Resective Epilepsy Surgery, QUality of life and Economic evaluation (RESQUE): the change in quality of life after resective epilepsy surgery-protocol for a multicentre, prospective cohort study.

INTRODUCTION: Resective epilepsy surgery is often seen as a last resort when treating drug-resistant epilepsy. Positive results on quality of life (QoL) and economic benefits after surgery argue for a less restrictive attitude towards epilepsy surgery for drug-resistant epilepsy. QoL and economic benefits are country-dependent. The objective of the Resective Epilepsy Surgery, QUality of life and Economic evaluation (RESQUE) trial is to evaluate the change in QoL before and after epilepsy surgery in Dutch people with drug-resistant epilepsy. The results will form part of an economic evaluation of epilepsy surgery in people with epilepsy (PWE) in The Netherlands. METHODS AND ANALYSIS: A longitudinal prospective multicentre cohort study involving 100 PWE undergoing epilepsy surgery between 2019 and 2025 is being performed in three Dutch academic hospitals. Excluded are PWE who have a lower level of intelligence (TIQ<70) or who do not master the Dutch language. Before surgery and 3, 6, 12 and 24 months after surgery, PWE receive validated online questionnaires (QOLIE-31, EQ-5D, iMCQ and iPCQ) on QoL, cost of care, expectations and satisfaction. Primary outcome is the change in QoL. Secondary outcomes are change in generic QoL, seizure reduction (International League Against Epilepsy Outcome Classification), medical consumption, productivity, the correlation between QoL and seizure reduction and expectation of and satisfaction with the surgery. ETHICS AND DISSEMINATION: The study design has been approved by the Medical Ethics Review Committee (METC) of Maastricht UMC+ (2019-1134) and the Amsterdam UMC (vu). At the time of writing, UMC Utrecht is in the process of considering approval. The study will be conducted according to the Dutch Medical Research Involving Human Subjects Act and the Declaration of Helsinki. The results will be publicly disclosed and submitted for publication in international peer-reviewed scientific journals. There is no veto on publication by the involved parties. TRIAL REGISTRATION: NL8278; Pre-results.

Predictive value of functional MRI and EEG in epilepsy diagnosis after a first seizure.

It is often difficult to predict seizure recurrence in subjects who have suffered a first-ever epileptic seizure. In this study, the predictive value of physiological signals measured using Electroencephalography (EEG) and functional MRI (fMRI) is assessed. In particular those patients developing epilepsy (i.e. a second unprovoked seizure) that were initially evaluated as having a low risk of seizure recurrence are of interest. In total, 26 epilepsy patients, of which 8 were initially evaluated as having a low risk of seizure recurrence (i.e. converters), and 17 subjects with only a single seizure were included. All subjects underwent routine EEG as well as fMRI measurements. For diagnostic classification, features related to the temporal dynamics were determined for both the processed EEG and fMRI data. Subsequently, a logistic regression classifier was trained on epilepsy and first-seizure subjects. The trained model was tested using the clinically relevant converters group. The sensitivity, specificity, and AUC (mean ±â€¯SD) of the regression model including metrics from both modalities were 74 ±â€¯19%, 82 ±â€¯18%, and 0.75 ±â€¯0.12, respectively. Positive and negative predictive values (mean ±â€¯SD) of the regression model with both EEG and fMRI features are 84 ±â€¯14% and 78 ±â€¯12%. Moreover, this EEG/fMRI model showed significant improvements compared to the clinical diagnosis, whereas the models using metrics from either EEG or fMRI do not reach significance (p > 0.05). Temporal metrics computationally derived from EEG and fMRI time signals may clinically aid and synergistically improve the predictive value in a first-seizure sample.

Volumetric and Functional Activity Lateralization in Healthy Subjects and Patients with Focal Epilepsy: Initial Findings in a 7T MRI Study.

BACKGROUND AND PURPOSE: In 30% of the patients with focal epilepsy, an epileptogenic lesion cannot be visually detected with structural MRI. Ultra-high field MRI may be able to identify subtle pathology related to the epileptic focus. We set out to assess 7T MRI-derived volumetric and functional activity lateralization of the hippocampus, hippocampal subfields, temporal and frontal lobe in healthy subjects and MRI-negative patients with focal epilepsy. METHODS: Twenty controls and 10 patients with MRI-negative temporal or frontal lobe epilepsy (TLE and FLE, respectively) underwent a 7T MRI exam. T1 -weigthed imaging and resting-state fMRI was performed. T1 -weighted images were segmented to yield volumes, while from fMRI data, the fractional amplitude of low frequency fluctuations was calculated. Subsequently, volumetric and functional lateralization was calculated from left-right asymmetry. RESULTS: In controls, volumetric lateralization was symmetric, with a slight asymmetry of the hippocampus and subiculum, while functional lateralization consistently showed symmetry. Contrarily, in epilepsy patients, regions were less symmetric. In TLE patients with known focus, volumetric lateralization in the hippocampus and hippocampal subfields was indicative of smaller ipsilateral volumes. These patients also showed clear functional lateralization, though not consistently ipsilateral or contralateral to the epileptic focus. TLE patients with unknown focus showed an obvious volumetric lateralization, facilitating the localization of the epileptic focus. Lateralization results in the FLE patients were less consistent with the epileptic focus. CONCLUSION: MRI-derived volume and fluctuation amplitude are highly symmetric in controls, whereas in TLE, volumetric and functional lateralization effects were observed. This highlights the potential of the technique.

Single-Cell Recordings to Target the Anterior Nucleus of the Thalamus in Deep Brain Stimulation for Patients with Refractory Epilepsy.

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a promising treatment for patients with refractory epilepsy. However, therapy response varies and precise positioning of the DBS lead is potentially essential for maximizing therapeutic efficacy. We investigate if single-cell recordings acquired by microelectrode recordings can aid targeting of the ANT during surgery and hypothesize that the neuronal firing properties of the target region relate to clinical outcome. We prospectively included 10 refractory epilepsy patients and performed microelectrode recordings under general anesthesia to identify the change in neuronal signals when approaching and transecting the ANT. The neuronal firing properties of the target region, anatomical locations of microelectrode recordings and active contact positions of the DBS lead along the recorded trajectory were compared between responders and nonresponders to DBS. We obtained 19 sets of recordings from 10 patients (five responders and five nonresponders). Amongst the 403 neurons detected, 365 (90.6%) were classified as bursty. Entry into the ANT was characterized by an increase in firing rate while exit of the ANT was characterized by a decrease in firing rate. Comparing the trajectories of responders to nonresponders, we found differences neither in the neuronal firing properties themselves nor in their locations relative to the position of the active contact. Single-cell firing rate acquired by microelectrode recordings under general anesthesia can thus aid targeting of the ANT during surgery, but is not related to clinical outcome in DBS for patients with refractory epilepsy.

Structural covariance networks relate to the severity of epilepsy with focal-onset seizures.

PURPOSE: The brains of patients with epilepsy may exhibit various morphological abnormalities, which are often not directly visible on structural MR images, as they may be focally subtle or related to a more large-scale inconspicuous disorganization of brain structures. To explore the relation between structural brain organization and epilepsy characteristics, including severity and cognitive co-morbidity, we determined structural covariance networks (SCNs). SCNs represent interregional correlations of morphologic measures, for instance in terms of cortical thickness, between various large-scale distributed brain regions. METHODS: Thirty-eight patients with focal seizures of all subtypes and 21 healthy controls underwent structural MRI, neurological, and IQ assessment. Cortical thickness was derived from the structural MRIs using FreeSurfer. Subsequently, SCNs were constructed on a group-level based on correlations of the cortical thicknesses between various brain regions. Individual SCNs for the epilepsy patients were extracted by adding the respective patient to the control group prior to the SCN construction (i.e. add-one-patient approach). Calculated network measures, i.e. path length, clustering coefficient and betweenness centrality were correlated with characteristics related to the severity of epilepsy, including seizure history and age at onset of epilepsy, and cognitive performance. RESULTS: Stronger clustering in the individual SCN was associated with a higher number of focal to bilateral tonic-clonic seizures during life time, a younger age at onset, and lower cognitive performance. The path length of the individual SCN was not related to the severity of epilepsy or cognitive performance. Higher betweenness centrality of the left cuneus and lower betweenness centrality of the right rostral middle frontal gyrus were associated with increased drug load and younger age at onset, respectively. CONCLUSIONS: These results indicate that the correlations between interregional variations of cortical thickness reflect disease characteristics or responses to the disease and deficits in patients with epilepsy with focal seizures.

High field imaging of large-scale neurotransmitter networks: Proof of concept and initial application to epilepsy.

The brain can be considered a network, existing of multiple interconnected areas with various functions. MRI provides opportunities to map the large-scale network organization of the brain. We tap into the neurobiochemical dimension of these networks, as neuronal functioning and signal trafficking across distributed brain regions relies on the release and presence of neurotransmitters. Using high-field MR spectroscopic imaging at 7.0 T, we obtained a non-invasive snapshot of the spatial distribution of the neurotransmitters GABA and glutamate, and investigated interregional associations of these neurotransmitters. We demonstrate that interregional correlations of glutamate and GABA concentrations can be conceptualized as networks. Furthermore, patients with epilepsy display an increased number of glutamate and GABA connections and increased average strength of the GABA network. The increased glutamate and GABA connectivity in epilepsy might indicate a disrupted neurotransmitter balance. In addition to epilepsy, the 'neurotransmitter networks' concept might also provide new insights for other neurological diseases.

Anti-GAD antibodies in a cohort of neuropsychiatric patients.

OBJECTIVE: Antiglutamate decarboxylase (anti-GAD) antibodies are associated with several neurological manifestations, like epilepsy and movement disorders. However, in daily neurological practice, it remains hard to define when to test for anti-GAD antibodies in patients with neurologic and/or psychiatric symptoms. Therefore, here, we report the patient characteristics of a large retrospective cohort of patients tested for anti-GAD antibodies in clinical practice and compare the characteristics of anti-GAD positive and anti-GAD negative patients. METHODS: We blindly assessed relevant clinical symptoms and comorbidities and functional outcome with the modified Rankin Scale (mRS) in a retrospective observational cohort of all patients in which the decision to assess anti-GAD levels had been made based solely on the presence of possible associated neurological and/or psychiatric symptoms (N=119). RESULTS: Out of 119 patients, 17 (14.3%) were anti-GAD positive. The anti-GAD positive patients had a median age of 30years (range: 3-64; 2 children). They all had epilepsy, with 8 (47%) patients reporting cognitive complaints. Psychiatric symptoms were less prevalent in anti-GAD positive patients, only 1 anti-GAD positive patient (6%) versus 34 anti-GAD negative patients (33%) reported psychiatric symptoms (p=0.021). The most frequent comorbidity of anti-GAD positive patients was diabetes mellitus type 1 (n=8). Twelve (71%) and 13 (78%) of the anti-GAD positive patients were functionally independent at the time of diagnosis and after one year, respectively (mRS score: 0 to 2). There was no significant difference in functional status at any time during follow-up compared with the anti-GAD negative group. CONCLUSION: Antiglutamate decarboxylase (anti-GAD) antibodies relate to epilepsy with or without cognitive complaints. However, psychiatric symptoms were almost absent in anti-GAD positive patients, and the presence of anti-GAD antibodies contributed little to the prognosis in our cohort.

Mortality after primary intracerebral hemorrhage in relation to post-stroke seizures.

Seizures after intracerebral hemorrhage are repeatedly seen. Whether the development of seizures after intracerebral hemorrhage affects survival in the long term is unknown. This study aims to determine the relation between seizures (i.e., with and without anti-epileptic therapy) and long-term mortality risk in a large patient population with intracerebral hemorrhage. We retrospectively included patients with a non-traumatic ICH in all three hospitals in the South Limburg region in the Netherlands between January 1st 2004 and December 31st 2009, and we assessed all-cause mortality until March 14th 2016. Patient who did not survive the first seven days after intracerebral hemorrhage were excluded from analyses. We used Cox multivariate analyses to determine independent predictors of mortality. Of 1214 patients, 783 hemorrhagic stroke patients fulfilled the inclusion criteria, amongst whom 37 (4.7%) patients developed early seizures (within 7 days after hemorrhage) and 77 (9.8%) developed late seizures (more than 7 days after hemorrhage). Seizure development was not significantly related to mortality risk after correction for conventional vascular risk factors and hemorrhage severity. However, we found a small but independent relation between the use of anti-epileptic drugs and a lower long-term mortality (HR = 0.32, 95% CI 0.11-0.91). In our large population, seizures and epilepsy did not relate independently to an increased mortality risk after hemorrhage.

Towards prognostic biomarkers from BOLD fluctuations to differentiate a first epileptic seizure from new-onset epilepsy.

OBJECTIVE: The diagnosis of epilepsy cannot be reliably made prior to a patient's second seizure in most cases. Therefore, adequate diagnostic tools are needed to differentiate subjects with a first seizure from those with a seizure preceding the onset of epilepsy. The objective was to explore spontaneous blood oxygen level-dependent (BOLD) fluctuations in subjects with a first-ever seizure and patients with new-onset epilepsy (NOE), and to find characteristic biomarkers for seizure recurrence after the first seizure. METHODS: We examined 17 first-seizure subjects, 19 patients with new-onset epilepsy (NOE), and 18 healthy controls. All subjects underwent clinical investigation and received electroencephalography and resting-state functional magnetic resonance imaging (MRI). The BOLD time series were analyzed in terms of regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFFs). RESULTS: We found significantly stronger amplitudes (higher fALFFs) in patients with NOE relative to first-seizure subjects and healthy controls. The frequency range of 73-198 mHz (slow-3 subband) appeared most useful for discriminating patients with NOE from first-seizure subjects. The ReHo measure did not show any significant differences. SIGNIFICANCE: The fALFF appears to be a noninvasive measure that characterizes spontaneous BOLD fluctuations and shows stronger amplitudes in the slow-3 subband of patients with NOE relative first-seizure subjects and healthy controls. A larger study population with follow-up is required to determine whether fALFF holds promise as a potential biomarker for identifying subjects at increased risk to develop epilepsy.

Abnormal Profiles of Local Functional Connectivity Proximal to Focal Cortical Dysplasias.

INTRODUCTION: Focal cortical dysplasia (FCD) is a congenital malformation of cortical development that often leads to medically refractory epilepsy. Focal resection can be an effective treatment, but is challenging as the surgically relevant abnormality may exceed the MR-visible lesion. The aim of the current study is to develop methodology to characterize the profile of functional connectivity around FCDs using resting-state functional MRI and in the individual patient. The detection of aberrant connectivity may provide a means to more completely delineate the clinically relevant lesion. MATERIALS AND METHODS: Fifteen FCD patients (age, mean±SD: 31±11 years; 11 males) and 16 matched healthy controls (35±9 years; 7 males) underwent structural and functional imaging at 3 Tesla. The cortical surface was reconstructed from the T1-weighted scan and the registered functional MRI data was spatially normalized to a common anatomical standard space employing the gyral pattern. Seed-based functional connectivity was determined in all subjects for all dysplasia locations. A single patient was excluded based on an aberrant FCD seed time series. Functional connectivity as a function of geodesic distance (along the cortical surface) was compared between the individual patients and the homotopic normative connectivity profiles derived from the controls. RESULTS: In 12/14 patients, aberrant profiles of functional connectivity were found, which demonstrated both hyper- and hypoconnectivity as well as combinations. Abnormal functional connectivity was typically found (also) beyond the lesion visible on structural MRI, while functional connectivity profiles not related to a lesion appeared normal in patients. CONCLUSION: This novel functional MRI technique has potential for delineating functionally aberrant from normal cortex beyond the structural lesion in FCD, which remains to be confirmed in future research.

Metabolic and functional MR biomarkers of antiepileptic drug effectiveness: A review.

As a large number of patients with epilepsy do not respond favorably to antiepileptic drugs (AEDs), a better understanding of treatment failure and the cause of adverse side effects is required. The working mechanisms of AEDs also alter neurotransmitter concentrations and brain activity, which can be measured using MR spectroscopy and functional MR imaging, respectively. This review presents an overview of clinical research of MR spectroscopy and functional MR imaging studies to the effects of AEDs on the brain. Despite the scarcity of studies associating MR findings to the effectiveness of AEDs, the current research shows clear potential regarding this matter. Several GABAergic AEDs have been shown to increase the GABA concentration, which was related to seizure reductions, while language problems due to topiramate have been associated with altered activation patterns measured with functional MR imaging. MR spectroscopy and functional MR imaging provide biomarkers that may predict individual treatment outcomes, and enable the assessment of mechanisms of treatment failure and cognitive side effects.

Early seizures after intracerebral hemorrhage predict drug-resistant epilepsy.

Seizures are a common complication after an intracerebral hemorrhage (ICH) and the epilepsy might even be drug resistant. It is not known which factors determine the treatment response in post-ICH epilepsy. We included ICH patients retrospectively who survived at least the first 7 days, in the period from 2004 to 2009 and assessed seizure occurrence up to May 2013. We defined early seizures (ES) as seizures occurring within the first 7 days after the ICH, and late seizures (LS) as seizures occurring later than 7 days after the ICH. We defined drug-resistant epilepsy as a non-response to two adequately chosen and dosed drug regimens. In 857 patients surviving at least 7 days after ICH 69 (8.1 %), patients developed ES whereas LS occurred in 84 (9.8 %) subjects. Patients with ES had higher odds to develop LS, as compared to patients without ES [OR 3.4; 95 % confidence interval (CI) 2.1-5.6]. Drug-resistant post-ICH epilepsy occurred in 19 patients (22.6 %). The most important independent risk factor was the occurrence of ES (OR 3.0; 95 %-CI 1.1-8.4). ES are the main independent risk factor for the development of LS and for the development of drug-resistant epilepsy. Thus, ES might hallmark the start of chronic epilepsy after intracerebral hemorrhage and are not to be considered of no significance.

White matter network abnormalities are associated with cognitive decline in chronic epilepsy.

Patients with chronic epilepsy frequently display cognitive comorbidity and might have widespread network abnormalities outside the epileptic zone, which might affect a variety of cognitive functions and global intelligence. We aimed to study the role of white matter connectivity in cognitive comorbidity. Thirty-nine patients with nonsymptomatic localization-related epilepsy and varying degrees of cognitive impairment and 23 age-matched healthy controls were included. Whole brain white matter networks were constructed from fiber tractography. Weighted graph theoretical analysis was performed to study white matter network abnormalities associated with epilepsy and cognition. Patients with severe cognitive impairment showed lower clustering (a measure of brain network segregation) and higher path length (a measure of brain network integration) compared with the healthy controls and patients with little or no cognitive impairment, whereas whole brain white matter volume did not differ. Correlation analyses revealed that IQ and cognitive impairment were strongly associated with clustering and path lengths. This study revealed impaired white matter connectivity, associated with cognitive comorbidity in patients with chronic epilepsy. As whole brain white matter volumes were preserved in the patient group, our results suggest an important role for the network topology rather than volumetric changes, in epilepsy with cognitive decline.

Memory processes and prefrontal network dysfunction in cryptogenic epilepsy.

PURPOSE: Impaired memory performance is the most frequently reported cognitive problem in patients with chronic epilepsy. To examine memory deficits many studies have focused on the role of the mesiotemporal lobe, mostly with hippocampal abnormalities. However, the role of the prefrontal brain remains unresolved. To investigate the neuronal correlates of working memory dysfunction in patients without structural lesions, a combined study of neurocognitive assessment, hippocampal and cerebral volumetry, and functional magnetic resonance imaging of temporal and frontal memory networks was performed. METHODS: Thirty-six patients with cryptogenic localization-related epilepsy and 21 healthy controls underwent neuropsychological assessment of intelligence (IQ) and memory. On T(1) -weighted images obtained by 3-Tesla magnetic resonance imaging (MRI), volumetry of the hippocampi and the cerebrum was performed. Functional MRI (fMRI) was performed with a novel picture encoding and Sternberg paradigm that activated different memory-mediating brain regions. Functional connectivity analysis comprised cross-correlation of signal time-series of the most strongly activated regions involved in working memory function. KEY FINDINGS: Patients with epilepsy displayed lower IQ values; impaired transient aspects of information processing, as indicated by lower scores on the digit-symbol substitution test (DSST); and decreased short-term memory performance relative to healthy controls, as measured with the Wechsler Adult Intelligence Scale subtests for working memory, and word and figure recognition. This could not be related to any hippocampal volume changes. No group differences were found regarding volumetry or fMRI-derived functional activation. In the Sternberg paradigm, a network involving the anterior cingulate and the middle and inferior frontal gyrus was activated. A reduced strength of four connections in this prefrontal network was associated with the DSST and word recognition performance in the patient group. SIGNIFICANCE: Deficits in the processes involved in transient working memory, and to a lesser extent in short-term memory, in patients with localization-related epilepsy of both temporal and extratemporal origin cannot be attributed to hippocampal atrophy or function only, but are also related to reduced functional connectivity in the prefrontal brain. Because patients with symptomatic lesions or mesiotemporal sclerosis were excluded from this study, the results cannot be explained by structural lesions. Therefore, the current findings highlight the influence of epilepsy on the prefrontal network integrity as a possible underlying problem of memory impairment.

Hippocampal MRI volumetry at 3 Tesla: reliability and practical guidance.

OBJECTIVES: Although volumetry of the hippocampus is considered to be an established technique, protocols reported in literature are not described in great detail. This article provides a complete and detailed protocol for hippocampal volumetry applicable to T1-weighted magnetic resonance (MR) images acquired at 3 Tesla, which has become the standard for structural brain research. MATERIALS AND METHODS: The protocol encompasses T1-weighted image acquisition at 3 Tesla, anatomic guidelines for manual hippocampus delineation, requirements of delineation software, reliability measures, and criteria to assess and ensure sufficient reliability. Moreover, the validity of the correction for total intracranial volume size was critically assessed. The protocol was applied by 2 readers to the MR images of 36 patients with cryptogenic localization-related epilepsy, 4 patients with unilateral hippocampal sclerosis, and 20 healthy control subjects. RESULTS: The uncorrected hippocampal volumes were 2923 +/- 500 mm3 (mean +/- SD) (left) and 3120 +/- 416 mm3 (right) for the patient group and 3185 +/- 411 mm3 (left) and 3302 +/- 411 mm3 (right) for the healthy control group. The volume of the 4 pathologic hippocampi of the patients with unilateral hippocampal sclerosis was 2980 +/- 422 mm3. The inter-reader reliability values were determined: intraclass-correlation-coefficient (ICC) = 0.87 (left) and 0.86 (right), percentage volume difference (VD) = 7.0 +/- 4.7% (left) and 6.0 +/- 3.8% (right), and overlap ratio (OR) = 0.82 +/- 0.04 (left) and 0.82 +/- 0.03 (right). The positive Pearson correlation between hippocampal volume and total intracranial volume was found to be low: r = 0.48 (P = 0.03, left) and r = 0.62 (P = 0.004, right) and did not significantly reduce the volumetric variances, showing the limited benefit of the brain size correction. CONCLUSIONS: A protocol was described to determine hippocampal volumes based on 3 Tesla MR images with high inter-reader reliability. Although the reliability of hippocampal volumetry at 3 Tesla was similar to the literature values obtained at 1.5 Tesla, hippocampal border definition is argued to be more confident and easier because of the improved signal-to-noise characteristics.

White matter lesions in patients with localization-related epilepsy.

OBJECTIVES: White matter lesions (WML) have been proven to be associated with cognitive impairment. As (1) the decline of cognitive function is the most frequent comorbid disorder in epilepsy, and (2) patients with epilepsy have a relatively high prevalence of WML, the question is raised whether WML in patients with epilepsy are also associated with cognitive decline. MATERIALS AND METHODS: A high-resolution magnetic resonance imaging examination was performed at 3.0 T, comprising T1-weighted, T2 relaxometry, and fluid-attenuated inversion recovery (FLAIR) sequences. Patients with localization-related epilepsy with impaired and unimpaired cognitive functioning and a healthy control group were included. Furthermore, the performance of an automated WML detection algorithm, based on regional intensity evaluation, was assessed. RESULTS: The prevalence of WML, detected on 3.0 T FLAIR images, is 63% in healthy volunteers and 46% in patients with localization-related, cryptogenic epilepsy. No relationship between WML volume and cognitive performance was observed. The WML volumes from the automated segmentation method were found to be significantly correlated to the volumes obtained by neuroradiologic assessment. CONCLUSIONS: No relations could be found between WML and cognition in the well-defined population of patients with epilepsy. Other clinical characteristics of chronic epilepsy, such as seizures, age of onset, and medication are more likely to play an important role in cognitive decline. Furthermore, the automated WML detection algorithm using a regional Z-score analysis can successfully segment and quantify the WML on FLAIR images.

Cognitive fMRI and neuropsychological assessment in patients with secondarily generalized seizures.

OBJECTIVES: Cognitive dysfunction is a frequent comorbid disorder in epilepsy which has been associated with high seizure frequency. We examined the effect of secondarily generalized tonic-clonic seizures (SGTCS) on cognitive dysfunction using neuropsychological assessment and fMRI. PATIENTS AND METHODS: Sixteen patients with localization-related epilepsy of varying etiologies and SGTCS underwent extensive neuropsychological assessment. Functional MRI was performed probing the frontal and temporal lobes with two paradigms aimed at investigating speed of mental processing and working memory. RESULTS: A high number of total lifetime SGTCS was associated with lower intelligence scores. Moreover, a trend towards cognitive decline related to the number of SGTCS was observed. A relatively increased prefrontal activation related to the number of SGTCS was demonstrated, plus a trend towards a decreased activation in the frontotemporal areas. CONCLUSION: High numbers of SGTCS are associated with a drop in intelligence scores and altered prefrontal brain activation. A shift from frontotemporal to prefrontal activation seems to have occurred, suggesting that a functional reorganization of working memory is induced by a high number of SGTCS. It remains uncertain if this reorganization reflects a compensation mechanism, or the underlying pathological processes of cognitive dysfunction.