Variation in seizure risk increases from antiseizure medication withdrawal among patients with well-controlled epilepsy: A pooled analysis.

OBJECTIVE: Guidelines suggest considering antiseizure medication (ASM) discontinuation in seizure-free patients with epilepsy. Past work has poorly explored how discontinuation effects vary between patients. We evaluated (1) what factors modify the influence of discontinuation on seizure risk; and (2) the range of seizure risk increase due to discontinuation across low- versus high-risk patients. METHODS: We pooled three datasets including seizure-free patients who did and did not discontinue ASMs. We conducted time-to-first-seizure analyses. First, we evaluated what individual patient factors modified the relative effect of ASM discontinuation on seizure risk via interaction terms. Then, we assessed the distribution of 2-year risk increase as predicted by our adjusted logistic regressions. RESULTS: We included 1626 patients, of whom 678 (42%) planned to discontinue all ASMs. The mean predicted 2-year seizure risk was 43% [95% confidence interval (CI) 39%-46%] for discontinuation versus 21% (95% CI 19%-24%) for continuation. The mean 2-year absolute seizure risk increase was 21% (95% CI 18%-26%). No individual interaction term was significant after correcting for multiple comparisons. The median [interquartile range (IQR)] risk increase across patients was 19% (IQR 14%-24%; range 7%-37%). Results were unchanged when restricting analyses to only the two RCTs. SIGNIFICANCE: No single patient factor significantly modified the influence of discontinuation on seizure risk, although we captured how absolute risk increases change for patients that are at low versus high risk. Patients should likely continue ASMs if even a 7% 2-year increase in the chance of any more seizures would be too much and should likely discontinue ASMs if even a 37% risk increase would be too little. In between these extremes, individualized risk calculation and a careful understanding of patient preferences are critical. Future work will further develop a two-armed individualized seizure risk calculator and contextualize seizure risk thresholds below which to consider discontinuation. PLAIN LANGUAGE SUMMARY: Understanding how much antiseizure medications (ASMs) decrease seizure risk is an important part of determining which patients with epilepsy should be treated, especially for patients who have not had a seizure in a while. We found that there was a wide range in the amount that ASM discontinuation increases seizure risk-between 7% and 37%. We found that no single patient factor modified that amount. Understanding what a patient's seizure risk might be if they discontinued versus continued ASM treatment is critical to making informed decisions about whether the benefit of treatment outweighs the downsides.

Reduced total number of enlarged perivascular spaces in post-traumatic epilepsy patients with unilateral lesions - a feasibility study.

BACKGROUND: We investigated the value of automated enlarged perivascular spaces (ePVS) quantification to distinguish chronic traumatic brain injury (TBI) patients with post-traumatic epilepsy (PTE+) from chronic TBI patients without PTE (PTE-) in a feasibility study. METHODS: Patients with and without PTE were recruited and underwent an MRI post-TBI. Multimodal auto identification of ePVS algorithm was applied to T1-weighted MRIs to segment ePVS. The total number of ePVS was calculated and corrected for white matter volume, and an asymmetry index (AI) derived. RESULTS: PTE was diagnosed in 7 out of the 99 participants (male=69) after a median time of less than one year since injury (range 10-22). Brain lesions were observed in all 7 PTE+ cases (unilateral=4, 57%; bilateral=3, 43%) as compared to 40 PTE- cases (total 44%; unilateral=17, 42%; bilateral=23, 58%). There was a significant difference between PTE+ (M=1.21e-4, IQR [8.89e-5]) and PTE- cases (M=2.79e-4, IQR [6.25e-5]) in total corrected numbers of ePVS in patients with unilateral lesions (p=0.024). No differences in AI, trauma severity and lesion volume were seen between groups. CONCLUSION: This study has shown that automated quantification of ePVS is feasible and provided initial evidence that individuals with PTE with unilateral lesions may have fewer ePVS compared to TBI patients without epilepsy. Further studies with larger sample sizes should be conducted to determine the value of ePVS quantification as a PTE-biomarker.

Screening of attention and executive functions in pediatric patients at a tertiary epilepsy center.

OBJECTIVE: Executive dysfunction is prevalent in children with epilepsy, and associated with poor psychosocial outcome. Sensitive and time effective tools are needed, which capture executive dysfunction across a wide range of impairment. The present study evaluates the applicability of EpiTrack Junior® (EpiTrackJr) as a screening tool at a tertiary epilepsy center, and explore how EpiTrackJr in combination with a subjective measure of everyday attention and executive functions (EFs) may provide clinically important information. METHODS: Retrospective study including 235 pediatric patients admitted to the Norwegian National Centre for Epilepsy. EpiTrackJr and Behavioral Rating Inventory of Executive Functioning (BRIEF) were used to assess attention and EFs. RESULTS: 27,7% obtained a score categorized as "average/unimpaired", 23% as "mildly impaired", and 47.7% as "significantly impaired" on EpiTrackJr. The distribution of age-corrected EpiTrackJr scores was satisfactory. Performance was related to numbers of anti-seizure medication (ASM load), comorbidity and IQ. We found a significant, but weak correlation between EpiTrackJr performance and the BRIEF Metacognitive Index (r = -0.236, n = 108, p=.014), but no significant correlation with the Behavioral Regulation Index (r = -0.178, n = 108, p=.065). SIGNIFICANCE: Our results indicate that EpiTrackJr is applicable as a screening tool for attention and EFs in pediatric patients at a tertiary epilepsy center. Impaired test performance was associated with greater ASM load, comorbidity and lower IQ. Performance based measures and behavior ratings likely capture different aspects of EFs. In combination, the two provide important and nonredundant information about the child's EFs in different settings.

Use of screening tools to assess comorbidities and adverse events in patients with epilepsy. A European Reference Network for Rare and Complex Epilepsies (EpiCARE) survey.

PURPOSE: As comorbidities can affect treatment decisions, quality of life, and prognosis in epilepsy, it is important that they are detected and addressed as soon as possible. Screening tools can help by rapidly assessing various additional challenges in epilepsy. METHODS: To map the use and perceived benefit of different screening instruments for quality of life, psychiatric comorbidity, and cognition, along with side effects from anti-seizure medication in Europe, we sent an online questionnaire to dedicated epilepsy centres departments within the European Reference Network for Rare and Complex Epilepsies (EpiCARE). RESULTS: Among the 40 hospitals in the EpiCARE network, we received responses from 25 (63%), with 28 individual respondents. Most respondents reported using screening for quality of life (86%) and psychiatric comorbidity (82%), but relatively few (14%) screen for sexual problems. Many (47) different tools were used for evaluation of cognitive dysfunction, but just a few (5) different tools were used to screen for adverse events. The optimization of individual patient care was one main reason given for using screening tools (58%-100% - depending on purpose of tool), another was research (50% - 88% - depending on purpose of tool). A major benefit of using screening tools perceived by the respondents is the detection of "hidden" comorbidity (67% - 90% - depending on purpose of tool). CONCLUSION: In the absence of a broad consensus regarding use of screening tools, practices vary considerably among epilepsy centres. Greater emphasis should be directed towards harmonizing use of screening tools. Future research should address how screening results influence treatment choices, and how these might affect clinical care.

Reappraisal of the Medical Research Council Antiepileptic Drug Withdrawal Study: Contamination-adjusted and dose-response re-analysis.

OBJECTIVE: The 1991 Medical Research Council (MRC) Study compared seizure relapse for seizure-free patients randomized to withdraw vs continue of antiseizure medications (ASMs). We re-analyzed this trial to account for crossover between arms using contamination-adjusted intention to treat (CA ITT) methods, to explore dose-response curves, and to validate predictions against external data. ITT assesses the effect of being randomized to withdraw, as-treated analysis assesses the confounded effect of withdrawing, but CA ITT assesses the unconfounded effect of actually withdrawing. METHODS: CA ITT involves two stages. First, we used randomized arm to predict whether patients withdrew their ASM (logistic) or total daily ASM dose (linear). Second, we used those values to predict seizure occurrence (logistic). RESULTS: The trial randomized 503 patients to withdraw and 501 patients to continue ASMs. We found that 316 of 376 patients (88%) who were randomized to withdraw decreased their dose at every pre-seizure visit, compared with 35 of 424 (8%) who were randomized to continue (p < .01). Adjusted odds ratios of a 2-year seizure for those who withdrew vs those who did not was 1.3 (95% confidence interval [CI] 0.9-1.9) in the as-treated analysis, 2.5 (95% CI 1.9-3.4) comparing those randomized to withdraw vs continue for ITT, and 3.1 (95% CI 2.1-4.5) for CA ITT. Probabilities (withdrawal vs continue) were 28% vs 24% (as-treated), 40% vs 22% (ITT), and 43% vs 21% (CA ITT). Differences between ITT and CA ITT were greater when varying the predictor (reaching zero ASMs) or outcome (1-year seizures). As-treated dose-response curves demonstrated little to no effects, but larger effects in CA ITT analysis. MRC data overpredicted risk in Lossius data, with moderate discrimination (areas under the curve ~0.70). SIGNIFICANCE: CA ITT results (the effect of actually withdrawing ASMs on seizures) were slightly greater than ITT effects (the effect of recommend withdrawing ASMs on seizures). How these findings affect clinical practice must be individualized.

Efficacy, tolerability and pharmacokinetic variability of brivaracetam in adults with difficult-to-treat epilepsy.

PURPOSE: Brivaracetam (BRV) is one of our latest antiseizure medications (ASMs). It is an analogue of levetiracetam with limited real-life experience. The purpose of this study was to evaluate clinical experience with BRV with focus on efficacy, tolerability and pharmacokinetic variability among adult patients with difficult-to-treat epilepsy. METHODS: We retrospectively collected clinical and laboratory data from patients aged > 18 years who initiated treatment with BRV during 2016-2019 and were followed for > one year or cessation of BRV. RESULTS: The study cohort consisted of 120 adults with drug-resistant epilepsy. Serum concentrations of BRV were available in 72 patients. After one-year follow-up, the retention rate of BRV was 52%. Fifty-seven patients (48%) were responders (>50 reduction of seizure frequency), of whom six became seizure free. Adverse effects were reported in 78 patients (65%); 37 (31%) experienced psychiatric problems like increased irritability, anxiety and depressive symptoms. The mean daily BRV dose was 159 mg (SD 80 mg) and the mean serum concentration 5.4 µmol/L (SD 4.1 µmol/L). In 24 patients, BRV replaced levetiracetam. Pharmacokinetic variability between patients was considerable; 14-fold variation in concentration/dose (C/D)-ratios. Concomitant use of enzyme-inducing ASMs decreased the C/D-ratio by 48%. There were no significant differences in serum concentrations between responders vs. non-responders, or those who experienced adverse effects or not. CONCLUSION: After > 1 year of treatment with BRV, we found a responder rate of 48% in adult patients with difficult-to-treat epilepsy. The drug was largely well tolerated, but one third experienced psychiatric adverse effects. The combination of clinical and pharmacokinetic data provides insight into factors contributing to efficacy and tolerability of new ASMs.

People with epilepsy still feel stigmatized.

OBJECTIVES: Those affected with epilepsy have long been subject to stigmatization. This may have manifold negative effects, for example social isolation, low self-esteem, reduced quality of life and worsening of seizures. In Norway educational programs have been arranged at the National Centre for Epilepsy, aiming at reducing stigma and shame associated with epilepsy, and thereby increase the quality of life for those affected and their families. Thus, we wanted to explore the extent of self-reported perceived stigma and experienced discrimination in a Norwegian cohort with epilepsy. MATERIALS AND METHODS: We conducted a web-based questionnaire survey in Norway. Participants were asked to provide background and epilepsy-related information. In addition, they were encouraged to answer questions regarding felt stigmatization in different situations and to rate stigma according to the Jacoby stigma scale. RESULTS: Of 1182 respondents, 56% reported to have felt being stigmatized, and 35% reported to have experienced discrimination solely on the ground of the disease. 70% of respondents reported at least one type of perceived or experienced stigma. After controlling for gender, age, perceived depression and seizure freedom, reports of experienced stigmatization was a statistically significant independent predictor for reduced quality of life. CONCLUSIONS: A considerable proportion of people with epilepsy in Norway feel stigmatized and/or subject to discrimination, which negatively affects their quality of life.

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.

Assisted reproductive treatment in women with epilepsy. / Assistert befruktning blant kvinner med epilepsi.

BACKGROUND: Women with epilepsy give birth to fewer children than women without epilepsy. We wished to compare the use of assisted reproductive technology in Norwegian women who have epilepsy with Norwegian women in general. MATERIAL AND METHOD: In an international prospective registry study, the purpose of which was to identify the teratogenic effects of antiepileptic drugs, we included a total of 1510 births among Norwegian women who have epilepsy in the period 2000-2017. The women were recruited from 18 hospital neurological departments, and a protocol was completed for each pregnancy with demographic and clinical data. The use of assisted fertility among Norwegian women in general in the same period was retrieved from the medical birth registry. RESULTS: In women with epilepsy, altogether 96 of 1510 births (6.4 %) were a result of assisted reproductive technology, whereas the corresponding figure in the general population in the same period was 285 474 of 1 052 901 (2.7 %) (p<0.001). Among women with epilepsy, the proportion who used carbamazepine in pregnancy was significantly higher among those who conceived using assisted reproductive technology than among those who had become pregnant in the regular manner (p=0.02). INTERPRETATION: Compared to healthy Norwegian women, the use of assisted reproductive technology was more than twice as high among women with epilepsy. This may be an intimation of reduced fertility among these women.

Clinical experience combined with therapeutic drug monitoring of lacosamide.

OBJECTIVE: Lacosamide (LCM) is an antiepileptic drug (AED) with insufficient clinical experience in patients with intellectual disability (ID). They often have more severe epilepsy with comorbidities. The objective was to evaluate the efficacy and tolerability of lacosamide (LCM) in patients with refractory epilepsy with and without ID in a real-life setting, taking drug monitoring (TDM) data into account therapeutic. METHODS: Retrospectively, we identified 344 patients using LCM from the TDM service covering the majority of the country, at the National Center for Epilepsy in Norway (2013-2018). Clinical and TDM data were available for 132 patients. RESULTS: Forty-four of the 132 patients (33%) had ID. The retention rate was significantly higher in the ID vs the non-ID group after 1 year (84% vs 68%, P < .05). By combining clinical and TDM data, we demonstrated that 37/38 responding patients had serum concentrations above the lower limit of the reference range (>10 µmol/L), and 16/17 with lower concentrations were non-responders. Mean serum concentration/dose ratios were similar in both groups, 0.06 and 0.07 µmol/L/mg. There were no significant differences regarding efficacy and tolerability. The risk of LCM withdrawal was significantly higher when LCM was added to sodium channel blockers, even if the latter was discontinued. SIGNIFICANCE: Lacosamide was generally well tolerated in patients with drug-resistant epilepsy, where one third had ID, and in these patients the retention rate was higher. The combination of clinical and TDM data could possibly facilitate LCM therapy in these vulnerable patients.

Refractory epilepsy and nonadherence to drug treatment.

In patients with epilepsy, nonadherence to agreed antiepileptic drug (AED) treatment may result in seizure relapse, and at worst sudden unexpected death. The aim of this study was to examine the extent of both unintentional and intentional nonadherence among Norwegian patients with refractory epilepsy and try to identify possible risk factors. At the National Centre for Epilepsy in Norway, 333 consecutive adult in- and outpatients with refractory epilepsy participated in an anonymous survey about adherence to drug treatment. Twenty-two percentages admitted that they sometimes or often forgot to take their drugs as scheduled, and 19% reported that they, rarely, sometimes or often intentionally did not follow the AED treatment plan agreed upon with their physician. Young age and depression were significantly correlated with unintentional nonadherence. Intentional nonadherence was associated with young age (36 years or younger). We found nonadherence not to be associated with any specific AED. In conclusion, about one-fifth of patients with refractory epilepsy admitted that they did not adhere to the agreed drug treatment plan, either intentionally or unintentionally. Measures to reduce nonadherence in this patient group may improve seizure control and should be tailored to address both unintentional and intentional lack of adherence.

A call for better information about epilepsy: The patients' perspective-An online survey.

PURPOSE: For people with epilepsy (PWE), insufficient information and knowledge about the disease might have a negative influence on outcome and lead to poorer quality of life. In contrast, good information may increase empowerment and reduce stigma. This study investigated whether Norwegian PWE want information about different epilepsy-related issues, whether they actually obtain the information that they seek, and the extent to which they are satisfied with the information they receive. Furthermore, we examined which factors that might have influenced the degree of specific information given to PWE. METHODS: We invited PWE visiting the homepage of the Norwegian Epilepsy Association to complete a web-based questionnaire about their perspective on obtaining information about epilepsy-related issues. The survey was accessible for a four-month period during 2017. RESULTS: More than 90% of respondents (n = 1182) wished general information about epilepsy, and over 75% wanted information on more specific issues, like epilepsy surgery. Depending on the subject, the proportion of respondents that reported receiving the information they wished varied from 6.6% to 91.9%. Obtaining information about epilepsy surgery and neurostimulation was significantly associated with male gender. Having tonic-clonic seizures was associated with obtaining information about the diagnosis, an organized lifestyle, regular sleep, and consumption of alcohol. CONCLUSIONS: This study provides insights on how PWE experience provision of relevant information about epilepsy. Although most PWE considered that they obtained information on general epilepsy issues, most PWE interested in information on non-medical treatments and psychosocial issues reported that they did not obtain the information they wanted.

Challenges in epilepsy-The perspective of Norwegian epilepsy patients.

OBJECTIVES: For most people with epilepsy (PWE), problems that are not directly related to seizures may constitute major challenges in everyday life. The purpose of this study was to determine the extent of these challenges and any risk factors for their occurrence among PWE in Norway, based on the patients' own perspective. MATERIALS AND METHODS: We used a web-based survey to ask PWE visiting the homepage of the Norwegian Epilepsy Association about different everyday challenges. A link to the survey was accessible via the members' homepage for a 4-month period during 2017. RESULTS: One thousand one hundred eighty-two PWE responded to the questionnaire. Although more than 40% of the cohort reported that they had been seizure free for at least 1 year, the majority reported that tiredness (71%), memory problems (70%), concentration problems (68%), headache or vertigo (51%), and feeling depressed (59%) continued to represent challenges. In addition, fear of being alone, sexual problems or difficulties in social settings were reported by about one-third of the patients. Reporting having these challenges was significantly associated with female gender, polytherapy, experiencing seizures during the previous 12 months and feeling blue or depressed. CONCLUSIONS: The results of this study, reflecting a self-selected Norwegian population, provide insights into the challenges not directly associated with seizures that impact on the quality of life of PWE. The impacts of such challenges may be underestimated as components of the entire burden of epilepsy.

Nonadherence to treatment regimens in epilepsy from the patient's perspective and predisposing factors: Differences between intentional and unintentional lack of adherence.

Nonadherence to recommended antiepileptic drug (AED) treatment regimens can result in seizure relapse with increased health risks. Nonadherence can be unintentional (eg, patients forget to take a dose), or intentional, when patients consciously decide not to follow the agreed AED treatment regimen. We aimed to determine the extent to which Norwegian patients with epilepsy (PWEs) report taking their AED differently from prescribed, either intentionally or unintentionally, and to identify risk factors for either form of nonadherence. Of 1182 PWEs who completed an online survey presented on the website of the Norwegian Epilepsy Association, 40% reported that they sometimes or often forget to take their AED as scheduled, and about 30% reported that they consciously chose not to follow the AED treatment plan agreed upon with their physician. Independent variables significantly associated with unintentional nonadherence include the following: feeling depressed, being younger than the mean age, and having memory problems. Independent factors significantly associated with intentional nonadherence include the following: feeling depressed, male gender, and perceptions of stigmatization. To improve the treatment of PWEs, it is important to distinguish between intentional and unintentional nonadherence to AED treatment regimens, as different risk factors and reasons associated with nonadherence to AED treatment regimens might require different interventions.

Tested and reported executive problems in children and youth epilepsy.

Objectives: Executive problems in children and youth with epilepsy influence their ability to handle important aspects of daily life activities. The present study sought to explore factors associated with executive problems for patients with epilepsy in this age group. Methods: The cohort consisted of 97 consecutive patients at the National Centre for Epilepsy in Norway, aged 10-19 years, with focal or genetic generalized epilepsy. All underwent tests of executive functions (D-KEFS), the Behavior Rating Inventory for Executive Function (BRIEF), and screening for psychiatric symptoms, using the Strengths and Difficulties Questionnaire (SDQ). Results: Parent-reported cognitive executive dysfunction (BRIEF, Metacognitive Index) was the strongest independent predictor for tested executive dysfunction and vice versa. Furthermore, male gender correlated strongest with parent-reported behavioral regulation problems (BRIEF, Behavioral Regulation Index) along with borderline/pathological score on the SDQ and parent-reported cognitive executive dysfunction. Conclusions: A strong association between parent-reported cognitive executive dysfunction and tested executive dysfunction was found. Male gender correlated strongest with parent-reported behavioral regulation problems. The latter was probably related to a higher frequency of symptoms associated with psychopathology among the boys than the girls. The frequency of executive deficits according to the different modes of measurement varied from 16% to 43%, suggesting that they capture different aspects of behavior under the executive umbrella.

Short-term Seizure Outcomes in Childhood Epilepsy.

BACKGROUND AND OBJECTIVES: Seizure freedom is the optimal response to antiepileptic treatment. In previous studies, it has been shown that between 61% and 71% of children with epilepsy achieve seizure freedom, whereas 7% to 20% have drug-resistant epilepsy. The definition of drug resistance has not been consistent across studies, and there is a lack of contemporary population-based data. We used data from a large nationwide child cohort to provide such information, implementing the current standard definition of drug resistance. METHODS: The study was based on the Norwegian Mother and Child Cohort Study. Potential epilepsy cases were identified through registry linkages and parental questionnaires. Medical record reviews and parental interviews were used to collect clinical information and to classify seizures, epilepsies, and etiologies. RESULTS: The cohort included 112 745 eligible children aged 3 to 13 years (median age 7 years) at end of follow-up. Of these, 600 were epilepsy cases with at least 1 year of follow-up since epilepsy onset (median follow-up time: 5.8 years). There were 178 (30%) who had developed drug-resistant epilepsy, 353 (59%) who had been seizure free for ≥1 year, and 69 (12%) with intermediate seizure outcomes. Having an identified cause of epilepsy (genetic, structural, metabolic, or infectious) was associated with unsatisfactory seizure outcome (48% drug resistance) and influenced the relative risk associated with other prognostic factors. Sociodemographic characteristics were not associated with short-term seizure outcomes. CONCLUSIONS: Drug resistance occurs in 3 out of 10 children with epilepsy, whereas 6 out of 10 become seizure free. Having an identified cause of epilepsy is associated with poor response to treatment.

People with epilepsy and their relatives want more information about risks of injuries and premature death.

For most people with chronic diseases such as epilepsy, thorough knowledge of the disease is important in order to reduce feelings of insecurity and to enable better management of everyday life. Whether and when to inform patients and their families about all the risks associated with epilepsy is a matter of controversy. Using a web-based survey, patients with epilepsy (PWE) (n=1183) and carers, family members, or guardians of PWE, who could either answer on behalf of the patients (CBP) (n=676) or on their own behalf (CAR) (n=231) were asked whether they wanted information about the risk of epilepsy-related injuries and premature death and also whether they had received such information. Ninety percent or more of PWE, CBP, and CAR reported that they wanted such information, and 50% of CAR, 81% of CBP, and 70% of PWE had received some information about seizure-related injuries. Regarding risk of unexpected death, 31% of PWE, 35% of CBP, and 28% of CAR had received information on this issue. Those with tonic-clonic seizures were most eager to obtain information on these matters, and those best informed about epilepsy-related risks were males and the youngest part of the cohort. The wish for more information or the likelihood of having already received information was independent of the individual's seizure situation. This study demonstrates that there is a considerable gap between what the patients want regarding information and what they are actually given by healthcare providers.