How often do doctors discuss drug withdrawal with their seizure-free patients with epilepsy?

Among patients with epilepsy, almost 70% become seizure-free with the current antiseizure drugs (ASDs) within 20 years following seizure onset. Of those who have been seizure-free for many years, around 70% remain seizure-free after withdrawal of ASDs. The purpose of this study was to determine the extent to which seizure-free patients with epilepsy in Norway discuss drug discontinuation with their physician. An online questionnaire was used; among the respondents were 186 adult patients who had been seizure-free for at least five years and were still using ASDs. Of these, 60 patients (32%) reported that they had discussed the question of drug withdrawal with their treating physician. Those patients who reported being involved in treatment decisions were more likely to have discussed ASD withdrawal. In conclusion, it is our opinion that discontinuation of drug treatment in patients with long-term seizure freedom is discussed far too seldom and that many patients may be living with an unnecessary drug burden.


Introduction
About 65 million people suffer from epilepsy worldwide [1]. In Western countries, about 25 antiseizure drugs (ASDs) are currently available on the market, and following treatment with these drugs, about 70% of the patient population achieves long-term seizure freedom [2]. Almost 90% of patients using ASDs experience adverse effects [3], and reducing these side effects can contribute to a better quality of life [4].
When a patient with epilepsy has been seizure-free for a certain period of time, discontinuation of ASD therapy may be considered. Two randomized controlled trials have been conducted to explore whether ASD withdrawal is justifiable in patients who have been seizure-free for at least two years [5,6]. These studies showed that the risk of seizure recurrence in the withdrawal group was about twice that of those who continued their drug treatment; 40% vs. 20% [5,6] and 15% vs. 7% [5,6]. In a meta-analysis of withdrawal studies (n = 45) including 7082 patients, Lamberink and coworkers found that the cumulative relapse rate either 1, 2, or 3-4 years after discontinuation was 22%, 28%, and 34%, respectively [7].
In a later systematic review and individual participant data metaanalysis by the same group, an individualized prediction model of seizure recurrence and long-term outcome was developed [5,6]. An online tool to assess risk and prognosis associated with ASD withdrawal in individual patients was developed and is available at http:// epilepsypredictiontools.info/aedwithdrawal [8].
However, the extent to which treating physicians discuss the possibility of withdrawing ASD treatment with their patients has received sparse attention in the epilepsy community. Thus, the purpose of this study was to explore whether seizure-free patients with epilepsy in Norway have discussed ASD withdrawal with their doctor.

Online questionnaire
This was a collaborative study between the National Centre for Epilepsy in Norway and the Norwegian Epilepsy Association (NEA). A questionnaire appeared as a pop-up on NEA's homepage between April 1st 2017 and September 5th 2017. Visitors to the page were asked questions about various aspects of epilepsy, including background information, current treatment, epilepsy etiology, epilepsy severity, medical follow-up, and whether they had discussed withdrawal of ASDs with their doctor.
Approximately 100,000 persons visit NEA's homepage every year, and the page is regarded as an important source of information about

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Epilepsy & Behavior j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y e b e h epilepsy in Norway. For this survey, participants could register as patients with epilepsy, primary caregivers/guardians, or family members of a patient with epilepsy.
For addressing the question of discussion of ASDs, data were only included in the analyses derived from adult patients (N18 years) with epilepsy who answered the questionnaire for themselves. As the study was anonymous the respondents consented by participation. The study was evaluated by the Regional Ethics Comittee (ref.no.:2017/563)

Statistics
The Statistical Package for the Social sciences (SPSS) from the International Business Machiens Corperation (IBM) Statistics version 25, (SPSS Inc., Chicago, IL, USA) was used for statistical analyses. All P values reported here are based on two-sided tests, with a significance level of 0.05. To test possible group differences for categorical variables, Pearson's chi-square tests were performed.
Odds ratios (OR) for factors associated with having discussed ASD withdrawal with their physician were estimated using bivariate and multivariate logistic regression analyses with 95% confidence intervals (CIs).
We applied Hosmer's step-down procedure, which means that variables that were significant at the 0.25 level were included in the multivariate logistic regression model.

Results
A total of 1172 adult patients participated in the study. Not all questionnaires were completed fully. Of these 1172 patients, 469 (41%) reported that they had been seizure-free for at least 12 months and 211 (18%) that they had been seizure-free for at least five years. Of these 211 patients, 186 (88%) were still using ASDs. Table 1 shows the epilepsy etiologies reported by the respondents. All 1172 patients responded to the question: "have you and your doctor considered whether you should stop your epilepsy medication?" Of the 186 patients who had been seizure-free for at least five years, 60 (32%) had discussed ASD withdrawal with their physician. Characteristics of the 186 patients who had been seizure-free for at least five years are presented in Table 2, according to whether or not they report discussing ASD withdrawal with their doctor.
Those patients reporting involvement in treatment decisions had discussed ASD withdrawal with their doctor significantly more often than those not involved in treatment choices (OR: 2.27, CI: 1.11-4.63; p = 0.02) Other variables like known epilepsy etiology or follow-up by a specialist were not significantly associated.

Discussion
The main finding in this study is that among patients who had been seizure-free for at least five years, fewer than 1/3 had discussed ASD withdrawal with their doctor. This indicates that the majority of clinicians are reluctant to discuss termination of drug treatment with their patients, even with those who have been seizure-free for many years. One reason for such reluctance might be the fear of seizure relapse, with the many subsequent potential consequences, including psychological strain, loss of driving license, and risk of sudden death.
In most patients, epilepsy is not a lifelong condition. In a Finnish cohort of patients with childhood-onset epilepsy, after over 30 years of follow-up, 64% of cases were in five-year terminal remission, of which 74% were off medication [9]. The best time for drug withdrawal has not been established and should be tailored to the individual patient. Each patient for whom ASD withdrawal is under consideration should undergo an appropriate risk assessment; online tools for this purpose are available. As in medicine in general, a holistic approach should be used, and it is important that patients are warned against abrupt selfwithdrawal [10,11].
We are not aware of any studies that address the extent to which ASD withdrawal is discussed with patients. However, the impact of counseling about the risk of seizure relapse was investigated in one study, and it was found that the patients were more reluctant to consider drug withdrawal after the counseling [12]. In our study, we found that the likelihood of patients having discussed ASD withdrawal with their doctor more than doubled if the patients felt they had been involved in treatment decisions; i.e., shared decision-making. This probably reflects an open and trust-based doctor-patient relationship.
There are some limitations to our study. Although a web-based questionnaire was used with the intention of obtaining data from a representative sample of Norwegian patients with epilepsy, the percentage of respondents who had been seizure-free during the previous year (41%) was lower than expected from a representative sample of the Norwegian epilepsy population. This may indicate a bias towards patients with more severe epilepsy responding to the questionnaire.
Our dataset was based solely on the information provided by the respondents. Thus, we were not able to confirm whether those patients who reported being seizure-free for five years actually were so. In addition, we could not determine whether patients actually had or had not discussed withdrawal of ASD with their physicians, as they reported. Given that memory problems occur frequently in patients with epilepsy, errors could have occurred here that could have resulted in either underreporting or overreporting of discussions about ASD withdrawal between patients and their doctors.
Furthermore, we had no information about the intellectual capacity of the respondents although we assume at least a basic intellectual capacity as all respondents needed to access, open, and navigate the survey. Further limitations are the known problems with validity of close-ended questionnaires, such as lack of alternative answers. In addition, we have no information on the results of electroencephalogram (EEG) examinations of the respondents. Such results may influence a doctor's decision on whether it is appropriate to discuss drug withdrawal.

Conclusion
Based on these survey results, discussion with doctors of drug withdrawal in adult patients who have been seizure-free for many years should occur more often in our opinion. The subject should be addressed regularly, and the decision on whether ASD withdrawal should be tried, should be based on a risk-benefit analysis, with the ultimate decision taken by the patients themselves, after a thorough and supported discussion of all aspects.