Multiple AED Use Lowers Risk of SUDEP, Generalized Tonic-Clonic Seizures

Torbjorn Tomson, MD, PhD

A nationwide case-control study revealed that intensified antiepileptic drug (AED) treatment, especially with 3 or more, may be the most effective treatment strategy for patients with poorly controlled generalized tonic-clonic seizures (GTCS) in the effort to reduce sudden death in epilepsy (SUDEP) risk. Results also suggest that comedication with statins may reduce risks as well.

Senior author Torbjorn Tomson, MD, PhD, professor of neurology and epileptology, Karolinska Institute, in Sweden, and colleagues found that polytherapy, especially taking 3 or more AEDs was associated with a substantially reduced risk of SUDEP (odds ratio [OR], 0.31; 95% CI, 0.14–0.67).

In an effort to test the hypothesis that AEDs, mono- and polytherapy, adherence, antidepressants, neuroleptics, beta-blockers, and statins are associated with SUDEP risk, investigators included 255 cases of SUDEP and 1148 matched controls in their analysis. They used ORs with 95% confidence intervals adjusted for potential risk factors including type of epilepsy, living conditions, comorbidity and frequency of GTCS to assess the association between SUDEP and medications.

The use of statins was also associated with a reduced risk of SUDEP, whereas there was no reduced risk with selective serotonin rebuke inhibitors (SSRIs) or other antidepressants, neuroleptics, or beta-blockers.

“Given the conflicting results with some previous reports, our data on polytherapy should be interpreted cautiously, although adding an AED to existing baseline AED treatment of patients with refractory seizures has been associated with a reduced SUDEP risk in the context of randomized controlled trials,” Tomson and colleagues concluded.

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The investigators noted that although the numbers were small in the analyses of specific monotherapies, levetiracetam was the only AED which was associated with a significantly lower SUDEP risk when compared to no AED treatment (OR, 0.10; 95% CI, 0.03–0.61). The combination of lamotrigine (OR, 0.55; 95% CI, 0.31–0.97), valproic acid (OR, 0.53; 95% CI, 0.29–0.98), and levetiracetam (OR, 0.49; 95% CI, 0.27–0.90) were associated with reduced risk.

Notably, levetiracetam was the only AED that did not follow the trend towards lower risk when used in polytherapy compared with monotherapy. None of the AEDs used in the study led to the increased risk of SUDEP. This pattern was also observed in the sensitivity analysis, which included only cases and controls with a history of GTCS.

A separate analysis on SUDEP risk was calculated in relation to time since last dispensing of AEDs as a measure of persistence or adherence to AED medication. The analysis was restricted to individuals for which medical record stated that AEDs were prescribed during the last year of observation. After using 0 to 90 days as reference, individuals with 181 to 365 days since last dispensing had an OR of 2.96 (95% CI, 0.46–18.86). Additionally, nonadherence was associated with an OR of 2.75 (95% CI, 1.58–4.78).

Taking no AED was more common among controls (23.1%) than cases (18.4%) and the most frequently used AED overall was carbamazepine (33.3%) among cases and lamotrigine (24.5%) among the controls. Cases by AED treatment had longer duration of epilepsy, and were more likely to have history of GTCS, presence of GTCS and nocturnal GTCS during the preceding year, intellectual disability, a history of substance abuse, and were less likely to share a bedroom compared to controls.

The investigators concluded, “Our data furthermore indicate that AEDs may lower the risk of SUDEP not just by reducing the frequency of GTCS and that treatment with statins may be protective. Efforts should also be made to enhance medication adherence as this is likely to reduce SUDEP risks.”

REFERENCE

Sveinsson O, Andersson T, Mattsson P, Carlsson S, Tomson T. Pharmacological treatment and SUDEP risk: A nationwide population-based case-control study. Neurology. Published online September 23, 2020. doi: 10.1212/WNL.0000000000010874