Antiepileptic drug utilization in Bangladesh: experience from Dhaka Medical College Hospital

Epilepsy is a common and chronic neurologic disorder worldwide. The risk of having epilepsy at some point in average life span of any individual varies between 2%-5% [1]. Some hospital and community based studies from South East Asian countries (SEAR) have reported the incidence of epilepsy from 2–10 per thousand population [1]. WHO estimates that there are at least 1.5-2.0 million people with epilepsy in Bangladesh [1]. The incidence and prevalence of epilepsy being higher in poor areas (49 to 225 per 100,000 people per year) [2], poses a huge social and economic burden to the poor. About half of the total epilepsy population lives in Asia [3]. Though most of the AEDs are cheap, the volume of prescription and duration of treatment often makes the expenditure high enough for the poor. As the definition implies, epilepsy is a disorder of uncertainty and unpredictability. A seizure event can occur anytime, anywhere without warning; causing embarrassment, injury or even death of the person [4]. This may have a disastrous effect on employment and independence [5]. About 50% of the patients become seizure free with the first drug tried and can lead a normal life [6]. Seizure can be controlled with monotherapy in majority of them [7].

This usually requires careful and rigid adherence to drug regimens, which involve taking tablets regularly, two or three times each day for many years, sometimes for a lifetime. Physicians often judge the effectiveness of treatment by gross clinical response. There are wide variations in each person’s response to treatment, and the plasma concentration of AEDs provides little information about a person’s likelihood of reduction of seizures or side-effects. The available data on effectiveness of drugs are mostly from the western studies [8]. But the drug response and effectiveness may vary depending on the genetic, environmental, pharmacodynamic and pharmacokinetic interaction in different racial groups. Moreover, the cost of AEDs often poses a treatment gap in management of epilepsy, especially in least developed country like Bangladesh. So our aim was to find out the effectiveness and side effect profile of AEDs used in epilepsy clinic of Dhaka medical college, especially the low cost ones.

Epilepsy imposes a huge economic burden on health care system, especially in resource poor countries where the incidence may be as high as 190 per 100,000 people [10]. The Global Campaign Against Epilepsy was established by the International League Against Epilepsy (ILAE), the International Bureau for Epilepsy (IBE), and WHO in order to tackle the management issues related to epilepsy [11]. WHO suggests that medical disorders that require a low technological approach should be managed at the primary health-care level. There are studies from both developed and developing countries on economic analysis of epilepsy which have shown significant economic burden of epilepsy [12]–[14]. These evidences from research in rich countries may or may not accurately predict similar outcome in poor countries. In this context of low priority and high treatment gap of epilepsy care in developing countries, the study was done to establish the low cost and effective first line AED for Bangladesh.

Most of our index population was younger age group (55.2% belonging to 11-30 years age group). The report coincides with Mannan et al. [15] (16-31 years) in Bangladesh. Mac et al. [16] showed a bimodal age distribution of epilepsy patients in developed country with a first peak in childhood and another one in old age. Except for Shanghai in China, most of the Asian countries have younger patients with epilepsy. The probable reason for the missing peak in the older age group in many Asian countries is due to the fact that most of the population are younger compared to number of old people [16, 17]. Similar to reports from other Asian countries, there was slightly male predominance [18].

In contrast to the reports from most of the Asian countries, where the IGE ranges from 50-69% and partial seizure from 31-50%, our index population predominantly had partial epilepsy (53%) [19]–[22]. Often it is quite difficult to compare the results of these studies due to lack in application of standardized classification system in epilepsy research in Asia and lack of imaging and electroencephalographic studies, which probably had lead to predominance of IGE in most of the studies. We had the advantage of tertiary care facilities in this context which might be the reason behind dominance of LRE/focal epilepsy in our study. In a similar hospital based study in Srilanka, Senanayake classified 59.7% patients as secondary generalized seizure. Several series of studies from Liberia, Mumbai, Madras, Brazil reported the frequency between 40-50% [23, 24].

Monotherapy has been the gold standard of epilepsy treatment for last 20 years. Most (67%) of the patients in our study was successfully maintained on monotherapy. Various first generation AEDs like PHB, PHT, CBZ, VPA and clonazepum are widely used as monotherapy in most of the Asian countries [25]–[30]. A series of trials by Reynolds and Shorvon [31]–[33] also showed similar effectiveness with monotherapy. Not surprisingly CBZ was the most common (67%) AED prescribed as LRE was encountered more frequently. The choice of AED as monotherapy varied between studies, where VPA may be first choice as broad spectrum AED or both used equally [34]–[36]. Conventionally, most of the neurologists prefer VPA for IGE and CBZ for LRE. The Cochrane review [37] provides very little support for this, where VPA showed marginally favorable outcome for IGE. In the Cochrane review of five head-to-head studies in partial epilepsy, CBZ was just superior to VPA. In our study PHT and PHB had the highest level of effectiveness in terms of reduction of seizure frequency, but had very low retention rate than CBZ and VPA due to higher rate of adverse events in the former drugs. The difference was also statistically significant across the AED used in terms of both the treatment retention rate (p value <0.001) and seizure freedom rate (p value <0.001) at the end of follow up. In contrast to this a published clinical trial from Caucasian and Japanese study showed only 30% retention rate at a median follow up period [38].

PHB was recommended by WHO as the treatment of choice for partial and tonic clonic seizures in resource restricted countries [39]. The strategy had been questioned because of low tolerability with PHB than other antiepileptic drugs [40]. Concerns apply particularly to children, who are especially vulnerable to cognitive and behavioural adverse effects of PHB [41]. But in a study by Banu [42] and colleagues in Bangladesh found no significant difference in behavioral problems such as restlessness and hyperactivity between PHB and CBZ (7% v 11%). Though more efficacious in seizure reduction, the treatment retention rate at the end of follow up period on PHB and PHT were very low compared to CBZ and VPA. The discontinuation of former drugs is probably due to their ADR profile. For causality assessment of ADR we only have considered those on monotherapy. Henceforth, we could not evaluate the side effect profile of LTG and TOP, as they were used only as add on therapy. Most adverse effects of AEDs belong to the type A category, that is, they are predictable, dose dependent, and explained by the known pharmacological properties of individual agents [43]. The overall rate of adverse events in our study was higher than that of Mathur et al. [44] (4.67%), but similar to Roopa et al. [45] (10.2%) who reported from a tertiary care hospital like ours. Similar to other studies the ADR was maximum with PHT, followed by VPA and PHB [46]. Most of the side effects correspond well with the known adverse effect profile of PHT [47]. Coinciding our report, Carpay et al. [48] also observed more weight gain with the VPA and PHT, compared o CBZ. VPA has traditionally been associated with a greater incidence of weight gain than that of other AEDs [49]. The percentage of patients requiring changes in their dose regimen due to ADR was comparable for both VPA and CBZ.

This type of cost effectiveness analysis helps in setting the priority for allocation of public health research. Beyond efficacy and cost, availability of AED is also a critical factor for successful implementation of wide range of health care delivery though out the whole nation. The WHO CHOICE [50] work program was under taken in different developing countries to find out effective strategy to combat epilepsy. Such process involved different key parameters like effective treatment coverage, drug price and unit cost of health care service delivery. PHB and PHT are the cheapest AED found in Bangladesh. But the cost of newer generation AEDs like TOP and LTG are six to eight times higher. This is a vital economic factor when the cost of long term treatment is borne mostly by patients themselves.

The major limitations in the study include the retrospective nature and the variability in treatment of epilepsy patients by different neurologists at the epilepsy clinic. We tried to reduce the observer biasness by following the ILAE classification system and common treatment guideline followed by the responsible consultants. We had to exclude a large number of patients who either did not return to follow up or did not complete two years of follow up. The poor follow up may be due to the fact that, the epilepsy clinic of DMCH which is the highest center of referral for patients with epilepsy, encounters patients from all the corners of Bangladesh. Most of them are poor. It often becomes quite difficult for them to come to Dhaka for follow up. Though we have considered the treatment retention rate and number of patient being seizure free at the end of follow up as the measure of effectiveness, the severity of individual seizure events were not considered for analysis. We also could not measure the drug adherence based on medication collection or follow up. Because in Bangladesh there is no database system for recording the medication dispensed or collected by the patients. Moreover, the study from hospital records may not completely represent the scenario in the community.

The use of older AEDs in primary health care settings is expected to be a very cost effective approach due to lower price and established effectiveness profile. The four conventional old generation drugs (PHB, PHT, CBZ and VPA) recommended by WHO is still effective in our population. Though PHT and PHB are least expensive drugs, their use is limited by the higher rate of adverse event. Henceforth, CBZ and VPA may be effective, less costly and well tolerated drugs in our settings where resources are limited. So the routine use of these four low cost AED may avert the burden of epilepsy treatment in developing and under developed countries.