“Fasting? Not too Fast”;a Clinical Insight into the Impact of Fasting on Seizure Control in Patients with Epilepsy

Abstract

Ramadan Fasting in Adolescents With Epilepsy: Seizure Control and Behavioral Outcome.

Magdy R, Kishk N, Al-Azayem SA, Hussein M, Yassine IA, Tarek MA, Elsebaie EH, Abdeltwab MA, Othman AS. Seizure. 2025;124:85-88. doi:10.1016/j.seizure.2024.12.007

Data about the effect of Ramadan fasting on seizure control among adolescents with epilepsy (AWE) is scarce. Several psychobehavioral problems have also been encountered in this teenage group. This study aimed to assess seizure frequency and behavioral outcomes after Ramadan fasting in a sample of AWE. Methods: In this prospective study, AWE who completed fasting during Ramadan 2024 were evaluated regarding the seizure frequency of each type during Shaban (the month immediately preceding Ramadan) and Ramadan. Three questionnaires were requested to be answered at the end of two months. They were Patient Health Questionnaire (PHQ-9), Modified Overt Aggression Scale (MOAS), and Barratt Impulsiveness Scale-Short Form (BIS-11-SF) for assessment of depression, aggression, and impulsivity, respectively. Results: One hundred twenty AWE, with a median age of 15 and interquartile range: 13-17, were evaluated. There was a statistically significant reduction in seizure frequency regarding focal onset seizures during Ramadan compared to Shaaban (P .009), as well as generalized nonmotor (absence) seizures (P .027). The MOAS-total scores significantly reduced during Ramadan than Shaaban (P .003), as well as the scores of nonplanning impulsivity of BIS-11-SF (P 0.005). On the other hand, depression assessed by PHQ-9 did not significantly differ between the two months. Conclusion: Fasting Ramadan is associated with better control of multiple seizure types, including focal and generalized-onset nonmotor (absence) seizures, besides psychobehavioral aspects of aggression & nonplanning impulsivity, without worsening of other seizure types nor depression, among AWE.

Commentary

In the time of Classical Greece, Hippocrates of Kos (c.460—c.370 BC), a physician and philosopher was credited with a report on a man who had been seized by epileptic convulsions; “Complete abstinence from food and drink was prescribed, and the cure was achieved”. Later, in the modern medicine era, Guelpa and Marie, French physicians, were the first to report in the scientific literature on the value of fasting to reduce severity of epileptic seizures. A decade later across the Atlantic, an American physician, Russell M. Wilder, introduced the ketogenic diet (KD), a medical diet that contains high fat, low carbohydrate, and moderate protein as a potential treatment of epilepsy with the rationale of mimicking the fasting state. Since then, ketogenic diet therapy (KDT) has been widely used, studied, and eventually proven to be a highly potent and effective treatment of epilepsy for patients of all age groups, and has become one of the main pillars of epilepsy treatment alongside medications, surgery, and neurostimulation devices.

We now know the KD is not fasting. While fasting is abstinence from food and water, KDT is to consume a medical diet that is crafted with high fat, low carbohydrate content, to induce the body's metabolic pathways into the biochemical state called ketosis, hence “ketogenic.” These metabolic alterations from the KDT can essentially ameliorate seizures. However, KDT and fasting both still share some commonalities. One of the shared commonalities between KDT and fasting is that when the body is in the low glycemic state from carbohydrate depletion, the glycolytic restriction will result in increased production of the glucose analog 2-deoxyglucose (2-DG), a reversible inhibitor of glycolysis. ¹ 2-DG has been shown to exert broad activities both in vivo and in vitro models of acute seizure and epilepsy by markedly blocking epileptiform activity in both interictal and ictal states, and thus negating seizures. ¹ Additionally, in the low glycolytic state from the KDT or fasting, the hormone leptin is secreted, which was found to efficiently reduce neuronal excitation by inhibiting glutamate transmission via blockade of the α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor. ² Lastly, if the fasting state becomes prolonged, once glycogen stores are depleted, the glycolytic diversion will result in the body switching to utilize fat as a primary energy fuel and producing ketone bodies, ultimately reaching the metabolic state called ketosis, which is the same biochemical and physiological state induced by KDT. Ketone bodies, especially beta-hydroxybutyrate and acetoacetate, have been shown to have multiple antiseizure properties including increasing the intracerebral level of gamma-aminobutyric acid (GABA), a main inhibitory neurotransmitter, through the GABA shunt in the tricarboxylic acid (TCA) cycle, increases in ATP production and mitochondrial biogenesis which can lead to further biochemical effects that contribute to seizure control and neuroprotection. ¹ Ketone bodies also inhibit vesicular glutamate transporters (VGLUTs), which are required for exocytotic release of the excitatory neurotransmitter glutamate. ³

In this study, the authors found fasting in the Holy Month of Ramadan had some positive impact on seizure control and behavior in adolescents with epilepsy when compared to baseline seizures and behavior during Shaban (the month immediately before Ramadan). In terms of seizure control, the study mainly looked at the changes in frequency of seizures based primarily on the seizure types which showed a significant reduction in focal seizures and absence seizures (p value 0.009 and 0.027, respectively). The study also found improvement in verbal aggression and non-planning impulsivity scores but not in other domains of the psychiatric and behavioral assessment. ⁴ Previous studies on this topic, however, found mixed results. A prospective study done by Alqadi et al ⁵ that looked at the effect of fasting during Ramadan on seizure control and quality of life in 37 adults with epilepsy showed an average reduction of seizure frequency by 21% during the fasting month, but 29% in Shawaal (the month immediately followed Ramadan when the fasting has stopped). No significant change in quality of life was observed. ⁵ On the contrary, Shaaban et al ⁶ reported that prolonged fasting during Ramadan was linked to increased seizure risk and breakthrough seizures (p-value 0.02) in adults with epilepsy, despite a higher average concentration of beta-hydroxybutyrate level during the fasting month.

These mixed results may be due to the heterogeneity of study designs and lack of a control group. No studies have yet looked at the glycemic state (via glucose level) of patients during the fasting month, which may play a pivotal role in seizure control. The amount of carbohydrate consumption and glucose level during the fasting month, when eating and drinking are still permitted after sunset, may also be an important contributor as rebound hyperglycemia after prolonged fasting may cause fluctuation of the glucose level which can lower the seizure threshold, at least as shown in the animal model. ⁷ Aetiology of the epilepsy and epilepsy syndrome diagnosis may also be contributing factors to the response rate of fasting as some of the epilepsy syndromes or genetic epilepsies have shown more favorable response to dietary therapy with KDT and its variants than others, for example, epilepsy with myoclonic-atonic seizures (Doose syndrome), SCN1A Dravet syndromes, and glucose transporter 1 deficiency syndrome (GLUT1DS). ⁸ In terms of the psychological and behavioral changes from fasting during Ramadan, it may be difficult to conclude with confidence that fasting is the sole factor contributing to the outcome because human behavior is complex, and cultural and religious influence and expectations during the Holy Month may have been a strong contributor as well.

The topic of the impact of fasting on seizure control is interesting. Future investigators may want to consider a prospective controlled trial with biochemical monitoring, such as blood glucose, serum ketone, electrolytes, and food record in a more homogenous patient population with similar aetiology of epilepsy or epilepsy syndromes rather than the seizure types. Another interesting aspect for the study is to incorporate some form of fasting to KDT. A pilot study from Hartman et al ⁹ combined intermittent fasting with KDT by asking patients to skip 2 consecutive meals on 2 non-consecutive days a week in children who had been on KDT but did not achieve seizure freedom. The authors reported that 4 out of 6 children showed significant improvement in seizure control with this combined approach.

In summary, fasting has long been suggested to have a positive impact on patients with epilepsy, especially regarding seizure control. KDT, which shares some metabolic commonalities with fasting, has been used as a mainstream non-pharmacological treatment for epilepsy with high efficacy and good tolerability. The effect of fasting alone on seizure control and behavioral and cognitive improvement in patients with epilepsy is still unclear. More studies with control groups, larger sample size, innovative approaches, and biochemical and physiological monitoring are needed.