levetiracetam and Brain-Ischemia

Several new antiepileptic drugs (AEDs) have been introduced for clinical use recently. These new AEDs, like the classic AEDs, target multiple cellular sites both pre- and postsynaptically. The use of AEDs as a possible neuroprotective strategy in brain ischemia is receiving increasing attention and the antiepileptic drug levetiracetam, a 2S-(2-oxo-1-pyrrolidiny1) butanamide, belonging to the pyrrolidone family, could have a crucial role in regulation of epileptogenesis and neuroprotection. Recent observations suggest that levetiracetam is both safe and effective against post-stroke seizures. In this review, the potential neuroprotective role in brain ischemia and the therapeutic implications of levetiracetam in post-stroke epilepsy are discussed.

Topics: Animals; Anticonvulsants; Brain Ischemia; Clinical Trials as Topic; Disease Models, Animal; Epilepsy; Humans; Levetiracetam; Neuroprotective Agents; Piracetam; Stroke

Levetiracetam (LEV) monotherapy was investigated in 35 patients (pts) (16M/19F, 71.9+/-7.3 years of age) with late-onset post-stroke seizures (i.e. seizures occurring at least 2 weeks after an ischemic stroke) in a prospective open-label study. Overall, 27 pts (77.1%) achieved a condition of seizure freedom (defined as 1 year without seizures): 19 (54.3%) at a daily LEV dose of 1000mg, 7 (20.0%) at 1500mg, 1 (2.8%) at 2000mg. Four pts (11.4%) discontinued the drug because of intolerable side effects (drowsiness associated to gait disturbance in 1 pt, and aggressive behaviour in the remaining 3 pts); 3 pts were unresponsive at a dose of 3000mg, and 1 pt was lost at follow-up. These observations suggest that LEV exhibits safety and efficacy profiles which make it an optimal candidate as a first-choice drug against post-stroke seizures.

Topics: Aged; Aged, 80 and over; Aggression; Anticonvulsants; Brain Ischemia; Cardiovascular Agents; Drug Interactions; Epilepsy; Female; Fibrinolytic Agents; Gait Ataxia; Humans; Levetiracetam; Male; Middle Aged; Piracetam; Sleep Stages

Neuroelectric disruptions such as seizures and cortical spreading depolarization may contribute to the development of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH). However, effects of antiepileptic drug prophylaxis on outcomes remain controversial in SAH. The authors investigated if prophylactic administration of new-generation antiepileptic drugs levetiracetam and perampanel was beneficial against delayed neurovascular events after SAH. This was a retrospective single-center cohort study of 121 consecutive SAH patients including 56 patients of admission World Federation of Neurological Surgeons grades IV - V who underwent aneurysmal obliteration within 72 h post-SAH from 2013 to 2021. Prophylactic antiepileptic drugs differed depending on the study terms: none (2013 - 2015), levetiracetam for patients at high risks of seizures (2016 - 2019), and perampanel for all patients (2020 - 2021). The 3rd term had the lowest occurrence of delayed cerebral microinfarction on diffusion-weighted magnetic resonance imaging, which was related to less development of DCI. Other outcome measures were similar among the 3 terms including incidences of angiographic vasospasm, computed tomography-detectable delayed cerebral infarction, seizures, and 3-month good outcomes (modified Rankin Scale 0 - 2). The present study suggests that prophylactic administration of levetiracetam and perampanel was not associated with worse outcomes and that perampanel may have the potential to reduce DCI by preventing microcirculatory disturbances after SAH. Further studies are warranted to investigate anti-DCI effects of a selective α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonist perampanel in SAH patients in a large-scale prospective study.

Topics: Anticonvulsants; Brain Ischemia; Cerebral Infarction; Cohort Studies; Humans; Levetiracetam; Microcirculation; Prospective Studies; Retrospective Studies; Seizures; Subarachnoid Hemorrhage

Post-stroke paroxysmal activity is a neurophysiological indicator of epileptogenesis and increase of seizure susceptibility, so treatments with neuroprotective activity and anti-paroxysmal activity can be more beneficial during post-ischemic period. The goal of this study was evaluation of levetiracetam (100 mg/kg, 7 days of administration) effect on behavior and brain bioelectric activity changes in the post-ischemic period. Global ischemia model was carried out with bilateral ligation of carotid arteries in rats. Neurological deficit and electrophysiological changes of brain structures (striatum, cortex, hypothalamus, hippocampus) were analyzed during 28 days. Paroxysmal activity was not observed on the 1st day after ischemia and had early (2nd day) and late (28th day) onsets. Spectral analysis showed that rats, that died by the 10th day, had delta wave increase and theta decrease on the 1st day and delta activity reduction on the 2-7th days. LEV did not affect survival rate, however, it contributed to neurological disorder regression towards lighter forms on the 1st day after ischemia. It suppressed paroxysmal activity with an early onset and affected delta and theta waves on the 1st day in all structures except hippocampus. On the 7th and 28th days LEV increased delta activity due to 1-3 Hz frequency. Thus, LEV eliminates early onset post-ischemic paroxysmal activity and contributes to normalization of delta waves activity on the 1st day after ischemia, that positively affects neurological status of animals in post-ischemic period. It allows one to make a conclusion about possible LEV application in the post-ischemic period.

Topics: Animals; Anticonvulsants; Behavior, Animal; Brain Ischemia; Cerebral Cortex; Electroencephalography; Hippocampus; Levetiracetam; Male; Neuroprotective Agents; Rats; Seizures

White matter lesions due to cerebral hypoperfusion may be an important pathophysiology in vascular dementia and stroke, although the inherent mechanisms remain to be fully elucidated. The present study, using a mouse model of chronic cerebral hypoperfusion, examined the white matter protective effects of levetiracetam, an anticonvulsant, via the signaling cascade from the activation of cAMP-responsive element binding protein (CREB) phosphorylation. Mice underwent bilateral common carotid artery stenosis (BCAS), and were separated into the levetiracetam group (injected once only after BCAS [LEV1] or injected on three consecutive days [LEV3]), the vehicle group, or the anti-epileptic drugs with different action mechanisms phenytoin group (PHT3; injected on three consecutive days with the same condition as in LEV3). Cerebral blood flow analysis, Y-maze spontaneous alternation test, novel object recognition test, immunohistochemical and Western blot analyses, and protein kinase A assay were performed after BCAS. In the LEV3 group, SV2A expression was markedly increased, which preserved learning and memory after BCAS. Moreover, as the protein kinase A level was significantly increased, pCREB expression was also increased. The activation of microglia and astrocytes was markedly suppressed, although the number of oligodendrocyte precursor cells (OPCs) and GST-pi-positive-oligodendrocytes was markedly higher in the cerebral white matter. Moreover, oxidative stress was significantly reduced. We found that 3-day treatment with levetiracetam maintained SV2A protein expression via interaction with astrocytes, which influenced the OPC lineage through activation of CREB to protect white matter from ischemia.

Topics: Animals; Astrocytes; Brain; Brain Ischemia; Carotid Stenosis; Cognition; Cognitive Dysfunction; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Levetiracetam; Membrane Glycoproteins; Memory; Mice; Microglia; Nerve Tissue Proteins; Neuroprotective Agents; Phosphorylation; White Matter

Perinatal arterial stroke is the most frequent form of cerebral infarction in children. Neonatal seizures are the most frequent symptom during the neonatal period. The current management of perinatal stroke is based on supportive care. It is currently unknown if treatment of the seizures modifies the outcome, and no clinical studies have focused on seizures during neonatal stroke. We studied the effect of phenobarbital and levetiracetam on an ischemic-reperfusion stroke model in P7 rats using prolonged electroencephalographic recordings and a histologic analysis of the brain (24h after injury). The following two types of epileptic events were observed: 1) bursts of high amplitude spikes during ischemia and the first hours of reperfusion and 2) organized seizures consisting in discharges of a 1-2Hz spike-and-wave. Both phenobarbital and levetiracetam decreased the total duration of the bursts of high amplitude spikes. Phenobarbital also delayed the start of seizures without changing the total duration of epileptic discharges. The markedly limited efficacy of the antiepileptic drugs studied in our neonatal stroke rat model is frequently observed in human neonatal seizures. Both drugs did not modify the stroke volume, which suggests that the modification of the quantity of bursts of high amplitude spikes does not influence the infarct size. In the absence of a reduction in seizure burden by the antiepileptic drugs, we increased the seizure burden and stroke volume by combining our neonatal stroke model with a lithium-pilocarpine-induced status epilepticus. Our data suggest that the reduction of burst of spikes did not influence the stroke volume. The presence of organized seizure with a pattern close to what is observed in human newborns seems related to the presence of the infarct. Further research is required to determine the relationship between seizure burden and infarct volume.

Topics: Animals; Animals, Newborn; Anticonvulsants; Brain; Brain Ischemia; Disease Models, Animal; Epilepsy; Female; Levetiracetam; Lithium Compounds; Male; Phenobarbital; Pilocarpine; Piracetam; Random Allocation; Rats, Wistar; Reperfusion Injury; Stroke

The purpose of this study is to explore the neuroprotection mechanism of levetiracetam (LEV) with acute focal cerebral ischemia-reperfusion (I/P) mouse. The cerebral artery I/P animal model was prepared with a middle artery cerebral occlusion method. For drug intervention, mice were intraperitoneally injected with LEV with a dose of either 15 or 150 mg/kg. Neuronal injury was evaluated by measuring the infarct area, apoptosis ratio, and observation of blood-brain barrier ultrastructure with transmission electron microscope. CD8(+) antibody and perforin antibody were used to make cross-reference screen through flow cytometry to determine a perforin-positive rate in CD8(+) T lymphocytes (PFN + %). Injection of LEV can reduce infarct area, apoptosis ratio, and blood-brain barrier damage 24 h later after acute I/P in WT mice. In vitro, perforin can lower hippocampal neuron viability. In vivo, removing perforin can relieve neuronal injury. High dose injection of LEV (150 mg/kg) can inhibit perforin secreting from CD8(+)T lymphocytes. In addition, LEV can still protect neurons with perforin knockout mice. Therefore, our results suggested that LEV may contribute to neuron protection after cerebral ischemia reperfusion. The possible mechanism may be related with perforin release. However, we cannot roll out other mechanisms.

Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Female; Levetiracetam; Male; Mice, Inbred C57BL; Mice, Knockout; Neurons; Neuroprotection; Neuroprotective Agents; Perforin; Piracetam; Reperfusion Injury

Current guidelines recommend against the use of phenytoin following aneurysmal subarachnoid hemorrhage (aSAH) but consider other anticonvulsants, such as levetiracetam, acceptable. Our objective was to evaluate the risk of poor functional outcomes, delayed cerebral ischemia (DCI) and delayed seizures in aSAH patients treated with levetiracetam versus phenytoin. Medical records of patients with aSAH admitted between 2005-2012 receiving anticonvulsant prophylaxis with phenytoin or levetiracetam for >72 hours were reviewed. The primary outcome measure was poor functional outcome, defined as modified Rankin Scale (mRS) score >3 at first recorded follow-up. Secondary outcomes measures included DCI and the incidence of delayed seizures. The association between the use of levetiracetam and phenytoin and the outcomes of interest was studied using logistic regression. Medical records of 564 aSAH patients were reviewed and 259 included in the analysis after application of inclusion/exclusion criteria. Phenytoin was used exclusively in 43 (17%), levetiracetam exclusively in 132 (51%) while 84 (32%) patients were switched from phenytoin to levetiracetam. Six (2%) patients had delayed seizures, 94 (36%) developed DCI and 63 (24%) had mRS score >3 at follow-up. On multivariate analysis, only modified Fisher grade and seizure before anticonvulsant administration were associated with DCI while age, Hunt-Hess grade and presence of intraparenchymal hematoma were associated with mRS score >3. Choice of anticonvulsant was not associated with any of the outcomes of interest. There was no difference in the rate of delayed seizures, DCI or poor functional outcome in patients receiving phenytoin versus levetiracetam after aSAH. The high rate of crossover from phenytoin suggests that levetiracetam may be better tolerated.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anticonvulsants; Brain Ischemia; Female; Follow-Up Studies; Hematoma; Humans; Incidence; Levetiracetam; Male; Middle Aged; Phenytoin; Piracetam; Seizures; Severity of Illness Index; Subarachnoid Hemorrhage; Time Factors; Treatment Outcome; Young Adult

Both valproic acid and levetiracetam are anti-epileptic drugs, often used either alone or in combination. The present study compares valproate (VPA) with levetiracetam (LEV) as an intravenous (i.v.) anticonvulsant treatment in intensive care patients suffering from aneurysmal subarachnoid hemorrhage (aSAH) with a high risk of seizures.. A prospective, single-center patient registry of 35 intensive care unit (ICU) patients with onset seizure and/or high risk of seizures underwent an anticonvulsive, first-line single treatment regimen either with VPA or LEV. Plasma concentrations (pc), interactions between drugs in the ICU context, adverse effects and seizure occurrences were observed and recorded.. A significant decrease in the pc in patients treated with LEV was observed after changing from intravenous (160±51μmol/l) to enteral liquid application (113±58μmol/l), corresponding to a 70.3% bioavailability for enteral liquid applications. The pc in VPA patients decreased significantly, from (491±138μmol/l) to (141±50μmol/l), after adding meropenem to the therapy (p<0.05). Three epileptic seizures occurred during anticonvulsive therapy in the LEV group, and two in the VPA group, including one non-convulsive status epilepticus (NCSE).. Though this finding needs further verification, the enteral liquid application of levetiracetam seems to be associated with lower bioavailability than the common oral application of levetiracetam. The use of the antibiotic drug meropenem together with valproic acid leads to lower pc levels in patients treated with of valproic acid. For clinical practice, this indicates the need to monitor the levels of valproic acid in combination with meropenem.

Topics: Administration, Oral; Aged; Aneurysm, Ruptured; Anti-Bacterial Agents; Anticonvulsants; Biological Availability; Brain Ischemia; Critical Care; Drug Interactions; Enteral Nutrition; Epilepsy; Female; Humans; Intensive Care Units; Levetiracetam; Male; Meropenem; Middle Aged; Piracetam; Prospective Studies; Seizures; Subarachnoid Hemorrhage; Thienamycins; Valproic Acid

Topics: Brain Ischemia; Cerebral Hemorrhage; Humans; Infarction; Levetiracetam; Male; Middle Aged; Nootropic Agents; Piracetam; Treatment Outcome; Tremor

Levetiracetam (LEV) is a new antiepileptic drug with a promising preclinical profile involving both anticonvulsant and antiepileptogenic effects in kindling models. The latter stimulated the present study to compare its neuroprotective properties with the potent and selective, non-competitive NMDA antagonist, MK-801, in the rat middle cerebral artery occlusion model. Twenty-four hours after a transient occlusion of 90 minutes the animals were sacrificed and infarct volume and lesion distribution were determined from stained coronal sections. LEV was administered by intraperitoneal (i.p.) bolus injections of 5.5, 11, 22 and 44 mg x kg(-1), 30 minutes before occlusion followed by a continuous 24 hour i.p. infusion of 1.25, 2.6, 5.1 and 10.2 mg x kg(-1) per hour, respectively. LEV administration did not alter body temperature but reduced the infarct volume by 33% (P< 0.05) at the highest dose tested. An i.p. bolus injection of 0.04, 0.12 and 0.4 mg x kg(-1) of MK-801 followed by continuous i.p. infusion of 0.036, 0.108 and 0.36 mg x kg(-1) per hour, reduced the infarct volume by 49, 51 and 74% (P< 0.05), respectively. However, only the highest dose of MK-801 induced a significant reduction in the infarct volume (P< 0.05) and this was associated with hypothermia. These results suggest that LEV possesses neuroprotective properties which may be relevant for its antiepileptogenic action.

Topics: Animals; Anticonvulsants; Arterial Occlusive Diseases; Body Temperature; Brain; Brain Ischemia; Cerebrovascular Circulation; Disease Models, Animal; Dizocilpine Maleate; Levetiracetam; Male; Middle Cerebral Artery; N-Methylaspartate; Neuroprotective Agents; Piracetam; Rats; Rats, Wistar