The ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet that has been used successfully in the treatment of refractory epilepsies for almost 100 years. There has been accumulating evidence to show that the KD may provide a therapeutic benefit in autism spectrum disorders, albeit by a yet-unknown mechanism. We report a case of a 6-year-old patient with high-functioning autism and subclinical epileptic discharges who responded poorly to several behavioural and psychopharmacological treatments. The patient was subsequently placed on the KD due to significant glucose hypometabolism in the brain as revealed by an 18FDG PET. As soon as one month after starting the KD, the patient’s behavior and intellect improved (in regard to hyperactivity, attention span, abnormal reactions to visual and auditory stimuli, usage of objects, adaptability to changes, communication skills, fear, anxiety, and emotional reactions); these improvements continued until the end of the observation period at 16 months on the KD. The 18FDG PET, measured at 12 months on the KD, revealed that 18F-FDG uptake decreased markedly and diffusely in the whole cerebral cortex with a relatively low reduction in basal ganglia in comparison to the pre-KD assessment. It warrants further investigation if the 18FDG PET imaging could serve as a biomarker in identifying individuals with autism who might benefit from the KD due to underlying abnormalities related to glucose hypometabolism.

Clavulanic acid (CLAV) inhibits bacterial β-lactamases and is commonly used to aid antibiotic therapy. Prompted by the initial evidence suggestive of the potential anticonvulsant and neuroprotective properties of CLAV, the present study was undertaken to systematically evaluate its acute effects on seizure thresholds in seizure tests typically used in primary screening of potential antiepileptic drugs (AEDs). In the present study, 6-Hz seizure threshold, maximal electroshock seizure threshold (MEST) test, and intravenous pentylenetetrazole (i.v. PTZ) seizure tests were used to determine anticonvulsant effects of intraperitoneally (i.p.) administered CLAV in mice. Acute effects on motor coordination and muscle strength were assessed in the chimney and grip-strength tests, respectively. Doses of CLAV studied in the present study were either comparable or extended the doses reported in the literature to be effective against kainic acid-induced convulsions in mice or behaviorally active in rodents and monkeys. CLAV had no effect on seizure thresholds in the 6-Hz (64 ng/kg to 1 mg/kg) and MEST (64 ng/kg to 5 mg/kg) seizure tests. Similarly, CLAV had no effect on seizure thresholds for i.v. PTZ-induced myoclonic twitch, clonic convulsions, and tonic convulsions (64 ng/kg to 5 mg/kg). Finally, CLAV (64 ng/kg to 5 mg/kg) had no effect on the motor performance and muscle strength in the chimney and grip-strength tests, respectively. In summary, CLAV failed to affect seizure thresholds in three seizure tests in mice. Although the results of the present study do not support further development of CLAV as an AED, its beneficial effects in chronic epilepsy models warrant further evaluation owing to its, for example, potential neuroprotective properties.

Among non-pharmacological treatments, the ketogenic diet (KD) has the strongest demonstrated evidence of clinical success in drug resistant epilepsy. In an attempt to model the anticonvulsant effects of the KD pre-clinically, the present study assessed the effects of the KD against electroshock-induced convulsions in mice. After confirming that exposure to the KD for 2 weeks resulted in stable ketosis and hypoglycemia, mice were exposed to electroshocks of various intensities to establish general seizure susceptibility. When compared to mice fed the standard rodent chow diet (SRCD), we found that mice fed the KD were more sensitive to electroconvulsions as reflected by a significant decrease in seizure threshold (3.86 mA in mice on the KD vs 7.29 mA in mice on the SRCD; P < 0.05) in the maximal electroshock seizure threshold (MEST) test. To examine if this increased seizure sensitivity to electroconvulsions produced by the KD would affect anticonvulsant effects of antiepileptic drugs (AEDs), anticonvulsant potencies of carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA) against maximal electroshock (MES)-induced convulsions were compared in mice fed the KD and SRCD. We found that potencies of all AEDs studied were decreased in mice fed the KD in comparison to those on the SRCD, with decreases in the anticonvulsant potencies ranging from 1.4 fold (PB) to 1.7 fold (PHT). Finally, the lack of differences in brain exposures of the AEDs studied in mice fed the KD and SRCD ruled out a pharmacokinetic nature of the observed findings. Taken together, exposure to the KD in the present study had an overall pro-convulsant effect. Since electroconvulsions require large metabolic reserves to support their rapid spread throughout the brain and consequent generalized tonic-clonic convulsions, this effect may be explained by a high energy state produced by the KD in regards to increased energy storage and utilization.