This prospective pre-post multicentered observational cohort study was initiated following ethical approval from the Health Research Ethics Committee of the Faculty of Medicine, University of Indonesia (Ethics Approval No. KET-267/UN2.F1/ETIK/PPM.00.02/2023), granted on 6 March 2023. Logistic regression sample size estimation was used to determine a sample size of 130 participants, adjusting for participant drop-out or missing data.

Data collection was conducted across two consecutive Ramadan fasting periods, corresponding to Hijri calendar years 1444 and 1445 (Gregorian years 2023 and 2024, respectively). During the first year, data collection commenced on 8 March 2023 and concluded on 21 May 2023, one month after the end of Ramadan fasting period. In the second year, data collection commenced on 12 February 2024, one month prior to Ramadan, and ended on 9 May 2024, one month after Ramadan fasting period.

Primary data sources included questionnaires administered starting one month before the start of Ramadan and repeated during Ramadan to assess changes in clinical outcomes. Secondary data sources were obtained from medical records. All data were collected at the outpatient neurology clinic of five hospitals from three different cities: Cipto Mangunkusumo National Referral Hospital (CMH), Atma Jaya Hospital (AJH), Pasar Minggu Hospital (PMH), Pasar Rebo Hospital (PRH), and Ciawi General Hospital (CGH).

The study population included Muslim patients aged 18 years or older, diagnosed with epilepsy and receiving treatment at the outpatient clinic. Patients with mental retardation, severe psychiatric disorders, or those unwilling to provide informed consent were excluded from the study. All participants gave informed consent before inclusion in the study.

Data were collected using both medical records and structured questionnaires administered one month before the start of Ramadan and repeated during Ramadan.

2.3.1 Baseline data

Baseline data were acquired using data from structured questionnaires that captured demographic information (e.g., age, gender, educational status, marital status, employment status). Information on seizure characteristics (e.g., seizure frequency, seizure type), number of ASMs used, seizure-free status, and duration of seizure freedom was collected from medical records. Seizure type was classified as either focal or general, while seizure freedom was defined as the absence of seizures for a minimum 12-month period before data collection. Sleep duration was defined as the number of hours spent asleep at night for the past month.

Medication adherence, which could change during Ramadan observance due to fasting, was measured in our study using the Morisky Adherence Questionnaire (MAQ), which consists of four yes/no questions. Responses were scored as either 0 (yes) or 1 (no), with total scores ranging from 0 to 4. Patients with a score of 4 were classified as adherent, while those scoring 0–3 were considered nonadherent. ⁸

2.3.2 Follow-up

Follow-up data was collected using structured questionnaires that captured information on whether or not participants participated in Ramadan observance and engaged in midnight prayers. The questionnaire also contained items collecting data of the volume of liquids consumed per day during Ramadan, and overconsumption of carbohydrates at iftar (breaking fast), which was defined as consumption of carbohydrates over twice the normal amount at Iftar and was assessed subjectively. Sleep duration and medication adherence during Ramadan was also included in the follow-up questionnaire.

2.3.3 Outcome

The outcome of this study, seizure frequency, was categorized as an increase or decrease in seizure frequency by comparing the number of seizures recorded in the one-month period before and during Ramadan.

Data were analyzed using SPSS software version 26.0 (IBM Corp., Armonk, NY, USA). The dependent variable was the change in seizure frequency one month before Ramadan and during Ramadan. Categorical variables were presented as percentages, while continuous variables were initially assessed for normality. Based on the results of the Kolmogorov-Smirnov test, they were then reported either as mean and standard deviation (SD) for normally distributed data or as median and range for non-normally distributed data.

For bivariate analysis, Chi-square tests, likelihood ratio tests, or Fisher’s exact tests were used for categorical variables, while Mann-Whitney U or independent T-tests were used for continuous variables. Multivariate logistic regression was performed to control for potential confounders, with variables showing a p-value < 0.1 in the bivariate analysis included in the multivariate model. All assumptions, including the absence of outliers and multicollinearity, were satisfied before performing regression analyses.

Of the144 individuals approached, 134 were eligible and consented, and 122 completed follow-up. CMH contributed the largest proportion (58.3%). The median age was 30.5 years (18-74), and slightly more than half were female. Most participants had completed senior high school. Among the employed population, 58.1% continued working during Ramadan. Table 1 summarizes all demographic and clinical characteristics.

Median age at seizure onset was 17 years (0.2-68), with a median epilepsy duration of 11 years (0.33-59). Only 21.3% were seizure-free. Focal epilepsy was the most common seizure type (68.9%). Polytherapy was used by 54.9% participants.

Among all participants, 83.6% fasted during Ramadan. Median fluid intake was 1,500 ml/day (400-3,000), and 29.4% reported carbohydrate overconsumption at iftar. Seizure frequency improved slightly during Ramadan, with a reduction in participants experiencing >5 seizures/month (from 9.8% to 7.4%). Medication adherence appeared higher during Ramadan (59%) compared to pre-Ramadan (48.4%). Sleep duration decreased from 7 hours pre-Ramadan to 5.5 hours during Ramadan ( Table 1).

Among those who fasted (n = 102), 25.9% experienced an increase in seizure frequency. Significant factors in bivariate analysis ( Table 2) included being non-seizure-free before Ramadan (p = 0.002), carbohydrate overconsumption at Iftar (p = 0.004), and longer sleep duration during Ramadan (p = 0.041). All pre-Ramadan seizure-free participants remained seizure-free.

Logistic regression analysis included carbohydrate overconsumption during iftar, and sleep duration during Ramadan. Seizure-free status was excluded from multivariate analysis due to zero events in that group. The analysis revealed that participants who overconsumed carbohydrates were 3.81 times more likely to experience an increase in seizure frequency. Sleep duration, however did not display a significant association with an increase in seizure frequency ( Tables 2 and 3).

All participants who were seizure-free before Ramadan remained seizure-free throughout the fasting month. This aligns consistent with prior studies showing that sustained pre-Ramadan seizure freedom is a strong predictor of safe fasting. ¹⁶ Although the sample size of seizure-free individuals was modest, the absence of any breakthrough events underscores the strength of pre-existing seizure control as a predictor of fasting safety. This is aligned with international Ramadan epilepsy recommendations, yet our data provide the first prospective Southeast Asian evidence confirming this pattern.

Carbohydrate overconsumption emerged as a significant predictor of seizure increase. Acute postprandial hyperglycemia may lower the seizure threshold through effects on ion channels, oxidative stress, and excitatory transmission. ^{17– 19} Evidence supporting this mechanism is indirectly reinforced by the anti-seizure effects of ketogenic and low-carbohydrate diets, which stabilized neuronal activity via ketone-mediated pathways. ^{20, 21}

Our finding likely reflects Indonesia dietary patterns, where iftar meals often include rice, noodles, sweet drinks, and fried foods – resulting in high glycemic loads. This culturally specific behavior may explain why similar studies in Middle Eastern populations have not highlighted carbohydrate excess as a major seizure trigger.

Although carbohydrate intake was assessed subjectively, the strength of the association suggest that the immediate metabolic transition following iftar may represent a vulnerable period for individuals with epilepsy. Rapid rises in postprandial glucose can enhance neuronal excitability through ion-channel modulation, oxidative stress pathway, and glutamatergic transmission, providing biological plausibility for our observation. ^{17– 19} This finding should therefore be interpreted not as evidence of a definitive causal mechanism, but as a clinically meaningful hypothesis that identifies a modifiable behavioral factor. Future studies employing quantitative dietary assessments or continuous glucose monitoring could further clarify the metabolic dynamics influencing seizures risk during Ramadan.

Contrary to expectations, longer – not shorter – sleep duration was associated with increased seizure frequency in bivariate analysis. This is likely confounded: individuals experiencing more seizures may have required additional restorative sleep. After adjustment in multivariate analysis, sleep duration was not an independent predictor. Prior studies also found no consistent link between sleep duration during Ramadan and seizure risk. ^{9, 10}

Evidence on Ramadan fasting and epilepsy from South-East Asia (SEA) is scarce. Indonesia and neighboring countries share dietary habits characterized by high carbohydrate consumption. Indonesian iftar meals commonly involve sweetened beverages, rice-based dishes, and fried snacks – patterns distinct from Middle Eastern diets that are relatively higher in protein and fat. These differences may influence glycemic fluctuations and seizure susceptibility.

Thus, this study provides the first multicenter prospective evidence describing seizure-related outcomes during Ramadan in Indonesian MPWE. These findings underscore the need for locally contextualized guidelines, rather than solely on data from other regions.

Although this study is observational and relies on self-reported measures, such an approach is appropriate and necessary for Ramadan-related research, where controlled fasting manipulation is neither ethical nor feasible. Observational methods also capture real-world behaviors that laboratory paradigm may miss, including cultural eating patterns, medication timing preferences, and personal fasting motivations. Importantly, the consistency of the seizure-free subgroup demonstrates a clinically meaningful pattern that is unlikely to be explained solely by measurement limitations. Thus, while caution is warranted in interpreting causal mechanisms, the findings provide actionable insights that reflect how MPWE actually experience and manage Ramada fasting.

Although adherence improved during Ramadan, no significant association was observed with seizure change. This may be due to the MAQ’s stringent scoring system; even minor delays in dosing classify participants as non-adherent. Minor schedule deviations may not meaningfully affect seizure risk, particularly for ASMs with long half-lives. Nonetheless, simplified once – or twice – daily dosing regimens remain ideal for fasting patients. ²²

Several limitations exist in this study. Participating in Ramadan observance constitutes significant lifestyle changes in multiple aspects, including but not limited to: changes in sleep pattern, eating patterns, work, and dosing regimens, which could all effect seizure frequency. While this study has managed to find the relationship of these major contributing factors towards seizure frequency, participating in observance during Ramadan may entail other changes that could affect seizure frequency (e.g. changes in physical activity, stress, dehydration status), which was not accounted for in our study. Future studies could also focus more on certain aspects such as changes in plasma drug concentrations with different dosing regimens during Ramadan fasting and its effect on seizure.

Observance during Ramadan also varies in different countries, most notably by difference of fasting duration (time from dusk to dawn), in which countries closer to the equator will have shorter fasting durations. This means that the results of this study might not be applicable to MPWE in other countries, especially those with significantly longer fasting duration.

As this was an observational study, causal inference cannot be established. Nonetheless, controlled experimental manipulation of fasting behavior is not ethically feasible, making observational approaches the most appropriated method for examining Ramadan practices. Additionally, the robust stability observed among seizure-free participants suggests that certain clinical patterns can still be discerned despite methodological limitations. Future studies incorporating objective metabolic measures (e.g., glucose or ketone monitoring), wearable sleep tracking, or quantitative dietary analysis would strengthen mechanistic interpretation.

The present findings support a practical, risk-stratified framework for guiding fasting decisions among MPWE. Patients who have maintained seizure freedom for at least 12 months appear to constitute a low-risk group, demonstrating high tolerance to the metabolic, behavioral, and medication timing changes inherent to Ramadan. Conversely, individuals with active seizures may benefit from close monitoring and targeted counseling- particularly regarding carbohydrate load at iftar, which emerged as a potentially modifiable contributor to seizure worsening. These results suggest that clinicians should move beyond generalized assumption about the risks of fasting and instead integrate individualized factors (i.e., seizure-free status, dietary habits, medication timing) into shared decision-making discussions before Ramadan.