KDT benefits beyond seizure control
“Most of us who work in the diet scene are aware that patients often report increased alertness, and sometimes improved cognition,” said Dr. Sharma.
That subjective experience is now supported by evidence from a randomized, controlled trial. Dutch investigators who randomized 50 drug-refractory pediatric epilepsy patients to KDT or usual care documented a positive impact of the diet therapy on cognitive activation, mood, and anxious behavior (Epilepsy Behav. 2016 Jul;60:153-7).
More recently, a systematic review showed that while subjective assessments support claims of improved alertness, attention, and global cognition in patients on KDT for refractory epilepsy, structured neuropsychologic testing confirms the enhanced alertness but without significantly improved global cognition. The investigators reported that the improvements were unrelated to decreases in medication, the type of KDT or age at its introduction, or sleep improvement. Rather, the benefits appeared to be due to a combination of seizure reduction and direct effects of KDT on cognition (Epilepsy Behav. 2018 Oct;87:69-77).
There is also encouraging preliminary evidence of a possible protective effect of KDT against sudden unexpected death in epilepsy (SUDEP) in a mouse model (Epilepsia. 2016 Aug;57[8]:e178-82. doi: 10.1111/epi.13444).
The use of KDT in critical care settings
Investigators from the pediatric Status Epilepticus Research Group (pSERG) reported that 10 of 14 patients with convulsive refractory status epilepticus achieved EEG seizure resolution within 7 days after starting KDT. Moreover, 11 patients were able to be weaned off their continuous infusions within 14 days of starting KDT. Treatment-emergent gastroparesis and hypertriglyceridemia occurred in three patients (Epilepsy Res. 2018 Aug;144:1-6).
“It was reasonably well tolerated, but they started it quite late – a median of 13 days after onset of refractory status epilepticus. It should come much earlier on our list of therapies. We shouldn’t be waiting 2 weeks before going to the ketogenic diet, because we can diagnose refractory status epilepticus within 48 hours after arrival in the ICU most of the time,” Dr. Sharma said.
Austrian investigators have pioneered the use of intravenous KDT as a bridge when oral therapy is temporarily impossible because of status epilepticus, surgery, or other reasons. They reported that parental KDT with fat intake of 3.5-4 g/kg per day was safe and effective in their series of 17 young children with epilepsy (Epilepsia Open. 2017 Nov 16;3[1]:30-9).
The future: nonketogenic diet therapies
KDT in its various forms is just too demanding and restrictive for some patients. Nonketotic alternatives are being explored.
Triheptanoin is a synthetic medium-chain triglyceride in the form of an edible, odorless, tasteless oil. Its mechanism of action is by anaplerosis: that is, energy generation via replenishment of the tricarboxylic acid cycle. After demonstration of neuroprotective and anticonvulsant effects in several mouse models, Australian investigators conducted a pilot study of 30- to 100-mL/day of oral triheptanoin as add-on therapy in 12 children with drug-refractory epilepsy. Eight of the 12 took triheptanoin for longer than 12 weeks, and 5 of those 8 experienced a sustained greater than 50% reduction in seizure frequency, including 1 who remained seizure free for 30 weeks. Seven children had diarrhea or other GI side effects (Eur J Paediatr Neurol. 2018 Nov;22[6]:1074-80).
Parisian investigators have developed a nonketotic, palatable combination of amino acids, carbohydrates, and fatty acids with a low ratio of fat to protein-plus-carbohydrates that provided potent protection against seizures in a mouse model. This suggests that the traditional 4:1 ratio sought in KDT isn’t necessary for robust seizure reduction (Sci Rep. 2017 Jul 14;7[1]:5496).
“This is probably going to be the future of nutritional therapy in epilepsy,” Dr. Sharma predicted.
She reported having no financial conflicts regarding her presentation.