Onset Of Status Epilepticus Research Articles

Treatment of status epilepticus with zonisamide: A multicenter cohort study of 34 patients and review of literature

IntroductionWe present a summary of clinical cases of oral zonisamide (ZNS) used to treat refractory and super-refractory episodes of status epilepticus (SE). MethodsZonisamide administration in SE was identified in the clinical records of patients treated in Frankfurt and Marburg between 2011 and 2017. ResultsZonisamide was administered during a total of 37 SE episodes in 34 patients with a mean age of 58.7 ± 17.8 years, 21 of them were female (61.7%). The median latency from the onset of SE to administration of ZNS was 6.3 days. Patients had already undergone unsuccessful treatment with a median of three other antiseizure drugs (ASDs).The median initial dose of ZNS was 100 mg/d, titrated to a median maintenance dose of 400 mg/d. Patients underwent ZNS treatment for a median period of 7 days. Zonisamide was the final drug administered in 9 of 37 (24.3%) episodes, with a clinical effect attributed to ZNS observed in 6 of 37 (16.2%) episodes. An effect attributed to ZNS was observed in 5 out of 30 episodes of refractory SE (RSE) and in one out of 7 episodes of super-refractory SE (SRSE). Possible negative side effects of ZNS were observed in two patients (one patient each with ataxia and skin rash). The mortality rate in hospitalized patients was 10.4% (n = 4). ConclusionThe rate of SE resolution attributed to ZNS treatment (16.2%) can be considered relevant, particularly since ZNS treatment tends to be administered only after several other options have been tried, and has a treatment latency of over six days. Zonisamide may therefore be considered as an alternative oral treatment option in RSE and SRSE.

Inverse Agonism of Cannabinoid Receptor Type 2 Confers Anti-inflammatory and Neuroprotective Effects Following Status Epileptics.

Prolonged status epilepticus (SE) in humans causes high mortality and brain inflammation-associated neuronal injury and morbidity in survivors. Currently, the only effective treatment is to terminate the seizures swiftly to prevent brain damage. However, reliance on acute therapies alone would be imprudent due to the required short response time. Follow-on therapies that can be delivered well after the SE onset are in an urgent need. Cannabinoid receptor type 2 (CB2), a G protein-coupled receptor that can be expressed by activated brain microglia, has emerged as an appealing anti-inflammatory target for brain conditions. In the current study, we reported that the CB2 inverse agonism by our current lead compound SMM-189 largely prevented the rat primary microglia-mediated inflammation and showed moderate neuroprotection against N-methyl-D-aspartic acid (NMDA) receptor-mediated excitotoxicity in rat primary hippocampal cultures containing both neurons and glia. Using a classical mouse model of epilepsy, in which SE was induced by systemic administration of kainate (30mg/kg, i.p.) and proceeded for 1h, we demonstrated that SE downregulated the CB1 but slightly upregulated CB2 receptor in the hippocampus. Transient treatment with SMM-189 (6mg/kg, i.p., b.i.d.) after the SE was interrupted by diazepam (10mg/kg, i.p.) prevented the seizure-induced cytokine surge in the brain, neuronal death, and behavioral impairments 24h after SE. Our results suggest that CB2 inverse agonism might provide an adjunctive anti-inflammatory therapy that can be delivered hours after SE onset, together with NMDA receptor blockers and first-line anti-convulsants, to reduce brain injury and functional deficits following prolonged seizures.

New-onset refractory status epilepticus and febrile infection-related epilepsy syndrome.

New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES) are relatively rare clinical presentations. They are characterized by de novo onset of refractory status epilepticus (RSE) without clearly identifiable acute or active cause (structural, toxic, or metabolic). We reviewed the literature using PubMed reports published between 2003 and 2019 and summarized the clinical, neurophysiological, imaging, and treatment findings. Focal motor seizures, which tend to evolve into status epilepticus, characterize the typical presentation. Disease course is biphasic: acute phase followed by chronic phase with refractory epilepsy and neurological impairment. Aetiology is unknown, but immune-inflammatory-mediated epileptic encephalopathy is suspected. Electroencephalograms show variety in discharges (sporadic or periodic, focal, generalized, or more frequently bilateral), sometimes with a multifocal pattern. About 70% of adult NORSE have abnormal magnetic resonance imaging (MRI); in paediatric series of FIRES, 61.2% of patients have a normal brain MRI at the beginning and only 18.5% during the chronic phase. No specific therapy for FIRES and NORSE currently exists; high doses of barbiturates and ketogenic diet can be used with some effectiveness. Recently, anakinra and tocilizumab, targeting interleukin pathways, have emerged as potential specific therapies. Mortality rate is around 12% in children and even higher in adults (16-27%).

TRPV1 Contributes to the Neuroprotective Effect of Dexmedetomidine in Pilocarpine-Induced Status Epilepticus Juvenile Rats.

To investigate the antiepileptic and neuroprotective effects of dexmedetomidine (Dex) in pilocarpine- (Pilo-) induced status epilepticus (SE) juvenile rats, rats were randomly assigned to the following six groups (n = 20): normal, normal+Dex, SE, SE+Cap, SE+Dex, and SE+Dex+Cap. The rats were treated with either diazepam (i.p., an antiepileptic drug) or Dex after the onset of SE. The Morris water maze was used to assess rat cognitive behavior. Flow cytometry was used to detect the concentrations of Ca2+, mitochondrial membrane potential, and reactive oxygen species. Transmission electron microscopy was performed to evaluate specimens of brain tissue. The levels of caspase 3 and TRPV1 were examined by western blot and immunohistochemistry (IHC). Treatment with Dex significantly decreased the escape latency of the SE rats (P < 0.05). Capsaicin, a TRPV1 agonist, delivery aggravated the performance of SE rats. Pathological changes in SE rat were attenuated by Dex and deteriorated by capsaicin. Swollen mitochondria and abnormal endoplasmic reticulum were found in SE rats and were then aggravated by capsaicin and reversed by Dex. Moreover, our data showed that Dex significantly restrained calcium overload, ROS production, and mitochondrial membrane potential loss, all of which were induced by Pilo and capsaicin (P < 0.05). Dex decreased the apoptotic rate in the Model SE group (P < 0.05) and TRPV1 and caspase 3 expression in the Dex treatment group (P < 0.05). Interestingly, all these effects of Dex were partially counteracted by the TRPV1 agonist, capsaicin (P < 0.05). Our study showed that Dex exerted a neuroprotective effect in Pilo-induced SE rats by inhibiting TRPV1 expression and provided information for therapy to SE patients.

Extinguishing FIRES using tocilizumab

AbstractFebrile infection–related epilepsy syndrome (FIRES) is a devastating epileptic encephalopathy with antecedent febrile infection preceding the onset of refractory status epilepticus (RSE), without the evidence of structural, toxic, or metabolic cause. The pathophysiology of FIRES is largely unknown but has been hypothesized to be due to excessive cytokine release perpetuating the underlying seizure. Conventional immunotherapies such as steroid, IVIG, plasma exchange, and rituximab have previously been considered for the treatment of FIRES but have been disappointing. We report a successful therapeutic encounter using tocilizumab, a humanized monoclonal antibody against interleukin‐6 receptor to treat RSE in a 14‐year‐old girl with FIRES following dismal outcome using conventional immunosuppressive strategies. The overproduction of cytokines and the poor performance of immunotherapies implicate a putative role of inflammation in FIRES. Our case showed that complete termination of RSE was achieved after tocilizumab administration suggesting it may be a lifesaving drug for this catastrophic condition.

The implications of hippocampal neurogenesis in adolescent rats after status epilepticus: a novel role of notch signaling pathway in regulating epileptogenesis.

Seizure-induced neurogenesis has a widely recognized pro-epileptogenic function. Given the critical role of Notch signaling during the maintenance and neurogenesis of neural stem cells, we hypothesized that Notch may affect epileptogenesis and its progression through its role in neurogenesis in the adolescent rat brain. We used the lithium-pilocarpine-induced epilepsy model in adolescent Sprague-Dawley rats in order to evaluate hippocampal neurogenesis and epileptogenesis following the onset of status epilepticus (SE). We used western blotting analyses and qPCR to measure levels of Notch signaling at different phases after seizures and immunofluorescence to detect the proliferation and differentiation of neural stem cells after seizure. Following the administration of DAPT, a Notch γ-secretase inhibitor, into the lateral ventricles, we observed a suppression of abnormal neurogenesis in the acute phase and a reduction of gliosis in the chronic phase after SE. Accordingly, the frequency and duration of spontaneous seizures in chronic phase were decreased. Our results clarify the basic concept regarding the involvement of Notch signaling in the regulation of hippocampal neurogenesis and epileptogenesis, thereby potentially offering a novel and alternative treatment for epilepsy.

The antiepileptic effect of Gastrodiae Rhizoma through modulating overexpression of mTOR and attenuating astrogliosis in pilocarpine mice model.

ObjectiveTo investigate the effect of water extract of Gastrodiae Rhizoma (GR) on the development of acquired temporal lobe epilepsy (TLE) and on regulating the expression of the mammalian target of rapamycin (mTOR) and semaphorin 3F (SEMA3F).MethodsA pilocarpine‐induced status epilepticus (SE) model was adopted to precipitate injury in the limbic systems. GR and carbamazepine (CBZ) treatments were given to mice for 14 days prior to SE induction to demonstrate the antiepileptic effects and continued for 5 more days to illustrate the effects on histologic studies.ResultsOur results consolidated that GR treatment (92.1 minutes) could delay the SE onset in comparison with the control group (61.5 minutes, P = .041). Fewer mice had reached SE with GR treatment (41.7%) when compared with the control group (83.3%, P = .044). GR treatment (2.1 hours/mouse) could suppress the number of acute seizures in post‐SE survival mice when compared with the control group (4.5 hours/mouse, P < .001). The effects of GR treatment were elucidated with the mechanism of actions. GR treatment reduced the overexpression of mTOR (0.27 vs 0.67 AU/mg protein, P = .047). GR treatment increased the underexpression of SEMA3F (0.51 vs 0.16 µg/mg protein, P = .034). In the histochemical study of microtubule‐associated protein 2 (MAP2) staining, our results showed that GR prevented neuronal loss in the GR treatment group (64.8% positively stained pixel area) as compared with the control group (59%, P = .014) in the hippocampus. In glial fibrillary acidic protein (GFAP) staining, the severity of astrogliosis was mitigated by the GR treatment (4.1% positively stained pixel area) when compared to the control group (5.6%, P = .047) in the hippocampus.SignificanceThese results provide preclinical evidence to support the use of GR, which could suppress acute seizures and relieve pathological changes in pilocarpine‐induced TLE mice. We demonstrated that the antiepileptic effects of GR could be accompanied by mTOR reduction and astrogliosis attenuation.

Refractory status epilepticus syndrome FIRES (febrile infection-related epilepsy syndrome) + NORSE (new-onset refractory status epilepticus): description of a rare clinical case

The paper describes a clinical case of the rare status epilepticus syndrome FIRES (febrile infection responsive encephalopathy) + NORSE (new-onset refractory status epilepticus). The difficulty of diagnosing this condition is due to the fact that it occurs extremely rarely and the laboratory and instrumental findings are nonspecific. The disease is characterized by acute onset, fever, and subsequent development of status epilepticus, cognitive impairment, and pharmacotherapy-resistant epilepsy. The paper describes a 19-year-old male patient who was observed to have a favorable course of FIRES + NORSE syndrome without pharmacotherapy-resistant epilepsy, motor deficiency, and with the preservation of self-care skills.

Assessing the Risk/Benefit at Status Epilepticus Onset: The Prognostic Scores.

Status epilepticus is a medical emergency with a wide range of etiology, severity, and outcome. Different scores that can help in the stratification of a patient's risk of mortality have been published. This study describes and compares the three available scores (Status Epilepticus Severity Score, Epidemiology-Based Mortality Score in Status Epilepticus and Encephalitis, Nonconvulsive, Diazepam resistance, Imaging, Tracheal intubation).

Factors predicting cessation of status epilepticus in clinical practice – data from a prospective observational registry (SENSE)

Objective To investigate the initial termination rate of status epilepticus (SE) in a large observational study and explore associated variables. Methods Data of adults treated for SE were collected prospectively in centers in Germany, Austria, and Switzerland, during 4.5 years. Incident episodes of 1,049 patients were analyzed using uni- and multivariate statistics to determine factors predicting cessation of SE within 1 hour (for generalized convulsive SE [GCSE]) and 12 hours (for non-GCSE) of initiating treatment. Results Median age at SE onset was 70 years; most frequent etiologies were remote (32%) and acute (31%). GCSE was documented in 43%. Median latency between SE onset and first treatment was 30 minutes in GCSE and 150 minutes in non-GCSE. The first intravenous compound was a benzodiazepine in 86% in GCSE and 73% in non-GCSE. Bolus doses of the first treatment step were lower than recommended by current guidelines in 76% of GCSE patients and 78% of non-GCSE patients. In 319 GCSE patients (70%), SE was ongoing 1 hour after initiating treatment and in 342 non-GCSE patients (58%) 12 hours after initiating treatment. Multivariate Cox regression demonstrated that use of benzodiazepines as first treatment step and a higher cumulative dose of anticonvulsants within the first period of treatment were associated with shorter time to cessation of SE for both groups. Interpretation In clinical practice, treatment guidelines were not followed in a substantial proportion of patients. This underdosing correlated with lack of cessation of SE. Our data suggest that sufficiently dosed benzodiazepines should be used as a first treatment step. ANN NEUROL 2019;85:421-432.

SCN1A-related phenotypes: Epilepsy and beyond.

SCN1A, encoding the alpha 1 subunit of the sodium channel, is associated with several epilepsy syndromes and a range of other diseases. SCN1A represents the archetypal channelopathy associated with a wide phenotypic spectrum of epilepsies ranging from genetic epilepsy with febrile seizures plus (GEFS+), to developmental and epileptic encephalopathies (DEEs). SCN1A disorders also result in other diseases such as hemiplegic migraine and autism spectrum disorder (ASD). Dravet syndrome (DS) is the prototypic DEE with an early onset of febrile status epilepticus, hemiclonic or generalized tonic-clonic seizures, and later onset of additional seizure types. Electroencephalography (EEG) and magnetic resonance imaging (MRI) are normal at onset. Development is normal in the first year of life but plateaus rapidly, with most patients ultimately having intellectual disability. Epilepsy is drug-resistant and necessitates polytherapy. Most pathogenic variants occur de novo in the affected child, but they are inherited from mosaic affected or unaffected parents in rare cases. The molecular finding of haploinsufficiency is consistent with a loss-of-function defect in cells and animal models. Although seizures are the most commonly reported symptom in DS, many additional issues critically affect patients' cognitive and behavioral functioning. Hemiplegic migraine (HM) is a rare form of migraine with aura, characterized by the emergence of hemiparesis as part of the aura phase. All SCN1A mutations reported in sporadic/familial HM3 are missense mutations. Most of the experimental results show that they cause a gain of function of NaV 1.1 as opposed to the loss of function of the epileptogenic NaV 1.1 mutations. SCN1A and SCN2A pathogenic variants have been identified in genetic studies of cohorts of patients with ASD. In addition, ASD features are often reported in patients with Dravet syndrome and other DEEs.

α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor Plasticity Sustains Severe, Fatal Status Epilepticus.

Generalized convulsive status epilepticus is associated with high mortality. We tested whether α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor plasticity plays a role in sustaining seizures, seizure generalization, and mortality observed during focal onset status epilepticus. We also determined whether modified AMPA receptors generated during status epilepticus could be targeted with a drug. Electrically induced status epilepticus was characterized by electroencephalogram and behavior in GluA1 knockout mice and in transgenic mice with selective knockdown of the GluA1 subunit in hippocampal principal neurons. Excitatory and inhibitory synaptic transmission in CA1 neurons was studied using patch clamp electrophysiology. The dose response of N,N,H,-trimethyl-5-([tricyclo(3.3.1.13,7)dec-1-ylmethyl]amino)-1-pentanaminiumbromide hydrobromide (IEM-1460), a calcium-permeable AMPA receptor antagonist, was determined. Global removal of the GluA1 subunit did not affect seizure susceptibility; however, it reduced susceptibility to status epilepticus. GluA1 subunit knockout also reduced mortality, severity, and duration of status epilepticus. Absence of the GluA1 subunit prevented enhancement of glutamatergic synaptic transmission associated with status epilepticus; however, γ-aminobutyric acidergic synaptic inhibition was compromised. Selective removal of the GluA1 subunit from hippocampal principal neurons also reduced mortality, severity, and duration of status epilepticus. IEM-1460 rapidly terminated status epilepticus in a dose-dependent manner. AMPA receptor plasticity mediated by the GluA1 subunit plays a critical role in sustaining and amplifying seizure activity and contributes to mortality. Calcium-permeable AMPA receptors modified during status epilepticus can be inhibited to terminate status epilepticus. ANN NEUROL 2020;87:84-96.

Pediatric status epilepticus: Identification of prognostic factors using the new ILAE classification after 5 years of follow-up.

Status epilepticus (SE) is the most common neurologic emergency in childhood. This study aimed to report on a large cohort of pediatric patients with SE, applying the International League Against Epilepsy (ILAE) Classification for SE to identify prognostic factors. We included 173 children treated at "Bambino Gesù" Children's Hospital in Rome for SE exceeding 30minutes (mean age 4.43±4.93years old, median 2.28, interquartile range [IQR] 0.41-7.32; follow-up for a mean of 4.9±3.4years, median 8.75, IQR 4,58-12.63). A multivariate model was constructed to predict neurocognitive outcome, recurrence of SE, development of epilepsy, and mortality. Adjusted odds ratios [ORs] were calculated with 95% confidence interval (OR, 95% CIs). We observed a different prevalence of etiologies for the different semiologies (P<.05) and for each age group (P<.05), overlapping only in part with the recent ILAE classification. After SE, patients showed 69.9% epilepsy (drug-resistant in half of them), 23.1% worsening of neurologic findings on examination, 28.9% cognitive deficit, and 28.3% recurrent SE. At multivariate analysis: superrefractory SE was correlated to an increased risk of developing cognitive (OR 6.00, 95% CI 2.09, 17.31) or neurologic sequelae (OR 4.9, 95% CI 1.75, 19.77). A similar finding was observed for patients with onset in the neonatal period for cognitive (OR 4.84, 95% CI 1.13, 17.3) and neurologic sequelae (OR 9.03, 95% CI 2.40, 34.04). Recurrence of SE was associated with unknown etiology (OR 6.15, 95% CI 1.43, 26.76), and myoclonic semiology (OR 6.1, 95% CI 1.23, 29.3).Patients with acute symptomatic etiology (OR 0.12, 95% CI 0.04, 0.40) had a lower risk for developing epilepsy. Age at onset and duration of SE were critical independent variables associated with worse neurocognitive outcome. The risk of developing epilepsy was lower after acute symptomatic and febrile SE. Semiology and age at onset correlate with etiology of SE. For this reason, ILAE classification with respect to four axes seems an appropriate advancement.

Treatment of refractory and superrefractory status epilepticus with topiramate: A cohort study of 106 patients and a review of the literature.

Novel treatments are needed to control treatment-resistant status epilepticus (SE). We present a summary of clinical cases where oral topiramate (TPM) was used in refractory SE (RSE) and superrefractory SE (SRSE). A review of medical records was carried out to detect TPM administration in SE patients treated in Frankfurt and Marburg between 2011 and 2016. The primary outcome question concerned SE resolution after TPM initiation. In total, TPM was used in 106 of 854 patients having a mean age of 67.4±18.1years, 61 of whom were female (57.5%). The median latency from SE onset to TPM initiation was 8.5days. Patients with SE had previously failed a median of five other antiepileptic drugs. The median initial TPM dose was 100mg/d, which was uptitrated to a median maintenance dose of 400mg/d. Treatment with TPM was continued for a median time of 12days. TPM was the last drug provided to 42 of 106 (39.6%) patients, with a resultant response attributed to TPM observed in 29 of 106 (27.4%) patients. A response was attributed to TPM in 21 (31.8%) of 66 RSE cases and eight (20%) of 40 SRSE cases. Treatment-emergent adverse events were attributed to TPM usage in two patients, one each with pancreatitis and hyperchloremic acidosis, and in 38 patients (35.8%), hyperammonemia was seen. Thirty-four of these patients received a combination of TPM and valproate and/or phenobarbital. The intrahospital mortality rate was 22.6% (n=24). The rate of SE cessation attributed to TPM treatment (27.4%) represents a relevant response given the late treatment position of TPM and the treatment latency of more than8 days. Based on these results and in line with the findings of other case series, TPM can be considered an alternative option for treating RSE and SRSE.

Clinical characteristics, EEG findings and implications of status epilepticus in patients with brain metastases

PurposeTo evaluate the clinical implications of status epilepticus in patients with metastases to the brain as well as associated demographic, clinical, EEG and radiographic features. MethodsRetrospective chart review of 19 patients with metastases to the brain who subsequently developed status epilepticus. ResultsOf the patients who developed status epilepticus only 36.8% had a prior history of seizures since diagnosis of brain metastases. Status epilepticus most commonly occurred in the setting of a new structural injury to the brain such as new metastases, increase in size of metastases or hemorrhage. 57.9% of patients had either refractory or super-refractory status epilepticus. Focal non-convulsive status epilepticus was the most common subtype occurring in 42.1% of patients. 31.6% of patients died within 30 days of the onset of status epilepticus. ConclusionStatus epilepticus eventually resolved with treatment in all patients with brain metastases; however, it is associated with poor outcomes as nearly one-third was deceased within 30-days of onset. Nevertheless, no patients died during status epilepticus. Thus, status epilepticus may be indicative of an overall poor clinical status among patients with brain metastases.

Febrile Infection-Related Epilepsy Syndrome

AbstractFebrile infection-related epilepsy syndrome (FIRES) is a subset or variant of new-onset refractory status epilepticus in children. FIRES is characterized by the occurrence of a febrile episode between 24 hours and 2 weeks before the onset of refractory status epilepticus. A infectious cause is rarely identified in FIRES and an inflammatory or autoimmune etiology is implied. Seizures in FIRES are very difficult to control, and treatments include antiepileptic drugs, ketogenic diet, intravenous immunoglobulin, plasmapheresis, and corticosteroid therapy. The prognosis for patients with FIRES is poor, and most children are left with refractory epilepsy and cognitive impairment. The new consensus guidelines on the terminology of FIRES and recent interest in new treatment approaches have been welcome developments for clinicians who face the challenge of diagnosing and managing status epilepticus in a previously healthy child that occurs following a minor febrile episode. This review aims to provide clinicians with an update on the current hypotheses for the etiology, pathogenesis, clinical evaluation, management, and future directions in the diagnosis and treatment of FIRES.

Peri-ictal magnetic resonance imaging in status epilepticus: Temporal relationship and prognostic value in 60 patients

Purpose. Magnetic resonance imaging (MRI) changes associated with status epilepticus (SE) have been described in recent studies. Our aim was to evaluate the diagnosis and prognosis of the peri-ictal MRI changes detected in SE patients.Method. All adults diagnosed with SE and examined by MRI within 240 h after SE onset were enrolled (2011–2017). Demographic, clinical and electroencephalography data, and functional status at admission and discharge were collected. MRI findings were recorded and relationships between clinical and MRI data, and between these data and functional outcome were analyzed.Results. Sixty patients included, 50% women, mean age 57.5 years. Median duration of SE was 51.46 h and median time from SE onset to MRI was 86.5 h. Of the total, 41.7% had a restricted diffusion pattern on diffusion-weighted imaging (DWI) and 63.3% had hyperintensities suggestive of edema on T2-weighted (T2WI)/FLAIR sequences. The factors independently associated with T2WI hyperintensities were the presence of acute cerebral lesions (p = 0.023), baseline STESS (p = 0.007), and MRI performed within 84 h (p = 0.007). Variables independently associated with diffusion restriction were a potentially fatal cause (p = 0.020), SE duration >24 h (p = 0.022), and MRI performed within the first 84 h (p = 0.045). In patients undergoing MRI within 84 h, the DWI and T2WI abnormalities were both highly associated with an unfavorable outcome.Conclusions. Characteristic signal changes on DWI and T2WI sequences were seen in approximately half our SE patients undergoing early (<84 h) brain MRI studies, and were independently related to the patients’ functional status at discharge.

Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy.

To establish the effects induced by long-term, unilateral stimulation of parvalbumin (PV)-positive interneurons on seizures, interictal spikes, and high-frequency oscillations (80-500Hz) occurring after pilocarpine-induced status epilepticus (SE)-a proven model of mesial temporal lobe epilepsy (MTLE)-in transgenic mice expressing or not expressing ChR2. PV-ChR2 (n = 6) and PV-Cre (n = 6) mice were treated with pilocarpine to induce SE. Three hours after SE onset, unilateral optogenetic stimulation (450nm, 25mW, 20-millisecond pulses delivered at 8Hz for 30 seconds every 2 minutes) of CA3 PV-positive interneurons was implemented for 14 continuous days in both groups. Rates of seizures (p < 0.01), interictal spikes (p < 0.001), and interictal spikes with fast ripples (250-500Hz) (p < 0.001) were lower in PV-ChR2 than in PV-Cre mice. Ripples (80-200Hz) occurring outside of interictal spikes had higher rates in the PV-ChR2 group (p < 0.01), whereas isolated fast ripples had lower rates (p < 0.01). However, seizure probability was higher during optogenetic stimulation in PV-ChR2 compared to PV-Cre animals (p < 0.05). Our findings show that the unilateral activation of CA3 PV-positive interneurons exerts anti-ictogenic effects associated with decreased rates of interictal spikes and fast ripples in this MTLE model. However, PV-positive interneuron stimulation can paradoxically trigger seizures in epileptic animals, supporting the notion that γ-aminobutyric acid type A signaling can also initiate ictogenesis. ANN NEUROL 2019;86:714-728.

Effects of Three Anti-Seizure Drugs on Cholinergic and Metabolic Activity in Experimental Status Epilepticus.

Status epilepticus (SE) is characterized by recurrent seizure activity and can be drug- resistant. Knowledge of neuronal and metabolic activity of the brain during SE may be helpful to improve medical care. We here report the effects of three anti-seizure drugs on changes of acetylcholine energy metabolites and oxidative stress during SE. We used the lithium-pilocarpine model in rats to induce SE and in vivo- microdialysis to monitor cholinergic and metabolic activity in the hippocampus. We measured extracellular concentrations of acetylcholine, glucose, lactate, pyruvate, glycerol and isoprostanes before and during SE, and after acute treatment with pregabalin, valproic acid, and levetiracteam. Upon onset of SE, acetylcholine (ACh) release increased six- to eightfold. Glucose was increased only transiently by 30% but lactate levels rose four-fold, and extracellular concentrations of glycerol ten-fold. Isoprostanes are markers of oxidative stress and increased more than 20-fold. Two hours after pilocarpine adminstration, rats were treated with pregabalin (100 mg/kg), levetiracetam (200 mg/kg) or valproic acid (400 mg/kg) by i.p. injection. All three drugs stopped seizure activity in a delayed fashion, but at the doses indicated, only animals that received levetiracetam reached consciousness. All drugs reduced ACh release within 60-120 minutes. Lactate/pyruvate ratios, glycerol and isoprostanne levels were also reduced significantly after drug administration. Hippocampal ACh release closely follows seizure activity in SE and is attenuated when SE subsides. Pregabalin, valproic acid and levetiracetam all terminate seizures in the rat SE model and attenuate cholinergic and metabolic changes within two hours.

Intravenous Brivaracetam in the Treatment of Status Epilepticus: A Systematic Review.

Brivaracetam is a high-affinity synaptic vesicle glycoprotein 2A ligand with high brain permeability and rapid onset of action. These properties make brivaracetam potentially an ideal compound in the emergency setting. The objective of our study was to review the evidence about the clinical efficacy and tolerability of intravenous brivaracetam in the treatment of status epilepticus. We systematically searched MEDLINE, EMBASE, Google Scholar, ClinicalTrials.gov, and conference proceedings to identify studies evaluating intravenous brivaracetam as treatment for status epilepticus of any type in patients of any age. Searches were conducted on 3 December, 2018. Seven studies were included (37 patients; aged 22-85 years; 21 were female). The type and etiology of status epilepticus varied across studies. The number of drugs used prior to brivaracetam to treat status epilepticus ranged from 1 to 8. The time from status epilepticus onset to brivaracetam administration ranged from 0.5 h to 105 days. The initial brivaracetam dose ranged from 50 to 400 mg. In case series, the proportion of patients achieving clinical status epilepticus cessation when brivaracetam was administered as the last drug varied from 27 to 50%; in case reports, all patients had status epilepticus cessation. The time from brivaracetam administration to status epilepticus cessation ranged from 15min to 94h. No serious adverse effects were reported. The available data suggested that brivaracetam can be a safe treatment option in patients with status epilepticus. The current evidence is however hampered by several confounding factors, and controlled studies are warranted to define the actual benefit of brivaracetam for the treatment of status epilepticus.