Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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Levetiracetam is a pyrrolidone derivative and not related to any of the antiepileptic drugs currently in use. It has been approved by the Food and Drug Administration in the United States and in the European Union and various other countries. Although levetiracetam is more expensive than traditional antiepileptic drugs, its cost is comparable to that of newer antiepileptic drugs.
The chemical name of levetiracetam is (S)-alpha-ethyl-2-oxo-pyrrolidine acetamide.
Pharmacodynamics. The exact mechanism of action of levetiracetam is not known. Levetiracetam binds selectively to a synaptic vesicle protein (SV2) involved with presynaptic neurotransmitter release. Glioma patients who respond well to treatment with levetiracetam for control of seizures have significantly stronger SV2A expression as demonstrated by immunohistochemical examination of tumor as well as in peritumoral tissue than patients who did not show such a response (05).
Unlike all other antiepileptic agents currently available, levetiracetam shows no activity in 2 standard acute seizure models used to screen new compounds for evidence of seizure control (the maximal electroshock model and the pentylenetetrazol seizure model). Paradoxically, however, levetiracetam is highly effective in animal models of chronic epilepsy, with broad spectrum activity in models for partial and generalized epilepsy. In vivo studies show that inhibitory CNS effects of levetiracetam are due to ion channel modulation.
Pharmacokinetics. Important points of pharmacokinetics of levetiracetam are as follows:
• It is completely absorbed after oral administration and has predictable, linear pharmacokinetics. The extent of absorption is unaffected by food. Two-thirds of the dose is excreted unchanged by the kidneys.
• With twice-daily dosing, steady state is reached after 48 hours.
• It is less than 10% protein-bound, and metabolism is not dependent on hepatic cytochrome P450.
• Plasma half-life is approximately 6 to 8 hours, but this is increased in patients with renal impairment.
• Both serum and cerebrospinal fluid levetiracetam concentrations rise essentially linearly and dose-dependently, suggesting that transport across the blood-brain barrier is not rate-limiting. Half-life in the central nervous system is longer than plasma half-life.
• Serum samples separated immediately from withdrawn blood are recommended for therapeutic monitoring of levetiracetam level, as B-esterases in whole blood can metabolize levetiracetam and cause spuriously low concentrations.
Therapeutic drug monitoring. In 1 study, blood levels of levetiracetam ranging between 20 and 40mg/L were helpful in the management of seizures, and impaired efficacy of the drug with drop in therapeutic levels were explained by interactions with other antiepileptic comedications (33). Another study concluded that routine therapeutic drug monitoring is not necessary but suggested the need for further investigations in special patient populations (30).
A simple, fast, and cost-effective method for the determination of levetiracetam in plasma/serum of patients using high performance liquid chromatography with ultraviolet detection requires minimal sample preparation and is suitable for daily routine use in therapeutic drug monitoring (08). A study has demonstrated transdermal extraction of measurable amounts of levetiracetam across the pig ear skin by reverse iontophoresis for noninvasive therapeutic drug monitoring (10).
Methods of administration. Although mostly used as oral preparation, intravenous formulations are also available. Continuous subcutaneous levetiracetam infusion has been used in the management of seizures at the end of life (36). An open study has shown that an extended-release formulation of levetiracetam was well tolerated when administered as long-term monotherapy or in combination with other AEDs in patients with inadequately controlled partial onset epilepsy (02). A controlled clinical trial has shown that extended-release and immediate-release formulations of levetiracetam are equivalent in reducing the frequency of partial-onset seizures and have a similar tolerability as an adjunctive treatment for adult patients with uncontrolled epilepsy (37).
The first clinical trials on which approval of levetiracetam was based, were conducted between 1995 and 2000. Levetiracetam has been investigated as add-on therapy for partial seizures in 3 placebo-controlled phase 3 studies. In these studies, 904 patients, in both the United States and Europe, had experienced refractory partial onset seizures with or without secondary generalization for at least 2 years and had taken 2 or more standard antiepileptic drugs. The measure of effectiveness included the responder rate (incidence of patients with a greater than 50% reduction from baseline in partial onset seizure frequency for the entire treatment period). The responder rate was statistically significantly greater in patients taking levetiracetam 1000 mg/day, 2000 mg/day, or 3000 mg/day as compared to placebo within each study. The responder rate was between 22.8% and 33% on 1000 mg, 31.6% on 2000 mg, and between 39.4% and 42.1% on 3000 mg, as compared to placebo rates of 10.9% to 16.7% (13). A few selected clinical trials of levetiracetam during the previous decade are cited in this article.
A randomized, single-blind, placebo-controlled study showed that levetiracetam administered by intravenous infusion was well tolerated in healthy subjects and the pharmacokinetic profile was consistent with orally administered levetiracetam.
In a prospective add-on study of children with refractory epilepsy, levetiracetam was effective in 54.3% of patients, decreasing seizure frequency to at least 50% of baseline frequency (34).
In Asia SKATE II study, levetiracetam was well tolerated and efficacious as adjunctive therapy for partial epilepsy in Asian populations (16).
A Cochrane review of 11 clinical trials concluded that it is reasonable to continue the use of levetiracetam in both adults and children with drug-resistant focal epilepsy, but longer-term effects of monotherapy on generalized seizures cannot be determined from these results (22).
An open phase II trial of levetiracetam following acute head injury in children who were at risk for developing posttraumatic epilepsy showed that only 1 child among 40 participants developed this complication (24). These results support the conduct of a prospective phase II levetiracetam trial following acute head injury in children at risk for posttraumatic epilepsy.
A metaanalysis of randomized-controlled trials of levetiracetam as an adjunctive therapy in epilepsy of multiple seizure types showed efficacy in reducing the frequency of seizures in partial as well as idiopathic generalized epilepsy in both adults and children, with good tolerance (09).
A randomized, double-blind, placebo-controlled crossover study of the effects of levetiracetam on cognition, mood, and balance in healthy older adults showed that the drug was well tolerated in this population and had pharmacokinetic advantages (28).
Levetiracetam is indicated as an adjunctive therapy in the treatment of partial seizures with or without secondary generalization in adults.
In 2006, the European Commission approved the use of levetiracetam as adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age or older with juvenile myoclonic epilepsy. In 2007, the European Commission approved a new indication for levetiracetam as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients with idiopathic generalized epilepsy.
Phenytoin is the current standard of care for second-line treatment of pediatric convulsive status epilepticus after failure of first-line benzodiazepines, but is only effective in 60% of cases and is associated with considerable adverse effects. Intravenous levetiracetam is used in patients with status epilepticus who do not respond to intravenous benzodiazepines. A review of case series and prospective studies shows the success rate of levetiracetam for termination of status epilepticus to be 55 % to 59.4 %, but its use in the treatment of generalized convulsive status epilepticus is still questionable because of delayed effect (25). Results of 2 randomized clinical trials show that levetiracetam is no better than phenytoin in terminating status epilepticus in children (04; 19). However, the relative safety and comparative ease of administration of levetiracetam suggest that it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of pediatric convulsive status epilepticus.
Other reported uses of levetiracetam include the following:
• Management of acute mania
• Treatment of paroxysmal kinesigenic choreoathetosis
• Levetiracetam reduces phasic spasticity but not tonic spasticity in multiple sclerosis.
• A double-blind, randomized controlled trial did not show efficacy of levetiracetam in generalized social anxiety disorder (32).
• Cluster headaches
• Pediatric migraine
• For the treatment of levodopa-induced dyskinesias in Parkinson disease (31)
• Tourette syndrome
• Tardive dyskinesia
• Meige syndrome
• As monotherapy in Alzheimer patients with late-onset seizures
• Adjunctive treatment for patients with anxiety disorders
• As add-on therapy in severe myoclonic epilepsy of infancy
• Treatment of lumbar radiculopathy
• Late-onset myoclonic epilepsy in Down syndrome (27)
• Most of the placebo-controlled clinical trials of levetiracetam for the treatment of neuropathic pain have not shown any benefit (06).
• In a mouse model of Alzheimer disease, chronic treatment with levetiracetam was shown to reverse behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory (26).
• Although open studies suggested usefulness of levetiracetam in alcohol withdrawal, a randomized-controlled trial showed it was ineffective (17).
• A multicenter, retrospective, open-label study has shown that levetiracetam is effective for electrical status epilepticus during sleep (01).
• Levetiracetam has been used for the treatment of epileptic seizures after liver transplantation (18).
• Levetiracetam has been used to increase survival in patients with glioblastoma multiforme receiving temozolomide-based chemotherapy. Results of a combined analysis of levetiracetam use at the start of chemoradiotherapy with temozolomide in 4 contemporary, randomized clinical trials of patients with glioblastoma did not show any survival benefits, and use of levetiracetam is not justified for reasons other than seizure control (12).
• Levetiracetam was used for successful control of clonic seizures in an infant with epileptic encephalopathy due to mutation of syntaxin binding protein 1 (STXBP1) gene after other antiepileptic drugs had failed (07). Levetiracetam acts by modulating the synaptic vesicle release, which is affected by STXBP1 mutation.
• A retrospective study has shown that levetiracetam is effective in treatment of seizures due to neonatal hypoxic ischemic encephalopathy (35).
Levetiracetam is contraindicated in patients with a demonstrated hypersensitivity to this compound.
The aim of treatment is control of seizures that have been refractory to other antiepileptic drugs. During the development program with treatment duration of between 1 and 8 years, 1393 adults and 29 children with epilepsy were exposed to levetiracetam. Using the Kaplan Meier method, the levetiracetam retention rate in this refractory population is estimated to be 58% after 1 year, 43% after 2 years, and 36% after 3 years; it then remains stable for up to 8 years. In a retrospective study on children with epilepsy due to lesions demonstrable on MRI and intellectual disability who were resistant to other antiepileptic drugs, oral levetiracetam treatment achieved control of seizures in over 50% of cases with tolerable adverse effects (23).
The effective daily starting dose is 500 mg twice daily. Dosing can be increased with 1000 mg increments to 3000 mg/day.
In 2006, the FDA approved levetiracetam injection 500 mg/5mL (100 mg/mL) for use as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy. This is an alternative for patients when oral administration is temporarily not feasible.
Pediatric. Levetiracetam is still in clinical studies for pediatric epilepsies. The pharmacokinetics of levetiracetam in children are like those in adults, except with a higher nonrenal clearance (approximately 40% greater), which may explain the need for higher doses in children compared to adults. Levetiracetam treatment is safe and effective in children younger than 2 years of age with various types of epilepsy. A randomized, blinded, phase IIb trial of efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment for neonatal seizures of any cause showed that phenobarbital was more effective than levetiracetam, although higher rates of adverse effects were seen with phenobarbital treatment (Sharpe et al 2020). Because an improvement in efficacy of levetiracetam was achieved with dose escalation, higher-dose studies of levetiracetam are warranted.
Geriatric. Dosage should be adapted in cases of renal insufficiency. In patients with moderate to severe renal dysfunction, the dose of levetiracetam should be reduced by 50%, still given twice daily.
Pregnancy. A study based on registers of epilepsy and pregnancy in UK and Ireland showed a low risk for major congenital malformations with levetiracetam monotherapy as compared to its use as a part of polytherapy regimen (21). Another retrospective study showed that the use of levetiracetam as monotherapy during pregnancy has the same risk level for fetal malformations as the group who never used antiepileptic drugs and that the risk increased when it was used as a part of polytherapy (15). No controlled studies have been performed in pregnant women. Because of the potential risk to the fetus during pregnancy, levetiracetam should be used only if the benefits outweigh the risks.
Anesthesia. No special precautions are listed.
Levetiracetam has no known interactions with other drugs. It may be given to women without reducing the effectiveness of oral contraceptives.
In clinical studies, levetiracetam was generally well tolerated by patients. When levetiracetam was given with other antiepileptics, the most frequently reported adverse events were somnolence, asthenia, and dizziness. Adverse events were usually mild to moderate in intensity. Some appeared to occur predominantly during the first 4 weeks of treatment. A case of cutaneous small-vessel vasculitis that occurred within 8 days of initiation of levetiracetam was successfully managed by discontinuation of medication and systemic corticosteroids (11).
A long-term follow-up study found levetiracetam to be effective and well tolerated, but the most common adverse event (24.3%) was irritability, which was higher in patients with a history of mood disorders (14).
Paradoxical aggravation of seizures. In some cases, levetiracetam may increase seizures. Some examples include the following:
• Mentally retarded patients with therapy-resistant seizures where high doses of levetiracetam are used.
• Myoclonic astatic epilepsy (20).
• Levetiracetam may possibly induce seizure exacerbation in a subset of patients with focal cortical dysplasia–related epilepsy (03).
K K Jain MD
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.See Profile
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