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Aim We observed a dramatic response to the ketogenic diet in several patients with highly refractory epilepsy whose seizure frequency had recently worsened. This study aimed to identify whether this characteristic was a useful indication for the ketogenic diet.
Method From the 70 patients who received the ketogenic diet during a 3-year period at our institution, we retrospectively selected patients with focal epilepsy. There were 22 children, 13 females and nine males, aged from 5 months to 18 years 6 months (mean 6y 9mo, SD 5y 11mo). Fifteen had symptomatic and seven had cryptogenic focal epilepsy. Seizure frequency 1 week before initiating the ketogenic diet was compared with that at 1 month and at the last visit on the diet.
Results Eleven patients were responders (defined as reduction of seizures by more than 50%) at 1 month. Responders were higher (p=0.046) in the group with a recent worsening of seizures than in those with stable seizure frequency. Seven patients were still seizure-free at 6 months on the diet. Tolerability was excellent in 10 patients. Five patients stopped the diet because of early side effects.
Interpretation The ketogenic diet may be a valuable therapeutic option for children with pharmacoresistant focal epilepsy, particularly those with a recent deterioration of seizure control and neurological status. Because of its rapid effect, the ketogenic diet may be a useful support to intravenous emergency drugs in such a situation.
The ketogenic diet has, for nearly a century, been repeatedly advocated in the treatment of childhood drug-resistant epilepsy.1,2 Many investigators have confirmed the benefits that this treatment can offer to young patients with epilepsy,3–6 including infants.7,8
However, the best indications for using the diet have not been clearly defined since it was shown to be helpful in treating a large range of different seizure types and epilepsy syndromes. Special interest has been given to various conditions associated with epilepsy including myoclonic astatic epilepsy,5,9 infantile spasms,7 Dravet syndrome,10 atypical absences,11 acquired epileptic aphasia,12 tuberous sclerosis,13 and Rett syndrome.14,15 One study found slightly better results in generalized as opposed to focal epilepsy although this was not significant.16 Lack of complex focal seizures was reported as a predictive factor for early, complete, and sustained response.3 However, studies that addressed the effects of the ketogenic diet according to the type of seizures or epilepsy failed to identify any significant difference.17,18 Animal studies have concentrated more on models for generalized convulsions19,20 than on focal seizures,21 although in both instances ketosis proved to be efficient. These models failed to generate any hypothesis regarding possible mechanisms of antiepileptic and anticonvulsive properties, despite the increase in neurogenesis after kainic-acid-induced seizures in mice.22 Therefore, the choice of the best candidate for a ketogenic diet remains to be determined.
We recently observed a dramatic response to the ketogenc diet in several patients with highly refractory focal epilepsy, in the setting of recent worsening, mainly in the form of nearly continuous seizures or status epilepticus. In order to ascertain whether this characteristic could be of interest as an indication for the ketogenic diet, we selected from our ketogenic-diet database a subgroup that was both exhaustive and as homogeneous as possible regarding the type of epilepsy. It consisted of children with focal epilepsy.
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This study shows that children with pharmacoresistant focal epilepsy who have experienced a recent severe worsening of seizure frequency with negative functional impact are likely to benefit from the ketogenic diet. This benefit most often occurs within the first week of the diet. The diet also permits cognitive and motor functions to return to previous levels.
We could find no evidence from the literature that a recent deterioration of seizure control in focal epilepsy is a particularly good indication for the ketogenic diet. Although one study reported a better response in generalized than focal epilepsies,16 others failed to identify any significant difference in response according to the type of epilepsy.17,18 We therefore decided to exclude this factor and to concentrate on a single type of epilepsy, selecting patients with focal epilepsy because they represent one major group of pharmacoresistant epilepsy.
This study is retrospective with a relatively small sample but the population of patients was fairly homogeneous, including patients with Rasmussen syndrome who had reached a stable condition before the recent worsening of seizures and returned to their previous condition after starting the ketogenic diet. We can therefore hypothesize that the worsening was mainly related to the seizure increase.
There are theoretical reasons to predict that recent seizure worsening is a good indication that a child may benefit from the ketogenic diet. Seizures increase cerebral glucose consumption, as shown by ictal positron emission tomography (PET).24,25 Increased seizure frequency accelerates this process, provided sufficient glucose supply is offered to the brain. The ketogenic diet reduces the consumption of glucose by the brain and provides ketone bodies as an alternative fuel.26 The delivery rate of ketone bodies to the brain is limited by the inability of the brain to generate reserves of this fuel.27 Therefore, the sudden increase of energy needs is likely to remain unmet, thus preventing seizure recurrence. Indeed, Noh et al. identified a protective effect of ketosis on the hippocampus in an animal model.21 This might explain the better response in patients with status epilepticus and nearly continuous seizure activity than in patients with stable sporadic seizures.
The ketogenic diet in our series was particularly useful for patients not responding to intravenous administration of benzodiazepines, phenytoin, or barbiturates. We recently applied the ketogenic diet to the management of status epilepticus in children suffering from devastating epileptic encephalopathy with dramatic efficacy in half the cases.28
Although our data are preliminary, they might suggest that a recent increase in seizure frequency, developing into very frequent seizures or status epilepticus resistant to standard emergency drugs, should be treated with the ketogenic diet, particularly when associated with neurological regression because of seizure worsening. Our results suggest the need for a prospective randomized trial in order to validate the place of the ketogenic diet in therapeutic guidelines.
It takes several hours for drugs to prove inefficacy. Although useless and dangerous escalation may then become tempting,29,30 doses should be reduced to prevent adverse effects. The issue is then the time lag to efficacy (ketosis) and tolerability. Intravenous fluid, if necessary in this context, could be free of glucose. A recently available liquid formulation of the ketogenic diet (KetoCal) is easily delivered through a gastric tube and offers a possible means for such emergency therapy. Median time lag to seizure improvement in our study was 3 days. Gradual initiation of the ketogenic diet without fasting results in better tolerability and allows ketosis to occur within 2 or 3 days,6 but glucose fasting generates ketosis within less than 15 hours27 and in one study the response was quicker for fasted children (within 5d vs 14d).31The question will then arise of the appropriate duration of the diet in this indication.