A New SV2A Ligand for Epilepsy.

Since the 1970s, racetams have been in use as cognitive enhancers. Levetiracetam was discovered to have antiseizure activity in animal models and was then found to bind to SV2A in synaptic and endocrine vesicles. Brivaracetam, an analog of levetiracetam, was identified in a medicinal chemistry campaign with the objective of discovering analogs with higher affinity at racetam-binding sites and greater antiseizure potency.

Optimal Dosing of Levetiracetam for Seizure Prophylaxis in Critically Ill Patients: A Prospective Observational Study.

OBJECTIVES: Critically ill patients eliminate levetiracetam (LEV) more rapidly than healthy controls, yet low doses are commonly used for seizure prophylaxis in the ICU setting. We compared the rates of achievement of target serum levels and new onset seizure (clinical and/or electrographic) among patients who received low (500 mg bid) versus high (750-1,000 mg bid) dose LEV. DESIGN: Prospective, observational study. SETTING: Tertiary care, academic center. PATIENTS: We included patients who received prophylactic LEV following traumatic brain injury, intracerebral hemorrhage, spontaneous subarachnoid hemorrhage, or supratentorial neurosurgery between 2019 and 2021. Patients with a history of seizure, antiseizure medication use, or renal failure requiring dialysis were excluded. INTERVENTIONS: None. MEASUREMENTS: LEV levels were obtained at steady state. The impact of low-dose versus high-dose LEV on the primary outcome of target LEV levels (12-46 µg/mL), and the secondary outcome of clinical and/or electrographic seizure, were assessed using multivariable logistic regression analyses adjusting for age, LEV loading dose, BMI, primary diagnosis and creatinine clearance (CrCl). MAIN RESULTS: Of the 205 subjects included in analyses, n = 106 (52%) received LEV 500 mg bid (median 13 mg/kg/d), and n = 99 (48%) received LEV 750-1,000 mg bid (median 25 mg/kg/d). Overall, 111 of 205 patients (54%) achieved target levels: 48 (45%) from the low-dose group versus 63 (64%) from the high-dose group (odds ratio [OR] 2.1; 95% CI, 1.1-3.7; p = 0.009). In multivariable analyses, high-dose LEV predicted target levels (adjusted OR [aOR] 2.23; 95% CI, 1.16-4.27; p = 0.016), and was associated with lower seizure odds (aOR 0.32; 95% CI, 0.13-0.82; p = 0.018) after adjusting for age, loading dose, BMI, diagnosis, and CrCl. CONCLUSIONS: Underdosing of LEV was common, with only 54% of patients achieving target serum levels. Higher doses (750-1,000 mg bid) were more than twice as likely to lead to optimal drug levels and reduced the odds of seizure by 68% compared with low-dose regimens (500 mg bid).

Rapid administration of undiluted loading doses of levetiracetam.

OBJECTIVE: Rapid administration of antiseizure medications is a critical concept in the treatment of status epilepticus. Although undiluted levetiracetam (LEV) doses of up to 2500 mg have been evaluated, minimal data exist to support the safety of loading doses up to 4500 mg. This study will evaluate intravenous (IV) push administration of undiluted LEV from 2500 to 4500 mg for safety outcomes as well as tolerability. METHODS: This is a retrospective, observational, cohort analysis of adult patients who received at least one loading dose of undiluted IV push LEV from October 15, 2019, to April 30, 2022, at a large academic medical center in Phoenix, Arizona. Relevant outcomes include the safety and tolerability of rapid administration of undiluted LEV at higher loading doses. RESULTS: We evaluated 518 loading doses in 518 unique patients included during the study period. LEV was a new medication for witnessed or suspected seizures in 80.3% of patients, with 31.2% having a documented history of epilepsy or seizure disorder. At the time of LEV administration, 52.9% of patients were on a general medicine floor, 34.3% were in the intensive care unit, and 12.7% were in the emergency department. The median loading dose of LEV was 3600 mg (3000-4000 mg), with 4000 mg being the most common loading dose given. Peripheral IV lines were documented as the only available line in 78.6% of patients for loading dose administration. No adverse events associated with LEV administration were documented. SIGNIFICANCE: Rapid IV administration of undiluted doses of LEV is both safe and tolerable in loading doses of 2500-4500 mg, allowing for rapid drug administration in the setting of status epilepticus.

Cost-effectiveness analysis of HLA-B*15:02 screening before treatment of epilepsy in Indonesia.

INTRODUCTION: Adverse skin reactions due to drugs such as Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) occur in 3% of people receiving anti epileptic drugs (AED). Although SJS/TEN has a low incidence, the mortality and morbidity rates are high. Indonesia has not adopted HLA-B*1502 screening prior to administration of carbamazepine (CBZ), although previous studies found a relationship between HLA-B*1502 and SJS/TEN. METHODS: A hybrid decision tree and Markov model was developed to evaluate three strategies for treating newly diagnosed focal epilepsy: CBZ direct therapy, levetiracetam (LEV) direct therapy, and therapy based on HLA-B*15:02 test results. From a societal perspective, base case and sensitivity analyses were carried out over a lifetime. RESULTS: Direct administration of CBZ appears to have a slightly lower average cost than the HLA-B*15:02 allele screening strategy. The increase in quality-adjusted life year (QALY) in HLA-B*15:02 screening before treatment related to the cost difference reached 0.519 with an incremental cost-effectiveness ratio (ICER) of around USD 984 per unit of QALY acquisition. Direct treatment of LEV increased treatment costs by almost USD 2000 on average compared to the standard CBZ strategy. The increase in QALY is 0.834 in direct levetiracetam treatment, with an ICER of around USD 2230 for each QALY processing. CONCLUSION: Calculation of the cost-effectiveness of lifetime epilepsy therapy in this study found that the initial screening strategy with the HLA-B*15:02 test was the most cost-effective.

Morphological and histopathological changes of maternal levetiracetam on the cerebellar cortex of the offspring of albino rat.

Levetiracetam (LEV) is being used by women with reproductive-age epilepsy at a significantly higher rate. The purpose of the study was to assess how levetiracetam treatment during pregnancy affected the offspring's weight and cerebellum. Forty pregnant rats were divided into two groups (I, II). Two smaller groups (A, B) were created from each group. The rats in group I were gavaged with approximately 1.5 mL/day of distilled water either continuously during pregnancy (for subgroup IA) or continuously during pregnancy and 14 days postpartum (for subgroup IB). The rats in group II were gavaged with about 1.5 mL/day of distilled water (containing 36 mg levetiracetam) either continuously during pregnancy (for subgroup IA) or continuously during pregnancy and 14 days postpartum (for subgroup IB). After the work was completed, the body weight of the pups in each group was recorded, and their cerebella were analyzed histologically and morphometrically. Following levetiracetam treatment, the offspring showed decreased body weight and their cerebella displayed delayed development and pathological alterations. These alterations manifested as, differences in the thicknesses of the layers of cerebellar cortex as compared to the control groups; additionally, their cells displayed cytoplasmic vacuolation, nuclear alterations, fragmented rough endoplasmic reticulum and lost mitochondrial cristae. Giving levetiracetam to pregnant and lactating female rats had a negative impact on the body weight and cerebella of the offspring. Levetiracetam should be given with caution during pregnancy and lactation.

Changes in the Dentate Gyrus Gene Expression Profile Induced by Levetiracetam Treatment in Rats with Mesial Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) is one of the most common forms of focal epilepsy. Levetiracetam (LEV) is an antiepileptic drug whose mechanism of action at the genetic level has not been fully described. Therefore, the aim of the present work was to evaluate the relevant gene expression changes in the dentate gyrus (DG) of LEV-treated rats with pilocarpine-induced TLE. Whole-transcriptome microarrays were used to obtain the differential genetic profiles of control (CTRL), epileptic (EPI), and EPI rats treated for one week with LEV (EPI + LEV). Quantitative RT-qPCR was used to evaluate the RNA levels of the genes of interest. According to the results of the EPI vs. CTRL analysis, 685 genes were differentially expressed, 355 of which were underexpressed and 330 of which were overexpressed. According to the analysis of the EPI + LEV vs. EPI groups, 675 genes were differentially expressed, 477 of which were downregulated and 198 of which were upregulated. A total of 94 genes whose expression was altered by epilepsy and modified by LEV were identified. The RT-qPCR confirmed that LEV treatment reversed the increased expression of Hgf mRNA and decreased the expression of the Efcab1, Adam8, Slc24a1, and Serpinb1a genes in the DG. These results indicate that LEV could be involved in nonclassical mechanisms involved in Ca2+ homeostasis and the regulation of the mTOR pathway through Efcab1, Hgf, SLC24a1, Adam8, and Serpinb1a, contributing to reduced hyperexcitability in TLE patients.

Treatment Efficacy of Pharmacotherapies for Frontotemporal Dementia: A Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: The neuropsychiatric symptoms of frontotemporal dementia (FTD) have a profound negative impact on disease outcomes and care burden. Available pharmacotherapies might be supported by small-scale randomized controlled trials (RCTs); however, clinical recommendations might not be conclusive. METHODS: We systematically searched several databases from inception to April 30, 2022, for RCTs of drug therapy in patients with FTD and neuropsychiatric symptoms (primary outcome). Secondary outcomes included changes in caregiver stress, daily interactive activities, cognitive function, and acceptability (adverse event or dropout rates). The network meta-analysis (NMA) procedure was performed under the frequency model, showing effect sizes as standardized mean differences (SMD) or odds ratios (OR) with 95% confidence intervals (95% CIs). RESULTS: Seven RCTs with 243 participants were included. Compared with placebo, high-dose oxytocin (72 international units) was associated with the greatest improvement in patients' neuropsychiatric symptoms (SMD = -1.17, 95% CIs = -2.25 to -0.08, z = -2.10, p = 0.035). Piracetam significantly worsened neuropsychiatric symptoms (SMD = 3.48, 95% CIs = 1.58 to 5.37, z = 3.60, p < 0.001) and caregiver stress (SMD = 2.40, 95% CIs = 0.80-4.01, z = 2.94, p = 0.003). Trazodone had significantly higher rates of adverse events (OR = 9.53, 95% CIs = 1.85-49.20, z = 2.69, p = 0.007). No pharmacological intervention significantly benefited cognitive function. CONCLUSIONS: This study provides the first NMA for clinical recommendation to support the use of high-dose oxytocin and caution regarding the use of piracetam for neuropsychiatric symptoms in patients with FTD.

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.

Contingency learning in zebrafish exposed to apomorphine- and levetiracetam.

Cognitive rigidity (CR) refers to inadequate executive adaptation in the face of changing circumstances. Increased CR is associated with a number of psychiatric disorders, for example, obsessive-compulsive disorder, and improving cognitive functioning by targeting CR in these conditions, may be fruitful. Levetiracetam (LEV), clinically used to treat epilepsy, may have pro-cognitive effects by restoring balance to neuronal signalling. To explore this possibility, we applied apomorphine (APO) exposure in an attempt to induce rigid cue-directed responses following a cue (visual pattern)-reward (social conspecifics) contingency learning phase and to assess the effects of LEV on such behaviours. Briefly, zebrafish were divided into four different 39-day-long exposure groups ( n  = 9-10) as follows: control (CTRL), APO (100 µg/L), LEV (750 µg/L) and APO + LEV (100 µg/L + 750 µg/L). The main findings of this experiment were that 1) all four exposure groups performed similarly with respect to reward- and cue-directed learning over the first two study phases, 2) compared to the CTRL group, all drug interventions, but notably the APO + LEV combination, lowered the degree of reward-directed behaviour during a dissociated presentation of the cue and reward, and 3) temporal and spatial factors influenced the manner in which zebrafish responded to the presentation of the reward. Future studies are needed to explore the relevance of these findings for our understanding of the potential cognitive effects of LEV.

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.

Use of antiepileptic drugs as prophylaxis against posttraumatic seizures in the pediatric population: a systematic review and meta-analysis.

We aim to assess the effect of anti-epileptic drug (AED) prophylaxis for early or late posttraumatic seizures, targeting the pediatric population with traumatic brain injury (TBI). We systematically searched for studies reporting the incidence of posttraumatic seizures in pediatric patients who suffered from TBI and received AEDs prophylactically following their TBI incident. Studies that included adult patients, adult and pediatric patients but did not report results for the pediatric population separately, and patients who did not suffer from a TBI were excluded. Studies that did not indicate the use of antiepileptic drugs prophylactically following TBI were excluded. A total of 10 studies were included involving 4621 posttraumatic brain injury patients of the pediatric age population (<18). Five studies assessed the effect of prophylaxis on early seizures, four on late seizures and one on any seizure. The mean incidence of posttraumatic seizures with AED prophylaxis was 8% for early seizures and 7.1% for late seizures. Moreover, one study revealed no benefit of AED prophylaxis for early posttraumatic seizures. Meta-analysis revealed a significant difference in the incidence of early posttraumatic seizures with antiepileptic prophylaxis. However, no significant difference for late posttraumatic seizures has been shown. In conclusion, AED prophylaxis seems to be effective against early posttraumatic seizures for the pediatric population, with levetiracetam possibly being more effective. Also, there is no observed benefit for late posttraumatic seizures.

Levetiracetam dosing for seizure prophylaxis in neurocritical care patients.

BACKGROUND/OBJECTIVE: Levetiracetam is used for seizure prophylaxis in patients presenting with subarachnoid hemorrhage (SAH) or traumatic brain injury (TBI). We aim to characterize the optimal levetiracetam dosage for seizure prophylaxis. METHODS: This retrospective cohort study included adult patients at an academic tertiary hospital presenting with SAH or TBI who received levetiracetam at a total daily dose (TDD) equivalent to or greater than 1000 mg. The primary outcome was combined seizure incidence, including clinical and subclinical seizures. RESULTS: We identified 139 patients (49.6% male, mean age 53 years) for inclusion. For patients receiving a 1000-mg TDD, the administration was 500 mg twice daily. For patients receiving >1000-mg TDD, 77/78 patients received 1000 mg twice daily and one patient received 750 mg twice daily. Patients receiving 1000-mg TDD had a higher seizure incidence than those receiving >1000-mg TDD (p = 0.01), despite no difference in examined confounders, including history of alcoholism (p = 0.49), benzodiazepine use (p = 0.28), or propofol use (p = 0.17). No difference in adverse effects was observed (anemia, p = 0.44; leukopenia, p = 0.60; thrombocytopenia, p = 0.86). CONCLUSIONS: Patients may experience a reduced incidence of clinical and electroencephalographic seizures with levetiracetam dosing >1000-mg TDD.

Evaluation of Levetiracetam Dosing Strategies for Seizure Prophylaxis Following Traumatic Brain Injury.

BACKGROUND: Although levetiracetam has been increasingly used as an alternative to phenytoin for early posttraumatic seizure prophylaxis following traumatic brain injury (TBI), an optimal dosing strategy has not been elucidated. The objective of this study is to determine whether different dosing strategies of levetiracetam are associated with the incidence of early posttraumatic seizures when used as prophylaxis following TBI. METHODS: This retrospective single-center cohort study included admitted patients ≥ 18 years of age with a diagnosis of TBI and receiving levetiracetam for early posttraumatic seizure prophylaxis between July 1, 2013, and September 1, 2019. The primary outcome of this study was to evaluate three different dosing strategies of levetiracetam (≤ 1000 mg/day, 1500 mg/day, and ≥ 2000 mg/day) and associated rates of early posttraumatic seizures. Secondary outcomes were to summarize absolute total daily maintenance doses of levetiracetam among patients who experienced early posttraumatic seizures compared with those who did not, to determine the impact of three different dosing strategies on hospital length of stay and in-hospital mortality, and to assess patient-specific variables on the occurrence of posttraumatic seizures. Overlap propensity score weighting was used to address the potential for confounding. RESULTS: Of the 1287 patients who received levetiracetam for early posttraumatic seizure prophylaxis during the study time frame, 866 patients met eligibility criteria and were included in the study cohort (289 patients in the ≤ 1000 mg/day group, 137 patients in the 1500 mg/day group, and 440 patients in the ≥ 2000 mg/day group). After weighting, the cumulative incidence of early posttraumatic seizure was 2.9% in the ≤ 1000 mg/day group, 8.8% in the 1500 mg/day group, and 9% in the ≥ 2000 mg/day group. The 1500 mg/day and ≥ 2000 mg/day levetiracetam groups had a 209% and 216% increase in the subdistribution hazard of early posttraumatic seizures compared with the ≤ 1000 mg/day levetiracetam group, respectively, but these differences were not statistically significant. CONCLUSIONS: In conclusion, the results of this study demonstrate no statistically significant difference in the cumulative incidence of early posttraumatic seizures within 7 days of TBI between three different levetiracetam dosing strategies. After weighting, the ≤ 1000 mg/day levetiracetam group had the lowest rates of early posttraumatic seizures, death without seizure, and in-hospital mortality.

Evaluation of levetiracetam for early post-traumatic seizure prophylaxis: A level II trauma center experience.

INTRODUCTION: Traumatic brain injury (TBI) can induce early or late post-traumatic seizures (PTS). While PTS incidence is low, prophylaxis is used despite a lack of consensus on agent or duration. Levetiracetam (LEV) for early PTS prophylaxis is preferred due to its safety and efficacy. The purpose of this study was to evaluate LEV for early PTS prophylaxis. METHODS AND MATERIALS: A single-center, retrospective chart review of TBI patients ≥18 years who received LEV for early PTS prophylaxis between August 2018-July 2019. The primary outcome was LEV duration. Secondary outcomes were incidence of seizure, intensive care unit (ICU) and hospital length of stay (LOS). RESULTS: Of the 137 included, mean age was 59 ± 20 years and 69.3% were male. The mean admission GCS was 13 ± 4 and 77.4% had mild TBI. Median LEV duration was 7 (IQR 4-10) days and 13.9% met recommended 7-day duration. Those prescribed LEV >7 days had more than twice the median LEV duration than those prescribed ≤7 days [10.25 (8.5-15.5) vs 4 (1.5-4.5) days, p < 0.0001]. Electroencephalography-confirmed PTS occurred in 2.2%, with an early PTS incidence of 0.73%. Median ICU and hospital LOS were 2 (IQR 1-7) and 7 (IQR 3-16) days, respectively. CONCLUSIONS: The incidence of PTS was low as most patients in our study had mild or moderate TBI. Early PTS prophylaxis with LEV for 7 days is appropriate, although the majority of patients did not meet the recommended duration. Efforts to standardize and implement PTS prophylaxis protocols are needed.

Neuroprotective effect of piracetam-loaded magnetic chitosan nanoparticles against thiacloprid-induced neurotoxicity in albino rats.

Thiacloprid (TH) is a neurotoxic agricultural insecticide and potential food contaminant. The purpose of this study was to investigate the relationship between TH exposure and memory dysfunction in rats, as well as the potential protective effect of piracetam and piracetam-loaded magnetic chitosan nanoparticles (PMC NPs). Rats were divided into five equal groups (six rats/group). The control group received saline. Group II was treated with PMC NPs at a dose level of 200 mg/kg body weight (Bwt); Group III was treated with 1/10 LD50 of TH (65 mg/kg Bwt); Group IV was treated with TH (65 mg/kg Bwt) and piracetam (200 mg/kg Bwt); Group V was co-treated with TH (65 mg/kg Bwt) and PMC NPs (200 mg/kg Bwt). All animal groups were dosed daily for 6 weeks by oral gavage. Footprint analysis, hanging wire test, open field test, and Y-maze test were employed to assess behavioral deficits. Animals were euthanized, and brain tissues were analyzed for oxidative stress biomarkers, proinflammatory cytokines, and gene expression levels of glial fibrillary acidic protein (GFAP), amyloid-beta precursor protein (APP), B-cell lymphoma 2 (Bcl-2), and caspase-3. Brain and sciatic nerve tissues were used for the evaluation of histopathological changes and immunohistochemical expression of tau protein and nuclear factor kappa B (NF-κB), respectively. The results revealed that TH-treated rats suffered from oxidative damage and inflammatory effect on the central and peripheral nerves. The administration of PMC NPs considerably protected against TH-induced neuronal damage, increased antioxidant enzyme activity, decreased inflammatory markers, and improved behavioral performance than the group treated with piracetam. The neuroprotective effect of PMC NPs was mediated through the inhibition of GFAP, APP, caspase-3, Tau, and NF-κB gene expression with induction of Bcl-2 expression. In conclusion, TH could induce oxidative stress, inflammatory and neurobehavior impairment in rats. However, PMC NPs administration markedly mitigated TH-induced brain toxicity, possibly via oxidative and inflammatory modulation rather than using piracetam alone.

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.

Levetiracetam ameliorates epileptogenesis by modulating the adenosinergic pathway in a kindling model of epilepsy in mice.

Background: Levetiracetam (LEV) has been found to have an antihyperalgesic effect via acting on the adenosine system. However, the effects of LEV on the modulation of the adenosine system in the brain have not been elucidated in the prevention of seizures and epilepsy. The present study aimed to explore the possible LEV mechanisms of action in the adenosine signaling systems in an animal model of epilepsy. Methodology: A docking study was initially performed to determine the possible interaction of LEV with adenosine A1 receptors (A1Rs) and equilibrative nucleoside transporters-1 (ENT1). The experimental study was divided into an acute seizure test (32 mice distributed into 4 groups) and a chronic kindling model study (40 mice distributed into 5 groups), followed by gene expression analysis and immunohistochemistry. The kindling model lasted 26 days and took 13 subconvulsive doses of pentylenetetrazole (PTZ) to completely kindle the mice in the PTZ control group. Gene expression changes in the A1Rs, potassium inwardly-rectifying channel 3.2 (Kir3.2), and ENT1 in the brain tissue samples of the mice following treatment with LEV were analyzed using reverse transcription-quantitative polymerase chain reaction, and immunohistochemistry was performed for the A1R protein expression. Results: Docking studies predicted a significant interaction of LEV with A1Rs and ENT1 proteins. Results from the acute testing revealed that caffeine (100 mg/kg) and 8-cyclopentyl-1,3-dipropylxanthine (25 mg/kg) significantly reversed the antiseizure effects of LEV by reversing the percent protection and shortening the onset of the first myoclonic jerk (FMJ) and generalized clonic seizures (GCSs). In the PTZ-induced kindling, LEV demonstrated an increased gene expression of A1Rs and Kir3.2 in the brain. LEV also significantly reduced the gene expression of ENT1. Furthermore, the immunohistochemical analysis showed that LEV increased the protein expression of A1Rs in the brain. Conclusion: Based on these results, it can be concluded that LEV modulates epileptogenesis by acting on the adenosine pathway in the central nervous system.

Perioperative levetiracetam for seizure prophylaxis in seizure-naive brain tumor patients with focus on neurocognitive functioning.

INTRODUCTION: In seizure-naive brain tumor patients, the efficacy of perioperative prophylactic antiepileptic drug treatment remains controversial. In case of administration, the common preferred drug is levetiracetam (LEV) because of its favorable pharmacological profile. Research to date has not sufficiently determined how LEV affects cognition in the short term, as is the case in the perioperative period. The objective of this prospective study was to examine the neurocognitive functioning of seizure-naive brain tumor patients after receiving LEV perioperatively. METHODS: Fortythree patients with supratentorial brain tumor scheduled for surgery received LEV three days before until six days after surgery as seizure prophylaxis. Cognitive functioning (NeuroCogFX), LEV plasma-levels, hematotoxicity, side-effects, as well as health-related quality of life (HRQoL, Qolie31), were recorded preoperatively before (Baseline) and after onset of LEV (Pre-Op), 4-6 days postoperatively (Post-Op) and 21 days postoperatively (Follow-Up). RESULTS: No significant changes in cognitive functioning and HRQoL were seen after onset of preoperative LEV. There was a significant improvement of NeuroCogFX total-score at Follow-Up (p = 0.004) compared to Baseline. The overall-score Qolie31 showed simultaneous improvement patterns as cognitive functioning (p < 0.001). The most frequent side effect related to study drug was somnolence (in 28.6% of patients). CONCLUSIONS: A significant improvement of cognitive functioning, as well as an improvement in HRQoL, were detected postoperatively. This is presumably due to the debulking effect of the surgery. Nevertheless, LEV has no detrimental effect on cognitive functioning in the perioperative phase in seizure-naive brain tumor patients. TRIAL REGISTRATION: This study was registered prospectively (Date: 25/11/2015; EudraCT: 2015-003,916-19).

The differential effect of levetiracetam on memory and anxiety in rats.

OBJECTIVE: One of the newest antiseizure medication is levetiracetam (LEV). It might be effective in various indications, not only related to convulsions. Central nervous system disorders are common during anticonvulsant therapy. The aim of this study was to assess the effect of LEV on various types of memory and anxiety in rats. METHODS: Adult male Wistar rats (n = 58) were given LV p.o. as a single (100 mg/kg or 500 mg/kg) or repeated doses (300 mg/kg). The effect of the drug on memory was assessed in the Morris water maze (MWM) (spatial memory), the passive avoidance (PA) (emotional memory) and the novel object recognition (NOR) (recognition memory). The anxiety was evaluated in the elevated plus maze (EPM). RESULTS: LEV administered as repeated doses disturbed the long-term recognition memory in NOR and locomotor activity in EPM. A single dose affected emotional memory in PA. LEV did not alter spatial memory in MWM. CONCLUSIONS: LEV may cause memory and locomotor disturbances, but some of these adverse effects seem to be temporary and limited to the effect of acute dose.

Vitamin B6 decreases the risk of levetiracetam discontinuation in children with epilepsy: A retrospective study.

OBJECTIVES: Levetiracetam (LEV) is an anti-seizure medication (ASM) known to have significant behavioral side effects in children with epilepsy. These side effects may be improved by supplemental vitamin B6 (pyridoxine) use. Our research aimed to study risk factors for LEV side effects and the role of vitamin B6 in altering this risk. METHODS: We retrospectively analyzed the demographic and clinical profile of all pediatric patients on LEV treatment between July 2019 and December 2020. T-tests, Chi-square and Fisher exact tests were used to assess predictors of LEV discontinuation. A p-value of <0.05 was considered statistically significant. RESULTS: 150/240 (62%) children were on additional medications besides LEV for epilepsy management. Thirty-five percent children reported side effects, especially behavioral and mood concerns. Of the patients who reported side effects on LEV, 71% were taking vitamin B6 (n = 59). The rate of LEV discontinuation was significantly lower for children on vitamin B6 than children not taking B6, regardless of monotherapy or polypharmacy (49% v 88% respectively, p = 0.001). Over half of the patients who were able to remain on LEV reported improved behavior with B6 supplementation as compared to those who were unable to continue LEV (17/30, 57% versus 0/26, 0%; p < 0.001). CONCLUSIONS: Levetiracetam side effects significantly impact the tolerability of this ASM in children with epilepsy. Our results suggest that vitamin B6 supplementation can significantly reduce the odds of discontinuing LEV due to its behavioral side effects.