EDITORIAL

How localized is localization-related epilepsy?

Kimford J. Meador, MD Bruce Hermann, PhD

Address correspondence and reprint requests to Dr. Kimford J. Meador, Department of Neurology, Emory University, Woodruff Memorial Research Building, 101 Woodruff Circle, Suite 6000, Atlanta, GA 30322 [email protected]

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The most common localization-related epilepsy is temporal lobe epilepsy (TLE). Traditionally, TLE has been considered a localized disorder given the focal mesial temporal onset of seizures, hippocampal atrophy and sclerosis, and therapeutic response to focal resection of the anteromedial temporal lobe. However, there is growing evidence of more diffuse anatomic and functional abnormalities. Patients with TLE exhibit dysfunction of the anterior temporal lobe (e.g., memory formation and naming), but they also can exhibit abnormal cognitive functions not associated with focal dysfunction of the anterior temporal lobes. The reason for these unanticipated cognitive findings is becoming clearer. MRI studies have provided evidence for reduced volumes in multiple brain regions in TLE including extrahippocampal temporal, frontal, parietal, and occipital lobes, and diverse subcortical structures, which involve not only the hippocampus and parahippocampal gyrus, but also the thalamus, caudate, amygdala, and cerebellum.1 Diffuse abnormalities of the cortical mantle also occur, including markers of gray matter complexity and thickness in temporal lobe and in extratemporal regions ipsilateral and contralateral to the side of temporal lobe seizure onset.2 Positron emission tomography studies demonstrate metabolic abnormalities not only in mesial temporal lobe, but also in the lateral temporal lobe, frontal lobe, basal ganglia, and thalamus.3 Magnetic resonance spectral imaging has shown abnormalities in the same structures.4 In the last few years, diffusion tensor imaging (DTI) has revealed white matter abnormalities that are most pronounced in the temporal lobe with the seizure focus, but extend beyond the temporal lobes and even to the opposite hemisphere. Diffusion abnormalities were first reported in the fornix and cingulum, and later found in frontal-temporal (uncinate fasciculus and arcuate fasciculus), temporal-occipital (inferior longitudinal fasciculus), frontal-occipital (inferior frontal occipital fasciculus), and interhemi-

spheric connections (corpus callosum).5 Parallel to the gray matter studies, the DTI studies show extensive bilateral abnormalities in cortical-cortical, cortical-subcortical, and interhemispheric connections, despite unilateral seizure onset. Overall, these distributed morphometric and metabolic abnormalities in cortical and subcortical regions, along with disrupted intrahemispheric and interhemispheric connectivity, provide new insights into the underlying architecture of cognitive impairment in epilepsy. Indeed, recent studies have examined the relationship of white matter integrity and functional connectivity to cognitive abilities. In patients with TLE, atypical language lateralization appears to be related to differences in organization of white matter tracts.6 In addition, the integrity of the temporal lobe white matter is related to postoperative changes in naming.7 Structural abnormalities in multiple white matter tracts as demonstrated by DTI tractography have been related to verbal memory and language impairments.8 In this issue of Neurology, Vlooswijk et al.9 extend this line of research by examining the relationship of language abilities to functional connectivity as measured by fMRI during performance of language tasks in patients with frontal or temporal lobe epilepsy. The patients had lower language performance than healthy controls, but the pattern of fMRI activations did not differ significantly. In contrast, the patients exhibited lower fMRI functional connectivity than controls, which was related to their language performance. Previous studies demonstrated that cognitive performance in patients with TLE is related to widespread changes in gray matter volumes10 and in white matter integrity.8 Vlooswijk and colleagues begin to bridge the gap between anatomic abnormalities and cognitive deficits in patients with focal epilepsy. Their study demonstrates disruption of normal physiologic interactions across widespread brain regions, which are related to reduced cognitive performance. A statistical correlation does not imply causation. The reduction in correlation of fMRI activity across

See page 395 From the Department of Neurology (K.J.M.), Emory University, Atlanta, GA; and the Department of Neurology (B.H.), University of Wisconsin, Madison. Disclosure: Author disclosures are provided at the end of the editorial. 386

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these regions may contribute to reduce cognitive performance, or it may be secondary to reduced cognitive performance. The reduced correlation of neural activity may be due, in turn, to loss of neurons, impaired white matter integrity, or direct effects of altered neuronal physiology. Further, it is unclear why these anatomic and functional abnormalities occur outside of the region of seizure onset. These widespread abnormalities might be due to direct effects of repetitive seizure spread, systemic effects of convulsions (e.g., hypoxia), distal effects of focal interictal discharges, antiepileptic drug effects, or disease processes predating seizure onset, which may also underline the etiology of the patient’s epilepsy. In addition, initial or recurrent seizures may alter brain development, affecting brain structure and function. Reorganization of cognitive functions (e.g., language lateralization or intrahemispheric representation) can occur in focal epilepsy (e.g., TLE), especially when onset is at younger ages. Further studies are needed to delineate the extent of these abnormalities, establish the role of such measures in the preoperative evaluation for epilepsy surgery, determine contributing factors and underlying mechanisms, and transform such knowledge to therapies that can improve function in patients with localizationrelated epilepsy. DISCLOSURE Prof. Meador serves on the editorial boards of Neurology® and Behavior & Neurology and on the Professional Advisory Board for the Epilepsy Foundation and has received/receives research support from GlaxoSmithKline, Eisai Inc., Marinus Pharmaceuticals, Inc., Myriad Genetics, Inc., NeuroPace, Inc., SAM Technology Inc., Schwarz Pharma (UCB), the NIH (NINDS 2RO1-NS38455 Meador [PI], NINDS R01-NSO31966-11A2 [consultant], NINDS N01-NS-5–2364 [consultant], NINDS R01NSO39466 [Co-I], and 1RC1MD004563 [Co-I]) and the Epilepsy Foundation. Dr. Hermann serves as an Associate Editor of Epilepsia and

receives research support from the NIH (NINDS 2RO1 NS44351 [PI], R01 AG027161 [Co-I], P50AG3314 [Co-I], 1R01NS064034 [Co-I], and RO1AG031790 [Co-I]).

REFERENCES 1. Keller SS, Roberts N. Voxel-based morphometry of temporal lobe epilepsy: an introduction and review of the literature. Epilepsia 2008;49:741–757. 2. Bernhardt BC, Worsley KJ, Besson P, et al. Mapping limbic network organization in temporal lobe epilepsy using morphometric correlations: insights on the relation between mesiotemporal connectivity and cortical atrophy. Neuroimage 2008;42:515–524. 3. Henry HR, Mazziotta JC, Engel J Jr. Interictal metabolic anatomy of mesial temporal lobe epilepsy. Arch Neurol 1993;50:582–589. 4. Hetherington HP, Kuzniecky RI, Vives K, et al. A subcortical network of dysfunction in TLE measured by magnetic resonance spectroscopy. Neurology 2007;69:2256 –2265. 5. Concha L, Beaulieu C, Collins DL, Gross DW. Whitematter diffusion abnormalities in temporal-lobe epilepsy with and without mesial temporal sclerosis. J Neurol Neurosurg Psychiatry 2009;80:312–319. 6. Powell HW, Parker GJ, Alexander DC, et al. Abnormalities of language networks in temporal lobe epilepsy. Neuroimage 2007;36:209 –221. 7. Powell HW, Parker GJ, Alexander DC, et al. Imaging language pathways predicts postoperative naming deficits. J Neurol Neurosurg Psychiatry 2008;79:327–330. 8. McDonald CR, Ahmadi ME, Hagler DJ, et al. Diffusion tensor imaging correlates of memory and language impairments in temporal lobe epilepsy. Neurology 2008;71: 1869 –1876. 9. Vlooswijk MCG, Jansen JFA, Majoie HJM, et al. Functional connectivity and language impairment in cryptogenic localization-related epilepsy. Neurology 2010;75: 395– 402. 10. Oyegbile TO, Bhattacharya A, Seidenberg M, Hermann BP. Quantitative MRI biomarkers of cognitive morbidity in temporal lobe epilepsy. Epilepsia 2006;47:143–152.

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