Evaluating Dietary Intervention Before surgicaL Treatment for Epilepsy

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].

We will conduct the first RCT for epilepsy surgery in children with FCD type II, to
prospectively evaluate the role of the KD prior to surgery.

120 children aged 3 - 15 years with a diagnosis of Focal Cortical Dysplasia (FCD) type II a
or b (with consistent MRI changes), treatment failure of at least two anti-epileptic drugs
(AEDs) in controlling continuing seizures, with seizure semiology consistent with focal onset
agreed to be surgically treatable through FCD resection and continuing seizures for less than
5 years, will be included in the trial after parental/ legal representative consent. Children
will be excluded if they have a history of less than two seizures in 6 months prior to
randomisation or they have previously used the Ketogenic diet (KD) or administration of the
KD is medically contraindicated. Patients will be recruited from 19 participating European
sites in 8 countries undertaking ketogenic diet and epilepsy surgery in children.

Participants will be followed-up for minimum 24 months/maximum 48 months (depending on the
timing of randomisation) after randomisation. Primary outcome will be time to 6 month
remission (i.e. the time to achieve a period of 6 months of seizure freedom from the date of
randomisation). Tissue removed at surgery will be assessed for DNA methylation.

Inclusion Criteria:

1. Children aged 3 - 15 years;

2. MRI changes consistent with a diagnosis of FCD type II a or b;

3. History of at least two epileptic seizures in the past 6 months before randomisation;

4. Seizure semiology consistent with focal onset, agreed after pre-surgical discussion to
be surgically treatable;

5. Parent/ legal representative willing to give consent.

Exclusion Criteria:

1. Previous use of the KD;

2. Not a surgical candidate for FCD resection;

3. Administration of the KD is medically contraindicated.