A Multicenter, Cross-Sectional, Observational Study on Epilepsy and its Management Practices in India
Keywords: Anticonvulsants, epilepsy, focal onset seizures, generalized onset seizures
Epilepsy is a common neurological condition that affects individuals of all ages. The 2016 Global Burden of Disease study on epilepsy showed that 45.9 million patients had active epilepsy with an age-standardized prevalence of 621.5 per 100,000 people. It is estimated that India has more than 10 million patients with epilepsy and more than 2 million patients with drug-resistant epilepsy.,, The burden of epilepsy as disability-adjusted life years accounts for 1% of the total burden of disease globally.,,
Despite advancements in treatment strategies, there exists a treatment gap in low- and middle-income countries (LMICs) with ~75% unable to receive treatment, primarily due to non-availability and unaffordability of antiepileptic drugs (AEDs).,,,, Monotherapy is the mainstay of treatment in epilepsy,, whereas combination therapy is indicated for patients with intractable or refractory epilepsy.,,,,, While some studies have assessed usage patterns of AEDs in single-center settings,,,,,, there is paucity of data from large multicenter studies on usage patterns, drug of choice for different seizure types, and sociodemographic and clinical factors affecting the treatment decisions in India.
In this large, cross-sectional study, we aimed to determine the sociodemographic and clinical profiles of patients with epilepsy, usage pattern, effectiveness, safety, and tolerability of AEDs, dosage modifications and switching pattern of AEDs, and quality of life of patients.
This cross-sectional, single-visit, multicenter, observational study was conducted from April 2019 to January 2020 at seven neurology centers across India. Patient data for the six months before enrollment were collected from individual case report forms (CRFs) by investigators or qualified designees from participant interviews and medical records. The study was conducted following the principles of the Declaration of Helsinki, International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines, and Indian regulatory guidelines. The study protocol and study-related documents were approved by the Independent Ethics Committees or Institutional Review Boards.
Adults aged 18–65 years, with confirmed diagnosis of epilepsy (primary [idiopathic] or secondary [from but not limited to head injury, neurocysticercosis, or stroke]) receiving any AED for six or more months and who provided written and informed consent were included in the study. Pregnant and lactating women, patients with reflex seizures, and patients with a history of poor compliance were excluded.
Sociodemographic and clinical characteristics
Sociodemographic characteristics assessed were age, gender, body mass index (BMI), education level, occupation, socioeconomic status per Kuppuswamy classification, and marital status.
Onset and duration of epilepsy and seizure frequency in the four weeks and six months before enrollment were also assessed. The International League against Epilepsy (ILAE) 2017 classification was used to categorize seizure types.
Usage pattern of AEDs
Usage of AEDs in the six months before enrollment was assessed as proportion of participants on monotherapy (treatment with a single AED) or combination therapy (treatment with two or more AEDs) overall and by seizure type.
Effectiveness of AEDs
Effectiveness was evaluated as proportion of patients achieving complete seizure freedom in the three or six months before enrollment, and those achieving >50% or >75% reduction in seizure frequency in the six months before enrollment versus baseline. For each therapy type, total number of patients achieving partial freedom was calculated by subtracting the proportion of patients with complete seizure freedom from the total number of patients on each therapy type.
Safety and tolerability of AEDs
Safety assessments included incidence of adverse events (AEs) or adverse drug reactions (ADRs), serious AEs or ADRs, and AEs or ADRs leading to treatment discontinuation in the past six months before enrollment. Any event with possible, probable, or certain causal relationship with the study drug was recorded as an ADR, while an event that was thought to be unlikely or unrelated with the study drug was recorded as an AE.
Dosage modification and switching of AEDs
Dosage modification was assessed as proportion of patients requiring dosage modification for monotherapy or combination therapy in the six months before enrollment. Switching pattern was assessed as proportion of patients who switched from monotherapy or combination therapy to any other AED over the six months before enrollment.
Quality of life
Quality of life (QoL) was measured using the quality of life in epilepsy (QOLIE)-31 questionnaire during the study visit; scores were assigned for emotional well-being, social functioning, energy/fatigue, cognitive functioning, seizure worry, and medication effects.
Continuous variables were summarized using descriptive statistics and reported as mean (standard deviation [SD]) for normally distributed data, or as median and ranges for variables with non-normal distribution. Categorical data were summarized as numbers and percentages.
An attempt was made to enroll adequate number of patients with epilepsy from various geographic regions of India to obtain generalizable results. Other cross-sectional, observational studies assessing sociodemographic and clinical profile and usage patterns of AEDs had sample sizes of 297, 451, and 973 patients.,, Thus, we planned to enroll 500-800 patients to achieve an effective size adequate for conclusive results.
Sociodemographic characteristics and clinical profiles
In all, 120 patients were enrolled from five centers each and 100 patients were enrolled from two centers each [Table S1]. Of the 800 enrolled patients, 60% were male [Table 1]. The median age and BMI of patients were 28.0 (18.0–65.0) years and 24.0 (11.3–50.1) kg/m2, respectively.
A total of 69.0% and 15.0% of patients had been diagnosed with generalized onset seizure and focal onset seizure, respectively [Table 1]. The most frequent seizure subtype was tonic–clonic or convulsive in the four weeks (50/102) and six months (147/271) before enrollment.
The median age of patients at epilepsy onset was 20.0 (1.0–64.0) years, and the median duration of epilepsy was 2065.5 (196.0–18392.0) days. Most patients (62.9%) had primary epilepsy, and only 2.5% had a triggering factor.
Usage pattern of AEDs
A total of 341 patients (42.6%) received monotherapy, whereas 459 patients (57.4%) received combination therapy. Levetiracetam (n = 126; 37.0%) was the most used monotherapy, followed by sodium valproate (n = 63; 18.5%), carbamazepine (n = 59; 17.3%), and phenytoin (n = 47; 13.8%) [Figure 1]a.
When assessed by seizure type, levetiracetam was the most used monotherapy for focal onset (18/52 [34.6%]) and generalized onset (87/230 [37.8%]) seizures, followed by sodium valproate (10/52 [19.2%] and 43/230 [18.7%]), carbamazepine (9/52 [17.3%] and 34/230 [18.7%]), and phenytoin (7/52 [13.5%] and 34/230 [14.9%]. For mixed seizures, phenytoin (5/16 [31.3%]) and sodium valproate (5/16 [31.3%]) were preferred over other drugs [Figure 1]b.
Clobazam (n = 274; 59.7%) was the most used drug as part of combination therapy, followed by levetiracetam (n = 243; 52.9%), carbamazepine (n = 121, 26.4%), sodium valproate (n = 114; 24.8%), and phenytoin (n = 110; 24.0%) [Figure 1]c. A similar trend was observed when usage patterns were compared by seizure types [Figure 1]d. Usage patterns of carbamazepine and sodium valproate were largely similar for all three seizure types, whereas the proportions of patients using phenytoin were 15.2% (12/79), 22.3% (87/389), and 30.0% (3/10) for focal onset, generalized onset, and mixed seizures, respectively.
Effectiveness of AEDs
Overall, 601 (75.1%) and 529 (66.1%) patients achieved complete seizure freedom in the three and six months prior to enrollment, respectively [Table 2]. Moreover, regardless of the type of AED used, the proportion of patients with complete seizure freedom was comparable or higher in the three months than in the six months before enrollment. Among the five most frequently used drugs as monotherapy, proportions of patients achieving complete seizure freedom with levetiracetam, sodium valproate, carbamazepine, phenytoin, and oxcarbazepine were 83.3%, 79.4%, 93.2%, 85.1%, and 71.4%, respectively, in the three months before enrollment. Furthermore, clobazam, levetiracetam, carbamazepine, sodium valproate, and phenytoin, as the five most frequently used drugs in combination therapy, helped achieve complete seizure freedom in 65.7%, 68.7%, 76.9%, 64.9%, and 75.4% of patients, respectively, in the three months before enrollment.
Out of 271 patients who did not experience complete seizure freedom in the six months before enrollment, reduction in seizure frequency by >50% and >75% was observed in 151 (55.7%) and 148 (54.6%) patients, and a greater proportion of patients achieved these reductions on monotherapy versus combination therapy (>50% reduction: 56/85 [65.9%] vs 95/186 [51.1%]; >75% reduction: 54/85 [63.5%] vs 94/186 [50.5%]). Phenobarbitone, carbamazepine, sodium valproate, lamotrigine, and phenytoin were the five leading AEDs that helped achieve >50% or >75% reduction in seizure frequency [Table 3].
Dose modification and switching
A total of 54 patients required dose modification in the six months before enrollment; out of these, 13 patients were on monotherapy, and 41 were on combination therapy. Switching occurred in 13/341 patients (3.8%) on monotherapy and 26/459 patients (5.7%) on combination therapy [Table S2], and all of these patients experienced breakthrough seizures during the switch. Lack of efficacy was the most frequent reason for switching drugs by patients on both monotherapy (5.4%) as well as on combination therapy (2.1%).
Quality of life
[Table S3] shows the overall and domain-wise QoL scores for each of the AEDs used. The mean (SD) overall QoL score was 66.5 (16.68). Within each domain, overall score was highest for cognitive functioning (64.0 [18.82]) and lowest for energy or fatigue (55.5 [14.84]). Among the five leading drugs used, overall QoL score was slightly higher with carbamazepine (68.8 [16.04]) and oxcarbazepine (68.4 [16.21]) and comparable with phenytoin (65.4 [15.17]), levetiracetam (65.9 [17.09]), and sodium valproate (65.7 [16.78]).
Safety and tolerability
In all, 34 patients experienced 43 AEs, and 20 ADRs were reported in 18 patients up to six months before enrollment. Of these, 13 were reported as ineffectiveness of drug, followed by two sedation events, and one event each of ataxia, dysarthria, constipation, gingival hypertrophy, and suicide attempt [Table 4]. The ADR of ineffectiveness of drug (n = 13) was mostly attributed to dose modification or switching between drugs. A total of five ADRs reported by 4 patients (0.5%) led to drug discontinuation. Two ADRs, ataxia and dysarthria, one each in a patient receiving phenytoin, were serious. No other serious ADRs were reported. No new safety concerns were identified.
In view of paucity of data, this study elucidated the sociodemographic and clinical characteristics of patients with epilepsy and current clinical practices with regard to usage of AEDs in the Indian setting.
Consistent with findings of the Global Burden of Disease study, a male preponderance of epilepsy was found in our study. However, a systematic review of studies from India previously reported a higher prevalence among women. The apparent lower prevalence in women may have been due to social stigma comprising of limited opportunities for education, employment, and marriage, which may have led to underreporting among women. Sociodemographic profile of patients from LMICs is characterized by unemployment, lower education and income, and single marital status, which have been associated with increased risk of hospitalization, drug-related side effects, and uncontrolled seizures.,, Contrary to previous studies, our study showed that most patients belonged to middle socioeconomic class with an education level above high school, and were graduates or postgraduates. This finding is consistent with that of the recent Global Burden of Disease study reporting a higher global prevalence among middle and upper-middle sociodemographic index groups versus lower-middle and low sociodemographic index groups.
Conflicting evidence exists on the prevalence of epilepsy by seizure type. Focal-onset seizures are the most common seizure type in children and adults globally, while generalized tonic–clonic seizures are predominant in LMICs. A systematic review and meta-analysis of international studies reported a higher prevalence estimate for active generalized seizures versus active focal seizures. Similarly, a systematic review of Indian studies revealed a high incidence of generalized-onset (mostly tonic–clonic) and focal–onset seizures (with impaired awareness) in community-based and hospital-based settings, respectively. In our study, the most common seizure type was generalized-onset seizure with idiopathic etiology.
Choosing the most appropriate AED is complicated by unpredictable efficacy and adverse effects, and the lack of data regarding optimal doses in individual patients. Current treatment guidelines recommend initial treatment with monotherapy, followed by combination therapy when monotherapy fails to achieve seizure freedom. A majority of the patients in our study were prescribed combination therapy (57%), and this trend was also observed in other Indian and global studies.,, The reasons behind increased treatment with combination therapy could be increased prescriptions of second-generation AEDs, most of which were previously approved only as add-ons.,,,,,, In our study, patients achieving complete seizure freedom were maintained mostly on monotherapy, and the overall QoL scores did not differ between various AEDs, probably because of the short duration of assessment of ≤ six months. The only randomized study that compared carbamazepine-controlled release monotherapy with lamotrigine + sodium valproate combination therapy showed no difference between the treatments., Therefore, identifying combination drug regimens exhibiting synergistic interactions that could provide better efficacy and tolerability would remain to be seen.
Trends suggest increased use of novel AEDs for the treatment of epilepsy. In our study, levetiracetam and clobazam were the more frequently used newer AEDs, both as monotherapy and combination therapy. Although none of the newer AEDs have shown superior efficacy to first-generation drugs, some have shown better tolerability. Therefore, they are now recommended as first-line drugs for specific seizure types or epilepsy syndromes, which could explain the more frequent use of these novel AEDs. Several studies from India have reported that the high costs of newer AEDs increase overall treatment cost.,,,, Therefore, due to their proven efficacy, older AEDs such as phenytoin, sodium valproate, and carbamazepine are still prescribed frequently in resource-limited countries, including India.,, Considering the comparable efficacy between new and old drugs, choosing evidence-based older AEDs for patients who cannot afford the newer drugs may be a reasonable alternative.
Evidence also shows that QoL is not different between newer and older AEDs, and this pattern was also observed in our study.,
Treatment gap, defined as the number of people with active epilepsy not on treatment or on inadequate treatment, is an important contributor to clinical decision-making., A recent systematic review showed a treatment gap of >75% in low-income countries, 50% in lower-to upper-middle-income countries, and <10% in high-income countries. Studies from India reported a treatment gap of 22%–95%. In this regard, it is important to note that a majority of the patients in our study, though literate, belonged to the lower-middle or upper-middle income class. Therefore, beside efficacy and tolerability of AEDs, in resource-limited countries like India, seizure semiology and the socioeconomic status should also be considered in clinical decision-making and management.
The main strengths of our study include a large sample size spanning different geographies in India and assessment of a wide range of variables from sociodemographic profiles to impact of AEDs on QoL, allowing generalizability of the results of countries with middle- to low-middle sociodemographic indices. The main limitations of the study were the possibility of recall bias owing to the cross-sectional, single-visit design and a potential referral bias as prescription practices may have been influenced by physician expertise. A potential selection bias was also possible though attempts were made to enroll consecutive patients across all centers.
In summary, results from this large, multicenter, cross-sectional study from diverse geographic and socioeconomic settings in India indicate that combination therapy, especially with levetiracetam and carbamazepine, was more frequently prescribed than monotherapy, and efficacy of first-generation AEDs was comparable to that of newer drugs in terms of complete seizure freedom, and/or >50% and >75% reduction in seizure frequency. Despite an increasing trend toward use of newer, second-generation AEDs, first-generation drugs like sodium valproate and phenytoin are still preferred in a substantial number of patients as both monotherapy and combination therapy. Prospective long-term studies are warranted to assess efficacy by type of seizures and type of therapy while preventing confounding factors like diverse management practices across centers and sectors, including diagnostic modalities, treatment compliance, referral practices varying based on expertise of practicing physician, and quality of care at participating centers.
Authors acknowledge CBCC Global Research LLP for providing medical writing assistance for this manuscript.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity.
Financial support and sponsorship
The study was funded by Abbott India Ltd.
Conflicts of interest
The study was funded by Abbott India Ltd. All authors were investigators in the study.
[Table 1], [Table 2], [Table 3], [Table 4]