While the KD has been established as an effective therapy for reducing seizures in patients with medication-resistant epilepsy, its broader effects on cerebral neurophysiology are less well understood. Our study, utilizing a large prospectively collected cohort and quantitative evaluation of EEGs, adds to the limited but growing body of literature suggesting that KD therapy is associated with improvement in electroencephalographic parameters in epilepsy patients (Freeman et al. 2009
; Hallbook et al. 2007
; Remahl et al. 2008
; Ross et al. 1985
). Prior studies evaluating KD induced EEG changes have focused on reduction in IEDs. The median spike frequency in 18 children undergoing 24 hour EEG monitoring was reduced after KD therapy, particularly during sleep, but the magnitude of changes at the individual level was not reported (Hallbook et al. 2007
). In 13 of 23 children whose IED frequency was assessed by categorical measures, improvement was seen 3 months after KD initiation, but with considerable variability in the degree of change among subjects (Remahl et al. 2008
). Our study assessed EEG changes during wakefulness, and found a reduction in epileptiform discharges in a majority of patients, though here too, the magnitude of the decline was highly variable among individuals. In our cohort, a reduction in epileptiform discharges was seen as early as one month after KD initiation, a change which was sustained at 3 months. Longer term favorable changes in EEG have been reported as well, with improvement in the rate of epileptiform discharges and background activity six months after KD initiation (Dressler et al. 2010
No predictors of response were found among the baseline clinical or electrographic characteristics we investigated, a finding consistent with prior studies. However, unlike prior studies where reduction in IED frequency failed to distinguish responders and non-responders (Remahl et al. 2008
), we observed that patients with substantial improvement in spike index at one month were six times more likely than those without improvement to be KD responders at three months. The practical utility of this finding may be limited in those who show clinical improvement as well at the one month mark, but EEG improvement may be an encouraging sign for patients whose seizure reduction is not immediate.
Our findings suggest that the KD may exert salutary electrophysiologic effects akin to some antiepileptic drugs, such as valproate and lamotrigine, which are known to reduce the frequency of IEDs (Bruni et al. 1980
; Loscher 2002
);(Eriksson et al. 2001
). Changes in EEG may be driven by different mechanisms than reduction in seizure frequency, accounting for subjects who continued to have seizures but showed improvement on EEG. In some clinical circumstances, EEG improvement may be a desirable outcome, independent of seizure control. For example, children with epileptic encephalopathy syndromes characterized by continuous spike and slow wave discharges in sleep (CSWS) may respond to KD diet treatment (Bergqvist et al. 1999
), though the overall effectiveness of the KD for this syndrome is still unclear (Nikanorova et al. 2009
In our cohort, reduction in background slowing was also seen as early as the one month time point, but did not distinguish between responders and non-responders. This finding suggests that the effect of the KD is not limited to its anticonvulsant effects. The most robust changes in power were seen over the central regions. Increases in beta frequency activity, akin to the drug effects of benzodiazepines or barbiturates, have been seen as a short term effect of the KD in normal human subjects (Cantello et al. 2007
), lending strength to the hypothesis that the KD affects GABAergic pathways. The magnitude of our findings regarding increases in beta power over the central regions mirrors what was reported in the Cantello study.
There were no differences in EEG outcome between the group of patients who were initiated on the KD using a gradual protocol compared to those initiated using a fasting protocol. This result is consistent with previous findings that initiation protocol does not influence treatment response at three months (Bergqvist et al. 2005
), suggesting that the fasting method, which may be less well tolerated method, is not necessary to achieve a benefit.
A key limitation to our study was the use of single 30 minute EEG recordings at each time point. Because spontaneous variability in IED frequency between recordings may be substantial, longer recordings may improve the ability to distinguish true improvement from expected variation (Camfield et al. 1995
; Martins da Silva et al. 1984
). Long term EEG monitoring for this cohort was not feasible at the time the data was collected, and in practice, evaluation of patients initiating the KD would be limited to routine outpatient EEG recordings. By keeping the time of day of recordings consistent, we attempted to limit the effects of medication level and circadian variability. By restricting observations to wakeful EEG, we limited variability due to behavioral state. Recordings of this length also allowed for manual evaluation of spike index, which we felt was a rigorous way to measure this parameter.
In addition, though ours is the largest cohort reported among studies of KD induced electrographic changes, our modest sample size limited the power to detect small differences between responders and non-responders. Finally, our sample size also limited evaluation of subgroups, such as those defined by location of IEDs.
In conclusion, the ketogenic diet had substantial effects on EEG, particularly on suppressing IEDs, as early as one month after initiation. Patients with reduced IED frequency at one month were more likely to have improved seizure control by three months. Improvement in background slowing was seen, but these changes were modest. Increases in beta frequency activity after short term exposure to the KD suggest a pharmacologic effect akin to that seen with drugs mediated by GABAergic mechanisms. The clinical utility of the findings in this exploratory study remain unclear. While EEG improvement may offer supportive evidence of KD response, we do not believe that the parameters we studied here are accurate enough predictors to act as surrogate markers of later KD success. Further studies are needed to understand the range of KD effects on the cerebral electrophysiology and resultant clinical response of children with medication resistant epilepsy.