Early EEG improvement after ketogenic diet initiation

https://doi.org/10.1016/j.eplepsyres.2011.01.012Get rights and content

Summary

Purpose

This study examines electroencephalographic (EEG) changes in children with medication resistant epilepsy treated with the ketogenic diet (KD).

Methods

Routine EEGs were obtained prior to KD initiation, then one month and three months later. Changes in EEG background slowing and frequency of interictal epileptiform discharges (IEDs) were evaluated using power spectrum analysis and manual determination of spike index. KD responders were compared to non-responders to determine if baseline or early EEG characteristics predicted treatment response (>50% seizure reduction) at three months.

Results

Thirty-seven patients were evaluated. No differences in baseline EEG features were found between responder groups. Frequency of IEDs declined in 65% of patients as early as one month, by a median of 13.6% (IQR 2-33). Those with a ten percent or greater improvement in IED frequency at one month were greater than six times more likely to be KD responders (OR 6.5 95% CI 0.85–75 p = 0.03). Qualitative and quantitative measures of EEG background slowing improved in the whole cohort, but did not predict responder status.

Conclusion

Baseline predictors of KD response remain elusive. Most patients experienced a reduction in IEDs and improvement in EEG background slowing after KD initiation. Reduction of IEDs at one month strongly predicted KD responder status at three months.

Introduction

The ketogenic diet (KD) is a high fat, low protein and low carbohydrate diet which is effective in the treatment of medication resistant epilepsy. Half of patients treated with the KD experience a 50% or greater reduction in seizure frequency, and one fifth achieve seizure freedom (Lefevre and Aronson, 2000, Neal et al., 2009, Thiele, 2003, Vining et al., 1998). Children initiating the KD are asked to complete a minimum three month course of dietary adherence before an assessment of efficacy is made. During this time, they are exposed to all of the risks and burdens of maintaining the KD. A better understanding of the baseline predictors and early indicators of response to the KD is necessary for beginning to characterize which patients are most likely to benefit from KD treatment.

Predictors of response to the KD are not well understood. Differences in age at KD initiation and sex have not been found between responders and non-responders (Vining et al., 1998), but shorter duration of epilepsy prior to KD initiation may increase likelihood of response (Dressler et al., 2010). In some studies, seizure type and epilepsy syndrome have differed between responders and non-responders, but the evidence is far from robust. Children with complex partial seizures as the major seizure type may have a lower likelihood of experiencing an early, dramatic response to the KD (Than et al., 2005), while the presence of generalized tonic clonic seizures may marginally predict an increased likelihood of response (Dressler et al., 2010). Other studies have shown no association between epilepsy type and KD efficacy (Neal et al., 2008, Vining et al., 1998). As noted in the recently issued recommendations of the International Ketogenic Diet Study Group, children with certain epilepsy syndromes and genetic disorders may derive greater benefit from the KD (Kossoff et al., 2009). Several groups have observed that the KD may be particularly effective in severe myoclonic epilepsy of infancy (SMEI; Dravet Syndrome) and myoclonic astatic epilepsy (MAE; Doose Syndrome), with larger than expected rates of seizure freedom in these patients (Caraballo et al., 2006, Kilaru and Bergqvist, 2007, Korff et al., 2007, Oguni et al., 2002).

Few studies have examined differences between KD responders and non-responders in electrophysiologic characteristics. A study of fifty patients who underwent routine EEGs within 6 months before starting the KD showed that subjects with interictal epileptiform discharges (IEDs) in the temporal regions were more likely to be non-responders to the KD treatment, but no other EEG characteristics were found to be predictive (Beniczky et al., 2010). No prospective investigations of the predictive value of baseline EEG, or early changes in EEG, for KD treatment response have been reported. One prior retrospective study of 18 children treated with the KD revealed that early reduction of IEDs correlated with a reduction in seizure frequency at three months (Hallbook et al., 2007). In 24 patients undergoing 24 h EEG recording, improvements in the amount of interictal epileptiform activity and background slowing was seen in slightly more than half (Remahl et al., 2008). The purpose of the present study was to examine whether KD responders had greater improvement in EEG characteristics compared to KD non-responders, and to evaluate whether EEG features at baseline or at one month predict treatment response at three months.

Section snippets

Subjects and protocol

This investigation was performed using a cohort study design, with prospectively collected data from a previously conducted randomized controlled trial examining two different approaches to KD initiation (Bergqvist et al., 2005). The exposure variables of interest were EEG variables, discussed below. The primary outcome was response to the KD, defined as a 50% or greater reduction in frequency of target seizures after three months of therapy compared to baseline. Forty-eight pre-pubertal

Patient characteristics

Of the 48 subjects enrolled in the original study, seven were excluded from this analysis because they exited the study early or lacked one or more EEGs. In addition, four subjects had baseline hypsarrhythmic EEGs. Because of the fundamentally different nature of this EEG background pattern, these subjects were excluded from subsequent spike index and power spectrum analyses. Among these four subjects, three were KD responders and demonstrated resolution of hypsarrhythmia at three months. One

Discussion

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

Conflicts of interest

None of the authors has any conflicts of interest to disclose.

Acknowledgements

This study was supported by NIH NCRR K23RR016074, CTRC UL1-RR-024134, and the Catherine Brown Foundation. Dr. Kessler receives support from NIH NINDS K12 NS049453. Dr. Shellhaas receives support from NIH NINDS K12 HD02882018. We would like to thank the children, parents, and care providers who participated in this research study. We would also like to thank Damon Lees for his help in converting EEG data, as well as the Children's Hospital of Philadelphia ketogenic diet team.

We confirm that we

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