted to a rural-dwelling African community, and the Oxford Cognition Screen-Plus were used to capture cognitive performance as five continuous traits (total cognition score, verbal episodic memory, executive function, language, and visuospatial ability) for 2,246 adults in this population of South Africans. A novel common variant, rs73485231, reached genome-wide significance for association with episodic memory using data for ~14 million markers imputed from the H3Africa genotyping array data. Window-based replication of previously implicated variants and regions of interest support the discovery of African-specific associated variants despite the small population size and low allele frequency. This African genome-wide association study identifies suggestive associations with general cognition and domain-specific cognitive pathways and lays the groundwork for further genomic studies on cognition in Africa.

Cognitive dysfunction is common in people with epilepsy (PWE). Although expectations exist for deficits based on diagnosis, phenotypic variation of cognitive deficits is observed within epilepsy subtypes. Classification by severity and type of cognitive deficits has been shown across multiple studies of people with temporal lobe epilepsy (TLE). In this study, we replicate these findings using robotic assessment in TLE and apply the same method in genetic generalized epilepsy (GGE) to uncover potential cognitive phenotypes. Participants with TLE and GGE were recruited to participate in robotic assessment battery of neurocognitive function. We used 7 task scores to form clusters that includes functions from various cognitive and motor domains. Calinski-Harabasz method seeded at zero was used to find the optimal value of c, and fuzzy C-means clustering was used to assess the cluster membership from the data in c-groups. We found 3 clusters among TLE (n=33): minimal deficits (45% of participants with TLE), partial deficits (27%), and global deficits (27%). Likewise, we found 3 clusters among GGE (n=25): memory and executive deficits (40% of participants with GGE), processing speed deficits (36%), and complex motor deficits (24%). Robotic assessment can be used with clustering methods to classify cognitive dysfunction in epilepsy. These clusters show similar patterns to previous research, which suggests that robotic assessment can distinguish the cognitive phenotypes of PWE.

In efforts to understand the cognitive heterogeneity within and across epilepsy syndromes, cognitive phenotyping has been proposed as a new taxonomy aimed at developing a harmonized approach to cognitive classification in epilepsy. Data- and clinically driven approaches have been previously used with variability in the phenotypes derived across studies. In our study, we utilize latent profile analysis to test several models of phenotypes in a large multicentre sample of patients with temporal lobe epilepsy and evaluate their demographic and clinical profiles. For the first time, we examine the added value of replacing missing data and examine factors that may be contributing to missingness. A sample of 1178 participants met the inclusion criteria for the study, which included a diagnosis of temporal lobe epilepsy and the availability of comprehensive neuropsychological data. Models with two to five classes were examined using latent profile analysis and the optimal model was selected based on fit indices, posterior probabilities and proportion of sample sizes. The models were also examined with imputed data to investigate the impact of missing data on model selection. Based on the fit indices, posterior probability and distinctiveness of the latent classes, a three-class solution was the optimal solution. This three-class solution comprised a group of patients with multidomain impairments, a group with impairments predominantly in language and a group with no impairments. Overall, the multidomain group demonstrated a worse clinical profile and comprised a greater proportion of patients with mesial temporal sclerosis, a longer disease duration and a higher number of anti-seizure medications. The four-class and five-class solutions demonstrated the lowest probabilities of a group membership. Analyses with imputed data demonstrated that the four-class solution was the optimal solution; however, there was a weak agreement between the missing and imputed data sets for the four-Class solutions (κ = 0.288, P < 0.001). This study represents the first to use latent profile analysis to test and compare multiple models of cognitive phenotypes in temporal lobe epilepsy and to determine the impact of missing data on model fit. We found that the three-phenotype model was the most meaningful based on several fit indices and produced phenotypes with unique demographic and clinical profiles. Our findings demonstrate that latent profile analysis is a rigorous method to identify phenotypes in large, heterogeneous epilepsy samples. Furthermore, this study highlights the importance of examining the impact of missing data in phenotyping methods. Our latent profile analysis-derived phenotypes can inform future studies aimed at identifying cognitive phenotypes in other neurological disorders.

Clinical Neurophysiology: EEG–Video Monitoring

Introduction This study aims to assess whether electroencephalogram (EEG) spectral power change scores (e.g. task spectral power subtracted from resting state spectral power) across three different frequency bands, alpha (8–12 Hz), theta (4–7 Hz), and beta (13–30 Hz), predicts self-reported attention-deficit hyperactivity disorder (ADHD) symptoms using the Adult ADHD Self-Report Scale (ASRS) over and above self-reported executive function (EF) abilities using the Behavior Rating Inventory of Executive Function (BRIEF-A) Global Executive Composite (GEC) T-scores for adults. Methods Data were collected at a rural, mid-sized southeastern university (N = 52) and participants received course credit for participation. Participants self-reported ADHD symptoms and EF abilities before completing eyes open resting state and the attention network test (ANT), a common flanker task that measures ability to orient attention, stay alert, and resolve conflict (i.e. distractor arrows) while recording EEG spectral power at electrodes F3 and F4. Bivariate correlations determine associations between EEG measures and self-reported ADHD symptoms and EF abilities. Linear regressions were used to assess whether EEG change scores were predictive of ADHD symptoms over and above EF abilities. Results High correlation coefficients were found only when comparing the ASRS and BRIEF-A GEC T-scores (r = .822, p <.001). Regression analyses produced significant results indicating EEG spectral change scores were predictive of ADHD symptoms, over and above GEC T-Scores, for the alpha band but not the theta and beta bands. Additionally, we found an inverse relationship when comparing change scores in the alpha band across the right (F4) and left (F3) hemispheres supporting the theory of frontal asymmetry for individuals with increased ADHD symptoms. Conclusion This study is the first to assess the predictive ability of EEG spectral power change scores in predicting ADHD symptoms, which are not solely explained by deficits in executive control. Past research has indicated significant differences when comparing task and resting state spectral power indicating change scores might have some utility in measuring cognitive load, specifically in the alpha band, which has been associated with inhibition, working memory, and anticipation of stimuli. Further research should be conducted to assess the utility change scores might have in providing an objective measure related to a clinical population with ADHD.

Odor identification dysfunction in late-life depression with suicidal ideation