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(Abst. 3.327), 2014

BLOOD BETA-HYDROXYBUTYRATE LEVELS CORRELATE WITH SEIZURE FREQUENCY IN EPILEPTIC PATIENTS TREATED WITH THE KETOGENIC DIET
Authors: Jeffrey Buchhalter, Jacklyn Smith, Sabrina D'Alfonso, Rachael Singer, Mary Connolly, Aspasia Michoulas, Ernest Fung, David Sinasac and Jong Rho
Content: Rationale: Despite use of the ketogenic diet (KD) for over 90 years, the relationships between blood ketone levels, seizure control and KD diet ratio remain unclear. The purpose of this study is to determine whether blood BHB levels correlate inversely with seizure control. Here, we report our preliminary findings in a prospectively enrolled cohort of children who were started on the KD for medically-intractable epilepsy or a metabolic disorder. Methods: This is a prospective, non-blinded study involving two paediatric epilepsy centers (Alberta Children's Hospital & British Columbia Children's Hospital) in which patients were enrolled at the time of KD initiation. Study dates were 2012-06-11 to 2014-10-07. Patients were aged 2 months to 18 years, inclusive. Those children who were being treated with the KD for seizures must have met inclusion criteria that included failure to respond to at least two appropriate antiepileptic drugs. One patient had GLUT1-deficiency, known to benefit from the KD. Exclusion criteria included a known metabolic disorder not compatible with the KD, pregnancy or lactation. Outpatient records and dieticians notes were reviewed. The seizure & epilepsy syndrome types, seizure frequency (scored using a standard scale) and duration at each visit were abstracted. Plasma D-3-hydroxybutric acid (BHB) was quantitated using a stable-isotope dilution method, with deuterium-labelled DL-3-hydroxybutyric acid as an internal standard, based on modification of the method by Tsutsui et al. (Anal Bioanal Chem [2012] 404:1925). Samples were collected after an overnight fast and frozen at -80°C until time of analysis. Results: 27 patients were enrolled (44% female). Age at first seizure was 0 to 59 mos (mean 17.7 mos), and mean age at the time of diet initiation was 58.3 mos (18 to 144 mos). Seizure types (Figure 1) were classified as either ‘Generalized (n = 21) or ‘Focal' (n = 16); the most common types were focal dyscognitive, bilateral convulsive, spasms and atypical absence. The majority of patents did not fall into an electroclinical syndrome, although epilepsy with myoclonic absences and epilepsy with myoclonic atonic seizures were most prevalent (12.5%). The relationship between seizure frequency and D-isomer levels are illustrated in Figure 2. This corresponds to an increased KD ratio with time (data not shown). In addition, the average seizure duration fell from approximately 90 to 11 seconds. Seizure frequency score was reduced by 80-100% for 33% of seizures recorded. Conclusions: Our study provides direct evidence that blood D-BHB concentration correlates with decreased seizure frequency score and duration, suggesting that ketone bodies may be reliable biomarkers of KD efficacy. These preliminary findings provide clear background data for a larger, prospective multi-center clinical study establishing the utility of blood BHB levels in the management of patients on the KD.
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