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Factors precipitating breakthrough seizures in childhood epilepsy

 Department of Pediatrics, Sri Manakula Vinayagar Medical College and Hospital, Puducherry, India

Date of Submission01-Oct-2020
Date of Decision01-Feb-2021
Date of Acceptance24-Mar-2021
Date of Web Publication11-Oct-2021

Correspondence Address:
Kanimozhi Thandapani,
Department of Pediatrics, Sri Manakula Vinayagar Medical College and Hospital, Puducherry.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpn.JPN_256_20



Background: Breakthrough seizures occur in 37% of epilepsy patients even though remission has been attained. Counseling on precipitating factors form an integral part of treatment along with anti-epileptic drugs (AEDs). Identification of precipitating factors may help in reducing unnecessary hospitalization and complications of breakthrough seizures. Materials and Methods: This retrospective study was conducted in a tertiary healthcare center in Puducherry. All children with epilepsy admitted with breakthrough seizures from January 2017 to December 2019 were included in the study. Those with neonatal seizures, diagnosis of either Neurocysticercosis or tuberculoma, cases without seizure free period of 6 months and case records without adequate details were excluded. Data regarding precipitating factors were collected from case records and analyzed using SPSS version 24.0 software. Results: Of the 80 children included in the study, mean age was 4.98 (±3.52) years and 56.3% were less than 5 years of age. In total, 90% (n = 72) of the participants had generalized epilepsy, of which 67 had generalized seizures, four had absence seizures and one had atonic seizures. Majority (85%) reported at least one possible precipitating factor for breakthrough seizures and common ones were fever (27.5%) and non-compliance to medication (26.25%). Most common reason for non-compliance was forgetting to take medication (38%). Also illiterate mothers and multiple AEDs had a significant association with non-compliance (P < 0.05). Conclusion: The results of our study stress the need on adequate counseling about possible precipitants and prescription on minimum AEDs whenever possible. Parents need to ensure strict adherence to AEDs and avoidance of trigger factors.

Keywords: Children, breakthrough seizures, epilepsy, precipitating factors

How to cite this URL:
Thandapani K, Revathi K, Kumar T B. Factors precipitating breakthrough seizures in childhood epilepsy. J Pediatr Neurosci [Epub ahead of print] [cited 2023 Dec 1]. Available from: https://www.pediatricneurosciences.com/preprintarticle.asp?id=327900

   Introduction Top

Epilepsy is the most common neurological disorder in children. Seizure is a clinical expression of abnormal, excessive, synchronous discharges of neurons residing primarily in the cerebral cortex. Around 4–10% have atleast one episode in their childhood.[1] Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate seizures and by the neurobiologic, cognitive, psychologic, and social consequences of this condition. Two or more unprovoked seizure in a time frame of more than 24h is considered as epilepsy and more than 50% cases have onset in childhood.[1] Anti-epileptic drugs (AEDs) form the main stay of treatment but surgery and other non-pharmacological measures may be required in selected cases.

Break through seizure is defined as an epileptic seizure which occurs despite use of AEDs that have otherwise successfully prevented seizures in the patient.[2] Around 37% of those in remission may still experience breakthrough seizures.[3] Breakthrough seizures are dangerous because they are unexpected by the patient. It can lead to injuries or sometimes progress to status epilepticus requiring hospitalization with significant effects on economic costs and mortality. Most common reason for breakthrough seizures is non-compliance to AEDs.[4] Patient factors like infection, sleep deprivation, stress, or provocative factors watching TV or playing video games also trigger seizure.[4] Natural history of underlying epileptogenic process like a child with global developmental delay and significant brain damage can have breakthrough seizures even with adequate compliance and no obvious triggers.[5] Reason for non-adherence to medication are many, like forgetting to take medication, side effects of drugs, child’s refusal, or lack of awareness on the need for strict compliance. Added factors could be non-affordability and non-accessibility to AEDs in rural low socioeconomic people. Hence, counseling on precipitating factors and need for strict adherence to anti-epileptic regimen forms an integral part of treatment along with AEDs.

Although breakthrough seizures are common, not many studies have been done in children. Identification of precipitating factors may help in reducing unnecessary hospitalization, change in dose of AED or add on AEDs, and improve their quality of life. Hence we conducted the present study to identify the precipitating factors for breakthrough seizures in childhood epilepsy.

   Subjects and Methods Top

This retrospective medical records review was conducted in a tertiary healthcare center at Puducherry. This hospital caters to the healthcare needs of mostly rural and suburban people in and around this region. Inclusion criteria were all children with epilepsy admitted to either PICU or ward with breakthrough seizures between January 2017 and December 2019. Exclusion criteria include neonatal seizures, diagnosis of either Neurocysticercosis or tuberculoma, those without seizure free period of 6 months prior to breakthrough seizure episode, and case records without adequate details.

After obtaining clearance from the Institute Ethics Committee (IEC no: EC/27/2020) all children satisfying the inclusion criteria were included in the study by continuous sampling method. Their case sheets were collected from medical records department after obtaining permission from the concerned authority. Co-investigator recorded the necessary data from case sheet in a proforma without patient identifier details. The principal investigator then analyzed the data.

Data collected include socio-demographic details like age, gender, residence, parent education, socio-economic status (graded as per Modified Kuppuswamy scale), and clinical data like epilepsy type and duration, AED with dose and duration, developmental delay, EEG findings, MRI brain findings, and possible seizure precipitants. Epilepsy type was classified as per International League Against Epilepsy.[6] The list of seizure precipitants was based on potential triggers identified from previous studies which include non-compliance, fever, sleep deprivation, stress, watching TV, fatigue, skipping meals, incorrect dosage, and infections.[7] Reason for non-compliance like forgot to take medicines, not affordable, not accessible, skipping of drugs if mentioned were collected.

The data were analyzed using SPSS version 24.0. Independent variables like age, gender, socio-economic status, epilepsy type and duration, developmental delay were expressed as mean or percentage. Dependant variable like seizure precipitants was expressed in percentage. Association between dependent and independent variables was analyzed using chi-square test. P-value <0.05 was considered statistically significant.

   Results Top

Children admitted with breakthrough seizures from January 2017 to December 2019 were included in the study. Case records were obtained and necessary data were collected. Ninety-eight children were admitted with breakthrough seizures during the study period. Six children with diagnosis of NCC, one with tuberculoma, six case records with inadequate details, and five children without seizure free period of 6 months were excluded.

Of the 80 children included in the study, mean age was 4.98 (±3.52) years and 56.3% were less than 5 years of age. In total, 57.5% were males; most participants belonged to rural area (72.5%) and Class 4 socio-economic status (67.5%) as per Modified Kuppuswamy scale. In 59.7%, the mother was illiterate, whereas the rest had a minimum high school education. [Table 1] shows socio-demographic details of participants.
Table 1: Socio-demographic details of participants (N = 80)

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Ninety percent (n = 72) of the participants had generalized epilepsy, of which 67 had generalized seizures, four had absence seizures, and one had atonic seizures. In total, 70% (n = 56) were on monotherapy and 30% (n = 24) were on more than one AED. Of which, 19 children were on two drugs and five children on three drugs. Thirty-one cases had developmental delay and most of them had cerebral palsy (n = 22). Others had either neurodegenerative disorder (n = 2) or cause is unknown. [Table 2] shows the clinical details of participants.
Table 2: Clinical profile of participants (N = 80)

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At least one precipitating factor for breakthrough seizures was identified in 85% of participants. Among the precipitants, fever is the most commonly reported factor accounting for up to 27.5% cases, closely followed by non-compliance in 26.25%. Less common precipitants were watching TV (7.5%), sleep deprivation (10%), and incorrect dosage (2.5%). Seven cases had more than one factor, which was fever with non-compliance in five cases, fever with sleep deprivation in one, and sleep deprivation with watching TV in one. In two children mentioned as others, one had varicella and one had co-existing pyoderma. [Figure 1] shows precipitating factors for breakthrough seizures.
Figure 1: Precipitating factors in breakthrough seizures (N = 80)

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Among the reasons for non-compliance, 38% (n = 8) reported forgot to take medicine as the most common cause followed by non-accessibility 19% (n = 4). Three (14.3%) intentionally skipped medicine since they were traveling in two cases and to attend family event in one child. Reason was unknown in 14.3% since it was not documented. [Figure 2] shows the reasons for non-compliance.
Figure 2: Reasons for non-compliance (N = 21)

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Analyzing the socio-demographic variables with non-compliance, mother’s education (P-value 0.007) and number of AEDs (P-value 0.0005) have a statistically significant association, whereas residence, socio-economic status and developmental delay did not have a significant association. [Table 3] shows association of socio-demographic variables with non-compliance.
Table 3: Association of demographic and clinical variables with compliance to AED (N = 21)

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   Discussion Top

The retrospective data on precipitating factors for breakthrough seizures were studied in 80 children. Majority (85%) reported at least one possible precipitating factor for breakthrough seizures and common ones are fever (27.5%) and non-compliance to medication (26.25%). Most common reason for non-compliance was forgetting to take medication (38%). Also illiterate mothers and multiple AEDs had a significant association with non-compliance (P < 0.05).

In our study population, mean age was 4.98 years (±3.52). Most of the previous studies were among adults. In one pediatric study by Kumar[4] mean age was 7.1 (range 3–17) years. Owing to the location of our hospital, our study population predominantly had children belonging to rural, low socio-economic strata with illiterate mothers. Clinical profile shows majority (90%) had generalized epilepsy which is in accordance to previous studies. This probably reflects the fact that generalized epilepsy is the most common type of epilepsy.

Studies have shown that there are at least 40 trigger factors for seizures.[7] Sometimes more than one factor may cluster together to precipitate seizures. Frutcht et al.[8] showed that seizure precipitant may differ depending on the epilepsy syndrome due to varied pathophysiology. Our results showed 85% (n = 68) had at least one identifiable trigger. This is consistent with previous studies.[7],[9],[10]

The most common precipitant in our study was fever (27.5%). Fever reduces seizure threshold level and thereby triggers seizures. This finding is unlike the other studies in adults where stress was the most common trigger.[10],[11],[12],[13],[14],[15] One possible explanation could be our study population was mostly under five children who are more prone for infections rather than adults. Also factors like stress and fatigue are usually under reported in this age group. In a study by Aziz et al.,[16] 29% had fever and by Frutcht et al. 14% had fever.[8]

The second common precipitant was non-compliance (26.25%). This is similar to many other studies.[9],[14] The most common reason was forgetting to take medicines which probably reflect inadequate counseling on the need for strict adherence and to maintain seizure diary. Hence it is not surprising that children with illiterate mothers had higher incidence than the others (P < 0.05). The next reason was non-accessibility since many patients from rural areas need to take two or three buses to reach hospital. Monthly drugs are not given during Sundays and other holidays which means take a day off from work and practically difficult every month. Intentional skipping in a few cases again stresses on proper counseling. Also compliance was poor in those taking multiple medications. It is a well-known fact that multiple drugs and multiple daily dosing makes the patient non-compliant. This is especially applicable to children with developmental delay who have difficult to control seizures and are usually uncooperative to take medication. Although side effects of drugs are not seen in our study as reason for non-compliance, some AEDs are known to cause significant side effects. The long-term usage of drug per se instills fear of side effects in parents discouraging their use. Also school going children if prescribed thrice daily dosing, forget and sometimes refuse to take mid-meal dose due to associated stigma. Hence, clinicians should always make sure to prescribe single drug in least effective dosage preferably single daily dosing to ensure compliance.

Next common precipitant is sleep deprivation (10%). The data are comparable to other studies.[4],[9],[16],[17],[18],[19] Sleep deprivation is very well known to increase interictal epileptiform discharges and used as a provocation maneuver in EEG.[20] Ironically not just sleep deprivation, even sleep has been identified to trigger seizures in some forms of epilepsies like Idiopathic extra temporal epilepsies and Autosomal dominant nocturnal frontal lobe epilepsy, and was found to be a precipitant in 14% patients in one study.[21],[22] This is supported by few animal studies that limbic seizures occur during daytime and extra limbic seizures during sleep.[23]

Next common precipitant is watching TV (7.5%). Watching TV, Flash lights, playing videogames all have been implicated in triggering seizures and statistics range from 4 to 13% in studies.[4],[24] Famous example is photosensitive seizures provoked by viewing a “made for television program” in Japan which reportedly affected more than 600 children.[25]

More than one precipitant was found in 8.75% (n = 7). This finding is supported by many studies suggesting a complex interplay of mechanism by various factors.[4],[9],[17] Stress, sleep deprivation, and fatigue usually exist together and it is difficult to discern their individual role in triggering seizures.

The strengths of our study are: (1) Not many studies are available in children with epilepsy regarding precipitating factors and ours is the first such study in children especially in those belonging to rural south India; (2) Includes children of diverse age group and epilepsy types. The limitations of our study include: (1) Being a retrospective study, details regarding all possible trigger factors mentioned in the literature could not be obtained; (2) There is no objective evidence to precipitants and is purely based on subjective perception by caretakers. Hence a causal relationship cannot be established; (3) Trough AED levels were not done to correlate with compliance/efficacy of drug.

In spite of limitations, results of our study will aid in better counseling of epilepsy patients on potential triggers and their avoidance. All clinicians should prescribe lesser drugs in minimum effective dosage and production of slow release preparations will help in prescribing single daily dosage to current multi-dosing drugs. Nevertheless adequate counseling using “talk back” technique should become a routine with each visit. All patients should maintain a seizure diary and have a regular follow up.

   Conclusion Top

The results of our study show that the most common trigger for breakthrough seizures is either fever or non-compliance to AEDs. Such events could have been avoided if the parents were aware of their role in triggering seizures. Also compliance can be improved if minimum possible AEDs are prescribed preferably avoiding afternoon dose in school going children. Although causal relationship cannot be established, counseling the parents and other care takers on possible precipitants will go a long way in preventing such clinically devastating episodes. More prospective studies could shed light on the etiological role of individual trigger factors in precipitating breakthrough seizures.

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Conflicts of interest

There are no conflicts of interest.

   References Top

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3]


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