Should substitution monotherapy or combination therapy be used after failure of the first antiseizure medication? Observations from a 30-year cohort study.

OBJECTIVES: To assess the temporal trends in the use of second antiseizure (ASM) regimens and compare the efficacy of substitution monotherapy and combination therapy after failure of initial monotherapy in people with epilepsy. METHODS: This was a longitudinal observational cohort study conducted at the Epilepsy Unit of the Western Infirmary in Glasgow, Scotland. We included patients who were newly treated for epilepsy with ASMs between July 1982, and October 2012. All patients were followed up for a minimum of 2 years. Seizure freedom was defined as no seizure for at least 1 year on unchanged medication at the last follow up. RESULTS: During the study period, 498 patients were treated with a second ASM regimen after failure of the initial ASM monotherapy, of whom 346 (69%) were prescribed combination therapy and 152 (31%) were given substitution monotherapy. The proportion of patients receiving second regimen as combination therapy increased during the study period from 46% in first epoch (1985-1994) to 78% in the last (2005-2015) (RR = 1.66, 95% CI: 1.17-2.36, corrected-p = .010). Overall, 21% (104/498) of the patients achieved seizure freedom on the second ASM regimen, which was less than half of the seizure-free rate on the initial ASM monotherapy (45%, p < .001). Patients who received substitution monotherapy had similar seizure-free rate compared with those who received combination therapy (RR = 1.17, 95% CI: 0.81-1.69, p = .41). Individual ASMs used, either alone or in combination, had similar efficacy. However, the subgroup analysis was limited by small sample sizes. SIGNIFICANCE: The choice of second regimen used based on clinical judgment was not associated with treatment outcome in patients whose initial monotherapy failed due to poor seizure control. Alternative approaches such as machine learning should be explored to aid individualized selection of the second ASM regimen.

Characteristics and treatment outcomes of newly diagnosed epilepsy in older people: A 30-year longitudinal cohort study.

OBJECTIVES: To describe the clinical characteristics and evaluate the long-term treatment outcomes in older people with newly diagnosed epilepsy over the past 30 years. METHODS: We included patients newly diagnosed with epilepsy and commenced on antiseizure medications (ASMs) at age 65 years or older between July 1982 and October 2012 at the Western infirmary in Glasgow, Scotland. They were followed up until April 2016 or death. Seizure freedom was defined as no seizure for at least 1 year on unchanged medication at the last follow-up. RESULTS: A total of 201 patients (median age 73 years, 59% male) were included. The median duration from initial seizure to starting treatment was 8 months (interquartile range: 3.0-24.0 months); 42.2% (85/201) patients had more than five seizures before commencing treatment. Brain imaging showed potentially epileptogenic lesions in 19.7% (38/193) of patients and other abnormalities in 56.5% (109/193); 78.6% patients (158/201) were seizure-free at the last follow-up, of whom 94.9% were taking monotherapy. Concomitant aspirin use (n = 80) was associated with a lower probability of being seizure-free (relative risk 0.82, 95% confidence interval 0.70-0.97; P = .02). The use of second-generation ASMs as the initial monotherapy increased from 31.5% (23/73) before 2000 to 70.3% (90/128, P < .001) from 2000 onward. However, the seizure freedom rates (67.1% vs 55.5%; P = .35) and intolerable adverse-effect rates (16.4% vs 19.5%; P = .45) did not show any significant difference. SIGNIFICANCE: There was often a long interval between seizure onset and the initiation of treatment in older people with new-onset epilepsy, although the majority responded well to ASM treatment. Brain imaging showed a high rate of abnormalities. Despite the increased use of second-generation ASMs, treatment outcomes in later-onset epilepsy have not improved over time. The possible effect of aspirin on treatment response warrants further investigation.

Tolerability of Antiseizure Medications in Individuals With Newly Diagnosed Epilepsy.

Importance: Tolerability is a key determinant of the effectiveness of epilepsy treatment. It is important to evaluate whether the overall tolerability has improved. Objective: To identify factors associated with poor tolerability of antiseizure medications (ASMs) and examine temporal changes in tolerability. Design, Setting, and Participants: This was a longitudinal cohort study at a specialist clinic in Glasgow, Scotland. Patients with newly diagnosed and treated epilepsy between July 1982 and October 2012 were included from 2282 eligible individuals. They were followed up until April 2016 or death. Data analysis was completed in August 2019. Exposures: Antiseizure medications. Main Outcomes and Measures: Univariable and multivariable survival analyses were performed to examine associations between potential risk factors and development of intolerable adverse effects (AEs). Intolerable AE rates of the ASMs as the initial monotherapy were compared between 3 epochs (July 1982-June 1992, July 1992-June 2002, and July 2002-April 2016). Results: Of 1795 patients, 969 (54.0%) were male, and the median (interquartile range) age was 33 (21-50) years. A total of 3241 ASMs were prescribed during the period, of which 504 (15.6%) were discontinued within 6 months owing to intolerable AEs. Children younger than 18 years had lower intolerable AE rates than adults (vs aged 18-64 years: adjusted hazard ratio [aHR], 1.58; 95% CI, 1.07-2.32; vs aged ≥65 years: aHR, 1.90; 95% CI, 1.19-3.02) while female individuals (aHR, 1.60; 95% CI, 1.30-1.96) and those who had more than 5 pretreatment seizures (aHR, 1.24; 95% CI, 1.03-1.49) were associated with having higher risk. For each ASM trial, the risk of intolerable AEs increased with the number of previous drug withdrawals due to AEs (aHR, 1.18; 95% CI, 1.09-1.28) and the number of concomitant ASMs (aHR, 1.31; 95% CI, 1.04-1.64). The proportion of second-generation ASMs prescribed as the initial monotherapy increased from 22.3% (33 of 148) in the first epoch to 68.7% (645 of 939) in the last (P < .001). Although differences in intolerable AE rates and types of AEs were found between the ASMs, there was no difference in the overall intolerable AEs rates to the initial monotherapy across the 3 epochs (first: 10.1% [15 of 148]; second: 13.8% [98 of 708]; third: 14.0% [131 of 939]; P = .41). Conclusions and Relevance: In this cohort study, the increased use of the second-generation ASMs had not improved overall treatment tolerability. Greater effort to improve tolerability in ASM development is needed.