Keppra (Levetiracetam)Epilepsy,Parkison's Bipolar Research Keppra (Levetiracetam) is primarily used as an anti epileptic for children, adults and the elderly. The research on this webpage also shows implications for bipolar, Parkinson's. idiopathic epilepsy and others. There are also warnings as to possible drug reactions from Keppra.
J Pharmacol Exp Ther. 2004 Mar 5 [Epub ahead of print] :
Levetiracetam potentiates the anti-dyskinetic action of amantadine in the MPTP-lesioned primate model of Parkinson's disease.
Hill MP, Ravenscroft P, Bezard E, Crossman AR, Brotchie JM, Michel A, Grimee R, Klitgaard H.
Manchester, M15 6SE, U.K.
Levetiracetam (LEV, Keppra) has recently been reported to have anti-dyskinetic activity against levodopa (L-DOPA)-induced dyskinesia in the MPTP-lesioned marmoset and macaque models of Parkinson's disease. Amantadine is frequently used as adjunctive therapy for L-DOPA-induced dyskinesia but adverse effects limit its clinical utility. The current study was designed to investigate whether LEV can potentiate the anti-dyskinetic action of amantadine. The anti-parkinsonian and anti-dyskinetic effects of LEV (13 and 60 mg/kg) and amantadine (0.01, 0.03, 0.1 and 0.3 mg/kg), administered alone and in combination, were assessed in the MPTP-lesioned marmoset model of L-DOPA-induced dyskinesia (n=12). LEV (60 mg/kg) and amantadine (0.3 mg/kg) administered alone significantly reduced L-DOPA-induced dyskinesia without compromising the anti-parkinsonian action of L-DOPA. Lower doses were without any significant effects. The combination of LEV (60 mg/kg) and amantadine (0.01, 0.03, 0.1 and 0.3 mg/kg) significantly decreased dyskinesia severity, without compromising the anti-parkinsonian action of L-DOPA, more efficaciously than LEV or amantadine monotherapy. These results support the concept that normalisation of different pathophysiological mechanisms (i.e. altered synchronization between neurons and enhanced NMDA transmission) has a greater efficacy. Combined LEV/amantadine therapy might be useful as an adjunct to L-DOPA to treat dyskinetic side effects and expand the population of Parkinson's disease patients that benefit from treatment with amantadine alone.
Headache. 2004 Mar;44(3):238-43. :
Efficacy and safety of levetiracetam in pediatric migraine.
Miller GS.
Pediatric Neurology Department, Hillcrest Healthcare System, Children's Medical Center, Tulsa, Okla. 74104, USA.
BACKGROUND: Headache is a frequent occurrence among children and adolescents. Chronic headaches can be severe and disabling, and require prophylactic treatment; however, additional data on the use of prophylactic medications for migraine in children are needed. OBJECTIVE: To review the efficacy and safety of levetiracetam (Keppra) in pediatric patients with a history of recurrent headache. DESIGN/METHODS: Data from 19 pediatric patients were retrospectively reviewed. The initial dose of levetiracetam was usually 125 or 250 mg twice daily, but varied depending upon clinical judgment. RESULTS: Charts of 9 girls and 10 boys (mean age, 11.9 years) were reviewed. A variety of medications, including triptans, had been used before initiating treatment with levetiracetam. Mean headache frequency before treatment was 6.3 per month (standard deviation [SD], 3.8; confidence interval [CI], 4.4 to 8.1). Duration of headaches ranged from 0.25 to 8 years. Migraine (63.2%) and migraine with aura (15.8%) were the most common types of headache reported. Most patients (89.5%) had headaches that were severe. After treatment, the mean headache frequency decreased to 1.7 per month (SD, 2.7; CI, 0.4 to 3.0), representing a reduction compared with baseline (P <.0001). Levetiracetam eliminated headaches in 10 patients (52.6%), and 7 patients (36.8%) had less severe and less frequent headaches. Levetiracetam did not have an effect on headaches in 2 patients (10.5%). Mean duration of treatment with levetiracetam was 4.1 months. Doses ranged from 125 to 750 mg twice daily. Sixteen patients (84.2%) reported no side effects on levetiracetam. One patient experienced asthenia/somnolence and dizziness, and irritable, hyperactive, and hostile behavior led to discontinuation of levetiracetam in another patient. A third patient experienced irritability and moodiness that attenuated after 1 month of treatment and did not require discontinuation. CONCLUSIONS: In this small retrospective review, levetiracetam was found to be generally well tolerated and appears to be a promising candidate for additional evaluation in well-controlled clinical trials of pediatric patients with migraine
JAMA. 2004 Feb 4;291(5):605-14. :
The new antiepileptic drugs: scientific review.
LaRoche SM, Helmers SL.
Department of Neurology, Emory University, Atlanta, Ga, USA.
Suzette_LaRoche@emoryhealthcare.org
CONTEXT: The past decade has brought many advances to the treatment of epilepsy, including many new pharmacological agents. Primary care physicians often care for patients with epilepsy and therefore should be familiar with the new options available. OBJECTIVE: To review data regarding the efficacy and tolerability of antiepileptic drugs introduced in the past decade. DATA SOURCES: A search of the Cochrane Central Register of Controlled Trials was performed to identify all published human and English-language randomized controlled trials evaluating the efficacy and tolerability of the antiepileptic drugs that have been approved for use in the United States since 1990. Additional reports evaluating pharmacokinetic properties were identified through a MEDLINE search as well as review of article bibliographies. STUDY SELECTION AND DATA EXTRACTION: Search terms included felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide. Studies were selected if efficacy and tolerability were reported as major outcome measures. Included studies (n = 55) enrolled a minimum of 20 adult subjects and had a treatment period of at least 6 weeks. DATA SYNTHESIS: Eight new antiepileptic drugs have been approved for use in the United States in the past decade. Each new antiepileptic drug is well tolerated and demonstrates statistically significant reductions in seizure frequency over baseline. No randomized controlled trials have compared the new antiepileptic drugs with each other or against the traditional antiepileptic drugs. Although there is no evidence to suggest that the newer medications are more efficacious, several studies have demonstrated broader spectrum of activity, fewer drug interactions, and overall better tolerability of the new agents. CONCLUSIONS: New antiepileptic drugs offer many options in the treatment of epilepsy, each with unique mechanisms of action as well as adverse effect profiles. The new antiepileptic drugs are well tolerated with few adverse effects, minimal drug interactions, and a broad spectrum of activity.
J Med Chem. 2004 Jan 29;47(3):530-49. :
Discovery of 4-substituted pyrrolidone butanamides as new agents with significant antiepileptic
activity.
Kenda BM, Matagne AC, Talaga PE, Pasau PM, Differding E, Lallemand BI, Frycia AM, Moureau FG, Klitgaard HV, Gillard MR, Fuks B, Michel P.
Chemical Research, Preclinical CNS Research, and In Vitro Pharmacology, UCB S.A., Pharma Sector, Chemin du Foriest, B-1420 Braine l'Alleud, Belgium.
benoit.kenda@UCB-group.com
(S)-alpha-ethyl-2-oxopyrrolidine acetamide 2 (levetiracetam, Keppra, UCB S.A.), a structural analogue of piracetam, has recently been approved as an add-on treatment of refractory partial onset seizures in adults. This drug appears to combine significant efficacy and high tolerability due to a unique mechanism of action. The latter relates to a brain-specific binding site for 2 (LBS for levetiracetam binding site) that probably plays a major role in its antiepileptic properties. Using this novel molecular target, we initiated a drug-discovery program searching for ligands with significant affinity to LBS with the aim to characterize their therapeutic potential in epilepsy and other central nervous system diseases. We systematically investigated the various positions of the pyrrolidone acetamide scaffold. We found that (i) the carboxamide moiety on 2 is essential for affinity; (ii) among 100 different side chains, the preferred substitution alpha to the carboxamide is an ethyl group with the (S)-configuration; (iii) the 2-oxopyrrolidine ring is preferred over piperidine analogues or acyclic compounds; (iv) substitution of positions 3 or 5 of the lactam ring decreases the LBS affinity; and (v) 4-substitution of the lactam ring by small hydrophobic groups improves the in vitro and in vivo potency. Six interesting candidates substituted in the 4-position have been shown to be more potent antiseizure agents in vivo than 2. Further pharmacological studies from our group led to the selection of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide 83alpha (ucb 34714) as the most interesting candidate. It is approximately 10 times more potent than 2 as an antiseizure agent in audiogenic seizure-prone mice. A clinical phase I program has been successfully concluded and 83alpha will commence several phase II trials during 2003.
Life Sci. 2004 Jan 23;74(10):1253-64. :
Levetiracetam protects against kainic acid-induced toxicity.
Marini H, Costa C, Passaniti M, Esposito M, Campo GM, Ientile R, Adamo EB, Marini R, Calabresi P, Altavilla D, Minutoli L, Pisani F, Squadrito F.
Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, Azienda Ospedaliera Universitario "G. Martino", Torre Biologica 5th Floor Via Consolare Valeria Gazzi, 98100 Messina, Italy.
We investigated the Levetiracetam (LVT) ability to protect the brain against kainic acid (KA) induced neurotoxicity. Brain injury was induced by intraperitoneal administration of KA (10 mg/kg). Sham brain injury rats were used as controls. Animals were randomized to receive either LVT (50 mg/kg) or its vehicle (1 ml/kg) 30 min. before KA administration. Animals were sacrificed 6 hours after KA injection to measure brain malonildialdehyde (MDA), glutathione levels (GSH) and the mRNA for interleukin-1beta (IL-1beta) in the cortex and in the diencephalon. Behavioral changes were also monitored. Intraperitoneal administration of LVT decreased significantly MDA in the cortex (KA + vehicle = 0.25 +/- 0.03 nmol/mg protein; KA + LVT = 0.13 +/- 0.01 nmol/mg protein; P < 0.005), and in the diencephalons (KA + vehicle = 1,01 +/- 0.2 nmol/mg protein; KA + LVT = 0,33 +/- 0,08 nmol/mg protein; P < 0.005), prevented the brain loss of GSH in both cortex (KA + vehicle = 5 +/- 1 micromol/g protein; KA + LVT = 15 +/- 2 micromol/g protein; P < 0.005) and diencephalons (KA + vehicle = 9 +/- 0.8 micromol/g protein; KA + LVT = 13 +/- 0.3 micromol/g protein; P < 0.05), reduced brain IL-1beta mRNA and markedly controlled seizures. Histological analysis showed a reduction of cell damage in LVT treated samples. The present data indicate that LVT displays neuro-protective effects against KA induced brain toxicity and suggest that these effects are mediated, at least in part, by inhibition of lipid peroxidation.
Clin J Pain. 2004 Jan-Feb;20(1):33-6. :
Levetiracetam in the treatment of neuropathic pain: three case studies.
Price MJ.
Wuesthoff Memorial Hospital, Rockledge, Florida, USA.
mjp@bv.net
CASE REPORTS: A 55-year-old woman presented with numbness and pain in both lower extremities. The pain was of sudden onset and of 4 months' duration. A nerve conduction study demonstrated a bilateral sensorimotor peripheral neuropathy with axonal and demyelinating features of a mild degree. Initial treatment with oral thiamine and topiramate had little efficacy and caused unacceptable side effects. A switch to 1500 mg bid levetiracetam plus nortriptyline resulted in a 60% improvement in pain symptoms. A 75-year-old man presented with numbness in both feet of 5 years' duration. The sensation of numbness had progressed to persistent pain, resulting in sleep disruption. The patient's use of oral thiamine did not lead to pain relief, but the addition of 500 mg levetiracetam once in the evening led to a complete resolution of his pain and to sleep improvement. A 67-year-old obese male was referred from a podiatrist with progressive dysfunction in both lower extremities that developed over a 1-year period. Walking more than a few steps resulted in sharp, shooting pain that at night disrupted sleep. A nerve conduction study demonstrated a severe bilateral sensorimotor peripheral neuropathy with axonal and demyelinating features. Treatment with 1000 mg levetiracetam bid resulted in complete absence of pain. CONCLUSIONS: In these 3 case studies, levetiracetam was demonstrated to be an effective therapy in the treatment of neuropathic pain. It has the benefits of a low incidence of adverse events and an improvement in patients' sleep
Epilepsia. 2004 Jan;45(1):90-1. :
Levetiracetam reduces spike-wave density and duration during continuous EEG monitoring in patients with idiopathic generalized epilepsy.
Gallagher MJ, Eisenman LN, Brown KM, Erbayat-Altay E, Hecimovic H, Fessler AJ, Attarian HP, Gilliam FG.
Publication Types:
Letter
Seizure. 2004 Jan;13(1):58-60. :
Levetiracetam monotherapy for elderly patients with epilepsy.
Alsaadi TM, Koopmans S, Apperson M, Farias S.
Department of Neurology, Epilepsy Treatment Center, University of California, Davis, Sacramento, CA 95817, USA.
taoufik.alsaadi@ucdmc.ucdavis.edu
We retrospectively identified 14 elderly patients with a history of partial seizures who received levetiracetam (LEV) monotherapy. Patients began LEV either as first line therapy (n=5) or were converted to LEV monotherapy (n=9) after failing prior antiepileptic medications (AEDs). Thirteen patients continued on LEV monotherapy for at least 6 months. One patient was lost to follow-up. Eight patients (61.5%) became seizure free. Four patients who began LEV as a first line therapy became seizure free, whereas the remaining four patients who converted to LEV after they failed their previous AEDs became seizure free. Four patients (30.7%) had more than a 50% seizure reduction of seizures. Only one patient had no significant change in seizure frequency after started on LEV. The total dosages used to control seizures were 500-3000 mg/day, (mean 1839.2 mg/day). LEV monotherapy can be effective and well tolerated in this group of patients. A prospective, larger, double blind monotherapy study is needed to confirm this finding.
Seizure. 2004 Jan;13(1):55-7. :
Psychiatric adverse events in patients with epilepsy and learning disabilities taking levetiracetam.
Mula M, Trimble MR, Sander JW.
Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London, UK.
marcomula@yahoo.it
PURPOSE: To investigate the prevalence and psychopathological features of psychiatric adverse events (PAEs) in patients with learning disabilities (LD) in therapy with levetiracetam (LEV). METHOD: From a population of 517 consecutively patients with epilepsy started on LEV, we identified 118 patients with epilepsy and LD. RESULTS: Fifteen patients (12.7%) experienced PAEs during LEV therapy. Two (1.7%) developed an affective disorder, nine (7.6%) aggressive behaviour, two (1.7%) emotion lability and two (1.7%) other personality changes such as agitation, anger and hostile behaviour. We observed a significant association with a previous history of status epilepticus and a previous psychiatric history. We did not find a statistically significant association with epilepsy diagnosis, age at onset or duration of the epilepsy, EEG or MRI features. The titration schedule of LEV appeared not to be relevant. CONCLUSIONS: LEV therapy was well tolerated in patients with epilepsy and LD and the main problems were related to aggressive behaviour. The titration schedule of LEV was not relevant and a subgroup of patients appeared to be biologically more vulnerable.
Arch Neurol. 2003 Dec;60(12):1772-4. :
Levetiracetam for phasic spasticity in multiple sclerosis.
Hawker K, Frohman E, Racke M.
University of Texas Southwestern Medical Center at Dallas, TX 75390-9036, USA.
BACKGROUND: Spasticity is a common and debilitating symptom of multiple sclerosis (MS). Current treatments are effective, but may be difficult to tolerate for many patients. OBJECTIVE: To determine if levetiracetam, a second-generation antiepileptic drug, may be useful for the treatment of spasticity in MS. METHODS: A retrospective medical record review of patients attending the Multiple Sclerosis Program at the University of Texas, Southwestern Medical Center at Dallas was performed. A series of 12 patients who had been treated with levetiracetam for spasticity was identified. Most of the patients were female (10/11), and the mean age was 41.0 years. The main outcome measure was a change in Penn spasm score or modified Ashworth score. Both scores are measured on a scale of 0 to 4. RESULTS: The Penn Spasm score (a measure of phasic spasticity) was decreased for all patients following treatment with levetiracetam. The mean +/- SD Penn Spasm score was 2.7 +/- 0.65 at baseline and decreased to 0.9 +/- 0.29 at follow-up. There was no change in modified Ashworth scores (a measure of tonic spasticity). Five patients reported adverse events; 1 patient discontinued treatment owing to an adverse event (edema). Three patients incidentally reported improvements in neuropathic pain. CONCLUSIONS: Levetiracetam was effective for reducing phasic spasticity but not tonic spasticity in this 12-patient case series. The drug was well tolerated and therefore shows promise as a treatment for phasic spasticity. Large, well-controlled trials are needed to confirm these findings.
Epilepsia. 2003 Dec;44(12):1487-93. :
Unidirectional cross-tolerance from levetiracetam to carbamazepine in amygdala-kindled seizures.
Zhang ZJ, Xing GQ, Russell S, Obeng K, Post RM.
Department of Psychiatry, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, U.S.A.
zzhang1@usuhs.mil
PURPOSE: Tolerance is a potential problem in long-term anticonvulsant therapy of epilepsy, bipolar disorder, and neuropathic pain. The present study was designed to determine whether cross-tolerance occurs between levetiracetam (LEV) and carbamazepine (CBZ) in amygdala-kindled rats. METHODS: Male Sprague-Dawley rats were implanted with an electrode into the left amygdala. While kindling stimulation was started, animals received repeated treatment (i.p.) with saline (n = 7) or LEV (150 mg/kg, n = 8). Saline-injected rats were subsequently challenged with a single dose of 150 mg/kg LEV when full kindling developed (stage > or =4). Both groups of rats were then administered long-term CBZ (5 mg/kg) until rats developed complete tolerance. All CBZ-tolerant rats were subsequently re-exposed to LEV (150 mg/kg) for an additional 10 consecutive days.RESULTS: Repeated LEV treatment significantly suppressed the increase in seizure stage, seizure duration, and afterdischarge duration induced by amygdala stimulation, markedly increasing the number of stimulations to achieve a kindling major motor seizure. The LEV challenge produced a more robust suppression of seizure stage in saline-injected rats compared with LEV-treated animals. CBZ treatment markedly suppressed fully kindled seizures in rats initially injected with saline, and then anticonvulsant tolerance rapidly developed after 3-4 days of repeated treatment. In contrast, rats that had initially received repeated LEV treatment did not show a response to treatment with CBZ (5 mg/kg). When CBZ-tolerant rats were subsequently exposed to LEV (150 mg/kg), noticeable anticonvulsant effects were observed; but these were gradually lost with increasing numbers of LEV exposures. CONCLUSIONS: Whereas LEV shows potent antiepileptogenic and anticonvulsant effects in amygdala-kindled rats, its repeated treatment induces anticonvulsant tolerance and unidirectional cross-tolerance to CBZ. In contrast, anticonvulsant tolerance to CBZ does not transfer to LEV. The mechanistic implications of the present results for clinical therapeutics remain to be evaluated.
Epilepsy Behav. 2003 Dec;4(6):702-9. :
Use of levetiracetam in a population of patients aged 65 years and older: a subset analysis of the KEEPER trial.
Ferrendelli JA, French J, Leppik I, Morrell MJ, Herbeuval A, Han J, Magnus L.
Department of Neurology, University of Texas-Houston School of Medicine, 6431 Fannin Street, Suite 7.044, 77030, Houston, TX, USA.
James.A.Ferrendelli@uth.tmc.edu
Levetiracetam (Keppra) was evaluated in a subset of patients aged >/=65 years (n=78) enrolled in a large (n=1030) open-label, phase IV trial (the KEEPER trial). A 4-week dose adjustment was followed by a 12-week evaluation period. An overall median reduction in partial seizures of 80.1% (n=65) was observed. Overall, 76.9% of patients were >/=50% responders, 56.9% were >/=75% responders, and 40.0% were 100% responders. Levetiracetam was well tolerated, with 42.3% of patients reporting one or more adverse events. A total of 15 patients (19.2%) experienced an adverse event that led to discontinuation. Somnolence (n=13,16.7%) and dizziness (n=7,9.0%) were the most commonly reported adverse events. Despite the limitations of the open-label study design, these data provide information regarding the use of levetiracetam as add-on therapy for the treatment of partial-onset seizures in patients >/=65 years of age, including those requiring concomitant medications.
Rev Neurol. 2003 Dec 1-15;37(11):1005-8. :
[Effectiveness and tolerability of levetiracetam in 43 children and adolescents with epilepsy]
[Article in Spanish]
Herranz JL, Rufo-Campos M, Arteaga R.
Servicio de Neuropediatria, Hospital Universitario Marques de Valdecilla, Universidad de Cantabria, Santander, Espana.
pedhfj@humv.es
INTRODUCTION: Levetiracetam (LEV) is the latest antiepileptic drug (AED) to be marketed, and is indicated for use in association in adults with focal seizures. AIMS: The purpose of this study is to report on our experience of administering LEV to children and adolescents with pharmacoresistant epilepsies. PATIENTS AND METHODS: Retrospective open trial involving the observation of 43 children and adolescents with refractory epilepsies, using associated LEV for more than 6 months on an individual basis, the aim of which was to evaluate the repercussions on the frequency of the seizures, together with the adverse and beneficial side effects of LEV administration. RESULTS: With mean doses of LEV of 45.01 +/- 33.02 mg/kg/day the frequency of seizures was reduced by >50% in 65% of patients, while seizures were completely eradicated in 14% of patients; adverse side effects were reported in 28% of patients, although these were usually transient or tolerable, as LEV administration only had to be stopped for this reason in two cases (4.65%). Relatives noted an improvement in social behaviour and in cognitive skills in the case of 15 children (34.9%). CONCLUSIONS: 1. LEV is an effective drug that is well tolerated in children and adolescents with refractory epilepsies; 2. Its effectiveness in different types of seizures suggests a broad therapeutic spectrum; 3. LEV is a well tolerated drug with favourable side effects, a fact that is rarely reported with regard to other AED.
Seizure. 2003 Dec;12(8):613-6. :
Levetiracetam in clinical use--a prospective observational study.
Bird JM, Joseph ZA.
Burden Centre for Neuropsychiatry, Neuropsychology and Epileptology, Frenchay Hospital, Bristol, UK.
jmbird@aol.com
This prospective observational study explored the efficacy and tolerability of levetiracetam (LEV) in a prospective series of 200 patients with refractory epilepsy attending a single epilepsy service. Patients were started on adjunctive LEV using one of two titration schedules (slow and fast) and patients were studied for at least 6 months after commencing LEV. Fifty-three patients had severe learning disabilities. 14.3% became seizure free, 57.7% showed >50% reduction, 15.4% showed seizure increase. Patients with learning disability showed less positive but still very worthwhile results. A highly significant improvement in clinical outcomes overall is shown (P<0.0001). 56.6% showed no adverse effects, 27.4% showed minor adverse effects, 16% were withdrawn. The most common adverse effect causing drug withdrawal was seizure exacerbation (12%) which was much commoner in primary generalised epilepsies (P=0.00035). LEV appears to be an effective and well-tolerated anti-epileptic drug in drug resistant partial epilepsies.
Seizure. 2003 Dec;12(8):617-20. :
Levetiracetam treatment of idiopathic generalised epilepsy.
Krauss GL, Betts T, Abou-Khalil B, Gergey G, Yarrow H, Miller A.
Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
gkrauss@jhmi.edu
Levetiracetam (LEV) is effective for treating localisation-related epilepsy, but it is uncertain whether it is effective for treating idiopathic generalised epilepsy. We compared 12-week baseline and LEV treatment periods for patients with generalised seizure types-myoclonic, tonic-clonic and absence seizures--who had failed other anticonvulsants. The majority of 55 patients (76%) had >50% seizure reduction with LEV therapy, 40% became seizure-free; 15% discontinued LEV due to adverse events, mostly sedation. This is preliminary evidence that LEV is effective for treating idiopathic generalised epilepsy.
Eur J Pharmacol. 2003 Nov 14;481(1):67-74. :
Anxiolytic effects of the novel anti-epileptic drug levetiracetam in the elevated plus-maze test in the rat.
Gower AJ, Falter U, Lamberty Y.
UCB S.A., Pharma Sector, Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium.
There is clinical evidence of anxiolytic action of several anti-epileptic drugs. We evaluated the effects of levetiracetam (Keppra), a new generation anti-epileptic drug, in the plus-maze animal test for anxiolytic activity. Levetiracetam at 17 and 54 mg/kg intraperitoneally (i.p.) was without effect when tested in naive rats. A modified version of the test was subsequently used in which open-arm exploration was decreased by exposure of the rats to a four-open-arm maze 24 h prior to drug treatment and testing. Under these conditions of enhanced anxiety, levetiracetam, 5.4 to 54 mg/kg, dose-dependently increased open-arm exploration. Chlordiazepoxide 5 mg/kg had similar effects although buspirone 0.1 to 1.0 mg/kg was inactive. The results with levetiracetam substantiate similar findings of its anxiolytic actions against chlordiazepoxide withdrawal-induced anxiety in mice and in a modified Vogel test in rats and support a potential clinical use of this drug in anxiety states.
Neurology. 2003 Nov 11;61(9):1218-21. :
Discontinuation of levetiracetam because of behavioral side effects: a case-control study.
White JR, Walczak TS, Leppik IE, Rarick J, Tran T, Beniak TE, Matchinsky DJ, Gumnit RJ.
MINCEP Epilepsy Care, Minneapolis, MN 55416, USA.
jrwhitemincep@msn.com
BACKGROUND: Levetiracetam (LEV) is a recently approved anticonvulsant with proven efficacy and safety in the treatment of partial seizures. LEV may cause behavioral abnormalities that can be severe and require discontinuation of this drug. Risk factors for discontinuing LEV have not been established. OBJECTIVE: To determine incidence of behavioral abnormalities severe enough to require discontinuation of LEV and identify risk factors for such behavioral abnormalities. METHODS: All patients treated with LEV at MINCEP between January 2000 and February 2002 constituted the study population (n = 553). Patients who had discontinued LEV for behavioral reasons were selected as index cases. Case controls were patients starting LEV immediately after the index case. Potential risk factors for LEV discontinuation included age, gender, cognitive function, history of psychiatric diagnosis, epilepsy syndrome, number of antiepileptic drugs, titration rate, maximum dose of LEV, and LEV level at maximum dose. RESULTS: Thirty-eight patients (6.9%) discontinued LEV because of behavioral abnormalities. Variables associated with LEV discontinuation included faster titration rate to maximal dose, history of a psychiatric disorder, and diagnosis of symptomatic generalized epilepsy. Patients who discontinued LEV owing to behavioral reasons had significantly lower maximum LEV doses than controls. CONCLUSIONS: This study identified variables associated with discontinuation of LEV due to behavioral abnormalities. Slower titration of LEV should be considered in those patients at higher risk of discontinuing LEV for behavioral reasons.
: Expert Opin Pharmacother. 2003 Nov;4(11):2079-88. :
Levetiracetam: treatment in epilepsy.
Ben-Menachem E.
University of Goteborg, Sahlgren Hospital, Goteborg, Sweden.
ebm@neuro.gu.se
A large number of new antiepileptic drugs (AEDs) have become available over the last 10 years. Results from placebo-controlled clinical trials and community-based practice have demonstrated that levetiracetam has a broad spectrum of activity in suppressing seizures as add-on treatment and monotherapy and that it is safe and well-tolerated. Levetiracetam also has a favourable pharmacokinetic profile characterised by rapid and nearly complete absorption, very low potential for drug interactions and a prolonged pharmacodynamic effect that permits twice-daily dosing. Although, the mechanism of action of levetiracetam is not completely understood, preclinical studies suggest that it may have antiepileptogenic and neuroprotective effects, with the potential to slow or arrest disease progression.
Mov Disord. 2003 Nov;18(11):1301-5. :
Novel antiepileptic drug levetiracetam decreases dyskinesia elicited by L-dopa and ropinirole in the MPTP-lesioned marmoset.
Hill MP, Bezard E, McGuire SG, Crossman AR, Brotchie JM, Michel A, Grimee R, Klitgaard H.
Motac Neuroscience Ltd, Manchester, United Kingdom.
Long-term dopamine replacement therapy of Parkinson's disease leads to the occurrence of dyskinesias. Altered firing patterns of neurons of the internal globus pallidus, involving a pathological synchronization/desynchronization process, may contribute significantly to the genesis of dyskinesia. Levetiracetam, an antiepileptic drug that counteracts neuronal (hyper)synchronization in animal models of epilepsy, was assessed in the MPTP-lesioned marmoset model of Parkinson's disease, after coadministration with (1) levodopa (L-dopa) or (2) ropinirole/L-dopa combination. Oral administration of levetiracetam (13-60 mg/kg) in combination with either L-dopa (12 mg/kg) alone or L-dopa (8 mg/kg)/ropinirole (1.25 mg/kg) treatments was associated with significantly less dyskinesia, in comparison to L-dopa monotherapy during the first hour after administration. Thus, new nondopaminergic treatment strategies targeting normalization of abnormal firing patterns in basal ganglia structures may prove useful as an adjunct to reduce dyskinesia induced by dopamine replacement therapy without affecting its antiparkinsonian action.
Epilepsy Behav. 2003 Oct;4(5):571-5. :
Landau-Kleffner syndrome responsive to levetiracetam.
Kossoff EH, Boatman D, Freeman JM.
Department of Neurology, The Johns Hopkins Hospital, Jefferson 128, 600 North Wolfe Street, Baltimore, MD 21287-1000, USA.
ekossoff@jhmi.edu
A 5-year-old girl with Landau-Kleffner syndrome is discussed. The child began having seizures at age 4 associated with language deterioration despite anticonvulsant therapy. With levetiracetam monotherapy to a dose of 60 mg/kg/day and discontinuation of carbamazepine and valproic acid, her language has improved and seizures are controlled. Levetiracetam should be considered as therapy for Landau-Kleffner syndrome.
Epilepsy Behav. 2003 Oct;4(5):537-47. :
Aggressive behavior of epilepsy patients in the course of levetiracetam add-on therapy: report of 33 mild to severe cases.
Dinkelacker V, Dietl T, Widman G, Lengler U, Elger CE.
Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud Strasse 25, 53105 Bonn, Germany.
vera.dinkelacker@ukb.uni-bonn.de
Levetiracetam (LEV) was shown to be very efficacious and well tolerated as add-on therapy for refractory epilepsy. Here we report 33 patients with longstanding histories of epilepsy who experienced aggressive episodes during LEV therapy. This corresponds to 3.5% of LEV-treated patients as compared with less than 1% of patients not on LEV. Among these cases, 24 showed only moderate, partly transient irritability, with 10 patients requiring reduction or discontinuation of LEV. More strikingly, 9 patients displayed severe symptoms of aggression with physical violence and, in 2 cases, the need for psychiatric emergency treatment. One patient developed additional psychotic symptoms. We suggest that, specifically in patients with a previous history of aggression, behavioral tolerability of LEV should be carefully monitored.
Epilepsy Res. 2003 Oct;56(2-3):121-6. :
Levetiracetam does not alter body weight: analysis of randomized, controlled clinical trials.
Gidal BE, Sheth RD, Magnus L, Herbeuval AF.
Department of Neurology, School of Pharmacy, University of Wisconsin, 777 Highland Ave., Madison, WI 53705, USA.
begidal@pharmacy.wisc.edu
INTRODUCTION: Increases in body weight gain are important, and clinically significant adverse effects of several antiepileptic drugs (AED) including valproate and gabapentin. Weight gain may contribute to medication non-compliance, discontinuation, and importantly, may have secondary medical implications as well. Levetiracetam (LEV) is indicated for adjunctive treatment of partial seizures. The objective of the present evaluation was to examine the effects of LEV treatment on body weight in adult patients. METHODS: We analyzed data derived from four prospective, placebo-controlled randomized, clinical trials conducted in both in the US and Europe. Patients included in the present analysis were both men and women, greater than 16 years old, and who had LEV exposure for at least 1 month. Body weight was measured at baseline and at the final LEV study visit. Data are analyzed for all patients, by gender, body mass index (BMI), duration of LEV exposure and by concomitant AED treatment. Wilcoxan Signed Rank, or Rank Sum test used where appropriate, with significance assigned at P<0.05. Data are presented as mean values+/-1 S.D. RESULTS: Nine-hundred and seventy patients (age=37.5 years, 54% men/46% women) were evaluated. There were no significant differences in baseline demographics between LEV (n=631) or placebo (n=339) treated patient groups. Mean LEV dose and duration of treatment were 2053 mg/day (maximum dose of 4000 mg/day) and 125 days (maximum=181 days), respectively. Concomitant AED therapy included CBZ, PHT, VPA, PB, GBP, LTG, and VGB. For LEV-treated patients, no significant changes in body weight were noted. Mean body weight at baseline versus final study visit for LEV was 74.3+/-16.6 kg and 74.3+/-16.6 kg, respectively. For placebo-treated patients, baseline versus end of treatment weight was 72.4+/-15.4 kg and 72.7+/-15.9 kg, respectively, representing a slight, yet clinically trivial increase. Clinically significant weight change as defined as >7% change from baseline weight, occurred in 9% of LEV-treated patients (4.5% had increase in weight/4.5% decrease) versus 9.4% (5.9% had increase/3.5% decrease) in placebo-treated patients. Weight changes were not significantly different between groups. Neither baseline BMI, gender, or background AEDs, appeared to predispose to significant weight change for LEV-treated patients. CONCLUSIONS: We conclude that treatment with LEV at clinically relevant dosages is not associated with significant weight change. LEV would, therefore, appear to be a weight neutral AED
Rev Neurol. 2003 Sep 16-30;37(6):558-60. :
[Levetiracetam in children and adolescents with epilepsy]
[Article in Spanish]
Herranz JL.
Neuropediatria, Hospital Universitario Marques de Valdecilla. Universidad de Cantabria, Santander, Espana.
pedhfj@humv.es
AIMS: The aim of this paper is to report on the clinical experiences that have been published concerning the association of levetiracetam (LEV) in children and adolescents with refractory epilepsies. DEVELOPMENT: Although LEV has been approved for use in polytherapy in patients over the age of 16, some short works (communications and posters in international congresses) and three open studies have already dealt largely with the fact that the drug has been associated in children and in adolescents under the age of 16, with all types of refractory seizures, especially focal seizures. Half the patients can be considered to be responders, since the seizure rate is reduced by more than 50% when LEV is associated, and were completely eradicated in 16% of cases. In a third of the cases side effects were reported, although they can be seen as being mild and transient since they meant that LEV application was interrupted in less than 10% of cases. CONCLUSIONS: LEV is a drug that is effective and well tolerated in children and adolescents with difficult-to-treat epilepsies; it is very straightforward to manage due to its excellent pharmacokinetic characteristics and suggested dosages at these ages are between 40 and 50 mg/kg/day (up to 3,000 mg per day, in two doses).
J Clin Psychiatry. 2003 Jul;64(7):781-4. :
Levetiracetam in the treatment of acute mania: an open add-on study with an on-off-on design.
Grunze H, Langosch J, Born C, Schaub G, Walden J.
Department of Psychiatry at the University of Munich, Germany.
grunze@psy.med.uni-muenchen.de
BACKGROUND: Levetiracetam is a novel antiepileptic drug with a broad spectrum of efficacy in epilepsy. We have tested the antimanic properties of the drug as an add-on to haloperidol in an open trial. METHOD: After giving informed written consent, 10 bipolar I acutely manic (DSM-IV) inpatients were investigated in an on-off-on study design. All patients were treated with 5 to 10 mg/day of haloperidol, depending on tolerability, throughout the investigation. Levetiracetam (up to 4000 mg/day) was added until day 14, then discontinued and reintroduced at day 21. The psychopathologic changes were assessed with the Young Mania Rating Scale (YMRS). RESULTS: After a mean decrease of the YMRS scores from 29.6 to 17.2 during the first "on" phase, manic symptoms worsened during the "off" period (YMRS score 20.9) and ameliorated again during the second "on" phase, with a decrease of the mean YMRS score to 14.7 at the end of the study. The mean dose of levetiracetam was 3125 mg/day. At day 14, only 2 (20%) of 10 patients were responders (defined as a decrease in YMRS scores of 50%) compared with 7 (70%) of 10 responders at the end of the study at day 28. CONCLUSION: The results from this open on-off-on add-on study suggest that levetiracetam exhibited additional antimanic effects. Controlled studies are clearly required.
Epileptic Disord. 2003 Jun;5(2):117-9. :
Acute psychosis associated with levetiracetam.
Youroukos S, Lazopoulou D, Michelakou D, Karagianni J.
First Department of Paediatrics, Athens University Medical School, "St. Sophia" Children's Hospital, Athens, Greece.
sotel@hol.gr
A twelve year-old-girl with idiopathic partial epilepsy with secondary generalization, developed acute psychosis 10 days after the administration of levetiracetam. The patient was already on sodium valproate, and levetiracetam was given as add on therapy. A final dosage of 60 mg/kg was used. Complete seizure control was achieved but the patient developed hallucinations, agitation and self-harming behaviour, as well as poor social contact.The psychotic behavior resolved completely soon after the discontinuation of levetiracetam
J Psychopharmacol. 2003 Jun;17(2):239-41. :
Levetiracetam in the treatment of rapid cycling bipolar disorder.
Braunig P, Kruger S.
Klinik fur Psychiatrie, Verhaltensmedizin und Psychosomatik, Chemnitz, University of Dresden, Dresden, Germany.
p.braeunig@skc.de
Levetiracetam (LEV) is a novel anticonvulsant that is currently investigated in bipolar disorder. It may be useful in the treatment of refractory and complicated cases, in which conventional mood stabilizers are not effective. We report two cases of rapid cycling bipolar disorder in which the add-on of LEV to a conventional treatment regimen improved symptoms of depression, as well as those of mania/mixed mania, and disrupted the severe rapid cycling pattern.s
