Abstract
Dear Sir We read with great interest the article ‘Use of the modified Atkins diet for adolescent with chronic daily headache’ by EH Kossoff et al. published in a recent issue of Cephalalgia (1).
The article reflects a renewed interest in the therapeutic use of ketogenic diets in treating neurological diseases other than epilepsy, including migraine (2–3).
The number of patients studied by Kossoff et al. (1) is small (eight) and the conclusion of the article is still interlocutory: ‘Even the three subjects with a reported improvement in headache severity and quality of life continued to have daily migraines and require pharmacological therapy … There does not appear to be any clear benefit for the modified Atkins diet in the treatment of adolescents with chronic daily headache. In addition, had improvement even been noted in this pilot study, this diet was perceived as too restrictive and most adolescents refused to try. Future studies could evaluate a younger, less intractable population using a less restrictive diet if desired’ (1).
In the references the authors (1) cited the only available article at that time on the topic, written by Strahlman (4) and reporting the case of his own wife, whose intractable migraine headaches resolved after a medically supervised low-calorie diet. Recently, two other cases have been described of a good response of migraine attacks during a ketogenic diet prescribed for obesity treatment (5). Moreover, two monozygotic twins who progressively developed, between the ages of 5 and 10, a combination of episodic neurological disorders including paroxysmal exercise-induced dyskinesia, migraine without or with aura, absence seizures and writer's cramp secondary to a novel SLC2A1 missense mutation, had a complete resolution of migraine attacks during ketogenic treatment, which immediately reappeared after the interruption of the diet (6).
We think it interesting to add to these recent reports of the literature a historical note on the use of ketogenic diet in migraine treatment. An improvement of epilepsy following fasting has been described since biblical times, but the first description in the modern medical literature was given in 1911, in France, by Guelpa and Marie (7). In 1921 Geyelin reported to the American Medical Association on Conklin’s successful use of fasting to treat epilepsy (8).
However, it is less well known that in 1928 a study was performed on the effectiveness of the ketogenic diet in migraine treatment (9). Schnabel’s study ‘An experience with ketogenic dietary in migraine’ presented to the American College of Physicians on 8 March 1928 in New Orleans and then published in same year in the Annals of Internal Medicine is, to the best of our knowledge, the first report on this topic (9).
In the article (9) the author explains his clinical observation and the supposed pathogenetic mechanism involved in triggering migrainous attacks, which induced him to test a ketogenic diet on migrainous patients: ‘ … very little justification for believing that a ketogenic diet would be of value in the latter disease (migraine) other than the fact that migraine and epilepsy are disease equivalents, and that what is therapeutically effectual in one might be so in the other. No one had shown that the ketones of themselves bring about the seemingly favorable results of starvation or a high fat diet in epilepsy. Besides this acidosis had and is put down in text book discussions as one of the possible causes of migraine … Although the evidence is rather meager to show that migraine attacks are accompanied by a change in the acid base equilibrium, we prescribed a relatively high fat diet in a group of hemicranial patients…’
Further on, he affirms that, ‘It is needless to say that for migraine as well as for epilepsy no one has been able to demonstrate a consistent pathological lesion nor an universally acceptable production mechanism’, and consequently, ‘Those who are confident that migraine is an allergic manifestation will look upon any success which a ketogenic diet may seem to accomplish as being the result of a chance specific protein withdrawal … Those who regard the liver as the seat of dysfunction will contend that a high fat diet achieves its results by promoting biliary drainage or in some other way influences hepatic function. Those who look to the intestinal tract…’, and so on.
After the detailed description of the diet composition and its modality of administration, Schnabel comments on the results: ‘…Of those whose attacks have recurred, three confessed to a break in diet and an examination of the urine failed to show ketones. It would seem to be a difficult matter for adults to remain on a ketogenic diet judging from our group of patients.’
Finally, the conclusion: ‘Obviously we cannot conclude anything on the strength of our experience. Nine cases out of 23 did show some improvement, however, and we feel sufficiently encouraged to continue with the high fat method … For those with attacks at longer intervals, we shall suggest a diet at least relatively high in fats and low in carbohydrates, and not too tiresome … It is hoped that others may have an opportunity to try out a series of patients in a similar way … ’ (9).
Despite this ‘encouraging result’, we have not found any further reports on this matter in the literature until recently (1,4–6). A possible explanation could be that, as for epilepsy after the introduction of diphenylhydantoin in 1938 followed by other anticonvulsants, the popularity of the ketogenic diet waned (10), so for migraine the increasing use of ergotamine, isolated by Stoll in 1918 (11), for the treatment of the attacks contributed to reduce the interest in the ketogenic diet.
However, some theoretical preliminary remarks allow us to think of the ketogenic diet as advantageous in migraine treatment. In fact, several mechanisms proposed to explain the effectiveness of a ketogenic diet in seizure treatment including changes in ATP production making neurons more resilient in the face of metabolic demands; altered brain pH affecting neuronal excitability; direct inhibitory effects of ketone bodies or fatty acids on ion channels; and shifts in amino acid metabolism to favour the synthesis of the inhibitory neurotransmitter GABA (10). Moreover, the experimental finding of a reduction in cortical spreading depression propagation (12) could act favourably both in epilepsy and migraine.
Further studies are needed in children and adults, possibly with less restrictive diets, as suggested recently by Kossoff et al. (1) and about a century ago by Schnabel (9), because the compliance of patients with ketogenic diet remains problematic.