Fasting has been practiced for thousands of years throughout the history of mankind, driven by various motives such as spiritual cleansing, cultivating a stronger connection with God, reaping health benefits, and engaging in acts of charity.

The utilization of dietary therapies for health purposes also boasts a rich historical foundation. Notably, Hippocrates, a revered figure in medical history, is quoted as saying, “Let food be thy medicine, thy medicine shall be thy food.” In his work “Sacred Disease,” he delved into the concept that the body of an epileptic patient was considered “polluted,” and dietary modifications played a role in purification.

The practice of fasting for health reasons is prevalent across different religions. In the King James Version of the Bible, a significant event unfolds as an epileptic child is brought to Jesus, who declares, “This kind can come forth nothing except by prayer and fasting.” Muslims globally observe a month-long (month of Ramadan) fast annually as prescribed in the Qur’an. God's mandate is clear, stating, "Fasting has been prescribed for you as it was for previous nations, fostering God-consciousness" (2:183). Prophet Muhammad, peace be upon him, reinforces the benefits of fasting with the affirmation, "Fast, and you will attain health" (Ibn Majah, Tabarani).

Fasting and epilepsy

In modern literature, the use of fasting as a medical therapy for neurological disorders was first mentioned by two French physicians, Guelpa and Marie, who published a report detailing their use of fasting to treat epileptic seizures. In their study of 26 patients, six showed a reduction in the severity or occurrence of seizures [1]. At the 1921 American Medical Association convention, Geyelin presented a controlled study that involved 36 epileptic patients who fasted for up to 25 days, using water only. The reported cure rates were 90% for juvenile patients and 50% for adults [2]. Due to the perceived challenges associated with fasting, different forms of the ketogenic diet have been developed to replicate its effects. These dietary therapies involve high-fat, adequate-protein, and low-carbohydrate approaches.

The primary emphasis of contemporary epilepsy treatment has largely centered on developing medications, attributed to the perceived difficulties in sustaining fasting therapies. However, the 1997 movie "First Do No Harm" portrayed the real-life experience of a young patient with refractory epilepsy and his family. Having encountered uncontrolled seizures and adverse side effects from numerous medications, the family discovered the ketogenic diet as an alternative therapy at Johns Hopkins University. The child became seizure-free, inspiring and challenging the scientific community's perception of epilepsy treatment.

Since then, research on fasting and dietary therapies like the ketogenic diet in epilepsy has flourished. Strong evidence-based research, including at least 12 good-quality randomized controlled trials (RCTs), and several systematic and meta-analysis review articles, supports the effectiveness of diet therapies in childhood epilepsy treatment [3,4,5]. While the evidence in adult treatment is not as robust, it is still considered clinically significant [6]. Further human studies should be considered to explore dietary treatments for epilepsy in adult patients.

How do ketones have an anti-epileptic effect?

Seizures happen when our brain cells become overly excited, a state known as neuronal hyperexcitability. Both fasting and the Ketogenic Diet (KD) have demonstrated effectiveness in seizure control. During fasting, the body produces substances that calm the excited brain cells. The KD, characterized by low carbohydrate and high-fat intake, has been shown to increase these calming substances (such as GABA) and reduce the ones (like glutamate) contributing to brain cell hyperexcitability. This diet also boosts ATP production, protecting brain cells from seizure-induced damage. Ketones, produced during fasting, activate a protective mechanism, enabling brain cells maintain resilience and withstand the stresses of seizures [7].

What else do ketones do in our brains?

It is well-known that during fasting, our glucose sources in the blood and liver are depleted, leading to the utilization of fat for energy production, resulting in the production of ketones. The ketogenic diet mimics fasting by consuming minimal amounts of carbs and protein, making fat the primary energy source, leading to the production of ketones in the body.

Neuroscientists theorize that ketone production makes neuronal cells more resilient to stressful environments, such as seizures, strokes, and neurodegenerative disorders, by involving various cellular and molecular pathways. This protection helps prevent neuronal hyperexcitability. When neuronal cells use ketones instead of glucose, it triggers alarm systems for cell protection, energy production, and cleansing processes [8].

A recent publication demonstrates that exposing neuronal cells to ketone bodies not only prevents neuronal death but also triggers autophagy, a cellular cleansing process [9]. Another review publication suggests that the protective mechanisms for neurons during intermittent fasting include robust mitochondrial regeneration and the production of Brain-Derived Neurotrophic Factor (BDNF) [10]. BDNF is recognized for its role in neuroplasticity, neurogenesis, and neuronal protection. Together, these intracellular processes collectively aid cells in overcoming stressful conditions such as stroke, seizures, and neurodegenerative disorders [11].

Intermittent fasting and Alzheimer's Disease

In Alzheimer's Disease (AD), the accumulation of excessive B-amyloid and tau proteins (misfolded and unprocessable proteins) inside cells leads to neuronal death. Intermittent fasting may combat Alzheimer's and other neurogenerative disorders through similar cellular mechanisms. Improved autophagy in neuronal cells is assumed to aid in clearing extracellular and intracellular matter [9]. A recent study further supports this idea, demonstrating that ketone bodies enhance B-amyloid clearance in human in vitro blood-brain barrier models [12]. This finding is supported by many animal disease models, illustrating how ketones can reduce B-amyloid and tau pathology [13]. Additionally, recognized cardiovascular risk factors such as diabetes, hypertension, and obesity are also well-known contributors to neurodegenerative disorders like dementia. Intermittent fasting has been proven effective in reversing diet-induced diabetes, improving cardiovascular health by reducing hypertension, and assisting obese patients in losing weight [14].

Most of our theories are based on animal and molecular studies, but a recent study in Malaysia, involving nearly 100 patients with mild cognitive impairment, showed that intermittent fasting, specifically on Mondays and Thursdays (a fasting recommendation by Prophet Muhammad, peace be upon him), reversed mild cognitive impairment in patients [15]. In another study conducted in Houston during Ramadan, around 14 healthy subjects participated. The study measured amyloid precursor protein levels at the end of Ramadan, revealing a decrease. This reduction in amyloid precursor protein is theorized to be one of the mechanisms underlying neurodegenerative disorders [16].

Intermittent fasting and other neurological disorders

Beyond its impact on vascular risk factors, intermittent fasting has shown clear protective effects against strokes or heart attacks, as evidenced in numerous animal models. Ongoing research explores the influence of intermittent fasting on stroke models in laboratory settings. Dr. Arumugam et al. demonstrated that animals subjected to one month of intermittent fasting experienced decreased stroke severity and improved mortality compared to those with the same vascular occlusion causing strokes [17]. Given the significant roles and mechanisms of intermittent fasting that may ameliorate various other neurological disorders, a recent review publication in Nutrients discusses these disorders. The publication includes a table explaining the strong evidence supporting intermittent fasting in alleviating underlying pathophysiology in animal models of epilepsy, Parkinson's, Alzheimer's, and multiple sclerosis [18].

Conclusions

In conclusion, the potential therapeutic benefits of fasting or the ketogenic diet in neurological disorders are supported by significant evidence in theoretical frameworks and animal studies. However, human research in this area remains limited. Despite this limitation, the existing body of literature highlights promising avenues for further exploration and underscores the importance of rigorous clinical investigations to validate these findings within human populations.

References and Recommended Read of Literature on the Subject

1. 7. Guelpa G., Marie A. La lutte contre l’epilepsie par la desintoxication et par la reeducation alimentaire. Revue de Therapie Medico-Chirurgicale. 1911;78:8–13.
2. Geyelin H.R. Fasting as method for treating epilepsy. Med. Rec. 1921;99:1037–1039. 
3. Martin-McGill KJ, Jackson CF, Bresnahan R, Levy RG, Cooper PN. Ketogenic diets for drug-resistant epilepsy. Cochrane Database Syst Rev. 2018 Nov 7;11(11):CD001903. doi: 10.1002/14651858.CD001903.pub4. Update in: Cochrane Database Syst Rev. 2020 Jun 24;6:CD001903. PMID: 30403286; PMCID: PMC6517043.
4. Li HF, Zou Y, Ding G. Therapeutic Success of the Ketogenic Diet as a Treatment Option for Epilepsy: a Meta-analysis. Iran J Pediatr. 2013 Dec;23(6):613-20. PMID: 24910737; PMCID: PMC4025116.
5. Henderson CB, Filloux FM, Alder SC, Lyon JL, Caplin DA. Efficacy of the ketogenic diet as a treatment option for epilepsy: meta-analysis. J Child Neurol. 2006 Mar;21(3):193-8. doi: 10.2310/7010.2006.00044. PMID: 16901419.
6. Manral M, Dwivedi R, Gulati S, Kaur K, Nehra A, Pandey RM, Upadhyay AD, Sapra S, Tripathi M. Safety, Efficacy, and Tolerability of Modified Atkins Diet in Persons With Drug-Resistant Epilepsy: A Randomized Controlled Trial. Neurology. 2023 Mar 28;100(13):e1376-e1385. doi: 10.1212/WNL.0000000000206776. Epub 2023 Jan 4. PMID: 36599697; PMCID: PMC10065201.
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10.1038/nrn.2017.156. Epub 2018 Jan 11. Erratum in: Nat Rev Neurosci. 2020 Aug;21(8):445. PMID: 29321682; PMCID: PMC5913738.

8. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. N Engl J Med. 2019 Dec 26;381(26):2541-2551. doi: 10.1056/NEJMra1905136. Erratum in: N Engl J Med. 2020 Jan 16;382(3):298. Erratum in: N Engl J Med. 2020 Mar 5;382(10):978. PMID: 31881139.
9. Camberos-Luna L, Gerónimo-Olvera C, Montiel T, Rincon-Heredia R, Massieu L. The Ketone Body, β-Hydroxybutyrate Stimulates the Autophagic Flux and Prevents Neuronal Death Induced by Glucose Deprivation in Cortical Cultured Neurons. Neurochem Res. 2016 Mar;41(3):600-9. doi: 10.1007/s11064-015-1700-4. Epub 2015 Aug 25. PMID: 26303508.
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12. Versele R, Corsi M, Fuso A, Sevin E, Businaro R, Gosselet F, Fenart L, Candela P. Ketone Bodies Promote Amyloid-β1-40 Clearance in a Human in Vitro Blood-Brain Barrier Model. Int J Mol Sci. 2020 Jan 31;21(3):934. doi: 10.3390/ijms21030934. PMID: 32023814; PMCID: PMC7037612.
13. Kashiwaya Y, Bergman C, Lee JH, Wan R, King MT, Mughal MR, Okun E, Clarke K, Mattson MP, Veech RL. A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease. Neurobiol Aging. 2013 Jun;34(6):1530-9. doi: 10.1016/j.neurobiolaging.2012.11.023. Epub 2012 Dec 29. PMID: 23276384; PMCID: PMC3619192.
14. Mattson MP, Moehl K, Ghena N, Schmaedick M, Cheng A. Intermittent metabolic switching, neuroplasticity and brain health. Nat Rev Neurosci. 2018 Feb;19(2):63-80. doi:
15. Ooi TC, Meramat A, Rajab NF, Shahar S, Ismail IS, Azam AA, Sharif R. Intermittent Fasting Enhanced the Cognitive Function in Older Adults with Mild Cognitive Impairment by Inducing Biochemical and Metabolic changes: A 3-Year Progressive Study. Nutrients. 2020 Aug 30;12(9):2644. doi: 10.3390/nu12092644. PMID: 32872655; PMCID: PMC7551340.
16. Mindikoglu AL, Abdulsada MM, Jain A, Choi JM, Jalal PK, Devaraj S, Mezzari MP, Petrosino JF, Opekun AR, Jung SY. Intermittent fasting from dawn to sunset for 30 consecutive days is associated with anticancer proteomic signature and upregulates key regulatory proteins of glucose and lipid metabolism, circadian clock, DNA repair, cytoskeleton remodeling, immune system and cognitive function in healthy subjects. J Proteomics. 2020 Apr 15;217:103645. doi: 10.1016/j.jprot.2020.103645. Epub 2020 Jan 9. PMID: 31927066; PMCID: PMC7429999.
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