Effect of levetiracetam on DNA oxidation and glutathione content in a temporal lobe epilepsy model.

Levetiracetam (LEV) is a drug commonly used as an anticonvulsant. However, recent evidence points to a possible role as an antioxidant. We previously demonstrated the antioxidant properties of LEV by significantly increasing catalase and superoxide dismutase activities and decreasing the hydrogen peroxide (H2O2) levels in the hippocampus of rats with temporal lobe epilepsy (TLE) showing scavenging properties against the hydroxyl radical. The aim of the present work was to evaluate, the effect of LEV on DNA oxidation, by determining 8­hydroxy­2­deoxyguanosine (8­OHdG) levels, and glutathione content, through reduced (GSH) and oxidized (GSSG) glutathione levels, in the hippocampus of rats with TLE. Male Wistar rats were assigned to the control (CTRL), CTRL+LEV, epileptic (EPI) and EPI+LEV groups. TLE was induced using the lithium­pilocarpine model. Thirteen weeks after TLE induction, LEV was administered for one week through osmotic pumps implanted subcutaneously. The determination of 8­OHdG, GSH and GSSG levels were measured using spectrophotometric methods. We showed that LEV alone significantly increased 8­OHdG and GSSG levels in the hippocampus of control rats compared to those in epileptic condition. No significant differences in GSH levels were observed. LEV could induce changes in the hippocampus increasing DNA oxidation and GSSG levels under nonepileptic condition but not protecting against the mitochondrial dysfunction observed in TLE probably by mechanisms related to changes in chromatin structure, neuroinflammation and alterations in redox components.

Modulation of hippocampal activity in schizophrenia with levetiracetam: a randomized, double-blind, cross-over, placebo-controlled trial.

Hippocampal hyperactivity is a novel pharmacological target in the treatment of schizophrenia. We hypothesized that levetiracetam (LEV), a drug binding to the synaptic vesicle glycoprotein 2 A, normalizes hippocampal activity in persons with schizophrenia and can be measured using neuroimaging methods. Thirty healthy control participants and 30 patients with schizophrenia (28 treated with antipsychotic drugs), were randomly assigned to a double-blind, cross-over trial to receive a single administration of 500 mg oral LEV or placebo during two study visits. At each visit, we assessed hippocampal function using resting state fractional amplitude of low frequency fluctuations (fALFF), cerebral blood flow (CBF) with arterial spin labeling, and hippocampal blood-oxygen-level-dependent (BOLD) signal during a scene processing task. After placebo treatment, we found significant elevations in hippocampal fALFF in patients with schizophrenia, consistent with hippocampal hyperactivity. Additionally, hippocampal fALFF in patients with schizophrenia after LEV treatment did not significantly differ from healthy control participants receiving placebo, suggesting that LEV may normalize hippocampal hyperactivity. In contrast to our fALFF findings, we did not detect significant group differences or an effect of LEV treatment on hippocampal CBF. In the context of no significant group difference in BOLD signal, we found that hippocampal recruitment during scene processing is enhanced by LEV more significantly in schizophrenia. We conclude that pharmacological modulation of hippocampal hyperactivity in schizophrenia can be studied with some neuroimaging methods, but not others. Additional studies in different cohorts, employing alternate neuroimaging methods and study designs, are needed to establish levetiracetam as a treatment for schizophrenia.

Evaluation of the safety and tolerability of intravenous undiluted levetiracetam at a pediatric institution.

STUDY OBJECTIVE: Recent studies suggest rapid administration of high-dose, undiluted levetiracetam is safe in adults; however, no information exists in pediatric patients. The purpose of this study was to evaluate the safety and tolerability of undiluted levetiracetam at a pediatric institution. DESIGN: Retrospective, single-center, cohort study. SETTING: Pediatric Academic Medical Center. PATIENTS: All patients who received high-dose >60 mg/kg (-10%) up to 4500 mg undiluted or diluted intravenous levetiracetam were included. INTERVENTION: Rapid intravenous administration of undiluted versus diluted levetiracetam. MEASUREMENTS AND MAIN RESULTS: A total of 776 levetiracetam doses were included, 358 doses administered and 418 doses wasted. The doses administered (61 undiluted and 297 diluted) accounted for a total of 252 patients (39 received undiluted, and 213 received diluted levetiracetam) (median [minimum-maximum range] age, 2 years [1 day to 32.7 years]; mean (standard deviation [SD]) weight, 20.1 kg [22.1 kg]). The incidence of hemodynamic disturbances and infusion-related reactions was not statistically significant between undiluted (24.6%) and diluted (26.3%) groups (p = 0.87). The median (interquartile range [IQR]) time difference between first-line antiseizure medication and levetiracetam administration in patients with status epilepticus was 18 min (10.5-30.5) in the undiluted group versus 36.5 min (21.8-67.3) in the diluted group (p < 0.01). Additionally, there was a significant amount of drug waste from dispensed but not administered doses of the diluted bag compared to undiluted vials (57.6% diluted vs. 18.7% undiluted, p < 0.001). CONCLUSION: Undiluted levetiracetam was not associated with an increased incidence of adverse effects compared to diluted levetiracetam in high-doses, up to 4500 mg given over 5 min in pediatric patients.

Successful use of intravenous and oral levetiracetam in a goat to control refractory seizures secondary to suspected polioencephalomalacia.

OBJECTIVE: To assess the clinical efficacy and plasma concentrations of levetiracetam in a goat with seizures. ANIMAL: A 5-month-old doeling. CLINICAL PRESENTATION, PROGRESSION, AND PROCEDURES: The goat was referred because of progressive anorexia and lethargy over 3 days. Clinical signs consisted of weakness, obtundation, opisthotonos, anisocoria, and cortical blindness. Initial evaluation was most consistent with polioencephalomalacia. TREATMENT AND OUTCOME: Neurologic improvement occurred within 4 hours of thiamine administration, with appetite returning over 12 hours. On day 3 of hospitalization, the goat suffered acute onset repetitive seizures that were incompletely responsive to standard interventions over 3 hours. Administration of IV levetiracetam (60 mg/kg) produced resolution of seizure activity within 20 minutes. Levetiracetam was continued twice daily IV, then PO after day 6. Plasma concentrations were above or within therapeutic ranges (5 to 45 µg/mL) as previously established for other species, following both IV and PO levetiracetam. Oral administration (60 mg/kg, PO, q 12 h) resulted in plasma levetiracetam concentrations of 48.1 µg/mL 2 hours after a dose and 23.4 µg/mL 2 hours prior to the next dose. CLINICAL RELEVANCE: Levetiracetam is a newer anticonvulsant commonly used in humans and small animals due to its efficacy, cost, and wide safety margin. Its use has not previously been reported in domestic small ruminants. In this case, levetiracetam showed excellent clinical efficacy in the face of refractory seizures, with no apparent side effects. Plasma concentrations during oral administration were at the high end of the therapeutic range, indicating absorption in a nonmonogastric species. Further studies are warranted to determine optimal dosing in small ruminants.

Dosage, time, and polytherapy dependent effects of different levetiracetam regimens on cognitive function.

OBJECTIVE: Cognitive impairment is a potential drawback of antiseizure medications. This study aimed to evaluate the impact of different levetiracetam drug regimens on cognitive function. METHODS: A retrospective analysis identified 221 patients diagnosed with seizures who underwent cognitive screening. Patients were categorized into four groups: no medications, non-levetiracetam medications, high and low dose levetiracetam. Composite scores determined low and high levetiracetam groups whereby one point was added for each increment in dosage, duration since uptake, and concurrent anti-seizure medication. Variables known to affect cognition were recorded and classified as demographic, seizure-related, diagnosis-related, and psychopathology. Logistic regression was used to identify variables associated with cognitive scores below cut-off. RESULTS: Multivariable analysis found being male, non-active in the community, less than 12 years of education, left temporal lobe epilepsy, high seizure frequency, and depression were associated with poor cognitive performance. In a final regression analysis, the high levetiracetam group exhibited a 4.5-fold higher likelihood of scoring below cut-off than the medication-free group (OR 4.5, CI 1.5-13.6, p<.08). Depression (OR 2.1, CI 1.1-3.9, p<.03), being male (OR 2.2, CI 1.1-4.3, p<.02), and not being active in the community (OR 3.8, 1.6-8.7, p <.003) remained significant contributors to the model. Language (p<.05), attention (p<.05), and delayed recall (p<.001) were the most affected cognitive domains. SIGNIFICANCE: When taken in small doses, for brief periods as monotherapy, levetiracetam minimally influences cognition. At higher doses, as part of long-term seizure management, in conjunction with multiple ASMs, LEV is associated with cognitive impairment.

Status epilepticus prognosis following levetiracetam administration: Analysis of loading doses.

BACKGROUND AND PURPOSE: Recommended loading doses of levetiracetam (LEV) for status epilepticus (SE) treatment have increased over time. However, this was not evidence-based, and the benefit of the increase remains unclear. The effect of different LEV loading doses on SE prognosis was explored. METHODS: This is a retrospective analysis of an SE adult registry (January 2016-December 2021), including patients receiving LEV as a second-line SE treatment. Patients were stratified according to LEV loading doses (threshold 35 mg/kg). Main outcomes were global mortality, LEV use as last SE treatment, and return to baseline conditions at discharge, exploring LEV as a dichotomized or continuous dose. RESULTS: Among 202 patients, 44 received LEV at ≥35 mg/kg and 158 below it. Global mortality, adjusted for SE severity and potentially fatal aetiology, was more frequent in the high LEV dose group (27.2% vs. 17.1%, odds ratio 3.14, 95% confidence interval 1.23-8.06; p = 0.017), whilst LEV prescription as last treatment and return to baseline conditions were comparable. Considering continuous LEV dosages or mortality in ongoing SE, however, no outcome reached statistical significance. CONCLUSIONS: Lower LEV loading doses do not seem to correlate with worse clinical outcome, challenging current guidelines. Further studies, ideally prospective, are needed on this topic.

Experience of Subcutaneous Levetiracetam in Palliative Care.

BACKGROUND: Seizures are common in palliative care patients and its control is essential in the management of these patients as it helps to reduce suffering at the end of life. Subcutaneous levetiracetam has been used off-license for seizure control in palliative care. OBJECTIVE: The objective of the study was to describe our experience with subcutaneous levetiracetam in two hospitals in Bogota, Colombia. METHODS: We conducted a retrospective review of patients treated with subcutaneous levetiracetam in two hospitals in Colombia during 2019-2021. Data were extracted from medical records, and participants were followed up as outpatients. RESULTS: Twenty-one patients were included into the study. No severe adverse effects or rise in ictal frequency were documented. Twelve patients died during hospitalization and nine continued treatments as outpatients. The principal diagnosis was structural focal epilepsy. The daily dose of levetiracetam ranged from 1,000 mg to 3,000 mg, and the duration of treatment varied among subjects between 1 and 360 days. CONCLUSION: Subcutaneous levetiracetam was well tolerated and effective in controlling seizures in palliative care when oral administration or intravenous access was not an option. Randomized controlled trials are needed to elucidate the efficacy and tolerability of subcutaneous levetiracetam in clinical practice.

Association of Levetiracetam Concentration With Seizure Frequency in Pregnant Women With Epilepsy.

BACKGROUND AND OBJECTIVES: Pharmacologic treatment of epilepsy in pregnant women is balancing between risks for the mother and fetus. Levetiracetam (LEV) is considered to be safe during pregnancy because of its low teratogenic potential and lack of drug-drug interaction with other antiseizure medications (ASMs). Recent studies have shown decline of ASM concentrations during pregnancy because of physiologically based pharmacokinetic changes. In this study, we established this decrease in LEV concentration during pregnancy. In addition, we aimed at investigating the effect of the low LEV levels during pregnancy and developing a target value for the level during pregnancy. METHODS: Pregnant patients using levetiracetam were studied in this retrospective cohort study. Blood samples were monthly collected through venous puncture or the dried blood spot method. ASM serum concentrations were determined at least 6 months before conception and for each month of pregnancy. Seizure frequency and ASM dosages during pregnancy were obtained from patient records. Patients were divided into 2 groups: a seizure-free group and a non-seizure-free group, which contained pregnancies in which the mother had experienced an epileptic seizure more than 12 months and less than 12 months before pregnancy, respectively. RESULTS: We found decreased concentration/dose ratios in 29 pregnancies throughout all months of pregnancy. In the non-seizure-free group, it was found that low LEV concentrations were associated with seizure increase frequency (p = 0.022). For this group, the cutoff value with the highest sum of sensitivity and specificity was 0.466. DISCUSSION: All in all, we recommend therapeutic drug monitoring for all pregnant patients on LEV as the concentrations of LEV significantly decrease throughout most months of pregnancy. However, this decrease in LEV concentration was only significantly correlated with seizure deterioration in patients who had a seizure in the year preceding the pregnancy. Therefore, we suggest more careful monitoring of non-seizure-free patients as they are at higher risk for experiencing an increase of seizure frequency. For this group, we advise physicians to keep LEV concentration above 65% of the preconceptional concentration. For seizure-free patients, we recommend an LEV threshold value of approximately 46% of the preconceptional concentration.

Pyridoxine for treatment of levetiracetam-induced behavioral adverse events: A randomized double-blind placebo-controlled trial.

BACKGROUND: Levetiracetam is a broad-spectrum antiseizure medication with known behavioral side effects. The possible beneficial effect of pyridoxine on improvement of these psychiatric problems has been suggested in few previous studies. This clinical trial aimed to investigate the effect of pyridoxine on behavioral side effects of levetiracetam in adult patients with epilepsy. METHODS: This study was a randomized double-blind placebo-controlled clinical trial on 53 adult patients with epilepsy with behavioral side effects after treatment by levetiracetam. Patients who met the study criteria were randomized to receive 40 mg/day pyridoxine or placebo. Their psychiatric state was surveyed by SCL-90-R questionnaire before and three weeks after initiation of treatment. RESULTS: There were no statistically significant differences in the behavioral adverse effects between the pyridoxine-treated group and the placebo group. CONCLUSION: Although this study showed no statistically significant beneficial effects of pyridoxine on the behavioral adverse effects of levetiracetam, placebo-controlled trials with a larger size and higher doses are needed to determine whether it is effective or not.

Irritability and its relationship with psychosocial symptoms and quality of life in adolescents with epilepsy receiving levetiracetam therapy: A case-control study.

BACKGROUND: Levetiracetam, a widely used anticonvulsant drug in children and adolescents, has been associated with irritability, psychosocial symptoms, and low quality of life, which are also influenced by other epilepsy variables. PURPOSE: The objective of this study was to investigate the level of treatment-related irritability in adolescents receiving levetiracetam, and to evaluate the relationship between irritability levels and psychosocial symptoms, and quality of life. METHODS: A cross-sectional, case-control study was conducted. Consecutive adolescent patients with epilepsy aged 11-17 years with partial or generalized seizures, treated with either levetiracetam or valproic acid for at least 6 months, and healthy controls were recruited. The Affective Reactivity Index parent report and self-report, Strengths and Difficulties Questionnaire, and Pediatric Quality of Life Inventory-Psychosocial subscale were utilized to assess irritability, psychosocial symptoms, and functioning. RESULTS: A total of 120 participants were analyzed; 33 patients in the LEV group, 45 patients in the VPA group, and 42 healthy controls. Both self and parent report irritability levels of the LEV group were found to be significantly higher than those of healthy controls. The irritability levels of the LEV and VPA groups were not statistically different, but still the LEV group had higher irritability levels on both scales. In the LEV group, irritability was positively correlated with behavioral, emotional, and attention/hyperactivity problems, and also negatively correlated with psychosocial quality of life. CONCLUSION: Adolescents with epilepsy using LEV have a high level of irritability and this is associated with some psychosocial symptoms and poor quality of life.

Subcutaneous Levetiracetam and Sodium Valproate Use in Palliative Care Patients.

Palliative care patients experience seizures in different stages of their disease and may not tolerate oral medications toward the end of life. Subcutaneous infusions of levetiracetam and sodium valproate are increasingly used off-label. This retrospective analysis (conducted from January 2019 to July 2020 in Australia) reports the effectiveness and adverse effects of levetiracetam and sodium valproate delivered via subcutaneous infusion. The doses ranged from 500 to 3000 mg/d of levetiracetam and 500 to 2500 mg/d of sodium valproate. The concentrations ranged from 20 to 83 mg/mL of levetiracetam and 20 to 50 mg/mL of sodium valproate. Subcutaneous levetiracetam was given for a median duration of 6.5 days, with no seizure recurrences in 75% of patients and no reported adverse effects in any patients. Subcutaneous sodium valproate was given for a median duration of 3.5 days, with no reported seizure recurrences in 83% of patients and one report of a localized skin reaction. This analysis suggests that subcutaneous levetiracetam and sodium valproate can effectively control seizures in palliative care populations, with minimal localized reactions.

Regulation of Inflammation-Related Genes through Fosl1 Suppression in a Levetiracetam-Treated Pilocarpine-Induced Status Epilepticus Mouse Model.

Levetiracetam (LEV) suppresses the upregulation of proinflammatory molecules that occurs during epileptogenesis after status epilepticus (SE). Based on previous studies, LEV likely helps prevent the onset of epilepsy after insults to the brain, unlike other conventional anti-epileptic drugs. Recently, we discovered that the increase in Fosl1 expression that occurs after lipopolysaccharide (LPS) stimulation is suppressed by LEV and that Fosl1 inhibition suppresses inflammation in BV-2 microglial cells. These data indicate that Fosl1 is an important target of LEV and a key factor in preventing epilepsy onset. In this study, we examined the effects of LEV on Fosl1 expression and neuroinflammation in vivo. During epileptogenesis, the post-SE upregulation of hippocampal levels of Fosl1 and many inflammatory factors were suppressed by LEV. Fosl1 expression showed a characteristic pattern different from that of the expression of Fos, an immediate-early gene belonging to the same Fos family. At 2 days after SE, Fosl1 was predominantly expressed in astrocytes but was rarely detected in microglia, whereas Fos expression was distributed in various brain cell types. The expression of A2 astrocyte markers was similar to that of Fosl1 and was significantly suppressed by LEV. These results suggest that LEV may regulate astrocyte reactivity through regulation of Fosl1.

The safety of rapid infusion levetiracetam: A systematic review.

Epilepsy is a common diagnosis and can quickly progress to status epilepticus which requires rapid treatment. Levetiracetam is a frequent treatment choice in these situations. The approved administration of intravenous levetiracetam is an infusion over 15 min. In recent years, studies have been published on faster infusion rates of levetiracetam. The objective of this review is to discuss the safety of levetiracetam as an intravenous push at a rate quicker than recommended. A literature search using PubMed, Cochrane Library, ClinicalTrials.gov, and Google Scholar resulted in 192 articles. Inclusion criteria consisted of English language, human studies, use of levetiracetam administered intravenously at a rate faster than 15 min, discussion of safety, and full-text availability. After screening, nine articles remained for inclusion. Of the nine articles, one was a prospective, open-label study, six were retrospective studies, and two were open-label, randomized controlled trials. The most common rapid infusion speed was 5 min and doses ranged from 280 to 4500 mg. Some of these trials used undiluted levetiracetam and many reported that peripheral access was used for a portion or all of the administrations. There were few adverse effects, including specific adverse effects relating to medication concentration and speed of infusion, in all the studies. Administration of intravenous levetiracetam at a rate faster than recommended in the labeling information appears to be safe and tolerable and can be given via a peripheral line. Rapid infusion of levetiracetam is a beneficial method of administration in an acute care setting where patients need rapid attainment of therapeutic levels of antiepileptic medications. Additional research is needed to ensure that rapid administration of intravenous levetiracetam is as efficacious as the traditional dosing method.

Effect of levetiracetam on nocturnal sleep in patients with epilepsy.

AIM OF THE STUDY: The purpose of our study was the evaluation of the effect of 2,000 mg levetiracetam monotherapy over a 3-month period on nocturnal sleep in patients with epilepsy. CLINICAL RATIONALE: Levetiracetam (LEV) is a novel antiepileptic drug with a unique anticonvulsive mechanism of action. It has been commonly reported to cause sleep disruption and daytime sleepiness in epilepsy patients. Its advantages (its broad antiepileptic spectrum, optimal pharmacokinetics, good safety and tolerability) have led to its frequent use in clinical practice, although little is yet known about LEV's effect on nocturnal sleep architecture. MATERIAL AND METHODS: The effect of LEV on nocturnal sleep was assessed through a full-night lab polysomnography (PSG), followed by a four-nap multiple sleep latency test. Both procedures were performed at baseline and after three months of LEV treatment. The dynamics of seven main PSG variables was evaluated prior to, and three months after, LEV therapy. RESULTS: Twenty five patients with newly diagnosed or untreated epilepsy completed the study. We found no statistically significant difference at baseline and after LEV therapy in the following sleep parameters: total sleep time, sleep onset, wake after sleep onset, N1 stage and rapid eye movement (REM) sleep (minutes and percentages), and latency of all sleep stages including REM sleep. However, we found a statistically significant increase in the number of awakenings and arousals, an increase in N2 and a decrease in N3 stages (minutes and percentages) after therapy. We also observed an increase in N1 stage and a trend toward a reduction in REM sleep (in both minutes and percentages), but they did not reach statistical significance. CONCLUSIONS: Levetiracetam 2,000 mg/day does not affect sleep continuity and may be considered a sleep-friendly antiepileptic drug.

Efficacy of intravenous levetiracetam versus phenytoin in convulsive status epilepticus and acute repetitive seizures in children.

PURPOSE: Phenytoin is one of the most used antiepileptic drugs (AEDs), but it has serious potential side effects and drug interactions. Although studies have shown levetiracetam to have a much lower side-effect profile, its efficacy when compared with phenytoin is debatable. In our study, we aimed to determine the factors that cause seizure recurrence and to compare the efficacy of levetiracetam and phenytoin in the treatment of convulsive status epilepticus (CSE) and acute repetitive seizures (ARS). METHODS: In this study, 185 patients diagnosed with CSE or ARS and aged between 1 month and 18 years who received intravenous levetiracetam or phenytoin as a second-line AED were retrospectively evaluated. RESULTS: A total of 185 patients were included in the study, 85 (45.9%) girls and 100 (54.1%) boys.While 54.1% (n = 100) of the patients were given phenytoin, levetiracetam was administered to 45.9% (n = 85) of them. The rates of cessation of seizure and prevention of seizure recurrence for 24 h were 84% for phenytoin and 78.8% for levetiracetam, without a significant difference (p > 0.05). Having active seizures on admission to the emergency department and an age of < 36 months were significantly related to seizure recurrence (p < 0.01). CONCLUSIONS: Our results support that the intravenous administration of levetiracetam as the second-line treatment for CSE and ARS in children is as effective as the intravenous administration of phenytoin.

Relationship between bone density and levetiracetam monotherapy in epilepsy patients.

PURPOSE: Levetiracetam (LEV) is an anti-seizure drug (ASD). A consensus has not been reached regarding its effects on bone health. This cross sectional study was planned to assess short, medium and long-term effects on bone density and blood parameters that are associated with bone metabolism. METHODS: The sample consisted of 47 patients with epilepsy, who had been on LEV monotherapy for more than six months. All participants were over 18 years of age and had no other risk factors for osteoporosis. None of them used any other anti-seizure drug before. Bone mineral density (BMD) was evaluated with dual energy X-ray absorptiometry (DEXA) and biochemical markers associated with bone health were measured. Patients were divided into three groups depending on how long they had been on LEV for (Group A: <1 year; Group B: 1-5 years, Group C: >5 years) and compared with each other in terms of BMD scores and blood parameters. RESULTS: The mean age of patients was 32. 6 ± 13.3 and 20 patients were female (42.5%). The mean onset age of epilepsy was 28.1 ± 13.4 years. Average LEV period of consumption was 2.7 ± 2.7 years and mean daily dose was 1041.7 ± 393.9 milligrams. Lumbar BMD scores of the group with LEV usage < 1 year were significantly lower than those of the group with LEV usage of 1-5 years (p < 0.05). Lumbar vertebra scores were found to be lower in group of LEV usage duration of < 1 year when compared with LEV usage duration > 5 years but the difference was not statistically significant. CONCLUSION: We argue that LEV might have a negative effect on bone densitometry at the lumbar level in short-time usage for less than one year. Furthermore, no deleterious impact on bone metabolism was observed in long-term treatment. LEV seems as a rational drug for treatment of epilepsy patients, particularly for those with osteoporosis, since the comparative results of one year and longer than 5-years usage data did not show any statistically significant difference.