ucb-34714 and Status-Epilepticus

Status epilepticus (SE) is an emergent neurologic condition that carries a high risk of morbidity and mortality. Intravenous brivaracetam (IV BRV) may be an alternative anticonvulsant against status epilepticus, although the sparseness of controlled studies on the topic limits its recommendation for this indication.. This systematic review aimed to determine the efficacy and safety of IV BRV in the treatment of status epilepticus.. A comprehensive literature search was conducted until December 2019 through several electronic databases (PubMed, Google Scholar, Scopus, OpenGrey, ScienceDirect, HERDIN, Epistemonikos, CENTRAL, ClinicalTrials.gov) to identify relevant studies. Studies that involved adult patients with SE who were given IV BRV were considered for inclusion in this review.. From a total of 34 studies identified, 5 uncontrolled studies with 77 patients were included in this review. Thirty-seven out of 77 patients (48%) with SE responded to IV BRV. Reported time to seizure cessation may be immediate from a few minutes to several hours after IV BRV treatment. Patients manifested with significant disability on Glasgow outcome scale (Median: 3) and modified Rankin scale (Mode: 5). Six patients [somnolence (5), worsening seizures (1)] had treatment emergent adverse events.. Limited evidence from 5 uncontrolled studies involving a limited number of patients suggests that IV BRV may be efficacious and safe in terminating seizures among patients with SE or refractory SE. Further studies employing either prospective, controlled trials or registry-based study designs are essential to determine the definitive role of IV BRV in patients with SE.

Topics: Adult; Anticonvulsants; Humans; Prospective Studies; Pyrrolidinones; Status Epilepticus; Treatment Outcome

The goal of pharmacologic therapy with antiseizure medications (ASMs) is to achieve a seizure-free state with minimal side effects. About one third of patients treated with available ASMs continue to experience uncontrolled seizures. There is still need for new ASMs with enhanced effectiveness and tolerability.. The present manuscript is based on an extensive Internet and PubMed search from 1999 to 2020. It is focused on the clinical and pharmacological properties of brivaracetam (BRV) in the treatment of epilepsy.. BRV is approved as add-on or monotherapy (in US) for the treatment of focal-onset seizures with or without secondary generalization. BRV is a high affinity synaptic vesicle glycoprotein 2A ligand, with 15-30-fold higher affinity than levetiracetam. The selectivity of BRV may be associated with fewer clinical adverse effects. BRV shares many of the pharmacokinetic characteristics of an ideal ASMs. Additionally, BRV has a low potential for clinically relevant drug-drug interactions. Its pharmacokinetic profile makes BRV a promising agent for the treatment of status epilepticus (SE). Although BRV is not approved for the treatment of SE, it has demonstrated promising preliminary results. Further studies are needed to explore the efficacy and tolerability of BRV in SE.

Topics: Animals; Anticonvulsants; Drug Interactions; Epilepsies, Partial; Humans; Pyrrolidinones; Status Epilepticus

Topics: Anticonvulsants; Clinical Trials as Topic; Epilepsy; Half-Life; Humans; Nitriles; Pyridones; Pyrrolidinones; Receptors, AMPA; Status Epilepticus; Treatment Outcome

Brivaracetam is a high-affinity synaptic vesicle glycoprotein 2A ligand with high brain permeability and rapid onset of action. These properties make brivaracetam potentially an ideal compound in the emergency setting.. The objective of our study was to review the evidence about the clinical efficacy and tolerability of intravenous brivaracetam in the treatment of status epilepticus.. We systematically searched MEDLINE, EMBASE, Google Scholar, ClinicalTrials.gov, and conference proceedings to identify studies evaluating intravenous brivaracetam as treatment for status epilepticus of any type in patients of any age. Searches were conducted on 3 December, 2018.. Seven studies were included (37 patients; aged 22-85 years; 21 were female). The type and etiology of status epilepticus varied across studies. The number of drugs used prior to brivaracetam to treat status epilepticus ranged from 1 to 8. The time from status epilepticus onset to brivaracetam administration ranged from 0.5 h to 105 days. The initial brivaracetam dose ranged from 50 to 400 mg. In case series, the proportion of patients achieving clinical status epilepticus cessation when brivaracetam was administered as the last drug varied from 27 to 50%; in case reports, all patients had status epilepticus cessation. The time from brivaracetam administration to status epilepticus cessation ranged from 15 min to 94 h. No serious adverse effects were reported.. The available data suggested that brivaracetam can be a safe treatment option in patients with status epilepticus. The current evidence is however hampered by several confounding factors, and controlled studies are warranted to define the actual benefit of brivaracetam for the treatment of status epilepticus.

Topics: Administration, Intravenous; Animals; Anticonvulsants; Humans; Pyrrolidinones; Status Epilepticus

Topics: Acetamides; Animals; Anticonvulsants; Carbamates; Disease Models, Animal; Fructose; Humans; Lacosamide; Pyrroles; Pyrrolidinones; Rats; Receptors, AMPA; Status Epilepticus; Tetrahydroisoquinolines; Topiramate; Treatment Outcome

First, a short history is given of the use of the EEG as a biomarker of efficacy in anti-seizure medication (ASM) development. The generalized epileptiform EEG response to Intermittent Photic Stimulation (IPS), the photoparoxysmal EEG response or PPR, in particular, is a reliable reproducible measure since the 1950s. Over time, a "Photosensitivity Model", testing within the same patients the impact of potential new oral ASMs, along with dose-ranging data, on PPRs, has been developed successfully. The classical Photosensitivity Model consists of IPS and blood sampling for ASM measurement performed hourly between 8 AM and 5 PM over three consecutive days. This single-blind, placebo-controlled, pharmacokinetic-pharmacodynamic (PK/PD) Model is now commonly utilized as a Proof-of-Concept Phase 2a trial. For Generalized Tonic-Clonic Status Epilepticus (GTCSE), it is especially relevant to know the time for CNS entry and effect minutes after i.v. ASM treatment, since "time is brain". We, therefore, adapted successfully the Model to a time-efficient Model with the determination of photosensitivity ranges in minutes after equivalent doses of iv brivaracetam (BRV) and levetiracetam (LEV). This modified design allows one to monitor the time to CNS effect (i.e., PPR elimination) of a quickly-acting FDA-approved ASM given i.v., a crucial element in status epilepticus treatment. This paper was presented at the 8th London-Innsbruck Colloqium on Status Epilepticus and Acute Seizures held in September 2022.

Topics: Anticonvulsants; Humans; Levetiracetam; Photosensitivity Disorders; Pyrrolidinones; Single-Blind Method; Status Epilepticus; Treatment Outcome

The pharmacokinetics of brivaracetam (BRV), added to its effectiveness observed in animal models of status epilepticus (SE), makes this drug attractive for use in emergency situations. Our objective was to evaluate the use of intravenous BRV in a multicenter study.. A retrospective multicenter registry of SE cases treated with BRV was created. These patients were evaluated between January and December 2018 at seven hospitals in Spain. Demographic variables, SE characteristics, concomitant drugs, loading doses, and response to treatment were collected.. Forty-three patients were registered. The mean age was 56 ± 23.1 years, 51.2% were male, 29 had previous epilepsy, 24 (55.8%) had prominent motor symptoms, and 19 had nonconvulsive symptoms. Regarding the etiology, 19 (44.2%) were considered acute symptomatic, 16 (17.2%) remote symptomatic, four (9.3%) progressive symptomatic, and four (9.3%) cryptogenic. Regarding concomitant antiepileptic drugs (AEDs), 17 had previously received levetiracetam (LEV). In 14 patients, BRV was used early (first or second AED). The median loading dose was 100 mg (range = 50-400), and the weight-adjusted dose was 1.8 mg/kg (range = 0.4-7.3). BRV was effective in 54% (n = 23), and a response was observed in <6 hours in 13 patients. We observed a tendency for it to be more effective when administered earlier (P = 0.09), but there were no differences regarding SE type and the concomitant use of LEV. In those with the fastest responses, we observed that both the total administered dose (300 mg vs 100 mg, P = 0.008) and the weight-adjusted dose (3.85 mg vs 1.43 mg, P = 0.006) were significantly higher. The receiver operating characteristic curve showed that the best cutoff point for a faster response was 1.82 mg/kg.. BRV is useful for the treatment of SE, even when patients are already being treated with LEV. The response rate seems higher when it is administered earlier and at higher doses (>1.82 mg/kg).

Topics: Anticonvulsants; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Pyrrolidinones; Registries; Retrospective Studies; Status Epilepticus

Nearly half of people with epilepsy (PWE) are expected to develop seizure clusters (SC), with the subsequent risk of hospitalization. The aim of the present study was to evaluate the use, effectiveness and safety of intravenous (IV) brivaracetam (BRV) in the treatment of SC.. Retrospective multicentric study of patients with SC (≥ 2 seizures/24 h) who received IV BRV. Data collection occurred from January 2019 to April 2022 in 25 Italian neurology units. Primary efficacy outcome was seizure freedom up to 24 h from BRV administration. We also evaluated the risk of evolution into Status Epilepticus (SE) at 6, 12 and 24 h after treatment initiation. A Cox regression model was used to identify outcome predictors.. 97 patients were included (mean age 62 years), 74 (76%) of whom had a history of epilepsy (with drug resistant seizures in 49% of cases). BRV was administered as first line treatment in 16% of the episodes, while it was used as first or second drug after benzodiazepines failure in 49% and 35% of episodes, respectively. On the one hand, 58% patients were seizure free at 24 h after BRV administration and no other rescue medications were used in 75 out of 97 cases (77%) On the other hand, SC evolved into SE in 17% of cases. A higher probability of seizure relapse and/or evolution into SE was observed in patients without a prior history of epilepsy (HR 2.0; 95% CI 1.03 - 4.1) and in case of BRV administration as second/third line drug (HR 3.2; 95% CI 1.1 - 9.7). No severe treatment emergent adverse events were observed.. In our cohort, IV BRV resulted to be well tolerated for the treatment of SC and it could be considered as a treatment option, particularly in case of in-hospital onset. However, the underlying etiology seems to be the main outcome predictor.

Topics: Anticonvulsants; Drug Therapy, Combination; Epilepsy; Epilepsy, Generalized; Humans; Middle Aged; Pyrrolidinones; Retrospective Studies; Status Epilepticus; Treatment Outcome

Urgent seizures are a medical emergency for which new therapies are still needed. This study evaluated the use of intravenous brivaracetam (IV-BRV) in an emergency setting in clinical practice.. BRIV-IV was a retrospective, multicenter, observational study. It included patients ≥18 years old who were diagnosed with urgent seizures (including status epilepticus (SE), acute repetitive seizures, and high-risk seizures) and who were treated with IV-BRV according to clinical practice in 14 hospital centers. Information was extracted from clinical charts and included in an electronic database. Primary effectiveness endpoints included the rate of IV-BRV responder patients, the rate of patients with a sustained response without seizure relapse in 12 h, and the time between IV-BRV administration and clinical response. Primary safety endpoints were comprised the percentage of patients with adverse events and those with adverse events leading to discontinuation.. A total of 156 patients were included in this study. The mean age was 57.7 ± 21.5 years old with a prior diagnosis of epilepsy for 57.1% of patients. The most frequent etiologies were brain tumor-related (18.1%) and vascular (11.2%) epilepsy. SE was diagnosed in 55.3% of patients. The median time from urgent seizure onset to IV treatment administration was 60.0 min (range: 15.0-360.0), and the median time from IV treatment to IV-BRV was 90.0 min (range: 30.0-2400.0). Regarding dosage, the mean bolus infusion was 163.0 ± 73.0 mg and the mean daily dosage was 195.0 ± 87.0 mg. A total of 77.6% of patients responded to IV-BRV (66.3% with SE vs. 91% other urgent seizures) with a median response time of 30.0 min (range: 10.0-60.0). A sustained response was achieved in 62.8% of patients. However, adverse events were reported in 14.7%, which were predominantly somnolence and fatigue, with 4.5% leading to discontinuation. Eighty-six percent of patients were discharged with oral brivaracetam.. IV-BRV in emergency settings was effective, and tolerability was good for most patients. However, a larger series is needed to confirm the outcomes.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Drug Therapy, Combination; Epilepsy; Humans; Middle Aged; Neoplasm Recurrence, Local; Pyrrolidinones; Retrospective Studies; Seizures; Status Epilepticus; Treatment Outcome

Status epilepticus (SE) is defined by abnormally prolonged seizures that may lead to brain damage and death. Our aim was to evaluate the efficacy and tolerability (effectiveness) of intravenous brivaracetam (BRV) as a second-line treatment.. Twenty-one patients (median age 68 years ± 17.28) were prospectively recruited between June 2019 and December 2022. Patients were treated with BRV (50-200 mg) as a second-line add-on therapy for SE. We evaluated the response of SE to the administration of BRV in terms of SE termination and recurrence of epileptic seizures at 6, 12, and 24 h, also monitoring safety. The first-line therapy was represented by intravenous benzodiazepines (mainly diazepam).. Almost a quarter of patients had generalized seizures, whereas the vast majority (76.2%) presented focal seizures. In 52.4% of patients, the underlying cause was cerebrovascular. Fourteen (66.7%) patients displayed a good early response in the subsequent 6 h. At 12 and 24 h, 8 (38%) and 11 (52.4%) patients, respectively, did not present seizures.. The present study highlights the potential of BRV when used as an early add-on therapy in SE, further confirming its good safety profile.

Topics: Aged; Anticonvulsants; Drug Therapy, Combination; Humans; Pyrrolidinones; Seizures; Status Epilepticus; Treatment Outcome

to evaluate the use, effectiveness, and adverse events of intravenous brivaracetam (BRV) in status epilepticus (SE).. a retrospective multicentric study involving 24 Italian neurology units was performed from March 2018 to June 2020. A shared case report form was used across participating centres to limit biases of retrospective data collection. Diagnosis and classification of SE followed the 2015 ILAE proposal. We considered a trial with BRV a success when it was the last administered drug prior the clinical and/or EEG resolution of seizures, and the SE did not recur during hospital observation. In addition, we considered cases with early response, defined as SE resolved within 6 h after BRV administration.. 56 patients were included (mean age 62 years; 57 % male). A previous diagnosis of epilepsy was present in 21 (38 %). Regarding SE etiology classification 46 % were acute symptomatic, 18 % remote and 16 % progressive symptomatic. SE episodes with prominent motor features were the majority (80 %). BRV was administered as first drug after benzodiazepine failure in 21 % episodes, while it was used as the second or the third (or more) drug in the 38 % and 38 % of episodes respectively. The median loading dose was 100 mg (range 50-300 mg). BRV was effective in 32 cases (57 %). An early response was documented in 22 patients (39 % of the whole sample). The use of the BRV within 6 h from SE onset was independently associated to an early SE resolution (OR 32; 95 % CI 3.39-202; p = 0.002). No severe treatment emergent adverse events were observed.. BRV proved to be useful and safe for the treatment of SE. Time to seizures resolution appears shorter when it is administered in the early phases of SE.

Topics: Anticonvulsants; Female; Humans; Italy; Male; Middle Aged; Pyrrolidinones; Retrospective Studies; Status Epilepticus; Treatment Outcome

We present a case of a woman affected by nonconvulsive status epilepticus (NCSE) caused by cerebral hyperperfusion syndrome (CHS) after carotid endarterectomy (CEA) who was successfully treated with Brivaracetam (BRV) administered via nasogastric tube (NGT).. An 82-years old woman was referred for increasing blood pressure, severe headache and two focal motor seizures on postoperative day four after right CEA. CT scan showed edema of the right hemisphere with a midline shift of 5 mm. The patient underwent daily Electroencephalography (EEG) monitoring which showed continuous epileptiform discharges over the right hemisphere, compatible with a diagnosis of status epilepticus. She was treated with standard antiepileptic drugs (Phenytoin, Lacosamide and Levetiracetam iv) without clinical response. A therapeutic trial with BRV 200mg administered via nasogastric tube (NGT) was tried which resulted in substantial clinical benefit.. The administration of new antiepileptic drugs (AEDs) such as BRV may result in significant clinical improvement in refractory cases of status epilepticus. The enteral administration of AEDs via NGT should always be considered for refractory cases of status epilepticus when standard iv treatment has failed or is not possible.

Topics: Aged, 80 and over; Electroencephalography; Female; Humans; Phenytoin; Pyrrolidinones; Status Epilepticus

Topics: Anticonvulsants; Electroencephalography; Humans; Pyrrolidinones; Status Epilepticus; Treatment Outcome; Young Adult

Diagnosis and management of status epilepticus (SE), including non-convulsive status epilepticus (NCSE), is challenging, with a reported 30%-50% of epilepticus patients not responding to available antiseizure medications (ASMs). Injectable benzodiazepines, fosphenytoin, valproate, levetiracetam, lacosamide and phenobarbital are commonly used for treating SE. Brivaracetam, a new ASM, with higher affinity and greater selectivity for the synaptic vesicle glycoprotein 2A than levetiracetam, has been approved as monotherapy or adjunct for treatment of focal onset seizures. Brivaracetam may have a role in the management of SE. However, limited data exist on brivaracetam's efficacy in SE. We describe a patient case with focal NCSE refractory to levetiracetam, fosphenytoin, lacosamide and valproate who demonstrated clinical and electrographic improvement on continuous electroencephalography monitoring after brivaracetam administration.

Topics: Administration, Intravenous; Aged; Anticonvulsants; Dose-Response Relationship, Drug; Electroencephalography; Female; Follow-Up Studies; Humans; Monitoring, Physiologic; Pyrrolidinones; Status Epilepticus

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.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anticonvulsants; Critical Care; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Pyrrolidinones; Retrospective Studies; Status Epilepticus; Treatment Outcome

Brivaracetam (BRV) is a high-affinity synaptic vesicle glycoprotein 2A ligand that is structurally related to levetiracetam (LEV). Compared to LEV, its affinity to the ligand is >10%-30% higher. Due to its more lipophilic characteristics, it might have a quicker penetration across the blood-brain barrier and potentially also a stronger anticonvulsant effect. Thus, we aimed to explore its usefulness in the treatment of status epilepticus (SE). We retrospectively assessed treatment response and adverse events in adjunctive treatment with intravenous BRV in patients with SE from January 2016 to July 2017 at our institution. Seven patients aged median 68 years (range = 29-79) were treated with intravenous BRV. Three patients had SE with coma and four without. SE arose de novo in two patients; etiology was remote symptomatic in four patients and progressive symptomatic in one patient. The most frequent etiology was remote vascular in two patients. BRV was administered after median four antiepileptic drugs (range = 2-11). Time of treatment initiation ranged from 0.5 hours to 105 days (median = 10.5 hours). Immediate clinical and electrophysiological improvement was observed in two patients (29%). Median loading dose was 100 mg intravenously over 15 minutes (range = 50-200 mg), titrated up to a median dose of 100 mg/d (range = 100-300). Median Glasgow Outcome Scale score was 3 (range = 3-5), with an improvement in 86% of patients compared to admission. We observed no adverse events regarding cardiorespiratory function. BRV might have potential as a novel antiepileptic drug in early stages of SE. Its potential may lie its ability to cross the blood-brain barrier more quickly than LEV and its favorable safety profile. Prospective studies for the use of BRV in SE are required.

Topics: Administration, Intravenous; Adult; Aged; Anticonvulsants; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Pyrrolidinones; Retrospective Studies; Status Epilepticus; Time Factors; Treatment Outcome

We aimed to ascertain the possible use of brivaracetam (BRV) as an option for treatment of status epilepticus (SE).. A review of medical records was carried out to detect BRV administration in SE patients treated in Frankfurt and Greifswald during the period February 2016 to January 2017. The primary outcome question concerned SE resolution after BRV initiation.. During that period, BRV was started with eleven adult patients with SE. Five of these were female, and the median age was 64 (interquartile range [IQR] 21years). The median SE duration before BRV initiation was 5days (IQR 9days); the median number of previous anticonvulsants used was 4 (IQR 5). Initial BRV doses ranged between 50mg and 400mg (median 100mg), titrated to a daily dose of 100 to 400mg (median 200mg). There was a cessation of SE in the first 24h of BRV in three patients (27%). While taking BRV, no serious side effects were seen.. Based on these cases and previous data from animal experiments, BRV may prove useful in SE treatment, and trials would be warranted to examine BRV's efficacy in treating SE and how this efficacy might be influenced by co-administration with levetiracetam.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Anticonvulsants; Cohort Studies; Drug Resistant Epilepsy; Female; Germany; Hospitals, University; Humans; Male; Middle Aged; Pyrrolidinones; Retrospective Studies; Status Epilepticus; Treatment Outcome; Young Adult

To evaluate acute and long-term effects of intravenous brivaracetam (BRV) and BRV + diazepam (DZP) combination treatment in a rat model of self-sustaining status epilepticus (SSSE).. Rats were treated with BRV (10 mg/kg) 10 min after initiation of perforant path stimulation (PPS) as early treatment; or BRV (10-300 mg/kg), DZP (1 mg/kg), or BRV (0.3-10 mg/kg) + DZP (1 mg/kg) 10 min after the end of PPS (established SSSE). Seizure activity was recorded electrographically for 24 h posttreatment (acute effects), and for 1 week at 6-8 weeks or 12 months' posttreatment (long-term effects). All treatments were compared with control rats using one-way analysis of variance (ANOVA) and Bonferroni's test, or Kruskal--Wallis and Dunn's multiple comparison tests, when appropriate.. Treatment of established SSSE with BRV (10-300 mg/kg) resulted in dose-dependent reduction in SSSE duration and cumulative seizure time, achieving statistical significance at doses ≥100 mg/kg. Lower doses of BRV (0.3-10 mg/kg) + low-dose DZP (1 mg/kg) significantly reduced SSSE duration and number of seizures. All control rats developed spontaneous recurrent seizures (SRS) 6-8 weeks after SSSE, whereas seizure freedom was noted in 2/10, 5/10, and 6/10 rats treated with BRV 200 mg/kg, 300 mg/kg, and BRV 10 mg/kg + DZP, respectively. BRV (10-300 mg/kg) showed a dose-dependent trend toward reduction of SRS frequency, cumulative seizure time, and spike frequency, achieving statistical significance at 300 mg/kg. Combination of BRV (10 mg/kg) + DZP significantly reduced SRS frequency, cumulative seizure time, and spike frequency. In the 12-month follow-up study, BRV (0.3-10 mg/kg) + low-dose DZP markedly reduced SRS frequency, cumulative seizure time, and spike frequency, achieving statistical significance at some doses. Early treatment of SSSE with BRV 10 mg/kg significantly reduced long-term SRS frequency.. These findings support clinical evaluation of BRV for treatment of status epilepticus or acute repetitive seizures.

Topics: Animals; Anticonvulsants; Dentate Gyrus; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electrodes, Implanted; Electroencephalography; Evoked Potentials; Infusions, Intravenous; Long-Term Care; Male; Perforant Pathway; Pyrrolidinones; Rats; Rats, Wistar; Signal Processing, Computer-Assisted; Status Epilepticus