The ketogenic diet and its impact on epilepsy

In the ancient world, dietary modifications were recommended for a range of disorders that we today classify as neurological, including epilepsy.  

In fact, early concepts regarding epilepsy in Indian traditional medicine (1) were first codified during the Vedic period, which was roughly 4500 to 1500 BC. The Ayurvedic medical text, the Charaka Samhita, epilepsy is described as apasmara, which means loss of consciousness. In ancient Greece, the Hippocratic Corpus, from 400 BC, disputed the prevailing view that epilepsy was supernatural in origin. 

In the modern world, in the first two decades of the last century, physicians and physical culture adherents advocated for the practice of fasting to treat epilepsy.  

The first American physician to be credited with proposing the use of a ketogenic diet, one that was designed to safely mimic fasting, but to also provide adequate protein and calories for growth for long-term epilepsy control, was Dr. Russell Wilder, at the Mayo Clinic, who proposed that, what he would call a “ketogenic diet,” should be studied in a series of patients with epilepsy (2).  

He postulated that a ketogenic diet could be as effective as fasting for epilepsy and could be maintained for a significantly longer period of time. Wilder would later report his findings in patients treated with a ketone‐producing diet (3,4). 

Ketogenic dietary modalities have been successfully used for: intractable epilepsy and status epilepticus, in addition to having been effectively used for conditions that feature epileptic components, such as Angelman syndrome and multiple acyl-CoA dehydrogenase deficiency (MADD). 

Refractory epilepsy 

Reviews 

Over the last 25 years, researchers have been applying the ketogenic diet for intractable epilepsy. Dhamija and colleagues reviewed the efficacy of 18 studies between 1971 and 2012, which included traditional ketogenic diets, medium-chain triglyceride (MCT) oil diets and modified Atkins diets (5). 

All seven ketogenic diets exhibited significant seizure reduction, with one of the accessed studies, a large single-center trial in a cohort of children with intractable epilepsy, showed marked improvement in over 60 percent of patients (6). 

In a literature review of 20 retrospective and prospective studies published between the 1920 and 2003, the author concluded that “the ketogenic diet appears to be a very effective treatment for epilepsy, particularly in childhood” (7). 

A meta-analysis of the ketogenic diet for epilepsy, one which included 19 observational studies, found that the pooled odds ratio of treatment success (>50 percent seizure reduction) in patients staying on the diet relative to those discontinuing the diet was 2.25 (8). 

In a 2019 study from South Korea, the medical records were reviewed for 16 patients with super-refractory status epilepticus who received a ketogenic diet (9). 

Clinical trials and interventions 

In a 2019 Rush University study of modified ketogenic diets in adults with drug-resistant epilepsy, 60 percent of patients reported seizure frequency improvement of ≥50 percent and 76 percent reported improvement in seizure severity, and 87 percent reported improvement in quality of life indicators (10). 

In a 2019 safety and tolerability study from Turkey (11), children with drug-resistant epilepsy received a ketogenic diet between 2012 and 2016. By 12 months, 83.1 percent of the children successfully responded to the diet. 

In a randomized controlled trial of 145 children who had refractory seizures for three months, the mean percentage of baseline seizures was significantly lower in the ketogenic diet group, and showed a 75 percent decrease in seizures (12). 

In a retrospective study (13), 13 of 460 patients were started on the ketogenic diet as early therapy for seizures (10). Of those remaining on the diet, 60 percent had an over 90 percent seizure reduction at six months and 100 percent had an over 90 percent reduction at 12 months. 

Other disorders with epileptic components 

Multiple acyl-CoA dehydrogenase deficiency (MADD) and Angelman syndrome 

Several case interventions using the ketone, beta hydroxybutyrate (BHB), were published between 2003 and 2015 (14-16), which led one group of these authors to conclude that BHB is a “highly effective and safe treatment” for MADD (14). 

In 2017, researchers from Massachusetts General Hospital conducted a retrospective review of records from 23 patients with Angelman syndrome who received low-glycemic index therapy (LGIT) (17). Twenty-two percent of subjects achieved complete seizure freedom and 43 percent maintained seizure freedom except with the presence of co-morbidity. In addition, 30 percent experienced a decrease in seizure frequency. 

In 2012, six children with genetically confirmed Angelman syndrome received an LGIT diet for four months (18). All subjects experienced a decrease in seizure frequency with LGIT diet, with five of the six patients achieving over an 80 percent reduction seizure frequency. Developmental gains were noted for all patients, as well. 

In a foundational animal model study from 2016, Angelman syndrome (AS) mice were supplemented with the acetoacetate di-ester ad libitum for eight weeks (19). Ketone administration improved motor coordination, learning, memory and synaptic plasticity in the mice. The ketone was also anticonvulsant and beneficially altered brain amino acid metabolism in AS-treated animals. 

References

  1. Eadie MJ and Bladin PF. A Disease Once Sacred: A History of the Medical Understanding of Epilepsy. Eastleigh: John Libbey, 2001.
  2. Wilder RM. “The effect on ketonemia on the course of epilepsy.” Mayo Clin Bull. 1921;2:307.
  3. Wheless JW. “History of the ketogenic diet.” Epilepsia. 2008;49 Suppl 8:3-5.
  4. Wilder RM and Winter MD. “The threshold of ketosis.” J Biol Chem. 1922;52:393-401.
  5. Dhamija R, et al. “Ketogenic diet.” Can J Neurol Sci. 2013;40:158-167.
  6. Kinsman SL, et al. “Efficacy of the ketogenic diet for intractable seizure disorders: Review of 58 cases.” Epilepsia. 1992;33:1132-1136.
  7. Thiele EA. “Assessing the efficacy of antiepileptic treatments: The Ketogenic diet.” Epilepsia. 2003;44 (Suppl 7):26-29.
  8. Henderson CB, et al. “Efficacy of the ketogenic diet as a treatment option for epilepsy: meta-analysis.” J Child Neurol. 2006;21(3):193-198.
  9. Park EG, et al. “The ketogenic diet for super-refractory status epilepticus patients in intensive care units.” Brain Dev. 2019;41(5):420-427.
  10. Roehl K, et al. “Modified ketogenic diets in adults with refractory epilepsy: Efficacious improvements in seizure frequency, seizure severity, and quality of life.” Epilepsy Behav. 2019;93:113-118.
  11. Guzel O, et al. “Efficacy and tolerability of olive oil-based ketogenic diet in children with drug-resistant epilepsy: A single center experience from Turkey.” Eur J Paediatr Neurol. 2019;23(1):143-151.
  12. Neal EG, et al. “The ketogenic diet for the treatment of childhood epilepsy: a randomized controlled trial.” Lancet Neurol. 2008;7(6):500-506.
  13. Rubenstein JE, et al. “Experience in the use of the ketogenic diet as early therapy.” J Child Neurol. 2005;20(1):31-34.
  14. Gautschi M, et al. “Highly efficient ketone body treatment in multiple acyl-CoA dehydrogenase deficiency-related leukodystrophy.” Pediatr Res. 2015;77(1-1):91-98.
  15. Van Rijt WJ, et al. “Favorable outcome after physiologic dose of sodium-D,L-3-hydroxybutyrate in severe MADD.” Pediatrics. 2014 Oct;134(4):e1224-8. doi: 10.1542/peds.2013-4254
  16. Van Hove JL, et al. “D,L-3-hydroxybutyrate treatment of multiple acyl-CoA dehydrogenase deficiency (MADD).” Lancet. 2003;361(9367):1433-1435.
  17. Grocott OR, et al. “Low glycemic index treatment for seizure control in Angelman syndrome: A case series from the Center for Dietary Therapy of Epilepsy at the Massachusetts General Hospital.” Epilepsy Behav. 2017;68:45-50.
  18. Thibert RL, et al. “Low glycemic index treatment for seizures in Angelman syndrome.” Epilepsia. 2012;53(9):1498-1502.
  19. Ciarlone SL, et al. “Ketone ester supplementation attenuates seizure activity, and improves behavior and hippocampal synaptic plasticity in an Angelman syndrome mouse model.” Neurobiol Dis. 2016;96:38-46.

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