Sunwoo JS and Jo HJ contributed to this work equally.
Individualized anti-epileptic drug (AED) selection in patient with epilepsy is crucial. However, there is no unified opinion in treating patients with drug resistant epilepsy (DRE). This survey aimed to make a consolidate consensus with epileptologists’ perspectives of the treatment for Korean DRE patients by survey responses.
The survey was conducted with Korean epilepsy experts who have experience prescribing AEDs via e-mail. Survey questionnaires consisted of six items regarding prescription patterns and practical questions in treating patients with DRE in Korea. The research period was from February 2021 to March 2021.
The survey response rate was 83.3% (90/108). Most (77.8%) of the responders are neurologists. The proportion of patients whose seizures were not controlled by the second AED was 26.9%. The proportion of patients who had taken five or more AEDs is 13.9%, and those who are currently taking five or more AEDs are 7.3%, of which 54.5% and 37.9% reported positive effects on additional AED, respectively. The majority (91.1%) of respondents answered that the mechanism of action was the top priority factor when adding AED. Regarding data priority, responders considered that expert opinion should have the top priority, followed by clinical experiences, reimbursement guidelines and clinical evidence. Responders gave 64.9 points (range from 0 to 100) about overall satisfaction on reimbursement system of Health Insurance Review and Assessment Service for AED.
This study on AED therapy for DRE patients is the first nationwide trial in Korean epilepsy experts. In five drug failure, the top priorities on AED selection are mechanism of action and expert opinion. These findings might help to achieve consensus and recognize the insight on optimal therapy of AED in DRE.
Epilepsy is a chronic disorder of the brain characterized by recurrent episodic attacks, epileptic seizures, and their somatic and psychiatric consequences.
Anti-epileptic drug (AED) therapy is the mainstay of epilepsy treatment. Current treatment of AED follows a step approach that comprises initial mono-therapy and subsequent secondary mono- or initial add-on therapy, followed by the next drug trials using either mono-therapy or polytherapy. A variety of AEDs have been developed over the past few decades. Some are under development right now. Recently developed AEDs are categorized as the third generation of AEDs. Several compounds are under clinical investigation. They will be introduced to the market in near future. In Korea, about 20 AED are available currently. A few drugs are in process of obtaining approval from the Korea Food & Drug Administration. Newly introduced AEDs show better safety profiles with new mechanisms of action. They have various mode of actions, including the following molecular mechanisms: 1) voltage-gated channel-related mechanism including blocking sodium or calcium channels or opening potassium channel; 2) neurotransmission-related mechanism such as modifying GABAergic or glutamatergic transmission; and 3) having specific molecular targets during synaptic vesicle transmission.
DRE patients face a significant trouble with potentially devastating neuropsychiatric dysfunction, psychosocial issues, a reduced quality of life, increased comorbidities, and even sudden unexpected death issues.
Despite many years of research, definitions of DRE still remain operational so far. An
Epilepsy experts in real practice struggle with diagnosis and treatment of those patients in terms of patient’s explanation, clinical application of treatment, determination of prognosis, a unified collection of patients for future research, and so on. The guidance for DRE patients has highlighted recent advances in patient-specific precision medicine.
Therefore, the Drug Committee of Korean Epilepsy Society performed this study to understand the perception of Korean epilepsy experts by analyzing approaches of AED selection for DRE patients in consideration of clinical experience along with the magnitude and location of the medical institution. Regarding treatment failure, the questions included both “two drug failure” and “five drug failure”, reflecting recent common polytherapy in treating DRE. It will be beneficial to apply these results to real clinicians, which support them to achieve consensus in the treatment of DRE patients as well as to recognize the insight into DRE.
The survey was conducted with 108 eligible experts (neurologists, neurosurgeons, and pediatricians) who actively participate in the treatment of patients with epilepsy. They were in the drug or epidemiology committees of Korean epilepsy society with experience in prescribing AEDs or at least 1-year clinical experience of epilepsy clinic practice. A total of 108 eligible participants received the survey e-mail for approximately 2 weeks. Responding e-mails were gathered within the first 2 weeks after receiving the first e-mail. Another 2 weeks after the second e-mail were allowed for participants who did not respond to the first email. The survey period was from February 2021 to March 2021 (4-week period) (
Of subjects of the survey, males accounted for 74.4% (n=67) and females for 25.6% (n=23). Regarding expertise, neurology (77.8%, n=70) occupied the highest percentage, followed by pediatrics (18.9%, n=17) and neurosurgery (3.3%, n=3). The median experience of the subjects was 15.0±8.22 years (range, 1 year to 34 years). Subjects who had ≥10 years but <20 years of experience accounted for 41.1% (n=37), those with ≥20 years but <30 years of experience for 30% (n=27), those with <10 years of experience for 21.1% (n=19), and those ≥30 years of experience for 7.8% (n=7). Those who worked mainly in tertiary and quaternary hospitals accounted for the most (68.9%, n=62), followed by those who worked in secondary hospitals (23.3%, n=21) and primary hospitals (8.9%, n=7). As for the working place locations, all provinces in Korea were included. Many of them were in Seoul and Gyeonggi (65.6%, n=59) (
The definition of DRE across survey items was developed referring to ILAE criteria. Overall survey questionnaires were composed of six items (
The primary objective of this survey was to evaluate the prescription pattern of AED for DRE patients treated with multiple AEDs in real world practice. We created the survey questionnaires concerning previous numbers of AEDs, factors for the next AED choice, and feasibility to reduction in seizure frequency for each patient. The survey includes questionnaires: 1) the proportion of patients who failed two AED treatments, 2) the reason for failure to achieve seizure reduction, 3) rates of patients experienced from five AEDs or more prior (with previous prescription), 4) the feasibility to achieve seizure control when adding AEDs, 5) the proportion of patients who failed five AED treatments or more (currently prescribed), 6) the feasibility to seizure control for the patients who failed five AEDs or more, 7) the importance of factors considering additional AED, 8) priorities of evidence for further AED prescription on those who failed to five AEDs or more, 9) and 10) satisfaction with AED reimbursements from HIRA government body (
The survey conducted with a total of 108 eligible responses, and results were collected via e-mail or replies with attachment. Data analyses were conducted in a descriptive way. To assess detailed items, all questions were computed with response rates individually. Among ranking responses at question number 4 and 5, rank 4 was a cut-off value. For sub-analysis, the Kruskal-Wallis test was used as a nonparametric statistical method. Overall data were divided by experience, region, hospital level, and expertise to confirm the statistical significance of each question. All analyses were performed using R program (version 4.0.5; R Foundation for Statistical Computing, Vienna, Austria).
The mean proportion of patients who failed in two AED treatments was 26.9±11.50% (range from 2% to 70%). The causes of the failure included lack of efficacy (57.4%), adverse event (20.4%), adherence (18.6%), and others (3.6%) (
The mean proportion of patients experienced five AEDs or more, including previous medications, was 13.3±9.48% (range, 1% to 60%). When asked about possible control of seizures in these patients by adding AED further, 48 epileptologists (54.5%) responded that it was feasible (
The mean proportion of patients currently taking five AEDs or more was 7.3±5.30% (
For patients failed to five AEDs or more, the following factors were considered as priorities: 1) mechanism of action, 2) adverse event, 3) other pharmacokinetics, and 4) liver metabolism derivatives in order (n=79) (
Under the same conditions, when it came to considering adding more AEDs, expert opinion was considered as top priority by respondents, followed by clinical experience, reimbursement guidelines, and clinical evidences in order from given items including expert opinion, meta-analysis, textbook, clinical experience, reimbursement guidelines, clinical evidences, and others (
Overall average points for satisfaction on HIIRA reimbursement system for AED as 64.9±16.91 points (range, 0 to 100) with very satisfied in one responder (1.1%), satisfied in 25 (27.8%), neutral in 34 (37.8%), dissatisfied in 22 (24.4%), and very dissatisfied in eight (8.9%) in detail (
This survey targeted epilepsy experts prescribing AEDs to establish a comprehensive opinion on the prescribing status of epilepsy patients, especially DRE patients and factors to consider when performing AED selection. It was the first trial conducted with 108 experts in epilepsy nationwide. These experts had a great deal of experience in prescribing AED with clinical experiences in epilepsy clinic for at least 1 year. The place of participants consisted of all provinces in Korea. The e-mail survey was sent to responders to complete the survey file as attachment or reply with answers. It was conducted from February 2021 to March 2021. The survey participants showed a high response rate of 83% during a short period of 4 weeks.
Drug resistance in epilepsy is common. In AED treatment of newly diagnosed epilepsy patient, the seizure free rate of initial monotherapy is nearly about 60%. The remaining patients are considered to become potentially DRE because the further seizure free rate in additional changed or combined AED therapy is less than 10%. Historically comparative polytherapy trials have found that 11% to 35% of patients with partial seizures become seizure free, and additional 12% to 29% of patients have more than 50% seizure reduction.
In the present study, the proportion of patients who failed five AEDs or more including history was 13.3±9.48%. There was a subsequent question on whether additional AED treatment could help seizure control even in the failed cases with five failed AEDs or more prior. About 55% of responders said that the treatment would be effective if adding another AED to them. This reveals that there is still room for new AED trial even in DRE with five previous failed drugs or more. In sub-analysis, it was confirmed that 59.4% of neurologist and 57.1% of those with clinical experience ≥30 years responded hopefully, indicating that neurology subspecialty and longer clinical experience tended to answer positively. Korean National Evidence-based Healthcare Collaborating Agency has reported that the percentage of AED 1 year before epilepsy surgery is 20.3% for those having ≤2 drugs, 28.3% for those having three drugs, 26.0% for those having four drugs, and 25.4% for those having ≥5 drugs (Chung CK, Lee JA;
In the present study, the percentage of patients taking five failed AEDs or more currently at the same time was 7.3±5.30%. The rate of responding that the treatment would be effective when another AED was added was 37.9% (62.1% of ‘No’). Considering positive thinking in more than one third of responders, an additional drug trial would be possible even for patients with five concurrent failed drugs or more. In sub-analysis, the majority (57.1%) of those with ≥30 years of clinical experience answered that it would be effective, while only 16.7% of those with <10 years of clinical experience mentioned that it would be effective. Depending on the medical institution and clinical experience, 100% of those in the primary hospital reported that it would not be effective, whereas 64% of them from quaternary hospital responded positively. Considering above results, a new drug trial in DRE could be much influenced by service level of the hospital and the degree of clinical experience.
In the present study, the reason for intractability in the patients with two failed AEDs medications was the lack of effectiveness in majority of respondents (57.4%). Next to ineffectiveness, adverse events (20.4%) and non-adherence (18.6%) were common causes of intractability. The most common factor that leads to AED failure for seizure control in patients with DRE was lack of effectiveness. This suggests that even though there are currently 18 kinds of AEDs on the market in Korea, there are still unmet needs for new AEDs in real practice. Moreover, if drugs with new act mechanisms are developed, they might be able to achieve better efficacy in patients despite their previous exposure to various AEDs. Combination therapy with new AED having newly acting mechanism is likely to become popular because it is difficult to alleviate the number of seizures with currently existing AEDs. Thus, conventional two drug criteria for DRE cannot be practical. Studies in developing countries have shown non-adherence to anti-seizure medications occurs in 48.1–65.4%.
In the present study, when adding drugs to patients whose seizures were not controlled despite the use of five AEDs in the past, “mechanism of action” was the first priority, followed by “adverse event”, “pharmacokinetics”, and “hepatic metabolism”. The percentage of selecting “mechanism of action” was absolutely high (91.1%). According to expertise, medical institution, clinical experience, and region, results have no significant changes. To make polytherapy efficacious, the combination should focus on synergistic effects with safety and without toxicity. These results of this survey confirmed that experts’ AED selection was identical to that shown in several well-known references, textbooks, and guidelines.
As in the epilepsy textbook, tailored AED selection for the optimal treatment is based on the individual condition of each patient as well as traditional epilepsy syndrome or seizure type. The impact of seizure can be different depending on individual patient. Thus, the different impacts may induce different disease/therapy-associated alterations that can affect intrinsic severity as well as seizure frequency. The disease/therapy-associated alterations include molecular, cellular, and network changes and disease modifying effects (anti-inflammation, AED metabolism or distribution, change of efflux transport P-glycoprotein).
However, the necessity of AED polytherapy is not needed for all patients. Especially for the elderly, women of child-bearing potential, and children, AED overtreatment should be avoided since they are vulnerable to undesirable combinations of AED and non-AED polytherapy and subsequent adverse effects posing significant risks.
Currently, 30 kinds of AEDs have been developed for decades. In Korea, 18 kinds of AEDs could be reimbursed. For epilepsy patients, customized precision medicine is essential based on individual seizure types and drug-related factors. From an epilepsy pathology point of view, it is a priority to select an AED with a suitable mechanism of action tailored to the patient in near future. In the case of recently developed third-generation drugs, brivaracetam (SV2A antagonist) and eslicarbazepine (persistent sodium channel blocker) have been developed and they show advanced mode of actions. AEDs having new mechanisms of action are also under development. They will be introduced in the near future. They are expected to contribute to personalized medicine for each patient based on clinical perspective.
In summary, we investigated how experts would approach, diagnose, and prescribe appropriate drugs to patients with refractory epilepsy in Korea. Medical staffs with a lot of clinical experience have positive mind about the treatment of most DRE. Results confirmed that DRE could be approached with a method centering on the mechanism of action of a drug. If the standards for DRE patients were changed from two AEDs to not less than five including the past, not less than five drugs currently, there was a tendency of drug failure rate to decrease from 26.9% to 13.3% and 7.3%, although there was no significant difference according to the characteristics of the respondents. In addition, many respondents affirmed that adding AEDs would have a positive effect even if patients had treatment failure with five AEDs. The mechanism of action of the AED as a factor for additional selection was considered first. Most epileptologists refer to the opinions of experts first. However, their satisfaction with the reimbursement system for the use of AEDs in the medical field seems to be limited to active treatment. The results of this survey are expected to contribute to the therapeutic significance, prognosis and future treatment considerations of Korean DRE patients in real clinical practice.
The authors declare that they have no conflicts of interest.
Study design. (A) Time schedule for the survey. (B) Responder disposition and key steps involved in the survey for anti-epileptic drug medication.
Survey form about anti-epileptic drug medication.
Characteristics of survey responders
Item | Value |
---|---|
Sex | |
Female | 23 (26.0) |
Male | 67 (74.0) |
Expertise | |
Neurology | 70 (78.0) |
Neurosurgery | 3 (3.0) |
Pediatrics | 17 (19.0) |
Duration of experience (years) | 16.6±8.22 |
≥30 | 7 (7.8) |
>30–20 | 27 (30.0) |
>20–10 | 37 (41.1) |
>10 | 19 (21.1) |
Type of hospitals | |
Primary | 7 (8.0) |
Secondary | 21 (23.0) |
Tertiary | 37 (41.0) |
Quaternary | 25 (28.0) |
Residential area | |
Seoul, Gyeonggi | 59 (66.0) |
Chungcheong, Jeolla, Jeju | 12 (13.0) |
Gyeonsang, Gangwon | 19 (21.0) |
Values are presented as mean±standard deviation or number (%).
Results of survey on items of drug failure and national insurance
Value | |
---|---|
Q1. The proportion of two drug failure (including secondary monotherapy and combination therapy) (%) | 26.9±11.50 |
Q1-1. Reasons of failure | |
Efficacy | 57.4% |
Adverse events | 20.4% |
Adherence | 18.6% |
Others | 3.6% |
Q2. The proportion of five drug failure (including past medications) (%) | 13.3±9.48 |
Q2-1. Expectation of efficacy in additional add-on therapy | |
Positive | 23 (54.5) |
Negative | 20 (45.5) |
Q3. The proportion of five drug failure in current medications (%) | 7.3±5.30 |
Q3-1. Expectation of efficacy in additional add-on therapy | |
Positive | 14 (37.9) |
Negative | 29 (62.1) |
Q4. Satisfaction on national medical insurance on anti-epileptic drug medications | |
Q4-1. Overall satisfaction score (on a scale from 1 to 100) | 64.9±16.91 |
Q4-2. Proportion according to degree of satisfaction | |
Very satisfied | 19 (1.1) |
Satisfied | 11 (28.1) |
Neutral | 9 (38.2) |
Dissatisfied | 4 (23.6) |
Very dissatisfied | 0 (9.0) |
Values are presented as mean±standard deviation or number (%) unless otherwise indicated.
Results of survey on selection priority of antiepileptic drug medications in refractory patients (survey question number Q4)
Item | Ranking | |||
---|---|---|---|---|
| ||||
1st | 2nd | 3rd | 4th | |
Mechanism of action | 72 (91.1) | 3 (3.8) | 1 (1.3) | 3 (3.8) |
Hepatic enzyme inducer | 0 (0.0) | 10 (12.7) | 28 (35.4) | 39 (49.4) |
Other pharmacokinetic event | 0 (0.0) | 20 (25.3) | 33 (41.8) | 25 (31.6) |
Adverse drug event | 6 (7.6) | 46 (58.2) | 17 (21.5) | 10 (12.7) |
Others | 1 (1.3) | 0 (0.0) | 0 (0.0) | 2 (2.5) |
Total | 79 | 79 | 79 | 79 |
Values are presented as number (%).
Results of survey on referential resources (survey question number Q5)
Item | Ranking | |||
---|---|---|---|---|
| ||||
1st | 2nd | 3rd | 4th | |
Expert opinion | 23 (31.5) | 15 (20.5) | 10 (13.7) | 11 (15.1) |
Meta-analysis | 4 (5.5) | 7 (9.6) | 13 (17.8) | 22 (30.1) |
Textbook | 9 (12.3) | 7 (9.6) | 9 (12.3) | 9 (12.3) |
Review, case series | 10 (13.7) | 14 (19.2) | 13 (17.8) | 12 (16.4) |
Guidelines | 13 (17.8) | 12 (16.4) | 12 (16.4) | 7 (9.6) |
Clinical experience | 14 (19.2) | 15 (20.5) | 12 (16.4) | 7 (9.6) |
Medical insurance | 0 (0.0) | 3 (4.1) | 3 (4.1) | 5 (6.8) |
Others | 0 (0.0) | 0 (0.0) | 1 (1.4) | 0 (0.0) |
Total | 73 | 73 | 73 | 73 |
Values are presented as number (%).