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Neuroprotective Effects of the Ketogenic Diet (Part 1: Historical Perspective)

by Milene Brownlow, PhD

Nowadays, blogging about ketogenic diets hardly requires an introductory paragraph. Most of us are bombarded with newsletters, emails, and personal stories of how cutting back on carbs and increasing consumption of healthy fats yield remarkable benefits. The popularity of the diet is largely due to its effects on weight loss and improved metabolism. Yet, long before a trending topic on every social media platform, ketogenic diets were specifically, clinically used for seizure control in the treatment of childhood epilepsy.1

In the early 1920s, the belief that seizures resulted from the improper functioning of the bowels led to the assumption that fasting could eliminate them by reducing systemic intoxication. Fasting children for as long as 25 days resulted in pronounced and long-lasting seizure control.1 Since fasting was a temporary solution, physicians searched for other methods to replicate and extend its therapeutic effects. They observed that fasting reduced levels of glucose and insulin and resulted in the appearance of ketone bodies (beta-hydroxybutyrate and acetoacetate) in blood and urine. Knowing that ketone bodies are byproducts of fat breakdown, they suggested that a diet rich in fatty foods and restrictive of starches could generate ketone levels high enough (hence the name ketogenic) to replicate the seizure reducing effects of fasting without its severe dietary restriction.2

Although not well received by the medical community, the physicians that did take a chance and prescribed the ketogenic diet observed striking results. Most of the children, afflicted by multiple daily seizures, experienced immediate and long-lasting remission.3 However, as advances were made in the development of anticonvulsant drugs in the late 1930s, pharmacotherapy became the first line of treatment for epilepsy. Compared to a dietary pattern that required significant time and effort, a therapeutic approach in the form of a pill was much more convenient. As a result, the ketogenic diet fell in disuse and was almost entirely forgotten.

In the decades that followed, research progressed in the field of energy metabolism and how it relates to brain health, physical performance, and age-related and metabolic disorders. In a noteworthy study performed in the late 1960s, subjects with obesity were fasted, with access to only water, for 4 to 6 weeks.4 Scientists observed that ketones replaced glucose as the predominant fuel for the brain, meeting up to 70% of the brain’s energetic demands. Several other findings pointed to benefits of this state of nutritional ketosis: medium-chain triglycerides (MCTs) showed anticonvulsant potential;5 impaired glucose utilization was identified in the brains of patient with Alzheimer’s disease;6 and the Atkins diet increased in popularity. But it wasn’t until the early 1990s when ketogenic diets started gaining attention again by the medical community.

Hollywood producer Jim Abrahams stumbled upon the diet after trying every available treatment to alleviate his son Charlie’s epilepsy. Despite all efforts, numerous medications, and one fruitless brain surgery, Charlie’s seizures (up to 100/day) remained unchanged and were affecting his neurological development. Having read about the ketogenic diet in a book written by Dr. John Freeman, a pediatric neurologist at Johns Hopkins, Abrahams decided to pursue this option as nothing else had worked. After meeting with Dr. Freeman, they started the protocol by fasting Charlie to transition him into a state of ketosis; forty-eight hours later, Charlie stopped having seizures. The remarkable impact the diet had on his son led him on a passionate journey to spread the word by creating the Charlie Foundation, dedicated to disseminating information about the ketogenic diet.7 This allowed families to have a platform for sharing stories, recipes, and seeking help when they had also failed to find reprieve in conventional pharmacotherapy. In addition, Abraham went on to produce a movie (First Do No Harm), narrating a family’s struggle to find treatment for their child with severe epilepsy.

Since then, medical and scientific communities have been more accepting of the ketogenic diet, although it is still rarely adopted as the first line of therapy in epilepsy centers. Despite that and in addition to cumulative evidence in support of its health promoting effects, researchers are now honing in on its underlying mechanisms and developing modified protocols to facilitate patient compliance.

The original version, referred to as the “classic” ketogenic diet was composed of a 4:1 ratio of fat to proteins and carbohydrates, with 90% calories coming from fat, 6% from protein and 4% from carbs. Although this ratio is considered the gold-standard for classic keto, less rigid versions of the diet have been proposed, for example: the MCT diet (addition of ketogenic MCTs allows for slightly higher carb amounts), modified Atkins (no strict protein limits), low glycemic index diet (less structured and does not focus on promoting ketosis).7

It is important to keep in mind that a ketogenic protocol can be personalized based on individual factors such as: age, gender, carbohydrate tolerance, physical activity, neurological and metabolic health, among others. Greater dietary flexibility results in increased adherence to a ketogenic lifestyle.2 It is now considered a promising metabolic therapy for several other neurological conditions (e.g. multiple sclerosis, Parkinson’s disease, traumatic brain injury, amyotrophic lateral sclerosis, autism spectrum disorder and brain tumors) currently being tested in both clinical and laboratory settings. New research findings are published every week, and exciting pieces of this intricate puzzle that is our metabolic machinery are slowly coming together in support of the neuroprotective properties of the ketogenic diet.


  1. Hartman AL et al. The neuropharmacology of the ketogenic diet. Pediatr Neurol. 2007;36(5):281-92.
  2. Freeman JM et al. Ketosis and the ketogenic diet, 2010: Advances in treating epilepsy and other disorders. Adv Pediatr. 2010;57(1):315-29.
  3. Kossoff E et al. Ketogenic diets: treatments for Epilepsy and other disorders. 5th New York: Demos Med. Publishing 2011.
  4. Owen OE et al. Brain metabolism during fasting. J Clin Invest. 1967;46(10):1589-95.
  5. Huttenlocher PR et al. Medium-chain triglycerides as a therapy for intractable childhood epilepsy. 1971;21(11):1097-103.
  6. Hoyer S et al. Abnormalities of glucose metabolism in Alzheimer’s disease. Journal of Neurology. 1988;235:143–48.
  7. Accessed by June 25, 2018.

Milene Brownlow, PhD

Dr. Milene Brownlow is a Nutrition Scientist for the Cognitive Platform at Metagenics. She has earned her PhD from the University of South Florida, studying the role of diet-induced ketosis and calorie restriction on Alzheimer’s pathology. During her postdoctoral fellowship at the Air Force Research Laboratory she investigated nutritional approaches to optimizing brain health and cognitive performance. Dr. Brownlow has extensive experience in designing, managing and executing studies in behavioral neuroscience and has authored over 12 peer-reviewed publications. In her spare time, she enjoys spending time with her husband and their daughter, exploring the beautiful Pacific Northwest.

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