Marielle C. G. Vlooswijk

Loss of network efficiency associated with cognitive decline in chronic epilepsy.

Objective: To study the relation between possibly altered whole brain topology and intellectual decline in chronic epilepsy, a combined study of neurocognitive assessment and graph theoretical network analysis of fMRI was performed. Methods: Forty-one adult patients with cryptogenic localization-related epilepsy and 23 healthy controls underwent an intelligence test and fMRI with a silent-word generation paradigm. A set of undirected graphs was constructed by cross-correlating the signal time series of 893 cortical and subcortical regions. Possible changes in cerebral network efficiency were assessed by performing graph theoretical network analysis. Results: Healthy subjects displayed efficient small world properties, characterized by high clustering and short path lengths. On the contrary, in patients with epilepsy a disruption of both local segregation and global integration was found. An association of more pronounced intellectual decline with more disturbed local segregation was observed in the patient group. The effect of antiepileptic drug use on cognitive decline was mediated by decreased clustering. Conclusions: These findings support the hypothesis that chronic localization-related epilepsy causes cognitive deficits by inducing global cerebral network changes instead of a localized disruption only. Whether this is the result of epilepsy per se or the use of antiepileptic drugs remains to be elucidated. For application in clinical practice, future studies should address the relevance of altered cerebral network topology in prediction of cognitive deficits and monitoring of therapeutic interventions.

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.

Functional connectivity and language impairment in cryptogenic localization-related epilepsy

Background: An often underestimated cognitive morbidity in patients with epilepsy is language dysfunction. To investigate the neuronal mechanisms underlying neuropsychological language impairment, activation maps and functional connectivity networks were studied by fMRI of language. Method: Fifty-two patients with cryptogenic localization-related epilepsy and 27 healthy controls underwent neuropsychological assessment of IQ, word fluency, and text reading. fMRI was performed with a standard covert word-generation and text-reading paradigm. Functional connectivity analysis comprised cross-correlation of signal time series of the characteristic and most strongly activated regions involved in the language tasks. Results: After careful selection, 34 patients and 20 healthy controls were found eligible for analysis. Patients displayed lower IQ, lower fluency word count, and lower number of words correctly read compared to controls. fMRI activation maps did not differ significantly between patients and controls. For the word-generation paradigm, patients with epilepsy had significantly lower functional connectivity than controls in the prefrontal network. Patients performing worse on the word-fluency test demonstrated a significantly lower mean functional connectivity than controls. Text reading demonstrated lower functional connectivity in patients with epilepsy in the frontotemporal network. Similarly, lower mean functional connectivity was observed in patients with lowest reading performance compared to controls. A relation between reduced functional connectivity and performance on word-fluency and text-reading tests was demonstrated in epilepsy patients. Conclusion: Impaired performance on language assessment in epilepsy patients is associated with loss of functional connectivity in the cognitive language networks.

Functional MRI in chronic epilepsy: associations with cognitive impairment

Chronic epilepsy is frequently accompanied by serious cognitive side-effects. Clinical factors are important, but cannot account entirely for this cognitive comorbidity. Therefore, research is focusing on the underlying cerebral mechanisms to understand the development of cognitive dysfunction. In the past two decades, functional MRI techniques have been applied extensively to the study of cognitive impairment in chronic epilepsy. However, because of wide variation in study designs, analysis methods, and data presentation, interpretation of these studies has become increasingly difficult for clinicians. In patients with localisation-related epilepsy, whether findings of functional MRI represent the underlying neuronal substrate for cognitive decline remains a subject of debate.

SUDEP in the Netherlands: A retrospective study in a tertiary referral center

OBJECTIVE To evaluate risk factors for sudden and unexpected death in epilepsy (SUDEP) in a high-risk population, i.e. patients treated in a Dutch tertiary referral center for epilepsy. METHODS All patients who died between January 1999 and April 2004 while under treatment of the epilepsy center were identified. Based on clinical data, deaths were classified as definite, probable, possible or non-SUDEP. Potential risk factors were compared in SUDEP cases and non-SUDEP cases. RESULTS SUDEP incidence was 1.24 per 1000 patient years. SUDEP patients died at a younger age than patients from the control group of non-SUDEP deaths with epilepsy and had an earlier onset of epilepsy. However, the frequently mentioned factors in previous studies, i.e. male sex, generalized tonic-clonic seizures, high seizure frequency, specific AEDs, polytherapy with several AEDs, mental retardation, psychiatric illness and psychotropic comedication, were not found to be correlated with SUDEP. CONCLUSIONS Even in this high-risk population of patients with refractory epilepsy, treated in a tertiary referral center, SUDEP is not a frequently occurring phenomenon. Specific risk factors could not be identified within an already high-risk population.

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.

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.

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.

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.

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.