Treatment-emergent adverse events and antiseizure medication actual drug load.

OBJECTIVE: The correlation between treatment-emergent adverse events (TEAE) and antiseizure medication (ASM) drug load is a controversial topic. Previous studies used daily defined dosage (DDD) to measure drug load. We aim to assess if ASM adjusted to body weight and plasma levels were associated with TEAE. METHODS: We analyzed clinical visits of a trial on therapeutic drug monitoring in outpatients with epilepsy. TEAE, treatment, and its changes, as well as ASM plasma levels, were recorded at each visit. Each medication level was stratified according to its position in relation to its proposed reference range (below, in the lower half, upper half, or above). RESULTS: We analyzed 424 visits (151 participants). Treatment-emergent adverse events were reported in 84 (20%) visits. There was no significant difference when comparing visits with TEAE with those without TEAE in terms of ASM drug load (calculated with DDD), corrected for body weight, their changes since the last visit, as well as summed plasma levels compared to reference ranges. SIGNIFICANCE: Actual drug load seems not to represent a major determinant of TEAE recorded during routine visits, even when accounting thoroughly for the patient's exposure to the treatment. The use of structured questionnaires and neuropsychometric tests may assess more accurately the potential consequences of drug loads.

Therapeutic drug monitoring of newer generation antiseizure medications at the point of treatment failure.

PURPOSE: The benefit of therapeutic drug monitoring (TDM) of newer generation antiseizure medications (ASM) has been little studied. A recent randomized study suggested that TDM at each medical visit did not bring a significant benefit, but the study did not investigate TDM in cases of treatment failure. Accordingly, we realized a post hoc analysis of this trial. METHODS: We analyzed 282 TDMs in 136 patients. We compared TDM performed at visits after treatment failure versus without treatment failure, reporting the proportion of drug levels out of range and the prescriber's adherence to dosage recommendations according to measured drug levels. RESULTS: There was no statistical difference in terms of proportion of out of range plasma drug levels (47% vs 50%, p = 0.7) or adherence of prescribers to the clinical pharmacologists' dosage recommendations (21% vs 30%, p = 0.6) between visits after treatment failure and visits without treatment failure, respectively. Knowledge of prior drug levels did not modify the results. CONCLUSION: Systematic TDM at appointments following treatment failure showed similar results to TDM at visits without treatment failure. The prescribers' adherence with dosage recommendations was low in both cases. It is not clear whether better prescriber adherence would improve patient outcome. Furthermore, the ability to detect poor patient compliance is limited in a planned outpatient appointment. The study setting does not reflect on the general usefulness of TDM.

Seizure freedom and plasma levels of newer generation antiseizure medications.

OBJECTIVES: Contrary to older antiseizure medications (ASM), correlation between plasma levels and seizure freedom is not well defined for newer generation ASM. We assessed correlations between efficacy and newer generation ASM plasma levels in patients with epilepsy. MATERIALS AND METHODS: Plasma medication levels were measured over two years in consecutive patients taking lamotrigine, levetiracetam, oxcarbazepine, topiramate, zonisamide, lacosamide, perampanel or pregabalin. Seizure freedom was defined as three times the longest inter-seizure pre-treatment interval, or at least one year. Each medication level was stratified according to its position in relation to its proposed reference range (below or in lower half vs upper half or above). RESULTS: 168 patients on stable therapy were included. ASM plasma levels of seizure-free patients were lower than those with ongoing seizures; 45/48 (93.7%) were in the lower half or below the reference ranges, compared to 86/106 (81.1%; p = .004). Lamotrigine plasma levels were significantly lower in seizure-free patients (median 2.4 mg/L range 0.4-6.5 mg/L, none above 6.5 mg/L) compared with those with ongoing seizures (5 mg/L, 0.5-14.2 mg/L; p < .0001). Levetiracetam showed similar results (7.2 mg/L, 1.6-15.1 mg/L; none above 15.1 mg/L in seizure-free patients vs 16.4 mg/L, 0.6-47.7 mg/L; p = .005). Demographics, epilepsy type and polytherapy did not influence the results. CONCLUSIONS: Efficacy of newer generation ASMs seems to be reached at the lower part or at times even below the reference ranges in drug responsive patients; this could inform regarding titrations of these treatments.

Therapeutic Drug Monitoring of Newer Antiepileptic Drugs: A Randomized Trial for Dosage Adjustment.

OBJECTIVE: Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) is widely established for older generation AEDs, whereas there is limited evidence about newer AEDs. Our aim is to assess the benefit of TDM of newer generation AEDs in epilepsy. METHODS: We performed a randomized, controlled trial comparing systematic with rescue TDM of lamotrigine, levetiracetam, oxcarbazepine, topiramate, brivaracetam, zonisamide, or pregabalin. Participants were adults with epilepsy, in whom treatment with newer generation AEDs was initiated or needed adjustment. In the systematic TDM arm, AED plasma levels were available at each appointment, whereas in the rescue TDM arm, levels were known only if a study endpoint was reached (inefficacy or adverse events). The primary outcome was the proportion of participants followed 1 year without reaching one of the predefined endpoints. RESULTS: A total of 151 participants were enrolled; global retention in the study was similar in both arms (56% overall, 58% in the systematic, and 53% in the rescue TDM arm, p = 0.6, Cox regression). There was no difference in terms of outcome regarding treatment efficacy or tolerability. Partial adherence of clinicians to TDM (adjusting or not AED dosage based on blood levels) did not explain this lack of benefit. INTERPRETATION: This study provides class A evidence that systematic drug level monitoring of newer generation AEDs does not bring tangible benefits in the management of patients with epilepsy. Poor correlation between clinical effects and drug levels likely accounts for this finding. However, TDM is useful in several situations, such as pregnancy, as well as when there are compliance issues. ANN NEUROL 2020;87:22-29.

Closed-loop Neuropharmacology for Epilepsy: Distant Dream or Future Reality?

Epilepsy is considered the most frequent severe neurological condition but most patients treated with medication become seizure free. The management of treatment, however, is highly empirical, mainly relying on observation. A closed-loop therapy for epilepsy would be very valuable for more efficient treatment regimens. Here we discuss monitoring treatment (therapeutic drug monitoring) and the potential developments in this field, as well as providing a review of potential biomarkers that could be used to monitor the disease activity. Finally, we consider the pharmacogenetic input in epilepsy treatment.

Intravenous brivaracetam in status epilepticus: Correlation between loading dose, plasma levels and clinical response.

Brivaracetam is available in intravenous formulation, and its favourable pharmacokinetic profile makes it a promising agent in the treatment of status epilepticus (SE). Its availability as an intravenous formulation and its favourable pharmacokinetic profile make it a promising agent in the treatment of status epilepticus. Our aim was to assess the correlation between BRV exposure and clinical response. We retrospectively studied all consecutive SE patients treated with BRV in our centre from September 2016 to March 2018. Correlations between loading doses, plasma concentrations, extrapolated exposures (approach based on a population pharmacokinetics model) and the clinical response (defined as BRV being able to resolve SE without the need of further treatment), were analysed. Among 14 patients, 7 (50%) responded to BRV. Responders received significantly greater median loading dosage per body weight (3.3 mg/kg) compared to non-responders (1.5 mg/kg) (p = 0.02); no responders had loading doses below 1.9 mg/kg. There was a significant correlation of the clinical response with calculated exposure parameters, whereas measured BRV concentrations did not. BRV doses higher than 1.9 mg/kg are associated with greater probabilities of response in SE; consequently, a minimum dose of 2 mg/kg seems advisable in treatment of SE. It is unclear whether increasing further BRV loading doses would provide any additional benefit. BRV concentrations performed outside the frame of a standardised protocol merely ascertain BRV administration. This study is however limited by its small sample size.

Suicide in primary headaches in 48 countries: A physician-survey based study.

Aim To investigate the relationship between primary headache types and accomplished or attempted suicide in countries from all world regions. Methods Data were obtained using a questionnaire about suicide due to headache in a face-to-face interview with 203 physicians with expertise in headaches. They came from 48 countries, and from all continents. Results Primary headaches cause one suicide per 1,000,000 population each year (1% of the suicide rate due to all causes). Cluster headache and migraines account for 70-80% of them. Suicide attempts are 10 times more frequent than accomplished suicides. Cluster headache poses more risk than migraine. This risk is not often acknowledged, and is increased if there is previous psychiatric history. More than half of the physicians interviewed think it could be reduced with a more aggressive treatment of headaches. Conclusions Cluster headache and migraine are not always benign, and are the cause of the majority of suicides due to headache.

Lower Cranial Nerves Paralysis Following Prone-Position Mechanical Ventilation.

OBJECTIVE: To communicate a complication of prone-position ventilation. DATA SOURCES: Case history. STUDY SELECTION: Case report. DATA EXTRACTION AND DATA SYNTHESIS: Clinical information from medical record. CONCLUSIONS: This is a very infrequent cause of dysphagia following prone-position ventilation.

Early Lance-Adams syndrome after cardiac arrest: Prevalence, time to return to awareness, and outcome in a large cohort.

INTRODUCTION: Early myoclonus after cardiac arrest (CA) is traditionally viewed as a poor prognostic sign (status myoclonus). However, some patients may present early Lance-Adams syndrome (LAS): under appropriate treatment, they can reach a satisfactory functional outcome. Our aim was to describe their profile, focusing on pharmacologic management in the ICU, time to return of awareness, and long-term prognosis. METHODS: Adults with early LAS (defined as generalized myoclonus within 96h, with epileptiform EEG within 48h after CA) were retrospectively identified in our CA registry between 2006 and 2016. Functional outcome was assessed through cerebral performance categories (CPC) at 3 months, CPC 1-2 defined good outcome. RESULTS: Among 458 consecutive patients, 7 (1.5%) developed early LAS (4 women, median age 59 years). Within 72h after CA, in normothemia and off sedation, all showed preserved brainstem reflexes and localized pain. All patients were initially treated with valproate, levetiracetam and clonazepam; additional agents, including propofol and midazolam, were prescribed in the majority. First signs of awareness occurred after 3-23 days (median 11.8); 3/7 reached a good outcome at 3 months. CONCLUSION: Early after CA, myoclonus together with a reactive, epileptiform EEG, preserved evoked potentials and brainstem reflexes suggests LAS. This condition was managed with a combination of highly dosed, large spectrum antiepileptic agents including propofol and midazolam. Even if awakening was at times delayed, good outcome occurred in a substantial proportion of patients.