Determinants of success in the use of oral levetiracetam in status epilepticus

doi:10.1016/j.yebeh.2006.01.006

Epilepsy & Behavior

Volume 8, Issue 3, May 2006, Pages 651-654

https://doi.org/10.1016/j.yebeh.2006.01.006 Get rights and content

Abstract

The use of new antiepileptic drugs for treatment of status epilepticus (SE) has not been studied systematically, particularly with respect to response predictors, the possibility of a dose–response relationship, and the efficacy of administration through a nasogastric tube. We analyzed 23 patients with SE treated with levetiracetam (LEV). The median daily dose of LEV was 2000 mg (range: 750–9000 mg). Ten patients (43%) responded; all had received LEV within 4 days after the beginning of their SE episode (P = 0.019 vs nonresponders), and were administered less than 3000 mg LEV/day (P = 0.046). No demographic or etiological variable was predictive. Among 16 patients given LEV through a nasogastric tube, administration was successful in 5; blood levels in 2 nonresponders were within or above the range 5–30 μg/mL. These data suggest that LEV may be a useful alternative in SE if administered early, even in intubated patients, and that escalating the dosage beyond 3000 mg/day will unlikely provide additional benefit.

Introduction

Status epilepticus (SE) represents an emergency neurological condition with an important clinical impact; its treatment is traditionally based on administration of older-generation antiepileptic drugs (AEDs) such as benzodiazepines, phenytoin, valproate, and phenobarbital, with the subsequent option of coma induction with an appropriate agent [1].

In this context, investigation of newer AEDs has received little attention, and no head-to-head comparisons are available to date. Topiramate has been reported to be effective in small case series of children [2] and adults [3] with SE. We recently reported the use of levetiracetam (LEV) in adults with SE [4]. This drug appears promising in this setting, especially owing to its wide spectrum of action [5], favorable pharmacokinetic profile [6], and the possibility of rapid titration.

However, to date, it is unknown whether particular subgroups of patients may be more suitable for this treatment, and whether a dose–response relationship exists. Furthermore, as for other newer AEDs, LEV bioavailability after administration through a nasogastric tube in comatose patients with impaired gastrointestinal motility has not been assessed. The objective of this observational study was to analyze the effects of LEV in adult patients with SE, including the effects after administration of LEV through a nasogastric tube.

Section snippets

Methods

We screened a retrospective SE database of two tertiary referral hospitals in Boston (Brigham & Women’s Hospital, Massachusetts General Hospital; January 2000–April 2004) [4] and a prospective SE database of consecutive patients treated for SE at our institution (July 2004–July 2005). The primary investigator (A.O.R.) had no influence on the prescription of AEDs. SE was defined in both series as ongoing seizures or seizures without recovery of consciousness or baseline clinical condition for at

Results

In the retrospective series, 8 of 68 subjects fulfilled the inclusion criteria (12%); in the prospective series, 15 of 30 were included (50%).

Among the resulting group of 23 subjects, 10 (43%) were women, mean age was 59.5 (±17.7), an acute etiology was found in 10 (43%), all had localization-related seizures, and 7 (30%) were on LEV treatment at the beginning of their SE episode. Nine subjects (39%) had refractory SE, defined as requiring coma induction according to the treating clinician; all

Discussion

Analysis of this ambispective series suggests that LEV may represent a useful alternative in SE if administered early in the course of the illness. Furthermore, it suggests that escalation of the dose beyond 3000 mg/day provides no additional benefit if a response does not occur at lower dosage.

We assume that a response within 72 hours would suggest a causal relationship, but this assumption is impossible to formally prove. As in our previous study [4], we found that a response to LEV was always

References (18)

G.L. Krauss et al.
Levetiracetam treatment of idiopathic generalized epilepsy
Seizure
(2003)
R. Atefy et al.
Nonconvulsive status epilepticus on treatment with levetiracetam
Epilepsy Behav
(2005)
R. Grant et al.
Efficacy and tolerability of 1000–4000 mg per day of levetiracetam as add-on therapy in patients with refractory epilepsy
Epilepsy Res
(2000)
D.H. Lowenstein et al.
Status epilepticus
N Engl J Med
(1998)
M. Kahriman et al.
Efficacy of topiramate in children with refractory status epilepticus
Epilepsia
(2003)
A.R. Towne et al.
The use of topiramate in refractory status epilepticus
Neurology
(2003)
A.O. Rossetti et al.
Levetiracetam in the treatment of status epilepticus in adults: a study of 13 episodes
Eur Neurol
(2005)
E. Perucca et al.
The ideal pharmacokinetic properties of an antiepileptic drug: how close does levetiracetam come?
Epileptic Disord
(2003)
Commission on Epidemiology and Prognosis, International League Against Epilepsy. Guidelines for epidemiologic studies...

There are more references available in the full text version of this article.

Cited by (88)

Intravenous levetiracetam in clinical practice - Results from an independent registry
2015, Seizure
Most common clinical studies with antiepileptic drugs do not reflect medical everyday practice due to their strict in- and exclusion criteria and specifications of treatment regimens. Here we present a large non-interventional registry with the intention to evaluate the spectrum of applications in daily use and the efficacy and tolerability of intravenously given levetiracetam (LEV-iv).
In a prospective approach of 17 neurological and neuropediatric centres in Germany LEV-iv treated patients of all ages were included over a period of 10 months. The observational period was 10 days with daily documentation of LEV-iv administration, type and frequency of seizures, currently used drugs and doses, and adverse events (AEs). In addition, treatment efficacy and tolerability were assessed by patients and physicians at study end as well as practicability of LEV-iv using a five-step scale.
In 95 patients LEV-iv was administered, 93 were included into the analysis. The median LEV-iv dose was 1500 mg (range 110–6000 mg) per day. Median age was 66 years (range 0.7–90.3 years). The majority of patients (n = 70, 75%) suffered from status epilepticus (SE, n = 55, 59%) and acute seizure clusters (n = 15, 16%). Of those with SE, 41 patients (75%) had SE for the first time. Acute seizure clusters and SE terminated in 83% after LEV-iv administration. A total of 29 adverse events were reported in 17 of the 95 patients from the safety set. Ten of these were at least possibly related to LEV-iv treatment. Slight decrease of blood pressure during the infusion (3 patients each) was captured most frequently. No serious side effect was observed. Physicians rated the efficacy and tolerability of LEV-iv treatment as good or very good in 78% and 82% of the cases, respectively.
In this large observational study of everyday practise the use of LEV-iv exhibited a remarkable good response and tolerability in patients with acute onset seizures (mostly SE). Further randomized controlled studies, like the established status epilepticus trial (ESET) are needed to confirm these findings.
E&B is 15: An attempt to explain the "paradox"
2014, Epilepsy and Behavior
Status epilepticus: Clinical considerations and therapeutic guidelines
2013, Neurologia Argentina
El estatus epiléptico es uno de los mayores problemas en la salud pública de todo el mundo. Constituye una emergencia médica frecuente, con costes elevados para la salud y elevada morbimortalidad. El advenimiento de nuevos fármacos antiepilépticos y formulaciones farmacéuticas nos obliga a revisar permanentemente las estrategias terapéuticas.
Actualizar las guías terapéuticas de estatus epiléptico publicadas por el Grupo de Trabajo de Epilepsia de la Sociedad Neurológica Argentina en el año 2007, con información adicional y nuevos resultados hasta la fecha, basándonos en la mejor evidencia médica disponible.
Se seleccionaron artículos de relevancia clínica de bases MEDLINE y Cochrane que incluyeron: estudios clínicos aleatorizados, metaanálisis, guías terapéuticas, revisiones sistemáticas, estudios no aleatorizados, de casos y opiniones de expertos.
Se establecieron y seleccionaron aquellos fármacos más eficaces para crisis que perduran más allá de los 5 minutos. Se determinó el tratamiento específico según etapas: prehospitalaria, hospitalaria y en terapia intensiva. Se tuvieron en cuenta los estadios evolutivos, la respuesta clínica y la necesidad de monitorización electroencefalográfica en instancias avanzadas.
Seguimos recomendando iniciar la terapéutica en toda crisis que se extienda más allá de los 5 minutos.
Aún no contamos con la evidencia suficiente que nos permita recomendar fuertemente un fármaco anestésico para el tratamiento del estatus refractario, así como tampoco para establecer el tiempo óptimo de duración del mismo. la monitorización electroencefalográfica continua es necesaria para un mejor manejo terapéutico del estatus epiléptico en etapas avanzadas. La mayor disponibilidad de la electroencefalografía permitirá detectar casos de estatus no convulsivos en los cuales las manifestaciones clínicas de crisis no son evidentes.
Status epilepticus is a major public health problem along the world. It represents a frequently medical emergency with elevated costs and high morbimortality. The prognosis depends on the duration and the phase in which the appropriate treatment is, age, ethiology, comorbidities and complications.
To establish therapeutic guidelines for those physicians who treat status epilepticus according to medical evidence available to date.
To update the previous guidelines published in 2007 with additional information and new results.
We selected articles of clinical relevance from databases MEDLINE and Cochrane.
Randomized clinical trials, meta - analyses, therapeutic guidelines, systematic reviews, cases series and experts opinions were included.
After an individualized assessment of different drugs useful for treatment of status epilepticus, we selected those more efficacious for seizures lasting more than 5 minutes. After the analysis, we designed an algorithm according to time of evolution, clinical response and electroencephalography monitoring.
Consensus has emerged concerning initial treatment of status epilepticus. For practical purposes treatment should be started after 5 minutes of continuous seizure activity. Treatment of refractory status was established according to the evidence available but the are not enough randomized trials that compare different therapeutic agents for this instance. Continuous EEG monitoring is needed for better management of status epilepticus in advance stages. The alarming high mortality rate of status epilepticus emphasizes the need of an high suspicion index with rapid recognition and urgent treatment.
Use of pregabalin for nonconvulsive seizures and nonconvulsive status epilepticus
2013, Seizure
To determine the efficacy of pregabalin (PGB) in treatment of frequent nonconvulsive seizures (NCS) and nonconvulsive status epilepticus (NCSE) in critically ill patients.
In this retrospective study, 21 patients were identified as having received pregabalin for the treatment of NCS as determined by continuous electroencephalographic monitoring. The patients were considered to be responders if their seizures were terminated within 24 h of initiation of PGB without the addition of another antiepileptic agent.
Of the 21 patients who received PGB for treatment of NCS or NCSE, 11 (52%) were responders. PGB was administered via a nasogastric tube or orally and was the 2nd to 4th agent used. The average initial dose and total daily dose of PGB was similar in the responders and non-responders (342 mg vs. 360 mg, respectively). PGB was more effective in aborting NCS (9 patients, 82%) than NCSE (2 patients, 18%). Of the 9 brain tumor patients, PGB resulted in seizure cessation in 67% (6 patients). In contrast, all patients with hypoxic injury (4) did not respond to PGB. The responders were noted to have better clinical outcome (64% vs. 9% discharged home). Most of the patients tolerated the medication without any significant short term adverse effects, except two patients who were noted to have dizziness and sedation.
Pregabalin may be safe option for add-on treatment for nonconvulsive seizures in critically ill patients when conventional therapy fails.
Newer antiepileptic drugs in the treatment of status epilepticus: Impact on prognosis
2012, Epilepsy and Behavior
Newer antiepileptic drugs (AEDs) are increasingly prescribed and seem to have a comparable efficacy as the classical AEDs; however, their impact on status epilepticus (SE) prognosis has received little attention. In our prospective SE database (2006–2010), we assessed the use of older versus newer AEDs (levetiracetam, pregabalin, topiramate, lacosamide) over time and its relationship to outcome (return to clinical baseline conditions, new handicap, or death). Newer AEDs were used more often toward the end of the study period (42% of episodes versus 30%). After adjustment for SE etiology, SE severity score, and number of compounds needed to terminate SE, newer AEDs were independently related to a reduced likelihood of return to baseline (p < 0.001) but not to increased mortality. These findings seem in line with recent findings on refractory epilepsy. Also, in view of the higher price of the newer AEDs, well-designed, prospective assessments analyzing the impact of newer AEDs on efficacy and tolerability in patients with SE appear mandatory.
Oral loading levetiracetam in the treatment of initial and refractory nonconvulsive status epilepticus
2012, Neurologia Argentina
El estatus epiléptico no convulsivo (SENC) es una entidad subdiagnosticada. Hay datos limitados sobre el rol de levetiracetam vía oral (LEV-VO) en el manejo del SENC.
: Analizar la respuesta del LEV-VO en pacientes con SENC.
Retrospectivamente se analizaron los casos de SENC tratados con LEV-VO entre 2007- 2008 de nuestro registro. Se definió SENC como actividad epiléptica continua o recurrente, generalizada o focal, de 30 minutos o más de duración, acompañada con signos motores sutiles y/o alteración del estado de conciencia-conducta. Utilizamos los criterios de Chong-2005 para definir actividad epiléptica. Se definió respuesta al tratamiento al observar mejoría clínica y electroencefalográfica (desaparición del estatus epiléptico). Se definió SENC refractario (SENC-R) como aquel sin respuesta completa al uso apropiado de dos fármacos antiepilépticos (fármaco de primera línea: benzodiacepina + fármaco segunda línea: fenitoína). La dosis total de LEV-VO usada fue 3.000 mg, administrando 500 mg cada 15-20 minutos.
Se incluyeron 12 pacientes con SENC tratados con LEV-VO de un total de 25. Se utilizó como fármaco de segunda línea para el tratamiento inicial SENC en tres pacientes y como fármaco de tercera o cuarta línea en el SENC-R en 9. Hubo una respuesta en el 100% de los casos (3/3) del SENC inicial. La tasa de respuesta en los SENC-R como fármaco de tercera y cuarta línea fue del 66% (4/6) y del 33% (1/3) respectivamente.
El uso LEV-VO tiene un potencial rol en el tratamiento del SENC inicial como refractario, el cual debería ser confirmado en estudios prospectivos, controlados y aleatorizados.
Nonconvulsive status epilepticus (NCSE) is an underdiagnosed condition. There is limited information about treatment with oral levetiracetam (LEV-VO) for NCSE.
To analyze NCSE response to LEV-VO treatment.
We retrospectively analyzed NCSE cases treated with LEV-VO, between 2007-2008, in our record. NCSE was defined as continuous or recurrent seizure activity, generalized or focal, 30 minutes or longer, accompanied by subtle motor signs and/or altered state of consciousness, behavior. Chong-2005 criteria were used for defining epileptic activity. We defined response to treatment if there were clinical and EEG improvement (disappearance of the status epilepticus). Refractory was defined (NCSE-R) when NCSE had no complete response to the appropriate use of two antiepileptic drugs (first-line drug: benzodiazepine + second-line drug: phenytoin). The total dose used (LEV-VO) was 3,000 mg, 500 mg administered every 15-20 minutes.
We identified 25 patients with NCSE, 12 treated with LEV-VO. LE-VO was used as second-line drug for initial treatment in 3 NCSE patients, and as a drug of third or fourth line in NCSE-R in 9 patients. There was a response in 100% cases (3/3) of the initial NCSE. The response rate in the NCSE-R as a drug of third and fourth line was 66% (4/6) and 33% (1/3) respectively.
LEV-VO has a potential role in the treatment of refractory and initial SENC, which should be confirmed in prospective, randomized and controlled studies.

View all citing articles on Scopus

^☆: This study was supported by UCB, Smyrna (GA), USA. Dr. Rossetti is supported by the Swiss National Science Foundation and the SICPA Foundation, Prilly, Switzerland.

View full text

Brief CommunicationDeterminants of success in the use of oral levetiracetam in status epilepticus☆

Abstract

Introduction

Section snippets

Methods

Results

Discussion

Seizure

Epilepsy Behav

Epilepsy Res

Status epilepticus

N Engl J Med

Efficacy of topiramate in children with refractory status epilepticus

Epilepsia

The use of topiramate in refractory status epilepticus

Neurology

Levetiracetam in the treatment of status epilepticus in adults: a study of 13 episodes

Eur Neurol

The ideal pharmacokinetic properties of an antiepileptic drug: how close does levetiracetam come?

Epileptic Disord

Brief Communication
Determinants of success in the use of oral levetiracetam in status epilepticus☆