Clonazepam Loading Dose in Status Epilepticus: Is More Always Better?

BACKGROUND AND OBJECTIVES: Benzodiazepines are the first treatment line in status epilepticus (SE). Despite their well-established benefit, benzodiazepines are frequently underdosed with potential detrimental consequences. In some European countries, clonazepam (CLZ) is commonly used as the first line treatment. The aim of this study was to explore the correlation between CLZ loading doses and SE outcome. METHODS: This study included a retrospective analysis of a prospective registry in Lausanne, Switzerland (CHUV Lausanne University Hospital), including all SE episodes treated between February 2016 and February 2021. Only adults (> 16 years old) were included with CLZ used as the first treatment line. Post-anoxic SE were excluded because of significant differences in physiopathology and prognosis. Patient characteristics, SE features, the validated SE severity score (STESS), and treatment characteristics were prospectively recorded. We considered loading doses of 0.015 mg/kg or higher (following commonly recommended loading doses) as high doses. We analyzed outcome in terms of number of treatment lines after the CLZ, proportion of refractory episodes, intubation for airways protection, intubation for SE treatment, and mortality. We performed univariable analyses to investigate the association between loading doses and clinical response. A multivariable stepwise backward binary logistic regression was applied for adjusting for potential confounders. Multivariable linear regression was similarly used to analyze CLZ dose as a continuous variable. RESULTS: We collected 251 SE episodes in 225 adult patients. Median CLZ loading dose was 0.010 mg/kg. CLZ high doses were used in 21.9% of SE episodes (in 43.8% for > 80% of the high dose). Thirteen percent of patients with SE were intubated for airways control, while intubation was needed in 12.7% for SE treatment. High CLZ loading doses were independently associated with younger age (median 62 versus 68 years old, p = 0.002), lesser weight (65 kg versus 75 kg, p = 0.001) and more frequent intubation for airways protection (23% vs 11%, p = 0.013), but differing CLZ dose was not associated with any outcome parameter. CONCLUSION: CLZ high doses were more frequently used for SE treatment in younger patients with healthy weight and were more often associated with intubation for airways protection, probably as an adverse event. Varying CLZ dose did not alter outcome in SE, raising the possibility that commonly recommended doses are above what is needed, at least in some patients. Our results suggest that CLZ doses in SE may be individualized depending on the clinical setting.

Lamotrigine serum levels: Ceiling effect in people with epilepsy in remission?

BACKGROUND: Antiepileptic drug titration in epilepsy remains mostly empirical. Since in practice seizure remission may be obtained with low doses, we aimed to determine whether patients in remission have lower lamotrigine levels than those with ongoing seizures. METHODS: Retrospective comparison of the distribution of lamotrigine levels among unselected patients in remission and with ongoing seizures. Remission was defined as 3 times the longuest interseizure interval and at least one year. Only trough levels were analyzed. RESULTS: Between 2009 and 2014, we identified 93 adults, among whom 10 were in remission. Patients in remission had significantly (p=0.008) lower serum levels (median 2.3mg/L, range: 0.7-8.2) than those with ongoing seizures (median 5.4mg/L, range: 1.1-18.2). We did not find any patient in remission with levels higher than 8.2mg/L. Distribution of dosages also differed among the groups, but less significantly (median: 175 vs 300mg, p=0.03). CONCLUSION: An association between lamotrigine serum levels and seizure response can be observed. This suggests the existence of a ceiling level, above which remission is unlikely and should prompt antiepileptic medication switch rather than further up-titration of lamotrigine in drug-naïve patients with epilepsy.