A Randomised Controlled Trial to Compare Seizure Remission Outcome Following Resective Surgery With or Without Prior Treatment With Ketogenic Diet in Children With Epilepsy the Result of Focal Cortical Dysplasia Type II

Epilepsy surgery is now an accepted and effective management for individuals with drug resistant focal onset epilepsy in carefully selected candidates. This aside, only two RCTs have been performed in adults in temporal lobe epilepsy [1,2], and none in children . Malformations of cortical development are the most common pathology responsible for drug resistant focal epilepsy in childhood [3}. In retrospective studies, successful surgical resection resulting in seizure freedom in malformations of cortical development has been reported in 42-87% of cases [4], dependent on the series reviewed and the completeness of resection. Outcome is related to extent and completeness of resection, but the extent of tissue to be removed remains a challenge, especially in very young patients, where the limits of a lesion may be unclear and eloquent cortex may be involved.

FCD is one specific type of malformation, of localised areas of abnormal cortex that may be subdivided into I, II and III dependent on the pattern determined and cell types involved. This is by definition a histological diagnosis as was recently classified by the International League Against Epilepsy [5]. Specifically FCD type II can usually be suggested by characteristic changes on an MRI scan. These changes include increased cortical thickness, blurring of the cortical-white matter junction, increased signal on T2-weighted images, a radially oriented linear or conical transmantle strip of T2 hyperintensity, cortical thinning and localized brain atrophy. FCD type II may be subdivided histopathologically into IIa and IIb but it can be difficult to distinguish between the two radiologically.

The KD is a high fat diet with a proven efficacy in the treatment of drug resistant epilepsy in children [6]. An RCT performed in children aged 2-16 years diagnosed with drug resistant epilepsy utilising either a classical or medium chain triglyceride KD, demonstrated >50% reduction in seizures in 38% of participants after 3 months compared to 6% where there was no change in standard treatment, with no difference seen between the two diets [7,8]. A further RCT utilising a more relaxed approach of the KD, the modified Atkins diet, demonstrated similar results [9]. One open label study suggested particular efficacy in children with epilepsy due to FCD [10].

Clinical trials of epigenetic pharmacological treatment are promising and already have been approved for cancer [11]. Intriguingly, the most commonly used AED is valproic acid (VPA), in which histone deacetylase (HDAC) inhibitor activity was discovered in 2001 [12]. The HDAC antagonizing effect of VPA is, however, considerably low compared to second generation HDAC inhibitors suberoylanilide hydroxamic acid (SAHA, Zolinza, Vorinostat), LBH598 or Romidepsin [11]. Unfortunately, all HDAC inhibitors bear the risk of severe side effects when systemically administered during pregnancy. Nevertheless, there is also evidence that the epigenetic machinery can be modified by nutrition and dietary concepts [13]; such a dietary concept is the KD. Stimulus-induced DNA methylation changes have been identified in postnatal brain [14], thus it can be anticipated that DNA methylation modifications contribute to the molecular memory of postmitotic neurons also in the epileptogenic network. We propose that therapies such as the KD that are directly or indirectly targeting the epigenetic machinery could be helpful to prevent, delay or retard drug-resistant epilepsy.

Recent experimental data in an animal model has shown that the classical KD attenuates epigenetic chromatin modifications (i.e. DNA methylation), a master regulator for gene expression and functional adaptation of the cell, thereby modifying disease progression [15]. This hypothesis suggests that epigenetic mechanisms play a pivotal role in epileptogenesis and that seizures can by themselves induce epigenetic chromatin modifications, aggravating the epileptogenic condition [15].