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  1. 1. Short Communication Gerontology 2009;55:27–31 Received: April 30, 2008 Accepted: September 11, 2008 DOI: 10.1159/000166610 Published online: October 27, 2008Intravenous Levetiracetam for EpilepticSeizure Emergencies in Older PeopleStefan Beyenburg a Markus Reuber b Nadja Maraite aa Département des Neurosciences, Centre Hospitalier de Luxembourg, Luxembourg, andb Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Sheffield, UKKey Words IntroductionEpilepsy ؒ Older people ؒ Elderly ؒ Intravenouslevetiracetam ؒ Seizure ؒ Status epilepticus ؒ Co-morbidity Levetiracetam (LEV) is one of the newer antiepileptic drugs (AEDs). It has a favourable pharmacokinetic pro- file and can be effective for a wide range of focal and gen-Abstract eralized seizures [1]. The exact mechanism of action isPurpose and Background: Clinical experience with intrave- unknown but it involves binding to a presynaptic vesiclenous levetiracetam (LEV IV) is still very limited, especially in protein [2]. It has recently attained a monotherapy licenceelderly subjects. The primary objective of this retrospective for partial-onset seizures in adults. In most countries, itobservational study was to describe the efficacy and toler- is also approved as adjunctive therapy in the treatment ofability of LEV IV in older patients presenting with epileptic adults and adolescents aged 612 years with juvenile myo-seizure emergencies. Methods: Medical records of 14 older clonic epilepsy. A parenteral intravenous (IV) formula-people treated with LEV IV were analysed retrospectively. All tion has recently become available [3]. In healthy volun-patients suffered from series of complex partial seizures or teers, LEV administered by single ascending doses of upconvulsive or non-convulsive status epilepticus needing to 4,000 mg was well tolerated, and the pharmacokineticemergent intravenous (IV) antiepileptic drug (AED) treat- profile was consistent with that for LEV administeredment. Nine patients were taking AED therapy when LEV IV orally [4]. No clear relation was noted between incidencewas administered. Results: Mean age was 73.9 years (range of adverse events and IV dose level or infusion rate. Ad-61–97). Mean dosage was 1,643 mg/day (range 500–4,000). verse events reported after IV administration of LEV (upSeizure control could be achieved in 11/14 patients (78.6%). to 4,000 mg infused over 15 min and up to 2,500 mg in-No significant adverse events were noted besides sedation. fused over 5 min) were: dizziness (52.8%), somnolenceConclusion: LEV IV was effective and well tolerated in these (33.3%), fatigue (11.1%), and headache (8.3%). The solu-critically ill older patients. LEV IV seems to be a reasonable tion was well tolerated even in higher doses or with fasterpractical alternative in multimorbid older patients who need infusion rates than proposed [4]. Furthermore, a singleIV treatment with an AED. Copyright © 2008 S. Karger AG, Basel dose of 1,500 mg LEV administered as a 15-min IV infu- sion was bioequivalent to 1,500 mg as oral tablets [5]. In a recent multicentre, open-label study the short-term tol- erability of LEV IV (500–1,500 mg/100 ml, infused over 15 min, twice daily) as a substitute for the same oral dose © 2008 S. Karger AG, Basel Stefan Beyenburg, MD 0304–324X/09/0551–0027$26.00/0 Department of Neurology, Centre Hospitalier de LuxembourgFax +41 61 306 12 34 4, rue BarbléE-Mail karger@karger.ch Accessible online at: LU–1210 Luxembourg (Luxembourg)www.karger.com www.karger.com/ger Tel. +352 44 11 66 27, Fax +352 44 11 40 20, E-Mail beyenburg.stefan@chl.lu
  2. 2. was evaluated in 25 adult epilepsy patients. No serious treated with conventional AEDs, serum levels of drugs were with-side effects or deaths were reported. Seizure worsening in the so-called ‘therapeutic range’ before treatment with LEV IV was started. Blood levels of ammonia concentration as well as liv-due to the drug was not observed. The authors concluded er enzymes were determined in all patients who were treated withthat LEV IV seems to be a well-tolerated, practical alter- VPA. Efficacy of LEV IV treatment was defined as complete sei-native in patients with partial-onset seizures temporarily zure cessation in the 24 h after starting LEV IV (as documentedunable to take the drug orally [6]. in the medical records). The role of LEV for the treatment of seizure emergen-cies and status epilepticus (SE) remains uncertain. Initialanimal experiments yielded ambivalent results: high- Resultsdose LEV failed to terminate seizures in a rat model ofself-sustaining limbic SE. However, administration of The clinical characteristics of patients treated with1,000 mg/kg had protective effects against status-induced LEV IV are shown in table 1. The most frequent underly-mitochondrial dysfunction, indicating that LEV may ing pathology was cerebrovascular disease. The mean agehave some neuroprotective effects [7]. Although LEV is was 73.9 years (range 61–97). In view of the advanced agecurrently not licensed for the treatment of SE, the safety of the patients, relatively low doses of LEV were admin-and efficacy of LEV IV in humans has been demonstrat- istered (mean 1,643 8 949.3 mg/day). Complete seizureed by a small open-label study and some case reports [8– control was achieved in 11/14 patients (78.6%) as docu-11]. Recently a first larger observational study of 50 criti- mented by termination of clinical and/or electrical sei-cally ill patients treated by LEV IV was published [12]. zure activity (EEG). Overall, the tolerability of LEV IVThe mean age of the patients studied was 59.7 years and was excellent. Four patients complained of sedation/som-LEV IV was effective in 82% of the patients. nolence during the course of IV treatment. In 3 patients, Our case series is intended to add to the published data on adverse events could not be obtained. No seriousclinical experience with LEV IV in humans by focusing side effects were observed. One patient died due to mul-especially on the use of LEV IV for seizure emergencies tiorgan failure resulting from septic shock with cardiacin older patients. In view of its favourable pharmacoki- arrest. No significant changes in laboratory values werenetic profile and limited potential for drug-drug interac- observed which could have been attributed to LEV use.tions, LEV IV could be an AED treatment of particularinterest for older patients who often have other medicalco-morbidity and take other medications [1, 3, 8, 12]. Discussion The main findings of the present retrospective analy- Patients and Methods sis are that LEV IV may be an efficient and well-tolerated All 14 patients (10 females, 4 males) were admitted to the De- practical alternative for AED treatment in older patientspartment of Neurology, Centre Hospitalier de Luxembourg, dur- with seizure emergencies. LEV has become a widely useding the year 2007. The reason for admittance to the hospital was drug in patients with different epileptic syndromes [1].a series of complex partial seizures in most patients. Some pa- However, experience with IV treatment with LEV in sei-tients were treated in the intensive care unit. Medical records were zure emergencies is limited. The efficacy of IV loadingevaluated retrospectively. Four of the patients were already takingAEDs for known symptomatic epilepsy prior to admission. Three with LEV was demonstrated by Schulze-Bonhage et al.subjects were initially treated with valproate IV (VPA IV), and 2 [9] in a patient with non-convulsive complex partial SEpatients were treated with benzodiazepines IV (BZP IV). How- who was treated initially with lorazepam (3 mg) and IVever, all seizures were refractory to initial drug treatment when loading with phenytion (1,000 mg). Video-EEG monitor-LEV IV was started as documented by clinical examination and ing demonstrated a reduction of ictal EEG patterns andelectroencephalogram (EEG). Five patients received LEV IV asfirst-line drug treatment. The clinical records of each patient were clinical amelioration within 35 min of LEV administra-screened for clinical response and possible AED-induced adverse tion (1,000 mg). Another recent case report demonstrat-events. All patients received an EEG on admission as well as sev- ed that LEV IV may terminate refractory focal SE ini-eral follow-up EEGs depending on the clinical course, however, tially treated with BZP in a young patient [11]. Two oldercontinuous video-EEG monitoring was not performed. The ob- patients with non-convulsive SE that responded favour-servation period was at least 14 days, but some patients remainedin hospital beyond this time because of their serious underlying ably to LEV IV have also been described [10]. In bothdisorder. Serum levels of conventional AEDs were taken, however cases, electrographic SE stopped with marked clinicalserum levels of LEV were not obtained. In patients (n = 9) pre- improvement. No significant side effects were observed.28 Gerontology 2009;55:27–31 Beyenburg /Reuber /Maraite
  3. 3. Table 1. Clinical characteristics of patients treated with LEV IVCase Indication Initial LEV IV Initial Duration Aetiology and Main side Concomitant Follow-up (at least 14 days)(sex, age) for LEV dose, mg creatinine of LEV IV co-morbidity effects AEDs outcome IV levels treatment mg/dl days1 1 (F, 63) Series of CPS 500 bid 0.5 4 Meningoencephalitis Sedation Seizure control 2 (F, 97) Series of CPS 500 bid 1.1 2 Stroke, Sedation Lorazepam Seizure control atrial fibrillation 3 (M, 74) NCSE 250 bid (day 1), 1.2 2 Cardiac surgery 3 days Somnolence Midazolam Seizure control then 500 bid, before, ‘old’ vascular then 1,000 bid brain lesion 4 (M, 71) SE 1,000 bid 1.4 2 Right temporal AV Well Carbamazepine, Seizure control malformation tolerated lamotrigine, lorazepam 5 (F, 77) Series of CPS 250 bid 1.3 2 Cerebrovascular disease, Sedation Pregabalin Death due to multiorgan myocardial infarction, failure resulting from pneumonia septic shock with cardiac arrest 6 (F, 78) NCSE 500 bid 0.6 1 Hyponatraemia; Well Clonazepam, Seizures not completely meningoencephalitis tolerated phenytoin controlled by LEV, occasional focal seizures 7 (F, 84) Series of CPS 250 bid (day 1), 1.2 2 Stroke Well Seizure control with secondary then 500 bid tolerated generalized seizures 8 (F, 72) NCSE 500 bid (day 1), 0.5 9 Severe head trauma Not known Valproate, Electrical seizure activity then 1,000–2,000 Alcohol withdrawal phenytoin, not controlled by LEV IV, bid midazolam, intubation, later extuba- propofol tion and discharge from the ICU, some weeks later discharge from the Department Neurosurgery (other institution) 9 (M, 61) Series of CPS 500 bid (day 1), 0.94 9 Meningitis Well Seizure control with secondarily then 1,000 bid tolerated generalized seizures10 (M, 66) Series of CPS 500 bid 1.37 7 Systemic cancer Dizziness, Seizure control with secondarily somnolence generalized seizures11 (F, 65) NCSE 500 bid 0.52 4 Encephalitis Well Lorazepam Seizure control tolerated valproate12 (F, 75) NCSE 1,000 bid 1.4 5 Stroke Well Valproate (hyper- Seizure control tolerated ammonaemia)13 (F, 74) NCSE 1,000 bid on 0.98 5 Cardiac surgery, Not known Midozolam Seizure control day 1, stroke on day 1 then 1,500 bid14 (F, 77) NCSE 750 bid 1.38 5 Encephalitis Well Seizure control tolerated CPS = Complex partial seizures; NCSE = Non-convulsive status epilepticus; SE = Status epilepticus; bid = twice daily. 1 Thereafter switch to oral LEV, if possible.Intravenous Levetiracetam for Seizure Gerontology 2009;55:27–31 29Emergencies
  4. 4. Knake et al. [8] reported a series of 18 episodes of focal SE tabolism [1]. The pharmacokinetic profile of an AED be-in 16 patients initially treated with BZP. SE was controlled comes particularly important when treating older peoplein all patients by the combination of drugs administered, with epilepsy. Drug and toxicity levels may be affected byhowever, two episodes could only be controlled with the age-related changes in gastrointestinal absorption, distri-introduction of another AED after LEV had been started. bution of drugs due to changes in the fat and water con-The mean LEV IV loading dose was 944 mg, and the tent of the body, liver volume, metabolism and bloodmean maintenance dose over 24 h was 2,166 mg. No se- flow, or renal excretion rates. Drug binding to plasmavere adverse events were noted. Patients were discharged proteins decreases with advancing age [16, 17]. Further-with a mean oral dose of 2,058 mg/day. In demographic more, older patients often receive concomitant drug ther-terms, the patients described were similar to the group apy for conditions other than epilepsy. This means thatreported here, although they were somewhat younger. there is an increased risk of complex drug-drug interac- Our findings are in line with those of a recent study tions in this particular patient group making rationalwhich described the use of LEV IV in a heterogeneous treatment approaches very difficult [18, 19]. Parenteralsample of younger patients [12]. These authors retrospec- formulations of traditional AEDs (such as valproate, phe-tively reviewed the medical records of 50 critically ill nytoin or phenobarbitone) which are often used in olderadult patients who were treated with LEV IV (1,780 8 patients with epilepsy may have significant side effects,649 mg/day). There were several different indications for mainly due to their pharmacokinetic profiles and poten-treatment: SE (48%), seizures (19%), and seizure prophy- tial for drug-drug interactions [18, 19].laxis (14%). The aetiologies were similar to our patient The adverse events reported by our patients were verygroup, with cerebrovascular disease being the common- similar to those typically reported by patients treatedest underlying pathology. During a 7-day observation pe- with oral LEV. Somnolence was the most frequently re-riod, 82% of the patients became or remained seizure- ported side effect. In critically ill patients the clinicalfree. SE was successfully treated in 16/24 patients (67%). findings of somnolence or unusual fatigue may be diag-No serious adverse effects were observed (2 patients had nostically challenging because somnolence is also one ofslight transient thrombocytopenia). the commonest features of NCSE [18, 20]. It may be dif- There are also some retrospective studies suggesting ficult to make this diagnosis without prolonged or re-that oral loading with LEV can be helpful in seizure emer- peated EEG monitoring [18]. There is also one reportgencies. Rossetti and Bromfield [13] analysed 13 episodes about the possible induction of NCSE by LEV. Two pa-of SE in adult patients. These patients were treated with tients developed NCSE on treatment with 2,000 mg LEVoral LEV (mostly via nasogastric tube). Most were also [21]. No such event was observed in our patients.treated with other AEDs previously or concomitantly. In conclusion, the present study is limited by its retro-The daily LEV dose ranged between 1,000 and 6,000 mg. spective nature, a patient profile with different co-mor-Only 3 patients (23%) were regarded as responders, and bidities (that is, however, reflecting every-day clinicalin 4 patients (31%) SE continued despite the administra- practice), and the small sample size. Moreover, the major-tion of LEV. These patients had refractory SE requiring ity of patients were given LEV IV as co-medication re-general anaesthesia and ventilation. Nevertheless, the au- stricting our ability to evaluate adverse events and thethors concluded that LEV may be a useful alternative in effectiveness of the drug. Despite these limitations, ourthe treatment of SE. Another recent report suggests the findings extend the knowledge about the usefulness ofclinical usefulness of oral LEV in the treatment of focal LEV IV and suggest that this treatment is well toleratedSE (non-convulsive status epilepticus; NCSE). LEV was and can be effective in older, multimorbid patients withgiven mostly via nasogastric tube and was titrated from epileptic seizure emergencies. Because the choice of IVa starting dose of 500/1,000 mg twice daily up to a maxi- formulations of AEDs is still limited, LEV IV appears tomum dose of 2,000 mg/day within 2 days. NCSE ceased be a reasonable treatment option in patients needingin all patients within a time period of 1–3 days after oral emergent IV drug therapy, although prospective studiesadministration of LEV [14]. Even in refractory SE adjunc- are needed to define its role in the setting of seizure emer-tive oral loading with LEV (500–3,000 mg/day) may by gencies.helpful in achieving seizure control [15]. No serious ad-verse events were reported in these studies. LEV has a favourable pharmacokinetic profile withlack of significant interactions and lack of hepatic me-30 Gerontology 2009;55:27–31 Beyenburg /Reuber /Maraite
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