Identification of epileptogenic tubers in patients with tuberous sclerosis complex

Abstract

Identification of epileptogenic tubers in patients with tuberous sclerosis complex Tuberous sclerosis complex (TSC) is associated with epilepsy and mental retardation. The principal aim of this thesis was to identify epileptogenic tuber(s) enabling the selection of patients for epilepsy surgery. In addition we analysed possible determinants of cognitive functioning in patients with TSC. Genotype (different TSC1 and TSC2 mutations, tuber status and epilepsy variables were related to cognitive functioning. We found a statistically significantly lower cognition index in patients with a TSC2 mutation, but the overlap was considerable. A higher proportion of brain volume occupied by tubers was related to a lower intelligence equivalent and tended to be related to a lower cognition index. In a multivariable analysis age at seizure onset was identified as the only independent predictor of cognitive functioning. To date there is no strategy available to prevent seizure onset, prompting adequate treatment as soon as seizures occur. Epilepsy surgery is often not considered in patients with TSC as epileptogenicity from one tuber to another is feared. We found that patients with consistent localisation of interictal epileptiform EEG activity are characterised by an older at seizure onset, less often infantile spasms or generalised tonic clonic seizures, and a higher intelligence equivalent when compared to patients with inconsistent foci. Before epilepsy surgery can be performed the identification of the epileptogenic tuber is a prerequisite. Both magnetoencephalography (MEG) and diffusion weighted MRI (DWI) contributed significantly to the selection of TSC patients for epilepsy surgery. We found that MEG sources were closer to presumed epileptogenic tubers (mean distance of 13.8 mm) than EEG sources (mean distance of 24.7 mm) and MEG more often revealed unifocal epileptiform activity. Further, apparent diffusion coefficient (ADC) maps of four epileptogenic tubers (mean 1099 mm/s, SD 35.0) were statistically significantly higher than that of 18 non-epileptogenic tubers (mean 926 mm/s, SD 69.4) and of 16 regions of normal appearing cortex (mean 784 mm/s, SD 61.7). A systematic literature study on seizure outcome after epilepsy surgery in patients with TSC and multi-drug resistant epilepsy revealed that seizure freedom was achieved in 101 (57%) of the 177 included patients, from 25 studies. Seizure frequency was reduced by > 90% in another 32 patients (18%). Moderate or severe intellectual disability (defined as IQ <70) (RR 1.8; 95% CI 1.2- 2.8) and the presence of tonic seizures (RR 1.7; 95 % CI 1.2- 2.4) were related to seizure recurrence. Subsequently, we evaluated presurgical investigations in 25 Dutch TSC patients with multi-drug resistant epilepsy in whom epilepsy surgery was considered. Suitable candidates were identified by one region of seizure onset, or sufficient seizure burden. Six patients underwent epilepsy surgery. Four of these patients had excellent outcome. Differential accumulation of hamartin and tuberin in separate cellular compartments was found in giant cells of a resected epileptogenic tuber. An alternative mechanism for tuberogenesis is suggested by prevention of formation of the hamartin-tuberin complex and as a result increased S6 phosphorylation.