Association Between Antiseizure Drug Monotherapy and Mortality for Patients With Poststroke Epilepsy

Abstract

The relationship between epilepsy and stroke is complicated. While stroke is a major cause of epilepsy after middle age, there is also evidence that the risk of stroke is increased in persons with epilepsy. The overall aim of this dissertation is to elaborate on the prognosis and treatment of epilepsy in older adults and its association to stroke. It is based on four studies which have been conducted using information from linked national registers, which offer unique opportunities to follow thousands of patients over a long period of time.The results from Papers I-II indicate that a significant proportion of all newonset seizures after middle age will herald a subsequent stroke. Using incidence data and population statistics, we estimated the 10-year risk of stroke to be between 5-20%, depending on age group. In relative terms, the risk appears to be almost two-fold (odds ratio [OR] 1.77; 95% confidence interval [95%CI] 1.65-1.89) compared with age-matched controls from the general population -and highest during the first year after seizure onset (OR 2.21; 95 % CI 1.79-2.72).The studies described in Papers III-IV examined prognostic aspects of antiseizure medication (ASM) therapy in poststroke epilepsy. Paper III found the 5-year retention rate to be highest for lamotrigine (0.75, 95%CI 0.70-0.79) and levetiracetam (0.69, 95%CI 0.63-0.74), suggesting these drugs are well tolerated in this patient group. Paper IV used a similar methodology but investigated if mortality varied with different ASMs in monotherapy. Patients treated with lamotrigine had lower mortality (hazard ratio [HR] 0.72, 95%CI 0.60-0.86) than the reference group treated with carbamazepine, while patients treated with valproic acid had higher mortality (HR 1.40, 95%CI 1.23-1.59). Treatment with levetiracetam was associated with a reduced risk of cardiovascular death compared to carbamazepine (HR 0.77, 95%CI 0.60-0.99).In conclusion, this thesis supports a tailored management approach in adults with new-onset seizures late in life, particularly in those with a history of stroke. Persons with late-onset seizures have high vascular risk, potentially warranting screening and treatment for vascular risk factors. Moreover, the association between ASM selection and mortality raises concerns about clinically relevant drug-drug or drug-disease interactions that may modify vascular risk. Overall, lamotrigine and levetiracetam seem sensible initial treatment options in this patient group.

Pharmacological aspects of antiseizure medications: From basic mechanisms to clinical considerations of drug interactions and use of therapeutic drug monitoring

“…by valproic acid‐induced thrombocytopenia or bleeding with concomitant use of phenytoin, valproic acid, or levetiracetam 55 In a nested case–control study involving 89 284 patients with atrial fibrillation and venous thromboembolism, the use of DOACs combined with phenytoin, carbamazepine, valproic acid, and levetiracetam was associated with 2.18 higher risk of stroke and systemic embolism 56 . Levetiracetam has however been associated with a lower risk of cardiovascular death associated with levetiracetam compared with carbamazepine treatment in patients with poststroke epilepsy in a population‐based setting 57 . To date, the clinical significance of DOAC interactions with mild‐to‐moderate CYP3A4/P‐gp‐inducing ASMs such as oxcarbazepine and cenobamate or enzyme‐inhibiting ASMs (e.g., cannabidiol, felbamate) is unknown.…”

“…56 Levetiracetam has however been associated with a lower risk of cardiovascular death associated with levetiracetam compared with carbamazepine treatment in patients with poststroke epilepsy in a population-based setting. 57 To date, the clinical significance of DOAC interactions with mild-to-moderate CYP3A4/P-gp-inducing ASMs such as oxcarbazepine and cenobamate or enzyme-inhibiting ASMs (e.g., cannabidiol, felbamate) is unknown. According to the relevant European Heart Rhythm Association Guide, 55 when an ASM therapy should be started in a patient treated with a DOAC (or vice versa), interdisciplinary review with the treating cardiologist, neurologist, primary care physician, and clinical pharmacist is crucial, and measurement of DOAC serum concentrations and close follow-up is advised.…”

Association Between Angiotensin Receptor Blocker Therapy and Incidence of Epilepsy in Patients With Hypertension

“…Epilepsy has been found to be closely related to stroke and dementia . In the present study’s population, a previous diagnosis of stroke or dementia was associated with the occurrence of epilepsy (HR, 1.93; 95% CI, 1.65-2.67; P < .001 for stroke and HR, 1.66; 95% CI, 1.35-1.96; P < .001 for dementia).…”

Efficacy and safety of antiseizure medication in post-stroke epilepsy

“…Also, indirect comparisons of LEV and LTG did not reveal differences in seizure freedom (odds ratio 0.86; 95% CI: 0.15.− 4.89) [10]. However, significantly lower mortality was seen with LTG monotherapy compared to therapy with CBZ [18] and overall, therapy with newer ASMs showed better seizure control and better tolerability compared with older ASMs [19].…”