Epilepsy
deficiency) and pyruvate dehydrogenase deficiency. Furthermore, the phenotype of the epilepsy associated with GLUT1 deficiency may be wider than previously thought, with implications for the applicability of the KD in a wider population.25
Previous suggestions that
mitochondrial defects may be a contraindication to use of the KD now appear to be unfounded, with reports of successful use26 data to suggest the diet may be of benefit.27
and even
Behavioural problems overall are not a contraindication to the use of the diet, with such problems being common co-morbidities among children with complex epilepsy. This aside, behavioural issues around feeding times are a problem and need to be addressed prior to introduction. Furthermore, gastro-oesophageal reflux may be exacerbated by a high- fat diet due to delayed gastric emptying with high fat content.
Although data from the randomised controlled trials have not indicated specific efficacy in individual epilepsy syndromes,9
the
relatively small numbers involved probably preclude this. Certainly, data from other open-label trials suggest some epilepsy syndromes where the KD may be considered sooner rather than later, e.g. myoclonic astatic epilepsy28 infancy.29
seizures in three months. In a larger study in children a similar efficacy was demonstrated with similar retention rates. A further alternative suggested is the low-glycaemic-index diet, where the complexity of sugars is noted within the intake. The glycaemic index is calculated from the incremental area under the blood glucose curve after feeding; therefore, more complex sugars not leading to to a rapid rise in blood sugar have a low glycaemic index.37
In a series of
children reported from the Massachusetts General Hospital in Boston, 76 children were trialled, 50% of whom had more than a 50% reduction of seizures at three months, although 49 of the children discontinued the diet after a period of two to 108 weeks. These alternative diets require further evaluation as to their role, particularly in the older population (teenagers and adults) and in those where true dietary restriction is difficult.
and severe myoclonic epilepsy of
There are also data to suggest efficacy in infantile spasms,30 although differing availability of individual medications across countries may predetermine treatment protocols. There has also been a further suggestion about the role of the diet in the acute management of cluster seizures31
or status epilepticus.32 Role of Medication
The KD needs to be considered as additional anti-epileptic medication in the management of children with epilepsy. Consequently, introduction and weaning of other drugs is managed as in any other such situation. There is little information on the pharmacodynamic interactions that may occur with AEDs; this aside, there is also no evidence that serum levels will be affected by such a diet.33
The
possible increased risk of some side effects may need to be monitored if the child is also taking other medications with a similar risk profile to the KD; an example is renal calculi if the child is taking topiramate or zonisamide, although to date there is no evidence that this is problematic.34
AEDs, there is also no reason why the latter cannot be weaned completely and children left on the KD alone if effective.
Alternative Diets?
This aside, there may also be an issue about satiety versus hunger and the fact that adults have very different views about food intake from children, who will cease eating once full. In view of the restriction of the diet, other diets with similar effects on the body have been suggested – in the first instance the modified Atkins diet. This is very similar to the KD: a high-fat, low-carbohydrate diet but with a major difference of unlimited protein. A suggested limit of 20g of carbohydrate per day is given with no caloric or protein restriction.36
The KD in the classic or the MCT form has been noted to be very restrictive. Certainly, in the older population, namely teenagers and even adults, its use has been very limited in view of the concerns about hunger and poor tolerability. Use in adults has been reported but to a very limited degree, with limited recruitment into trials and high drop-out rates, primarily due to poor tolerability and lack of effect.35
Mechanisms of Action – Towards a Pill? Basic science research has attempted to elucidate the possible anti- epileptogenic (and potentially neuroprotective) effects of the KD.27,38 Many systemic and metabolic changes are induced, but, as with many of the anti-epileptic medications, it is unclear which changes are the most relevant. Early studies suggested that seizure reduction was related to the degree of ketosis; however, the relationship is not direct and, although acetone has been shown to prevent acutely provoked seizures in animals, there is no evidence that ketone bodies can have a direct effect on synaptic transmission or neuronal excitability. Experimental data have also suggested an increase in mitochondrial biogenesis and energy metabolism, or a role for polyunsaturated fatty acids.27
It is likely that the underlying changes
induced by the KD are multiple and synergistic in their anti-epileptic effect,39
Ways Forward Since the KD may be considered alongside other
There is little question that evidence is now weighted in favour of the efficacy of the KD in the treatment of childhood epilepsy. The question remains as to when it should be offered in the natural history of childhood epilepsy. Few would question the current practice of considering the diet should two AEDs fail. However, currently the resource is not sufficiently available (in view of dietician time) for this to be offered widely. Following the acknowledgement that data are now more readily available but insufficient to compose true guidelines, an international consensus document has been published to guide on the optimal implementation of the KD, acknowledging areas that require further work.24
There is no question that further data are
required, not least to evaluate the role of the diet in the younger population and specific epilepsy syndromes, the role of alternative diets and the role of the KD in conditions other than epilepsy. n
J Helen Cross is the Prince of Wales’s Chair of Childhood Epilepsy at University College London (UCL)– Institute of Child Health, Great Ormond Street Hospital for Children and the National Centre for Young People with Epilepsy in Lingfield. She is also Head of the Neurosciences Unit at the UCL–Institute of Child Health. Professor Cross has research interests in early-onset complex epilepsy, particularly outcomes and the role of intervention, including surgery and the ketogenic diet.
In a limited open-label study of 30 adults 18–50 years of age, 10 discontinued the diet before three months, but on an intention-to-treat analysis 47% had more than a 50% reduction of
90
She was Chair of the International League Against Epilepsy (ILAE) Commission for Paediatrics from 2005 to 2009. She is now Co-Chair of the Task Force of the Global Campaign and is a member of the ILAE Commission for European Affairs. Professor Cross is also Clinical Advisor to the current review of the National Institute of Health and Clinical Excellence (NICE) guidelines for epilepsy.
and it therefore appears unlikely that in the immediate future the diet will be replaced by a simple medication or pill alone.
EUROPEAN NEUROLOGICAL REVIEW
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