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|NI FEATURE: THE EDITORIAL DEBATE-- PROS AND CONS
|Year : 2016 | Volume
| Issue : 6 | Page : 1140-1142
Bridging the treatment gap in epilepsy-is there an emerging trend in the use of newer antiepileptic drugs?
Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology (SCTIMST), Trivandrum, Kerala, India
|Date of Web Publication||11-Nov-2016|
Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology (SCTIMST), Trivandrum, Kerala
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Radhakrishnan A. Bridging the treatment gap in epilepsy-is there an emerging trend in the use of newer antiepileptic drugs?. Neurol India 2016;64:1140-2
Epilepsy is treated in the World Healh Organisation (WHO) South East Asian Region (SEARO) with the following motto:
“With the availability of cost-effective medication for epilepsy, even one patient with uncontrolled seizure is unacceptable.”
According to the WHO, there are nearly 50 million people with epilepsy (PWE) worldwide and 80% of them reside in developing countries. Among them, nearly 12 million reside in India, amounting to nearly one-fifth of the global burden. The estimated proportion of the worldwide general population with active epilepsy [defined as “the affected person has had at least one seizure in the previous 5 years, regardless of the antiepileptic drugs (AEDs) used] at a given time is between 4 and 10 per 1000 people; however, in low and middle-income countries, the proportion is much higher, ranging between 7 and 14 per 1000 people. The treatment gap in epilepsy (i.e., the percentage of people with untreated epilepsy) in India ranges from 22% in the urban setting to as high as 90% in villages. In a recent population-based prospective study on epilepsy conducted over 5 years (2003–2008) in Kolkata, India, on randomly selected 100,802 participants (males 53209, females 47593), there were 476 participants with active epilepsy and the age-adjusted prevalence rate was 4.71 per 1000. Over 5 years, there were 197 incident cases of epilepsy, of whom 26 died. The age-adjusted annual incidence rate of epilepsy was 38.3 per 100,000, and the all-cause standardized mortality rate of epilepsy was 2.4. The burden of epilepsy during the years 2007–2008 revealed that the overall years of life lost (YLL) were 755 per 100,000 general population, and the overall years of lives lived with disability (YLD) ranged from 14.45 to 31.0 per 100,000 persons, depending on the clinical severity of epilepsy. Both YLL and YLD values were higher in male than in female patients.
There is a differential distribution of epilepsy among various demographic and economic strata with higher rates reported in the male gender, rural population, and those hailing from a low socioeconomic status. In our country, central nervous system infections, neurocysticercosis, head trauma, and birth injuries have emerged as major risk factors for secondary epilepsy. Despite these grim statistics, majority of epilepsies and epilepsy syndromes are treatable, especially with the emerging knowledge regarding each of them, and better treatment options available, both medical and surgical. In almost all of the studies done at any point of time in India, the prevalence of epilepsy was found to be more in the rural than in the urban population. In a population-based neuroepidemiologic survey among 102,557 individuals in urban and rural Bengaluru in Southern India, the prevalence of epilepsy was reported to be nearly two times higher in rural areas as compared to urban areas.
Regarding treatment of epilepsy, with more than a minimum of 20 AEDs available in the market at a given point of time, at least 200 dual therapies and more than 1000 combinations with three AEDs are possible. However, it is impossible to try every permutation of these in a single life time. PWE dwelling in rural areas cannot afford the annual price of newer AEDs. Moreover, in patients who are on AED polytherapy, the majority of seizures are precipitated by drug default. Most of the primary health centers provide drugs such as carbamazepine (CBZ), phenytoin (PHT), phenobarbitone (PB), and valproate (VPA) free of cost. Moreover, drugs such as CBZ and PHT still remain the first-line AEDs for treatment of focal epilepsy. VPA is the drug of choice for generalized epilepsy syndromes such as juvenile myoclonic epilepsy. PB likewise is a boon for poor patients, where the choice has to be made between PB versus “no-treatment,” rather than between PB versus “newer AEDs.”Neurocognitive deficits, which have been feared, are far and few and the efficacy of the primary anticonvulsants far outweigh the problems of the toxic reactions that occasionally occur.
The appropriate use of AEDs results in adequate seizure control in approximately 50–60% of PWE. Among the remaining people, usually in the context of an idiopathic focal epilepsy syndrome, 20% continue to experience a few seizures before spontaneous remission occurs. However, the remaining 20% continue having refractory seizures despite the use of AEDs, either as monotherapy or polytherapy. The pharmacological treatment of epilepsy has been extensively studied primarily in high income countries. In view of the refractory epilepsy, newer AEDs are constantly being developed with the precise aim to tackle epilepsy through different mechanisms of action, while ensuring better safety profile and fewer drug interactions. In addition, cognitive, psychosocial and gender issues have gained more attention, with the result that quality of life has become the central focus of epilepsy care. However, no AED has a perfect combination of high efficacy, low toxicity and cost, and a good pharmacologic profile. Moreover, in conditions such as temporal lobe epilepsy (TLE), it is well-known that people who undergo early epilepsy surgery have a better quality of life in terms of reduced seizure frequency, better neuropsychological outcome, and even a life free from AEDs.
Progress in epilepsy care has inevitably escalated its cost as well. There has been much debate on the economic aspects of newer AEDs used in the treatment of epilepsy. Most clinicians have little exposure to health economics because it is a relatively new discipline in health sciences. The International League Against Epilepsy (ILAE) Commission on economic aspects has highlighted the need for a thorough appraisal of the economic aspects of epilepsy. The annual cost of the commonly used AEDs is summarized in [Table 1].
|Table 1: List of antiepileptic drugs (AEDs), their average daily adult doses and daily cost of therapy|
Click here to view
In an article in this issue, Newale et al., have analyzed the demographic parameters, comorbidities, and AED utilization in PWE. They collected data from 973 patients from 57 centers across all geographical regions (east, west, north, and south) of India over a period of 10 months from December 2013 to October 2014. They found the incidence of male patients having epilepsy as being 1.5 times higher as compared to the females (61% versus 39%). This is in contrast to the findings from a recent study where the authors found that the difference in the prevalence of epilepsy between males and females has narrowed over the years. The social stigma associated with epilepsy and the under-reporting in rural areas may be contributing to this gender difference in cross-sectional studies.
Electroencephalography (EEG), as is well known, and was evident in this study too, will remain a valuable first-line investigation to be performed in PWEs. It helps in confirming the diagnosis of epilepsy and in differentiating focal and generalized epilepsy. Magnetic resonance imaging (MRI) is recommended in all patients having focal epilepsy and in those having late onset epilepsy. It helps to select those PWE amenable to resective surgery at the earliest.
With regard to treatment, it was found that “treatment effectiveness” and “safety/tolerability profile” were the two most important considerations for selecting the AEDs. These are the two well-accepted metrics world-wide for choosing any drug for any disease, and especially for epilepsy, where one needs to take the medication for a longer duration. However surprisingly, levetiracetam was found to be the mostly commonly used AED across all age-groups and in both genders in this study. If one has to analyze the results of this study, the study indicates a recent change in the existing treatment practices in India where older AEDs, especially phenobarbitone, phenytoin, valproate and carbamazepine, etc., which were being increasingly used in both urban and rural areas till recently. However, in a single hospital-based study from Delhi, it was found that despite the significant escalation in the cost of therapy, there is an increasing trend wherein newer AEDs are increasingly being used for treatment of epilepsy, although levetiracetam alone did not stand out significantly as the most preferred drug.
This study had certain limitations. The distribution of patients as per their residence in rural and urban areas has not been assessed. This fact, as discussed earlier in this commentary, can strongly influence the choice of AED, based on the affordability issues. Further, of the 900 or more PWE analyzed in this cross-sectional study, when it comes to certain states such as Rajasthan, Uttarakhand, Assam, Arunachal Pradesh etc., there is a steep downfall in the number of patients recruited to as low as 1–3 in each of these states. The term “brain injury” that was found to be evident in 1.2% of the study population, needs to be better defined. The authors also need to define how they classified the various types of epilepsies and the epilepsy syndromes and how they arrived at the diagnoses. TLE has been accurately identified by the authors, probably from the case records, whereas other focal epilepsies have not been defined properly (only a generic term of localization related epilepsy is used). As is well known, TLE remains the most common cause of a surgically remediable epilepsy syndrome, especially when there is a substrate visible on magnetic resonance imaging. In that case, is this study giving an indirect evidence that referral to a surgical centre is also not undertaken at the right time in India? The safety and efficacy of AEDs during pregnancy in women with epilepsy was also not analyzed. Among PWE whose seizures were controlled, which has been reported to be as high as 95%, with levetiracetam offering the best results, the results are far from being the expected ones. It is not specified if these better than expected results were obtained on monotherapy or polytherapy. The incidence of adverse effects may be falsely low because minor events may not have been recorded or recalled, and also due to the fact that those who have had pancreatitis, nephrolithiasis, hypercalciuria, or metabolic abnormalities may have been excluded from being administered an AED, facts which may skew the results. Avoiding AEDs in these situations would have precluded the precipitation of an adverse event and underestimated the adverse effects of the AEDs responsible for causing them.
It can be concluded that newer AEDs are relatively free of major adverse effects and have lesser drug interactions; however, their use is restricted still by their high cost in resource-poor countries. There is an increasing trend towards their use in India, irrespective of the cost factor, especially in urban areas. However, whether or not this fact has significantly altered the overall quality of life in PWE remains to be determined. The accurate trends in their efficacy and tolerability needs to be addressed through population-based, prospective, epidemiologic surveys from all parts of the country. However, as it stands, the continued use of cost-effective conventional AEDs with the judicious use of newer AEDs as mono or polytherapy can be advocated. Moreover, one must ensure that all patients with a surgically treatable epilepsy syndrome should undergo epilepsy surgery at the earliest in order to ensure better outcomes.
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