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To present the background, rationale, details pertaining to use and essential computational steps, synopsis of findings to date, and future directions for the International Classification of Cognitive Disorders in Epilepsy (IC‐CoDE)—an initiative of the ILAE Neuropsychology Task Force. Examined are: (a) the 6 steps leading to the derivation of a cognitive phenotype from neuropsychological test data with an accompanying case example, (b) concise review of all IC‐CoDE research to date, (c) summary of identified correlates of IC‐CoDE outcomes, and (d) future research and clinical directions for the initiative. The IC‐CoDE is computationally uncomplicated with individual or group data and represents a novel approach leading to new insights in the neuropsychology of epilepsy, with applications to diverse datasets internationally informing the reliability and validity of the approach. The IC‐CoDE represents a novel approach to the analysis and interpretation of neuropsychological data in epilepsy that offers to advance a global taxonomy of cognitive disorders in epilepsy facilitating international collaboration and big data science.

OBJECTIVE--Insulin resistance dysregulates glucose uptake and other functions in brain areas affected by Alzheimer disease. Insulin resistance may play a role in Alzheimer disease etiopathogenesis. This longitudinal study examined whether [...]

This study hypothesized that verbal memory decline following anterior temporal lobectomy (ATL) is associated with a lack of significant neuropathology in resected left, but not right, hippocampus and is limited to measures of episodic memory only. Tests of immediate (digit span), semantic (visual naming), and episodic memory as measured by the California Verbal Learning Test (CVLT) were administered before and 6 months after resection of the anterior left (n = 36) or right (n = 26) temporal lobe. There were no effects of hippocampal pathology on measures of immediate or semantic memory for either ATL group or for episodic memory for the right ATL group. Left ATL patients who demonstrated no/mild hippocampal sclerosis exhibited significantly greater postoperative decline in episodic memory compared with those with moderate/marked hippocampal sclerosis on multiple CVLT indices (recall measures, learning characteristics, and contrast measures).

It is generally agreed that epileptics as a group display a higher rate of psychopathology than the general population. It is not known why this is so, but speculation has focused on the physiological aspects of the disease. Possible psychosocial predictors of psychopathology in this population have been virtually ignored by researchers. Biological, social, pharmacological, and demographic measures were performed on 102 epileptic adults in an effort to make a more comprehensive evaluation of epilepsy. Data were collected in four primary areas: neurological variables such as age of onset, duration, and physiological measures; psychosocial variables including perceived stigma, limitations, and adjustments to seizures; demographics; and medications used. Among the questionnaires completed by subjects was the General Health Questionnaire (GHQ), which in this version included 30 items that assess overall psychiatric status. Seven variables were found to be significant predictors of psychopathology in epileptics on the GHQ: increased perceived stigma, a high number of stressful life events in the past year, poor adjustment to epilepsy, poor vocational adjustment, financial stress, external locus of control (interpretation of life events as external, or out of one's direct control), and earlier onset. Of these, six were psychosocial and one, age at onset, was neurological. This provides direct evidence of the importance of including psychosocial factors when assessing risk of psychiatric illness in epileptics, and the evidence underscores the need to consider all aspects of a patient's life when making such assessments. (Consumer Summary produced by Reliance Medical Information, Inc.)

There is increasing evidence that vascular disease risk factors contribute to evolution of the dementia syndrome of Alzheimer’s disease (AD). One important measure of cerebrovascular health is pulsatility index (PI) which is thought to represent distal vascular resistance, and has previously been reported to be elevated in AD clinical syndrome. Physical inactivity has emerged as an independent risk factor for cardiovascular disease. This study aims to examine the relationship between a measure of habitual physical activity, cardiorespiratory fitness (CRF), and PI in the large cerebral vessels. Ninety-two cognitively-healthy adults (age = 65.34±5.95, 72% female) enrolled in the Wisconsin Registry for Alzheimer’s Prevention participated in this study. Participants underwent 4D flow brain MRI to measure PI in the internal carotid artery (ICA), basilar artery, middle cerebral artery (MCA), and superior sagittal sinus. Participants also completed a self-report physical activity questionnaire. CRF was calculated using a previously-validated equation that incorporates sex, age, body-mass index, resting heart rate, and self-reported physical activity. A series of linear regression models adjusted for age, sex, APOE4 status, and 10-year atherosclerotic cardiovascular disease risk were used to analyze the relationship between CRF and PI. Inverse associations were found between CRF and mean PI in the inferior ICA (p = .001), superior ICA (p = .035), and basilar artery (p = .040). No other cerebral vessels revealed significant associations between CRF and PI (p≥.228). Higher CRF was associated with lower PI in several large cerebral vessels. Since increased pulsatility has been associated with poor brain health and reported in persons with AD, this suggests that aerobic fitness might provide protection against cerebrovascular changes related to the progression of AD clinical syndrome.

Traditional Doppler measures have been used to predict cognitive performance in patients with carotid atherosclerosis. Novel measures, such as carotid plaque strain indices (CPSIs), have shown associations with cognitive performance. We hypothesized that lower mean middle cerebral artery (MCA) velocities, higher bulb–internal carotid artery (ICA) velocities, the MCA pulsatility index (PI), and CPSIs would be associated with poorer cognitive performance in individuals with advanced atherosclerosis. Neurocognitive testing, carotid ultrasound imaging, transcranial Doppler imaging, and carotid strain imaging were performed on 40 patients scheduled for carotid endarterectomy. Kendall tau correlations were used to examine relationships between cognitive tests and the surgical‐side maximum peak systolic velocity (PSV; from the bulb, proximal, mid, or distal ICA), mean MCA velocity and PI, and maximum CPSIs (axial, lateral, and shear strain indices used to characterize plaque deformations with arterial pulsation). Cognitive measures included age‐adjusted indices of verbal fluency, verbal and visual learning/memory, psychomotor speed, auditory attention/working memory, visuospatial construction, and mental flexibility. Participants had a median age of 71.0 (interquartile range, 9.75) years; 26 were male (65%), and 14 were female (35%). Traditional Doppler parameters, PSV, mean MCA velocity, and MCA PI did not predict cognitive performance (all P> .05). Maximum CPSIs were significantly associated with cognitive performance (P< .05). Traditional velocity measurements of the maximum bulb‐ICA PSV, mean MCA velocity, and PI were not associated with cognitive performance in patients with advanced atherosclerotic disease; however, maximum CPSIs were associated with cognitive performance. These findings suggest that cognition may be associated with unstable plaque rather than blood flow.

Due to advances in the early detection of Alzheimer's disease (AD) biomarkers including beta-amyloid (Aβ), neuropsychological measures that are sensitive to concurrent, subtle changes in cognition are critically needed. Story recall tasks have shown sensitivity to early memory declines in persons with mild cognitive impairment (MCI) and early stage dementia, as well as in persons with autosomal dominantly inherited AD up to 10 years prior to a dementia diagnosis. However, the evidence is inconclusive regarding relationships between evidence of Aβ and story recall measures. Because story recall tasks require the encoding and delayed retrieval of several lexical-semantic categories, such as proper names, verbs, and numerical expressions, and because lexical categories have been shown to be differentially impaired in persons with MCI, we focused on item-level analyses of lexical-semantic retrieval from a quintessential story recall task, Logical Memory from the Wechsler Memory Scale-Revised. Our objective was to investigate whether delayed recall of lexical categories (proper names, verbs and/or numerical expressions), as well as the traditional total score measure, was associated with “preclinical AD,” or cognitively unimpaired adults with positive Aβ deposition on positron emission tomography (PET) neuroimaging using Pittsburgh Compound B (PiB). We developed an item-level scoring system, in which we parsed items into lexical categories and examined the immediate and delayed recall of these lexical categories from 217 cognitively unimpaired participants from the Wisconsin Registry for Alzheimer's Prevention (WRAP). We performed binary logistic regression models with story recall score as predictor and Aβ status (positive/negative) as the outcome. Using baseline Logical Memory data, proper names from delayed story recall were significantly associated with Aβ status, such that participants who recalled more proper names were less likely to be classified as PiB(+) (odds ratio = .58, p = .01). None of the other story recall variables, including total score, were associated with PiB status. Secondary analyses determined that immediate recall of proper names was not significantly associated with Aβ, suggesting a retrieval deficit rather than that of encoding. The present findings suggest that lexical semantic retrieval measures from existing story recall tasks may be sensitive to Aβ deposition, and may provide added utility to a widely-used, long-standing neuropsychological test for early detection of cognitive decline on the AD continuum.

Understanding how global brain networks are affected in epilepsy may elucidate the pathogenesis of seizures and its accompanying neurobehavioral comorbidities. We investigated functional changes within neural networks in temporal lobe epilepsy (TLE) using graph theory analysis of resting-state connectivity. 27 TLE presurgical patients (age 41.0 ± 12.3 years), and 85 age, gender and handedness equivalent healthy controls (HC) (age 39.7±16.9 years) were enrolled. Eyes-closed resting-state fMRI scans were analyzed to compare network properties and functional connectivity changes. TLE subjects showed significantly higher global efficiency, lower clustering coefficient ratio and lower shortest path lengths ratio compared to HC, as an indication of a more synchronized, yet less segregated network. A trend of functional reorganization with a shift of network hubs to the contralateral hemisphere was noted in TLE subjects. Support vector machine (SVM) with linear kernel was trained to separate between neural networks in TLE and HC subjects based on graph measurements. SVM analysis allowed separation between TLE and HC networks with 80.66% accuracy using 8 features of graph measurements. Support vector regression (SVR) was used to predict neurocognitive performance from graph metrics. A SVR linear predictor showed discriminative prediction accuracy for 4 key neurocognitive variables in TLE (absolute R-value range: 0.61 – 0.75) Despite temporal onset of epilepsy, our results showed both local and global network topology differences that reflect widespread alterations in functional connectivity in TLE. Network differences are discriminative between TLE and HCs using data driven analysis and predicted severity of neurocognitive sequelae in our cohort.

Cognitive slowing is a known but comparatively under-investigated neuropsychological complication of the epilepsies in relation to other known cognitive comorbidities such as memory, executive function and language. Here we focus on a novel metric of processing speed, characterize its relative salience compared to other cognitive difficulties in epilepsy, and explore its underlying neurobiological correlates. Research participants included 55 patients with temporal lobe epilepsy (TLE) and 58 healthy controls from the Epilepsy Connectome Project (ECP) who were administered a battery of tests yielding 14 neuropsychological measures, including selected tests from the NIH Toolbox-Cognitive Battery, and underwent 3T MRI and resting state fMRI. TLE patients exhibited a pattern of generalized cognitive impairment with very few lateralized abnormalities. Using the neuropsychological measures, machine learning (Support Vector Machine binary classification model) classified the TLE and control groups with 74% accuracy with processing speed (NIH Toolbox Pattern Comparison Processing Speed Test) the best predictor. In TLE, slower processing speed was associated predominantly with decreased local gyrification in regions including the rostral and caudal middle frontal gyrus, inferior precentral cortex, insula, inferior parietal cortex (angular and supramarginal gyri), lateral occipital cortex, rostral anterior cingulate, and medial orbital frontal regions, as well as three small regions of the temporal lobe. Slower processing speed was also associated with decreased connectivity between the primary visual cortices in both hemispheres and the left supplementary motor area, as well as between the right parieto-occipital sulcus and right middle insular area. Overall, slowed processing speed is an important cognitive comorbidity of TLE associated with altered brain structure and connectivity.

In our first paper in this series (Epilepsia2015; 56(5): 674–681), we published recommendations for the indications and expectations for neuropsychological assessment in routine epilepsy care. This partner paper provides a comprehensive overview of the more specialist role of neuropsychological assessment in the pre and postoperative evaluation of epilepsy surgery patients. The paper is in two parts. The first part presents the framework for the mandatory role of neuropsychologists in the presurgical evaluation of epilepsy surgery candidates. A preoperative neuropsychological assessment should be comprised of standardised measures of cognitive function in addition to wider measures of behavioural and psychosocial function. The results from the presurgical assessment are used to: (1) establish a baseline against which change can be measured following surgery; (2) provide a collaborative contribution to seizure characterization, lateralization and localization; (3) provide evidence‐based predictions of cognitive risk associated with the proposed surgery; and (4) provide the evidence base for comprehensive preoperative counselling, including exploration of patient expectations of surgical treatment. The second part examines the critical role of the neuropsychologist in the evaluation of postoperative outcomes. Neuropsychological changes following surgery are dynamic and a comprehensive, long‐term assessment of these changes following surgery should form an integral part of the postoperative follow‐up. The special considerations with respect to pre and postoperative assessment when working with paediatric populations and those with an intellectual disability are also discussed. The paper provides a summary checklist for neuropsychological involvement throughout the epilepsy surgery process, based on the recommendations discussed.

AbstractThe Epilepsy Connectome Project examines the differences in connectomes between temporal lobe epilepsy (TLE) patients and healthy controls. Using these data, the effective connectivity of the default mode network (DMN) in patients with left TLE compared with healthy controls was investigated using spectral dynamic causal modeling (spDCM) of resting-state functional magnetic resonance imaging data. Group comparisons were made using two parametric empirical Bayes (PEB) models. The first level of each PEB model consisted of each participant's spDCM. Two different second-level models were constructed: the first comparing effective connectivity of the groups directly and the second using the Rey Auditory Verbal Learning Test (RAVLT) delayed free recall index as a covariate at the second level to assess effective connectivity controlling for the poor memory performance of left TLE patients. After an automated search over the nested parameter space and thresholding parameters at 95% posterior probability, both models revealed numerous connections in the DMN, which lead to inhibition of the left hippocampal formation. Left hippocampal formation inhibition may be an inherent result of the left temporal epileptogenic focus as memory differences were controlled for in one model and the same connections remained. An excitatory connection from the posterior cingulate cortex to the medial prefrontal cortex was found to be concomitant with left hippocampal formation inhibition in TLE patients when including RAVLT delayed free recall at the second level.

AbstractThe National Institutes of Health-sponsored Epilepsy Connectome Project aims to characterize connectivity changes in temporal lobe epilepsy (TLE) patients. The magnetic resonance imaging protocol follows that used in the Human Connectome Project, and includes 20 min of resting-state functional magnetic resonance imaging acquired at 3T using 8-band multiband imaging. Glasser parcellation atlas was combined with the FreeSurfer subcortical regions to generate resting-state functional connectivity (RSFC), amplitude of low-frequency fluctuations (ALFFs), and fractional ALFF measures. Seven different frequency ranges such as Slow-5 (0.01–0.027 Hz) and Slow-4 (0.027–0.073 Hz) were selected to compute these measures. The goal was to train machine learning classification models to discriminate TLE patients from healthy controls, and to determine which combination of the resting state measure and frequency range produced the best classification model. The samples included age- and gender-matched groups of 60 TLE patients and 59 healthy controls. Three traditional machine learning models were trained: support vector machine, linear discriminant analysis, and naive Bayes classifier. The highest classification accuracy was obtained using RSFC measures in the Slow-4 + 5 band (0.01–0.073 Hz) as features. Leave-one-out cross-validation accuracies were ∼83%, with receiver operating characteristic area-under-the-curve reaching close to 90%. Increased connectivity from right area posterior 9-46v in TLE patients contributed to the high accuracies. With increased sample sizes in the near future, better machine learning models will be trained not only to aid the diagnosis of TLE, but also as a tool to understand this brain disorder.

IMPORTANCE: The effect of childhood epilepsy on later-life cognitive and brain health is an unclear and little-explored issue. OBJECTIVE: To determine whether adults with a history of childhood-onset epilepsy exhibit increased brain amyloid accumulation, possibly predisposing to accelerated cognitive impairment or even frank cognitive disorders in later life. DESIGN, SETTING, AND PARTICIPANTS: Forty-one adults from a population-based cohort of individuals with childhood-onset epilepsy in southwestern Finland, together with 46 matched population-based controls, underwent amyloid ligand carbon 11–labeled Pittsburgh Compound B (PiB) positron emission tomography after long-term prospective follow-up. The PiB uptake was quantified as a region to cerebellar cortex ratio. Tracer uptake was evaluated visually and analyzed voxel by voxel over the entire brain to investigate the spatial distribution of amyloid deposition. The study was conducted from May 2011 to October 2013; data analysis was performed from January 2014 to October 2016. MAIN OUTCOMES AND MEASURES: Brain amyloid accumulation. RESULTS: The 41 individuals with epilepsy were originally enrolled in the Turku Adult Childhood Onset Epilepsy study at the mean (SD) age of 5.1 (4.5) years (range, 0-14 years). After a mean 52.5 (4.0) years of follow-up, the participants were evaluated (26 [63%] were women; the mean [SD] age was 56.0 [4.3] years). Nine individuals with childhood-onset epilepsy (22%) and 3 control participants (7%) had a visually abnormal PiB scan showing high cortical uptake in at least 1 of the evaluated brain regions (P = .04). In semiquantitative analyses, there was a significant interaction effect indicating higher prefrontal cortex uptake in apolipoprotein E (APOE) ε4 allele carriers than in noncarriers in participants (mean [SD], 1.66 [0.41] vs 1.43 [0.15]) compared with controls (1.40 [0.26) vs 1.41 [0.12]) (group × APOE interaction, F = 6.8; P = .01). In addition, there was a significant group effect showing higher tracer uptake in participants compared with controls (group effect, F = 8.0; P = .006). CONCLUSIONS AND RELEVANCE: Adults with childhood-onset epilepsy, particularly APOE ε4 carriers, have an increased brain amyloid load at late middle age. Thus, epilepsy is linked with a biomarker that might be related to accelerated brain aging and can be considered a neurobiological predisposition to later-life cognitive disorders.

Aim. To determine whether first‐degree cousins of children with idiopathic focal and genetic generalized epilepsies show any association across measures of cognition, behaviour, and brain structure. The presence/absence of associations addresses the question of whether and to what extent first‐degree cousins may serve as unbiased controls in research addressing the cognitive, psychiatric, and neuroimaging features of paediatric epilepsies. Methods. Participants were children (aged 8–18) with epilepsy who had at least one first‐degree cousin control enrolled in the study (n=37) and all enrolled cousin controls (n=100). Participants underwent neuropsychological assessment and brain imaging (cortical, subcortical, and cerebellar volumes), and parents completed the Child Behaviour Checklist (CBCL). Data (based on 42 outcome measures) from cousin controls were regressed on the corresponding epilepsy cognitive, behavioural, and imaging measures in a linear mixed model and case/control correlations were examined. Results. Of the 42 uncorrected correlations involving cognitive, behavioural, and neuroimaging measures, only two were significant (p<0.05). The median correlation was 0.06. A test for whether the distribution of pvalues deviated from the null distribution under no association was not significant (p>0.25). Similar results held for the cognition/behaviour and brain imaging measures separately. Conclusions. Given the lack of association between cases and first‐degree cousin performances on measures of cognition, behaviour, and neuroimaging, the results suggest a non‐significant genetic influence on control group performance. First‐degree cousins appear to be unbiased controls for cognitive, behavioural, and neuroimaging research in paediatric epilepsy.

IMPORTANCE: Converging evidence suggests that Alzheimer disease (AD) involves insulin signaling impairment. Patients with AD and individuals at risk for AD show reduced glucose metabolism, as indexed by fludeoxyglucose F 18–labeled positron emission tomography (FDG-PET). OBJECTIVES: To determine whether insulin resistance predicts AD-like global and regional glucose metabolism deficits in late middle–aged participants at risk for AD and to examine whether insulin resistance–predicted variation in regional glucose metabolism is associated with worse cognitive performance. DESIGN, SETTING, AND PARTICIPANTS: This population-based, cross-sectional study included 150 cognitively normal, late middle–aged (mean [SD] age, 60.7 [5.8] years) adults from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) study, a general community sample enriched for AD parental history. Participants underwent cognitive testing, fasting blood draw, and FDG-PET at baseline. We used the homeostatic model assessment of peripheral insulin resistance (HOMA-IR). Regression analysis tested the statistical effect of HOMA-IR on global glucose metabolism. We used a voxelwise analysis to determine whether HOMA-IR predicted regional glucose metabolism. Finally, predicted variation in regional glucose metabolism was regressed against cognitive factors. Covariates included age, sex, body mass index, apolipoprotein E ε4 genotype, AD parental history status, and a reference region used to normalize regional uptake. MAIN OUTCOMES AND MEASURES: Regional glucose uptake determined using FDG-PET and neuropsychological factors. RESULTS: Higher HOMA-IR was associated with lower global glucose metabolism (β = −0.29; P &lt; .01) and lower regional glucose metabolism across large portions of the frontal, lateral parietal, lateral temporal, and medial temporal lobes (P &lt; .001). The association was especially robust in the left medial temporal lobe (R2 = 0.178). Lower glucose metabolism in the left medial temporal lobe predicted by HOMA-IR was significantly related to worse performance on the immediate memory (β = 0.317; t148 = 4.08; P &lt; .001) and delayed memory (β = 0.305; t148 = 3.895; P &lt; .001) factor scores. CONCLUSIONS AND RELEVANCE: Our results show that insulin resistance, a prevalent and increasingly common condition in developed countries, is associated with significantly lower regional cerebral glucose metabolism, which in turn may predict worse memory performance. Midlife may be a critical period for initiating treatments to lower peripheral insulin resistance to maintain neural metabolism and cognitive function.

IMPORTANCE: Although advancing age is the strongest risk factor for the development of symptomatic Alzheimer disease (AD), recent studies have shown that there are individual differences in susceptibility to age-related alterations in the biomarkers of AD pathophysiology. OBJECTIVE: To investigate whether cognitive reserve (CR) modifies the adverse influence of age on key cerebrospinal fluid (CSF) biomarkers of AD. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional cohort of 268 individuals (211 in a cognitively normal group and 57 in a cognitively impaired group) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center participated in this study. They underwent lumbar puncture for collection of CSF samples, from which Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) were immunoassayed. In addition, we computed t-tau/Aβ42 and p-tau/Aβ42 ratios. Cognitive reserve was indexed by years of education, with 16 or more years taken to confer high reserve. Covariate-adjusted regression analyses were used to test whether the effect of age on CSF biomarkers was modified by CR. The study dates were March 5, 2010, to February 13, 2013. MAIN OUTCOMES AND MEASURES: Cerebrospinal fluid levels of Aβ42, t-tau, p-tau, t-tau/Aβ42, and p-tau/Aβ42. RESULTS: There were significant age × CR interactions for CSF t-tau (β [SE] = −6.72 [2.84], P = .02), p-tau (β [SE] = −0.71 [0.27], P = .01), t-tau/Aβ42 (β [SE] = −0.02 [0.01], P = .02), and p-tau/Aβ42 (β [SE] = −0.002 [0.001], P = .004). With advancing age, individuals with high CR exhibited attenuated adverse alterations in these CSF biomarkers compared with individuals with low CR. This attenuation of age effects by CR tended to be more pronounced in the cognitively impaired group compared with the cognitively normal group. There was evidence of a dose-response relationship such that the effect of age on the biomarkers was progressively attenuated given additional years of schooling. CONCLUSIONS AND RELEVANCE: In a sample composed of a cognitively normal group and a cognitively impaired group, higher CR was associated with a diminution of age-related alterations in CSF biomarkers of AD. This suggests one pathway through which CR might favorably alter lifetime risk for symptomatic AD.

Normal childhood development is defined by age-dependent improvement across cognitive abilities, including language, memory, psychomotor speed and executive function. Epilepsy is often associated with a global disruption in cognitive development, however, it is still largely unknown how epilepsy affects the overall organization of overlapping cognitive domains. The aim of the study was to evaluate how childhood epilepsy affects the developmental interrelationships between cognitive domains.

To examine whether engagement in physical activity might favorably alter the age-dependent evolution of Alzheimer disease (AD)-related brain and cognitive changes in a cohort of at-risk, late-middle-aged adults.

Epilepsy is a common neurological disorder that is complicated by psychiatric, cognitive, and social comorbidities that have become a major target of concern and investigation in view of their adverse effect on the course and quality of life. In this report we define the specific psychiatric, cognitive, and social comorbidities of paediatric and adult epilepsy, their epidemiology, and real life effects; examine the relation between epilepsy syndromes and the risk of neurobehavioural comorbidities; address the lifespan effect of epilepsy on brain neurodevelopment and brain ageing and the risk of neurobehavioural comorbidities; consider the overarching effect of broader brain disorders on both epilepsy and neurobehavioural comorbidities; examine directions of causality and the contribution of selected epilepsy-related characteristics; and outline clinic-friendly screening approaches for these problems and recommended pharmacological, behavioural, and educational interventions.

This review examines the neurodevelopmental contribution to the cognitive and behavioural complications of epilepsy. Following a brief review of the lifespan complications of childhood epilepsies, attention turns to cognitive, psychiatric and social correlates of childhood epilepsies reported in population‐based and tertiary care studies. The focus then becomes the neurobehavioural status of children with new‐onset epilepsy; a point in time not confounded by the effects of years of recurrent seizures, medications, and social reactions to epilepsy. Recent research shows that abnormalities in cognition, brain structure and behaviour are present at or near the time of diagnosis. Further, careful history taking indicates that neurobehavioural problems may be present in advance of the first seizure suggesting the potential influence of epileptogenesis, antecedent neuro‐developmental abnormalities, genetic and environmental susceptibilities, and other risk factors. This becomes the substrate upon which to characterise the effects of epilepsy and its treatment on subsequent neurodevelopment. The review concludes with suggestions for future clinical care and research.

Cognitive impairment, particularly memory disruption, is a major complicating feature of epilepsy. This Review will begin with a focus on the problem of memory impairment in temporal lobe epilepsy (TLE). We present a brief overview of anatomical substrates of memory disorders in TLE, followed by a discussion of how our understanding of these disorders has been improved by studying the outcomes of anterior temporal lobectomy. The clinical efforts made to predict which patients are at greatest risk of experiencing adverse cognitive outcomes following epilepsy surgery are also considered. Finally, we examine the vastly changing view of TLE, including findings demonstrating that anatomical abnormalities extend far outside the temporal lobe, and that cognitive impairments extend beyond memory function. Linkage between these distributed cognitive and anatomical abnormalities point to a new understanding of the anatomical architecture of cognitive impairment in epilepsy. Clarifying the origin of these cognitive and anatomical abnormalities, their progression over time and, most importantly, methods for protecting cognitive and brain health in epilepsy, present a challenge to neurologists.

A new literature is now under way, one linking cognitive abnormalities directly to indices of structural, functional, metabolic, and other neurobiologic markers of cerebral integrity, independent of their association with clinical epilepsy characteristics. These trends are reviewed in this article. The focus is on temporal lobe epilepsy (TLE) as a model with which to address the core points because this form of localization-related epilepsy has been very carefully studied from both a cognitive and imaging standpoint. Some pertinent historical issues are touched on first, followed by more detailed reviews of the cognitive and neuroimaging abnormalities that have been found in TLE, followed by an overview of studies examining direct structure-function relationships in TLE and other epilepsies.

People with multiple sclerosis (MS) commonly experience cognitive impairment associated with the disease, but there is currently no agreed-upon operational definition for identifying the presence of that impairment, in either research or clinic contexts. The International MS Cognition Society (IMSCOGS) established a task force to begin to examine this issue and this paper represents the results of an initial pilot investigation. The aim of this paper was to compare two criterion sets to determine how to identify cognitive impairment among people with MS: the general Diagnostic and Statistical Manual (DSM-5) Criteria for neurocognitive disorders and criteria derived from existing MS research (scores in two domains fall 1.5 standard deviations below normative controls).

Recency refers to the information learned at the end of a study list or task. Recency forgetting, as tracked by the ratio between recency recall in immediate and delayed conditions, i.e., the recency ratio (Rr), has been applied to list-learning tasks, demonstrating its efficacy in predicting cognitive decline, conversion to mild cognitive impairment (MCI), and cerebrospinal fluid (CSF) biomarkers of neurodegeneration. However, little is known as to whether Rr can be effectively applied to story recall tasks. To address this question, data were extracted from the database of the Alzheimer’s Disease Research Center at the University of Wisconsin – Madison. A total of 212 participants were included in the study. CSF biomarkers were amyloid-beta (Aβ) 40 and 42, phosphorylated (p) and total (t) tau, neurofilament light (NFL), neurogranin (Ng), and α-synuclein (a-syn). Story Recall was measured with the Logical Memory Test (LMT). We carried out Bayesian regression analyses with Rr, and other LMT scores as predictors; and CSF biomarkers (including the Aβ42/40 and p-tau/Aβ42 ratios) as outcomes. Results showed that models including Rr consistently provided best fits with the data, with few exceptions. These findings demonstrate the applicability of Rr to story recall and its sensitivity to CSF biomarkers of neurodegeneration, and encourage its inclusion when evaluating risk of neurodegeneration with story recall.

Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion imaging technique, which can detect more distinct microstructural features compared to conventional Diffusion Tensor Imaging (DTI). NODDI allows the signal to be divided into multiple water compartments and derive measures for orientation dispersion index (ODI), neurite density index (NDI) and volume fraction of isotropic diffusion compartment (FISO). This study aimed to investigate which diffusion metric—fractional anisotropy (FA), mean diffusivity (MD), NDI, ODI, or FISO—is most influenced by aging and reflects cognitive function in a population of healthy older adults at risk for Alzheimer’s disease (AD). Age was significantly associated with all but one diffusion parameters and regions of interest. NDI and MD in the cingulate region adjacent to the cingulate cortex showed a significant association with a composite measure of Executive Function and was proven to partially mediate the relationship between aging and Executive Function decline. These results suggest that both DTI and NODDI parameters are sensitive to age-related differences in white matter regions vulnerable to aging, particularly among older adults at risk for AD.

Chronic treatment with antiepileptic medication is associated with reduced bone mineral density (BMD), which may underlie the two- to sixfold increase in fracture rates observed in patients with epilepsy. The objective was to determine the timing of the BMD deficit in ambulatory children with epilepsy.

Abnormalities in cognition, academic performance and brain volumetrics have been reported in children with chronic epilepsy. The nature and degree to which these problems may be present at epilepsy onset or may instead become more evident over time remains to be determined. This study characterizes neuropsychological status, brain structure and their interrelationship in children with recent-onset epilepsy compared with healthy controls. Children (age: 8–18 years) with recent-onset idiopathic epilepsy (n = 53) and healthy controls (n = 50) underwent comprehensive neuropsychological assessment and quantitative volumetric measurement of segmented (grey and white matter) volumes of total cerebrum and lobar regions. Compared with controls, children with recent-onset epilepsy exhibit a pattern of mild diffuse cognitive impairment, regardless of epilepsy syndrome, as well as academic underachievement that in a subset of children antedates the first recognized seizure. There are no overall differences in MR morphometric analyses of total cerebral or lobar tissue volumes. Controls show a strong association between cognitive development and increasing cerebral tissue volume (especially white matter volume), an association that is absent in children with epilepsy. Children with a history of academic achievement problems exhibit the most abnormal cognitive function and have significant volumetric reductions in left occipital and parietal lobe grey matter. Patients with idiopathic epilepsy exhibit cognitive dysfunction and academic underachievement at the onset of the disorder, irrespective of epilepsy syndrome, and indications of antecedent neurocognitive impairment are present in a subset of children. Volumetric abnormalities are not yet apparent in the epilepsy group as a whole, but there are indications of an altered structure–function relationship in epilepsy, and the subset of children with prior history of academic problems have abnormal volume of posterior left hemisphere grey matter. These early abnormalities need to be integrated into lifespan models of the neuropsychology of epilepsy.

BACKGROUND Ictal confusion, particularly if protracted, often presents a diagnostic challenge. OBJECTIVES To define protracted ictal confusion in elderly patients and to characterize its features and outcome. DESIGN Case series. SETTING Neurology outpatient and emergency departments at 2 tertiary care centers. PATIENTS Consecutive series of 22 ambulatory patients with acute ictal confusion. MAIN OUTCOME MEASURES Duration of ictal confusion was correlated with age and lesions noted on cerebral images and videoelectroencephalographic studies. RESULTS The ictal basis underlying confusion was not recognized for up to 5 days in 22 patients (mean ± SD age, 70 ± 8.5 years). Twenty patients had partial complex status epilepticus, and 2 patients had newly diagnosed primary generalized status epilepticus. Motor movements were not present in either group, although reduced mood states and ictal neglect were noted in some patients. Fifteen patients had previous episodes (2-10) of protracted ictal confusion. Once identified, treatment reversed confusion, and eventually patients were discharged to home, although a few patients sustained persistent reduction in baseline cognition. CONCLUSIONS Protracted ictal confusion is often not considered in the ambulatory elderly patient, with resulting delay in diagnosis. Electroencephalographic and videoelectroencephalographic studies performed while the patient is experiencing symptoms are crucial to early diagnosis and timely management.Arch Neurol. 2006;63:529-532 --

Confrontation naming ability entails the operation of distinct cognitive operations and the integrity of a distributed neural network. Previous research has indicated a critical role for the left temporal lobe region in naming ability, but there is less agreement about the relative role of distinct temporal lobe regions. In the current paper, we used quantitative MR volumetrics to investigate the relative contribution of the hippocampus and extrahippocampal temporal lobe (segmented gray and white matter) volumes to confrontation naming performance in 53 patients with temporal lobe epilepsy. Findings showed (1) a stronger relationship for left temporal lobe volume than right temporal lobe volume in predicting naming performance; (2) both left temporal lobe white matter volume and left hippocampus volume contributed a significant amount of unique variance to spontaneous naming performance; and (3) left temporal lobe white matter volume but not left hippocampus volume predicted recognition naming performance. (JINS, 2005, 11, 358–366.)

Thirty unilateral anterior temporal lobectomy (ATL) subjects (15 right and 15 left) and 15 controls were presented a multitrial learning task in which unfamiliar faces were paired with biographical information (occupation, city location, and a person's name). Face recognition hits were similar between groups, but the right ATL group committed more false-positive errors to face foils. Both left and right ATL groups were impaired relative to controls in acquiring biographical information, but the deficit was more pronounced for the left ATL group. Recall levels also varied for the different types of biographical information; occupation was most commonly recalled followed by city name and person name. In addition, city and person name recall was more likely when occupation was also recalled. Overall, recall of biographical information was positively correlated with clinical measures of anterograde episodic memory. Findings are discussed in terms of the role of the temporal lobe and associative learning ability in the successful acquisition of new face semantic (biographical) representations. (JINS, 2005, 11, 237–248.)

The background to this study began with the reporting of two Japanese kindreds with the S305N tau mutation. Although the pathological findings in the autopsied cases were well characterized, only limited ante-mortem data were presented. In this study, longitudinal characterization was carried out in two siblings of European ancestry found to have frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) through comprehensive neurobehavioural examinations and other scales at approximate 6-month intervals. Scales included the Mini-Mental State Examination, Short Test of Mental Status, modified motor subtest of the Unified Parkinson's Disease Rating Scale, detailed neuropsychological testing, and the Neuropsychiatric Inventory. Changes in whole-brain volume and ventricular volume were measured from serial MRI studies. All members of the kindred underwent molecular genetic analyses to elucidate the mechanism of inheritance. The missense mutation in tau, S305N, was detected in the proband (onset age 30), who has undergone serial evaluations for almost 4 years. Her older sister (onset age 36) was subsequently found to have the same mutation, and has undergone serial evaluations for 2 years. This mutation is absent in both parents and the only other sibling, and non-paternity was excluded by additional analyses. The siblings have exhibited cognitive and behavioural features typical of FTDP-17, which have proved challenging to manage despite aggressive pharmacological and behavioural therapies. The proband's sister has demonstrated an atypical profile of impairment on neuropsychological testing. Both siblings have developed striking atrophy of the anterior part of temporal lobes and moderate atrophy of the dorsolateral and orbitofrontal cortical regions, which in both cases is relatively symmetrical. The annualized changes in whole-brain volume and ventricular volume, respectively, were −35.2 ml/year (3.23% decrease per year) and +20.75 ml/year (16.93% increase per year) for the proband, and −30.75 ml/year (2.77% decrease per year) and +5.01 ml/year (3.11% increase per year) for the proband's sister. In conclusion, the mutation in these siblings may have arisen during oogenesis in the mother and probably represents germline mosaicism. Although both patients have exhibited the typical cognitive and behavioural features of FTDP-17, one patient is exhibiting an atypical neuropsychological profile. Also, despite a similar topographic pattern of progressive atrophy on MRI, the rates of change in whole-brain volume and ventricular volume between the two patients are quite different. These findings have implications for future drug trial development in FTDP-17 and the sporadic tauopathies.

It is well established that some individuals with temporal lobe epilepsy (TLE) demonstrate language deficits at the single word level. However, discourse production rarely has been examined quantitatively within this group. This study compared adult TLE patients with an early seizure onset (≤ age 14 years, n = 27) to a control group (n = 28) on narrative and procedural discourse tasks. As a group, the TLE patients performed normally on the procedural discourse task, but differed significantly from the controls on several narrative discourse variables. At the individual level, 30% of the TLE patients versus 4% of the controls demonstrated impaired discourse ability (p &lt; .01). Within this early onset TLE group, discourse performance was not associated with demographic or seizure history variables. Considering the cognitive domain, discourse performance correlated significantly with working memory. In summary, mild discourse dysfunction was present in a significant minority of early onset TLE patients, but this deficit was not closely associated with other language measures. Discourse ability and its neuropsychological, neuroanatomical and conversational speech correlates deserve further study in TLE patients. (JINS, 2003, 9, 733–739.)

Neuropsychological studies of temporal lobe epilepsy have focused heavily on the nature and extent of memory dysfunction and its relationship to the neuropathological status of the hippocampus and related mesial temporal lobe structures. In this study, we examined whole brain and lobar quantitative MRI volumes and comprehensive neuropsychological performance in 58 patients with temporal lobe epilepsy and 62 healthy controls in order to determine (1) the nature and degree of extratemporal structural abnormalities in localization-related temporal lobe epilepsy; (2) the nature and degree of cognitive abnormalities outside of anterograde memory function; and (3) the relationship of volumetric abnormalities to neuropsychological status. Temporal lobe epilepsy patients exhibited significant reduction in the volume of adjusted (age, gender, height) total cerebral tissue (−5.8%), more evident in white (−9.8%) compared to gray matter (−3.0%) tissue volumes. Significant volumetric reductions were evident across frontal, temporal and parietal but not occipital lobe regions. Subarachnoid but not total ventricular CSF was significantly increased in epilepsy patients. Neuropsychological abnormality was generalized in nature, consistent with the generalized nature of the morphometric abnormalities, and reductions in cerebral tissue volumes were directly associated with poorer cognitive performance. In summary, patients with temporal lobe epilepsy exhibited clinically significant structural and functional abnormalities that extended outside the epileptogenic temporal lobe. The degree to which these structural and cognitive abnormalities are due to factors that cause the epilepsy, as opposed to reflecting the consequences of chronic epilepsy (e.g., duration and severity of epilepsy), remain to be determined. (JINS, 2003, 9, 353–362.)

ABSTRACTThe purpose of this article is to review aspects of the neuropsychology of temporal lobe epilepsy. Evidence will be presented to demonstrate that the cognitive consequences of this focal seizure disorder can be more generalized in nature than expected. Consistent with the extratemporal neurocognitive findings, careful quantitative magnetic resonance imaging volumetrics have shown that structural brain changes may be detected outside the temporal lobes. Many factors can potentially affect cognition and brain structure. We focus on the potential neurodevelopmental impact of early-onset temporal lobe epilepsy on brain structure and cognition positing that this disorder can have both immediate and lifespan implications for cognition and psychosocial status.

The utility of the WMS–III in detecting lateralized impairment was examined in a large sample of patients with temporal lobe epilepsy. Methods of analysis included evaluation of group means on the various indexes and subtest scores, the use of ROC curves, and an examination of Auditory–Visual Index discrepancy scores. In addition, performance on immediate and delayed indexes in the auditory and the visual modality was compared within each group. Of the WMS–III scores, the Auditory–Visual Delayed Index difference score appeared most sensitive to side of temporal dysfunction, although patient classification rates were not within an acceptable range to have clinical utility. The ability to predict laterality based on statistically significant index score differences was particularly weak for those with left temporal dysfunction. The use of unusually large discrepancies led to improved prediction, however, the rarity of such scores in this population limits their usefulness. Although the utility of the WMS–III in detecting laterality may be limited in preoperative cases, the WMS–III may still hold considerable promise as a measure of memory in documenting baseline performance and in detecting those that may be at risk following surgery. (JINS, 2001, 7, 881–891.)

We evaluated the incidence of de novo nonepileptic seizures (NES), confirmed by EEG monitoring, after cranial surgery for intractable epilepsy in 228 surgery patients. Eight patients (3.5%) developed de novo NES at 6 weeks to 6 years (mean, 23 months) after surgery. Six had undergone a resection and two complete callosotomy. They did not differ from a larger surgical group with respect to sex, side of surgery, age at onset, or duration of epilepsy, Full Scale Intelligence Quotient, seizure outcome, or preoperative interictal dysphoric disorder (IDD), but there was a significant excess of postoperative IDD and operative complications (bone flap infections); the callosotomy patients had marked hemisphere disconnection syndromes. Repeat EEG videotelemetry monitoring is important to detect postoperative NES so that inappropriate therapeutic measures may be avoided. Risk factors may be exacerbation or persistence of IDD and surgical complications. The etiology of NES is discussed.

Purpose. The goals of this work were to determine: (1) the nature and extent of differences in self-reported psychiatric symptoms between patients with temporal lobe epilepsy and matched healthy controls, (2) the relationship between chronicity (duration) of temporal lobe epilepsy and comorbid interictal psychiatric symptoms, and (3) the impact of comorbid psychiatric symptoms on self-reported health-related quality of life.Methods. Patients with temporal lobe epilepsy (n = 54) and healthy controls (n = 38) were administered the Symptom Checklist-90-Revised (SCL-90-R) to assess the nature and severity of psychiatric symptomatology and epilepsy patients completed the Quality of Life in Epilepsy-89 (QOLIE-89) to define health-related quality of life. Among epilepsy patients the SCL-90-R scales were examined in relation to chronicity of temporal lobe epilepsy as well as the impact of comorbid emotional-behavioral distress on health-related quality of life.Results. Compared with healthy controls, patients with epilepsy exhibited significantly higher (worse) scores across all but one of the 12 SCL-90-R scales. Among patients with epilepsy, increasing chronicity was associated with significantly higher (worse) scores across all SCL-90-R scales and increased emotional-behavioral distress was associated with lower (worse) scores across all 17 QOLIE-89 scales.Conclusion. Comorbid interictal psychiatric symptoms are elevated among patients with temporal lobe epilepsy compared with healthy controls and appear to be modestly associated with increasing chronicity (duration) of epilepsy. This comorbid emotional-behavioral distress is specifically associated with a significantly poorer health-related quality of life, and suggests that quality-of-life research should devote greater attention to the potential impact of comorbid psychiatric distress.

Abstract: We have previously devised a semiquantitative grading system for hippocampal sclerosis (HS) in specimens resected for intractable temporal lobe epilepsy. The grades range from zero to four based on the amount and distribution of neuronal loss and gliosis. In the present study hippocampal sections from 25 patients who had temporal lobe epilepsy and had previously been assigned a grade were examined with synaptophysin immunohistochemistry, and the synaptic content in specific hippocampal fields was correlated with the results of the HS grading system. There was evidence of both significant synaptic loss and increased synaptic density in different fields of the hippocampus with increasing HS. A marked decrement of synaptic immunostaining was present in fields CA1 and CA4 that were highly correlated with HS grade. Sector CA4 seemed to respond in a more graded or continuous way to the pathological insults occurring in temporal lobe epilepsy than did CA1, which appeared to exhibit an all or nothing response. Also, while the width of the outer part of the molecular layer of the dentate (mld) gyrus decreased with increasing HS grade, the inner part of the mld became wider and showed an increased synaptic density so that the overall width of the mld was increased in the high-grade group. We conclude that quantitative measurement of synaptic loss in CA1 and CA4 using synaptophysin immunohistochemistry is a sensitive method for detecting HS and correlates well with the empirically derived HS grading scale, with CA4 exhibiting a more graded response than CA1. In addition, a plasticity response in the inner part of the mld in patients with high-grade HS has been confirmed and quantitated.

Neuropsychological and behavioral status were examined in 57 children aged 7 to 16 years with complex partial seizures (CPS) and compared with 27 sibling control children of the same age. Epilepsy had a significant effect on both cognitive and behavioral adjustment measures. Children with CPS had significant impairment across all seven cognitive domains assessed, reflective of a profile of relatively diffuse and generalized cognitive dysfunction. Age at onset of recurrent seizures was the strongest and most consistent predictor of adequacy of cognitive functioning; earlier age at onset was associated with poorer cognitive status. Children with CPS also had more problems compared with sibling control children on measures of social and school competence and internalizing behavior problems, but not externalizing behaviors. Further, frequency of seizure activity in the past year, rather than age at seizure onset, emerged as the strongest predictor of these behavioral difficulties. These findings are discussed in the context of understanding the impact of CPS on cognition and behavioral adjustment, and identifying the contribution of various aspects of the neurodevelopmental course of CPS to these issues.

No abstract.

OBJECTIVE: To identify the neuropsychological features of the syndrome of mesial temporal lobe epilepsy (MTLE), a surgically remediable epileptic syndrome defined by the presence of hippocampal sclerosis, using a broad and comprehensive neuropsychological test battery. SETTING: Epilepsy surgery center. PATIENTS: After scalp and invasive electroencephalographic monitoring, a consecutive series of 107 adults were found to have intractable complex partial seizures of unilateral left (n=62) or right (n=45) temporal lobe origin. Patients were included if they were not retarded and had left hemisphere dominance for speech but no magnetic resonance imaging abnormalities other than hippocampal sclerosis. Histopathological analyses of resected hippocamppi showed that 66 patients had hippocampal sclerosis (MTLE+), and 41 did not have evidence of significant hippocampal sclerosis (MTLE−). INTERVENTIONS: None. MAIN DEPENDENT MEASURES: A comprehensive battery of neuropsychological tests that included measures of intelligence, academic achievement, language, visuoperceptual or visuospatial function, memory and learning, attention, and problem-solving abilities. RESULTS: The syndrome of MTLE was associated with considerable generalized cognitive impairment (in intelligence, academic achievement, language, and visuospatial functions), but not related to adequacy of performances in other selected cognitive domains (attention or concentration, executive functions). Materialspecific memory effects were obtained—primarily for verbal memory in association with left-sided MTLE. CONCLUSIONS: Distinct neuropsychological features of spared, compromised, and laterality-specific cognitive impairments characterize the syndrome of MTLE. This information needs to be incorporated into formal syndrome criteria.

The present paper introduces the reader to the behavioral variability of patients with temporal lobe epilepsy. The neurobiological variability is evidenced by reviewing neurological, neurophysiological, and neuropsychological investigations. The behavioral variability of persons affected by epilepsy with a temporal focus is proposed to be an expression of the neurobiological complexity of temporal lobe epilepsy. The aim of this paper is to encourage endeavors in behavioral taxonomy. Efforts to foster homogeneity through improved classification are considered fundamental in behavioral science and should be applied to epilepsy. The achievement of a behavioral taxonomy may help in both understanding the mechanism(s) of these behavioral disorders and targeting more specific treatments.

Using the Luria-Nebraska Neuropsychological Battery (LNNB), Berg and Golden (1981) assessed 40 patients with epilepsy and reported a hit rate of 77.3% for idiopathic epilepsy and 88.9% for symptomatic epilepsy (82.5% overall). The purpose of this investigation was to attempt to replicate their important findings. A consecutive series of 31 patients with epilepsy was administered the LNNB and we obtained a hit rate of 47% for idiopathic epilepsy and 30% for symptomatic epilepsy (41% overall). Four possible methodological reasons for these disparate findings were offered.