Cortical Network Dysfunction in Epilepsy Caused by MCD
October 1, 2000 3 minutes read
Cortical Network Dysfunction in Epilepsy Caused by MCD
abstracts & commentary
Sources: Sisodiya SM. Surgery for malformations of cortical development causing epilepsy. Brain 2000;123:1075-1091; Duchowny M, et al. Aberrant neural circuits in malformations of cortical development and focal epilepsy. Neurology 2000;55:423-428.
Sisodiya performed a complete review of the English-language literature describing seizure outcome for surgical resection of malformations of cortical development (MCD). In contrast to temporal lobectomy, where about 70% of patients remain seizure-free at two years follow-up, he found that only 40% of MCD patients achieved this result. He further concluded that while focal cortical dysplasia and heterotopia appear to be intrinsically epileptogenic, cortical hyperexcitability in polymicrogyria and schizencephaly probably extends beyond the region of gross malformation.
Focusing their attention on children, Duchowny and colleagues note similar discouraging outcomes for MCD resection in pediatric epilepsy patients. All epileptologists who evaluate and treat patients with MCD develop an intuition that the grossly visible lesion represents only "the tip of the iceberg," as Duchowny et al put it. These two papers formalize the hypothesis that relatively poor outcome in surgical treatment of MCD is attributable to dysfunctional cortical networks. They marshal an abundance of basic and clinical neuroscience evidence in support of this hypothesis.
Commentary
Resective surgery has achieved widespread acceptance for treating patients with pharmacologically resistant focal epilepsy. With appropriate concordance of electroencephalographic and neuroimaging data, seizure-free outcomes can exceed 80% of cases involving hippocampal sclerosis. Nearly comparable success rates are seen with excision of extratemporal epileptogenic lesions, such as tumors and vascular malformations. The accumulated experience from resection of MCD for epilepsy, however, proves that not all lesions are alike. The value of the hypothesis that preservation of aberrant cortical networks leads to such poor outcomes lies in its implications for evaluating therapeutic options for refractory seizures.
Animal models for MCD have been developed (Chavassus-au-Louis N, et al. Epilepsia 1999;40:811-821). Depth electrode recording in at least one model, the telencephalic internal structural heterotopiatish (TISH) rat, demonstrates that normotopic neurons are actually more prone to epileptiform discharges than heterotopic cortex (Chen ZF, et al. Epilepsia 2000;41:493-501), suggesting that epileptogenicity arises from the network properties of cortical neurons. The implication of extrapolating these data to clinical management is that surgical resection may not be the answer for seizure control in certain MCD patients. It is legitimate for the non-epileptologist to ask whether there are even more specific risk factors that predict poor surgical outcome. Our experience has been that patients with multilobar or extensive lobar MCD on routine cerebral MRI are poor candidates for surgical resection. In addition, resection of periventricular heterotopias can potentially increase morbidity and has been demonstrated to be ineffective in achieving seizure control (Li LM, et al. Ann Neurol 1997;41:662-668).
Even for patients with such added risk factors, or without access to the resources of tertiary epilepsy centers, we need not resign ourselves to therapeutic nihilism. The broader influence of the dysfunctional network model should be to spur research into therapeutic options that disrupt intracortical and subcortical circuitry that recruits populations of cortical neurons to fire synchronously. Vagus nerve stimulation (VNS) is a possible example of such a therapy. Given the data supporting its clinical efficacy, VNS should be offered early to patients with MCD. On the other hand, patients who appear to have refractory temporal lobe epilepsy should certainly be fully evaluated for surgical resection.
Practically nothing is known about the mechanism of action of VNS. Rigorous neurophysiological experiments are needed to determine how VNS affects cortical excitability, which might suggest criteria for selecting patients for this therapy. Furthermore, given the rapidly expanding experience with deep brain stimulation (DBS) for movement disorders, subcortical targets for DBS should begin to be evaluated in clinical trials for epilepsy. Available data from animal models immediately suggest candidate targets, such as prepiriform cortex ("area tempestas") or the subthalamic nucleus (Dybdal D, Gale K. J Neurosci 2000;20:6728-6733). Finally, the result of exploring the hypothesis of aberrant cortical networks in MCD is certain to provide more general insights into the pathophysiology of epileptogenesis and seizure initiation and propagation. —andy c. dean (Dr. Dean is Assistant Professor of Neurology and Neuroscience, Comprehensive Epilepsy Center, Cornell University Medical Center, New York, NY.)
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