ABSTRACT
Background:
Breakthrough seizures are an essential aspect to consider while treating epilepsy. No study has been done on the precipitating factors for breakthrough seizures in the tribal area of Jharkhand. Hence, awareness regarding the possible precipitating factors of breakthrough seizures is vital to prevent their occurrence.
Aim:
To determine precipitating factors for breakthrough seizures among patients with epilepsy.
Materials and Methods:
This cross-sectional study was conducted between July 2022 and October 2023. The study included epileptic patients who had been receiving anti-epileptic drugs (AED) for at least 6 months before the survey.
Results:
300 patients with epilepsy were included. A total of 46% of epileptic patients had breakthrough seizures. Non-adherence to AED (P < 0.0001); the number of AED (P < 0.0006), duration of treatment (P < 0.05), level of education (P < 0.04), awareness of triggering factors (P < 0.05) and sleep deprivation (P < 0.05) carried the significant association with breakthrough seizures. In contrast, no association was found with gender, occupation, and stress.
Conclusions:
Breakthrough seizures are preventable. Hence, there is a need to create awareness of this issue to prevent its occurrence.
Keywords: Anti-epileptic drugs, breakthrough seizures, epilepsy, precipitating factors
Introduction
Even though the patients have reasonable control over anti-epileptic drugs (AEDs), still some of them experience breakthrough seizures. The international league against epilepsy (ILAE) defines breakthrough seizures as a result of inadequate control despite good compliance and planned dose reductions, resulting in treatment failure.[1] Some studies stated controlled epilepsy in those who had a seizure-free period for at least 6 months.[2] There is no data on breakthrough seizures in the tribal area of Jharkhand; hence, identifying the frequency and precipitating factors for breakthrough seizures in epilepsy is needed.
Breakthrough seizures occurring despite ongoing treatment is a great concern for epilepsy patients. By identifying the precipitating factors like non-adherence, duration of medication, and lifestyle factors for breakthrough seizures, healthcare providers can develop tailored strategies for seizure prevention and for the patients, it can help in better management of epilepsy, reducing the incidence of these seizures and improving the quality of life for patients. This is especially crucial in resource-limited and rural areas like tribal Jharkhand, where healthcare accessibility may be a challenge.
Methodology
Study design
In this retrospective cohort study, we examined the medical records of patients diagnosed with epilepsy and followed up on outpatient neurology days. In our study, the diagnosis of epilepsy was based on history and clinical assessment and using the ILAE definition for epilepsy.[3]
STROBE guidelines have been followed. All patients who had epilepsy, per the ILAE definition, with a seizure-free period on AED for at least 6 months before having any breakthrough seizure, and with standard imaging, normal electrolytes and biochemistry were included in the study. The patients on AED without a seizure-free period for at least 6 months before having breakthrough seizure episodes and patients with an incomplete history or abnormal imaging or deranged biochemistry or dyselectrolytemia were excluded.
Data collection
Following the Institutional ethical committee’s (IEC) approval, the current study will consider the cases reported between July 2022 and October 2023. By using a study-specific structured questionnaire, information available in case record forms was filled, and by using the same, a database was constructed for all records that satisfy the inclusion criteria and exclusion criteria. To measure the relationship with the prevalence of breakthrough seizures, some of the associated socio-demographic and clinical factors of patients with epilepsy have been taken into consideration, which includes their age, gender, marital status, education level, occupation, duration of treatment, number of antiepileptic drugs taken, adherence, duration of hours slept, and psychological stress. Patients’ age is grouped into five disjoint subgroups, viz., 10–20, 21–30, 31–40, 41–50, and 51 and above years. There are two categories for a patient’s educational background: illiterate and primary education. Duration of treatment is classified under the categories of ≤1 year and >1 year. The number of doses of medication missed by patients is categorized under adherence level into two classes: adherent and non-adherent. Doses missed are grouped into three categories: those who never missed the doses, those who missed one dose, and those who missed more than one dose. Two groups have been used to categorize hours slept by patients at night <8 hours and ≥8 hours. Seizure-precipitating factors were defined as those circumstances that preceded the onset of an epileptic attack and were considered by both the patient and neurologist to be a possible explanation for why the seizure happened when it did and not earlier or later.[4]
We used the four-item validated Morisky Medication Adherence Scale (MMAS-4), to measure adherence to AED.[4] Each of the four items has a dichotomous answer, either 0 (Yes) or 1 (No). Following this, the score of each item is summed to give a range of scores from 0 to 4. A score of 3–4 suggests that the patient is adherent, while a score of ≤2 indicates that the patient is nonadherent.[4] To minimize recall bias, we asked the patients about their adherence over the preceding 4 weeks before they visited the outpatient clinics.
Statistical analyses
Data were collected following the well-structured questionnaire and clinical records and entered in Statistical Package for Social Sciences (SPSS). Simple descriptive statistics have been used to estimate the prevalence of breakthrough seizures among epileptic cases. The statistical analysis would be done to characterize and assess the symptom profile of epilepsy patients who have a history of breakthrough seizures in comparison with non-breakthrough seizure patients, considering both demographic and clinical profiles. For all patient-related outcome analyses, dichotomous outcomes will be evaluated for any associated by using a chi-square test.
Results
Table 1 presents the socio-demographic variation in the prevalence of breakthrough seizures in patients diagnosed with epilepsy. The primary outcome of our study was that 46% of participants had breakthrough seizures. The study reported the least prevalence of breakthrough seizures (24.2%) in the age group of 31–40 years, while the maximum prevalence was seen in the age group of 21–30 years, which was 57%. Patients having primary education reported a higher prevalence of breakthrough seizures. The prevalence of breakthrough seizures among patients who never had access to any form of education was 20.29%, while 79.71% of patients with primary education reported breakthrough seizures. Among unemployed participants, the prevalence was 46.11%, while 45.83% of employed participants reported breakthrough seizures, which led to an insignificant association. Results show that the gender-wise gap in the prevalence of breakthrough seizures was insignificant; (Male-46.34%, Female-45.59%). Unmarried patients reported a higher prevalence of breakthrough seizures than married participants.
Table 1.
Demographic characteristics of participants
| Variable | Breakthrough seizure | P | |
|---|---|---|---|
|
| |||
| No [n (%)] | Yes [n (%)] | ||
| Age group (in years) | <0.001 | ||
| • 10–20 | 42 (50.6) | 41 (49.4) | |
| • 21–30 | 50 (42.7) | 67 (57.3) | |
| • 31–40 | 50 (75.8) | 16 (24.2) | |
| • 41–50 | 15 (60.0) | 10 (40.0) | |
| • >50 | 5 (55.6) | 4 (44.4) | |
| Sex | 0.896 | ||
| • Male (M) | 88 (53.66) | 76 (46.34) | |
| • Female (F) | 74 (54.41) | 62 (45.59) | |
| Marital status | 0.026 | ||
| • Unmarried (UNM) | 57 (46.34) | 66 (53.66) | |
| • Married (M) | 105 (59.32) | 72 (40.68) | |
| Level of education | 0.04 | ||
| • Illiterate (I) | 49 (63.64) | 28 (36.36) | |
| • Primary (P) | 113 (50.67) | 110 (49.33) | |
| Occupation | 0.96 | ||
| • Unemployed (UNE) | 97 (53.89) | 83 (46.11) | |
| • Employed (E) | 65 (54.17) | 55 (45.83) | |
The secondary outcome was that non-adherence to antiepileptic drugs (P < 0.0001); the number of AED (P < 0.0006), duration of treatment (P < 0.05), level of education (P < 0.04), awareness of triggering factors (P < 0.05) and sleep deprivation (P < 0.05) carried the significant association with breakthrough seizures as shown in Table 2 and Figure 1. In our study, the prevalence of breakthrough seizure among non-adherent patients was 85.91%, while 6.6% among adherent patients. It was estimated that with the increasing number of missed doses, the chances of breakthrough seizures increase. Our study found that 6.62% of participants experienced breakthrough seizures who never missed the dose. On missing a single dose of AED, the prevalence of breakthrough seizures was 80%, which increased to 94.92% on missing more than one dose of AED. The study also found that 61.1% of participants had breakthrough seizures who had been on AED therapy for 1 year and <1 year, while only 43.9% of participants had breakthrough seizures who were on AED therapy for more than 1 year. The participants who are on monotherapy, adherent to AED, and also aware of precipitating factors do have less prevalence of breakthrough seizures. A total of 53.37% of participants on polytherapy experienced breakthrough seizures, compared to 32.71% who were on monotherapy. Regarding unawareness of triggering factors, 94.2% experienced breakthrough seizures compared to 5.8% of participants who were aware of them. Considering the psychological stress factors, 41.18% of participants experienced breakthrough seizures, which carried an insignificant association. In our study, we also found that sleep deprivation contributed to a 66.7% prevalence of breakthrough seizures, which had a significant association. Table 3 shows the joint distribution of demographic characteristics and breakthrough seizures; results have shown that the maximum prevalence was seen in 65% of participants who were unmarried having primary education, while minimal prevalence was seen in 36.36% of participants who were married and illiterate. Participants who were married having primary education reported a 44% prevalence of breakthrough seizures. Table 4 and Figure 2 show the joint distribution of clinical characteristics and prevalence of breakthrough seizures where we found that those epileptic patients who had taken AED for more than 1 year, took adequate sleep (i.e. >8 h) and were adherent whether on monotherapy or polytherapy had minimal breakthrough seizures, that is 7.7% and 5.8%, respectively. Less than 1-year duration of AED caused a 33.33% prevalence of breakthrough seizures despite good adherence and adequate sleep. Non-adherent patients reported a higher prevalence of breakthrough seizures, that is >50%. The maximum prevalence of breakthrough seizures was seen in 87.5% of participants who took AED for less than 1 year besides being non-adherent and having adequate sleep. The prevalence decreased to 82.5% if the duration of AED is more than 1 year besides being non-adherent and having adequate sleep. However, the study also reported that 69.23% of participants had breakthrough seizures if they were sleep-deprived besides being non-adherent and antiepileptic drug intake for more than 1 year. The percentage may vary due to the number of doses missed in cases of non-adherence.
Table 2.
Clinical characteristics of participants.
| Variable | Breakthrough seizure | P | |
|---|---|---|---|
|
| |||
| No [n (%)] | Yes [n (%)] | ||
| Adherence | <0.0001 | ||
| • Adherent | 141 (93.38) | 10 (6.62) | |
| • Non-adherent | 21 (14.09) | 128 (85.91) | |
| Psychological stress | 0.292 | ||
| • Yes | 50 (58.82) | 35 (41.18) | |
| • No | 112 (52.09) | 103 (47.9) | |
| Duration of treatment | 0.052 | ||
| • ≤1 year | 14 (38.9) | 22 (61.1) | |
| • >1 year | 148 (56.1) | 116 (43.9) | |
| Drugs | <0.0006 | ||
| • Monotherapy (Mono) | 72 (67.29) | 35 (32.71) | |
| • Polytherapy (Poly) | 90 (46.63) | 103 (53.37) | |
| Awareness of triggering factors | 0.052 | ||
| • Yes | 20 (12.35) | 8 (16.67) | |
| • No | 142 (87.65) | 130 (94.20) | |
| Hours slept | 0.024 | ||
| • ≤8 hours | 9 (33.33) | 18 (66.67)) | |
| • >8 hours | 153 (56.04) | 120 (44.0) | |
| Doses missed | <0.0001 | ||
| • 0 | 141 (93.38) | 10 (6.62) | |
| • 1 | 18 (20.0) | 72 (80.0) | |
| • >1 | 3 (5.08) | 56 (94.92) | |
| Flickering lights | 0.29 | ||
| • No | 155 (55.96) | 122 (44.04) | |
| • Yes | 7 (30.43) | 16 (46.9) | |
| Alcohol use | 0.39 | ||
| • No | 155 (54.88) | 129 (45.42) | |
| • Yes | 7 (43.83) | 9 (56.25) | |
| Knowledge of disease | 0.41 | ||
| • No | 91 (52) | 84 (48) | |
| • Yes | 71 (56.8) | 54 (43.2) | |
Figure 1.
Clinical characteristics of participants
Table 3.
Joint distribution of demographic characteristics and breakthrough seizure.
| Marital | Education | Breakthrough | Total | Prevalence (%) |
|---|---|---|---|---|
| M | I | 28 | 77 | 36.36 |
| M | P | 44 | 100 | 44 |
| UNM | P | 66 | 123 | 65 |
Table 4.
Joint distribution of clinical characteristics and breakthrough seizure.
| Drugs | Duration of AED | Hours slept | Adherence | Breakthrough | Total | Prevalence (%) |
|---|---|---|---|---|---|---|
| Poly | >1 | <8 | No | 9 | 13 | 69.23 |
| Poly | >1 | ≥8 | No | 70 | 85 | 82.35 |
| Poly | <1 | ≥8 | No | 14 | 16 | 87.5 |
| Poly | >1 | ≥8 | Yes | 4 | 69 | 5.8 |
| Mono | >1 | ≥8 | Yes | 5 | 65 | 7.7 |
| Poly | <1 | ≥8 | Yes | 1 | 3 | 33.33 |
Figure 2.
Distribution of combination of precipitating factors in case of breakthrough seizures among epileptic patients (Abbreviation: Poly = polytherapy; Mono = monotherapy; AED = antiepileptic drugs; Sleep A = sleep adequate; Sleep D = sleep deprived; Adherence - Yes = adherent to drugs; Adherent - No = Not adherent)
Discussion
The prevalence rate of epilepsy in India varies between 4.15 and 7.03 per 1000 population.[5] A large number of epileptic patients become drug defaulters due to several socio-economic factors and cultural beliefs leading to the occurrence of breakthrough seizures. To our knowledge, no study has been done in the tribal area of Jharkhand to determine the precipitating factors of breakthrough seizures. Hence, we aimed to analyze the precipitating factors to avoid them. In our study, there was a significant difference in the level of education and age group, marital status, adherence, sleep duration, number of AEDs, duration of treatment, and awareness of triggering factors. In contrast, we found no association of breakthrough seizures with gender, occupation, and psychological stress.
Our study showed that breakthrough seizures were most common in the age group between 20 and 30, while they were least common in the 30–40 age groups. Meanwhile, education significantly impacted the prevalence of breakthrough seizures. Those who had primary education reported a higher prevalence of breakthrough seizures (49.33%) than illiterate (36.36%) people, which may be due to awareness.
Our study reported a higher prevalence of breakthrough seizures in unmarried people (53.66%) than in married people (40.68%). This may be due to the reason that in our country, epilepsy is considered a taboo, causing a lot of difficulty in getting married, and hence, unmarried participants are very conscious regarding their disease and its treatment.
In our study, the most common precipitating factor was non-adherence, reported by 85.91% of participants. The second most common precipitating factor was sleep deprivation (66.7%), followed by duration of AED (61.1%). In our study, 85.91% of participants had breakthrough seizures due to non-adherence to AEDs, in contrast to 6.62% of participants who were adherent reported breakthrough seizures. The study also revealed that 94.92% of the participants had breakthrough seizures when they missed more than one dose, which decreased to 80% when only one dose was missed. In contrast, only 6.62% of participants had breakthrough seizures when they never missed any dose. A similar result was seen in a previous study, which revealed that 91.9% of the participants who were defaulters of more than three AED doses in the week were more likely to develop breakthrough seizures.[6]
A similar study involving 193 patients with breakthrough seizures showed that the most frequent precipitating factor was missed doses, leading to 46.6%cases of breakthrough seizures.[6] A study in the UK found that 31% of seizures may be attributable to medication noncompliance.[7] There are studies, which have shown that 30–50% of patients with epilepsy reported non-compliance thus interfering with optimal treatment and seizure control.[7,8] In contrast, non-compliance has contributed to 3.7% of studies done in Norway, Denmark, and the USA,[9] which is very low compared to our study.
The non-adherence in patients attending our tertiary center as a cause of breakthrough seizures may be due to various socio-economic factors and cultural beliefs. The cultural assumption that epilepsy is some supernatural power and incurable may be a reason for non-adherence. Lack of financial support, inaccessibility, and unavailability of drugs in the local areas may interfere with the maintenance of proper AED use. Non-adherence may lead to an unnecessary increase in the prescribed doses of AEDs, assuming that the current dose is insufficient to control seizures. This may further increase the costs of care, especially in resource-limited settings such as India. However, the limiting factors in our study may be recall bias and the study’s retrospective nature.
The lack of education regarding medication regimens and the adverse effects of AED may lead to discontinuation of AED during the follow-up period. The second most frequent precipitating factor reported by our patients was sleep deprivation (66.7%). Sleep deprivation may exacerbate seizures in some epilepsy patients. However, continuity of sleep can also be negatively affected by seizures and some AEDs, thus resulting in a vicious cycle.[10]
We found no association between breakthrough seizures and stress, which is similar to previous studies.[6] There was no significant difference in precipitating factors between males and females and between different age groups. Previous studies have reported that gender did not influence the seizure precipitants.[6,11] Moreover, in our study the types of epilepsy and previous frequency of seizures have no direct relationship as reasons behind their discontinuation of treatment in contrast to another study.[6]
Our study showed that patients who took AED for more than 1 year had less prevalence of breakthrough seizures than those who took AED for less than 1 year, indicating that reasonable control of seizures carries a lower chance of breakthrough seizures, which is similar to the previous studies.[6,12] This can also be explained by regular routine follow-ups, which emphasize good drug compliance and indirectly identify causes of irregular medication that can be corrected.
There was a significant association between the number of AEDs and breakthrough seizures. Our study also found that monotherapy was associated with a decreased prevalence of breakthrough seizures than polytherapy, which may be due to drug-drug interactions. Some drugs are potent enzyme inducers. For example, phenobarbital, phenytoin, and carbamazepine can influence other medications’ metabolism and subsequent effects,[12,13,14] increasing the metabolism of the co-administered drug and decreasing its plasma concentration and clinical efficacy. Secondly, the poor compliance associated with higher doses may be due to a higher number of total daily pills taken by the patients. A previous study also showed a similar result where the number of medications affects adherence to AEDs.[14,15]
In comparison to other studies,[6,7,8,9,14] this is the first study to compare multiple factors simultaneously). Table 3 shows that unmarried participants with primary education maximally reported breakthrough seizures, while married illiterate participants reported the fewest. This may be due to increased awareness in those with primary education, which led them to come to the hospital. Moreover, unmarried people showed high consideration toward treatment of their disease as in our country it is considered as a social taboo before getting married. In Table 4, the study revealed that adherence, in addition to adequate sleep and prolonged duration of AED, caused less prevalence of breakthrough seizures, that is 5.8% and 7.7%, whether they are on polytherapy or monotherapy, respectively, but the prevalence increases to 33.33% if they do not continue for more than 1 year. Hence, besides adherence, adequate sleep and duration of AED is also important for preventing breakthrough seizures. The prevalence of breakthrough seizures rapidly increases when the patients are non-adherent, as shown in Table 4 that is >50%. This emphasizes that high adherence can prevent breakthrough seizures. Besides non-adherence and adequate sleep, when the duration of AED was less than 1 year, there was a maximum prevalence of breakthrough seizures, that is 87.5%. While the prevalence of breakthrough seizures decreased that is 82.35% when the duration of AED was more than 1 year. It was also seen that besides non-adherence and AED intake of more than 1 year, 69.23% of patients suffered from breakthrough seizures if they were sleep-deprived. So, the duration of AED and sleep is important next to drug adherence. Hence, our study showed the need to compare multiple factors simultaneously.
This is the first study of its own kind that is conducted on the tribal population of Jharkhand. The study will provide some insight about the factors that can intact on the occurrence of breakthrough seizures among epileptic patients. The obtained evidence based on retrospective records will help the clinician for future studies and community habits and associated risk factors. Efforts should also be made simultaneously to increase education and awareness of the precipitating factors among caregivers or patients, as this will prevent breakthrough seizures. It is essential to identify the various socio-economic factors and cultural beliefs responsible for breakthrough seizures through detailed discussion to decrease the morbidity in patients with epilepsy. There is a need for conducting multiple epilepsy clinics at the peripheral and community health centers level, thereby increasing accessibility and availability of AED drugs, which will cause better health-seeking behavior of the epilepsy caregivers and routine follow-up to seek better control of breakthrough seizures among patients with epilepsy in the tribal area of Jharkhand, thereby decreasing morbidity and mortality. Studies have been done related to integrated care for epilepsy management in the community.[16,17,18]
However, there are certain limitations of the study. Since this is a retrospective study, the data relies on medical records or patient/family recall, which may be incomplete or inaccurate. Patients or caregivers may not remember events leading to seizures precisely, leading to bias in reporting. Many factors can contribute to breakthrough seizures, in addition to medication non-adherence, infections, stress, and environmental triggers. A retrospective study may have limited ability to control for all potential confounders, leading to difficulties in establishing clear cause-and-effect relationships. The study may shed light on how cultural beliefs, traditional healing practices, and socioeconomic factors impact the healthcare-seeking behavior of tribal communities. These insights are crucial for designing epilepsy care programs that are culturally sensitive and community-centered. Findings from the study could help public health authorities and policymakers design better epilepsy care infrastructure in tribal areas, focusing on education, awareness, and the availability of anti-epileptic medications.
Conflicts of interest
There are no conflicts of interest.
Acknowledgement
First author would like to acknowledge All India Institute of Medical Sciences, Deoghar, Jharkhand and second author would like to acknowledge DHR-ICMR (No. R.12016/16/2023-HR) & ICSSR, New Delhi (F.No. 19/LSS/2024-1054/HS&SP/SCD) for their support.
Funding Statement
Nil.
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