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CNS Drugs Oct 2023Status epilepticus in poststroke epilepsy is a challenging condition because of multiple vascular comorbidities and the advanced age of patients. Data on... (Observational Study)
Observational Study
Third-Generation Antiseizure Medication in the Treatment of Benzodiazepine-Refractory Status Epilepticus in Poststroke Epilepsy: A Retrospective Observational Register-Based Study.
BACKGROUND AND OBJECTIVE
Status epilepticus in poststroke epilepsy is a challenging condition because of multiple vascular comorbidities and the advanced age of patients. Data on third-generation antiseizure medication (ASM) in this condition are limited. The aim of this study was to evaluate the efficacy of third-generation ASMs in the second- or third-line therapy of benzodiazepine-refractory status epilepticus in poststroke epilepsy following acute ischemic stroke.
METHODS
Data on the effectiveness of third-generation ASMs in patients with status epilepticus in poststroke epilepsy were gathered from two German Stroke Registries and the Mainz Epilepsy Registry. We included only cases with epilepsy remote to the ischemic event. No patients with acute symptomatic seizures were included. The following third-generation ASMs were included: brivaracetam, lacosamide, eslicarbazepine, perampanel, topiramate, and zonisamide. The assessment of effectiveness was based on seizure freedom within 48 h since the start of therapy with the respective ASM. Seizure freedom was evaluated both clinically (clinical evaluation at least three times per day) and by daily electroencephalogram records.
RESULTS
Of the 138 patients aged 70.8 ± 8.1 years with benzodiazepine-refractory status epilepticus in ischemic poststroke epilepsy, 33 (23.9%) were treated with lacosamide, 24 (17.4%) with brivaracetam, 23 (16.7%) with eslicarbazepine, 21 (15.2%) with perampanel, 20 (14.5%) with topiramate, and 17 (12.3%) with zonisamide. Seizure freedom within 48 h was achieved in 66.7% of patients with lacosamide, 65.2% with eslicarbazepine, 38.1% with perampanel, 37.5% with brivaracetam, 35.0% with topiramate, and 35.3% with zonisamide (p < 0.05 for comparison of lacosamide or eslicarbazepine to other ASMs).
CONCLUSIONS
Based on these data, lacosamide and eslicarbazepine might be more favorable in the treatment of refractory status epilepticus in poststroke epilepsy, when administered as second- or third-line ASMs before anesthesia. Because of the fact that these ASMs share the same mechanism of action (slow inactivation of sodium channels), our findings could motivate further research on the role that this pharmaceutical mechanism of action has in the treatment of poststroke epilepsy.
CLINICAL TRIAL REGISTRATION
This study was registered at ClinicalTrials.gov (NCT05267405).
Topics: Humans; Anticonvulsants; Benzodiazepines; Epilepsy; Ischemic Stroke; Lacosamide; Retrospective Studies; Seizures; Status Epilepticus; Topiramate; Zonisamide; Middle Aged; Aged
PubMed: 37784006
DOI: 10.1007/s40263-023-01039-y -
Neurobiology of Disease Aug 2023Stroke is the most common cause of acquired epilepsy, but treatment for preventing the development of post-stroke epilepsy is still unavailable. Since stroke results in...
Stroke is the most common cause of acquired epilepsy, but treatment for preventing the development of post-stroke epilepsy is still unavailable. Since stroke results in neuronal damage and death as well as initial loss of activity in the affected brain region, homeostatic plasticity may be trigged and contribute to an increase in network hyperexcitability that underlies epileptogenesis. Correspondingly, enhancing brain activity may inhibit hyperexcitability from enhanced homeostatic plasticity and prevent post-stroke epileptogenesis. To test these hypotheses, we first used in vivo two-photon and mesoscopic imaging of activity of cortical pyramidal neurons in Thy1-GCaMP6 transgenic mice to determine longitudinal changes in excitatory activity after a photothrombotic ischemic stroke. At 3-days post-stroke, there was a significant loss of neuronal activity in the peri-injury area as indicated by reductions in the frequency of calcium spikes and percentage of active neurons, which recovered to baseline level at day 7, supporting a homeostatic activity regulation of the surviving neurons in the peri-injury area. We further used optogenetic stimulation to specifically stimulate activity of pyramidal neurons in the peri-injury area of Thy-1 channelrhodopsin transgenic mice from day 5 to day 15 after stroke. Using pentylenetetrazole test to evaluate seizure susceptibility, we showed that stroke mice are more susceptible to Racine stage V seizures (time latency 54.3 ± 12.9 min) compared to sham mice (107.1 ± 13.6 min), but optogenetic stimulation reversed the increase in seizure susceptibility (114.0 ± 9.2 min) in mice with stroke. Similarly, administration of D-cycloserine, a partial N-methyl-d-aspartate (NMDA) receptor agonist that can mildly enhance neuronal activity without causing post-stroke seizure, from day 5 to day 15 after a stroke significantly reversed the increase in seizure susceptibility. The treatment also resulted in an increased survival of glutamic acid decarboxylase 67 (GAD67) positive interneurons and a reduced activation of glial fibrillary acidic protein (GFAP) positive reactive astrocytes. Thus, this study supports the involvement of homeostatic activity regulation in the development of post-stroke hyperexcitability and potential application of activity enhancement as a novel strategy to prevent post-stroke late-onset seizure and epilepsy through regulating cortical homeostatic plasticity.
Topics: Mice; Animals; Optogenetics; Seizures; Epilepsy; Stroke; Mice, Transgenic
PubMed: 37468047
DOI: 10.1016/j.nbd.2023.106233 -
Brain Stimulation 2023Longitudinal EEG recorded by implanted devices is critical for understanding and managing epilepsy. Recent research reports patient-specific, multi-day cycles in...
BACKGROUND
Longitudinal EEG recorded by implanted devices is critical for understanding and managing epilepsy. Recent research reports patient-specific, multi-day cycles in device-detected epileptiform events that coincide with increased likelihood of clinical seizures. Understanding these cycles could elucidate mechanisms generating seizures and advance drug and neurostimulation therapies.
OBJECTIVE/HYPOTHESIS
We hypothesize that seizure-correlated cycles are present in background neural activity, independent of interictal epileptiform spikes, and that neurostimulation may temporarily interrupt these cycles.
METHODS
We analyzed regularly-recorded seizure-free data epochs from 20 patients implanted with a responsive neurostimulation (RNS) device for at least 1.5 years, to explore the relationship between cycles in device-detected interictal epileptiform activity (dIEA), clinician-validated interictal spikes, background EEG features, and neurostimulation.
RESULTS
Background EEG features tracked the cycle phase of dIEA in all patients (AUC: 0.63 [0.56-0.67]) with a greater effect size compared to clinically annotated spike rate alone (AUC: 0.55 [0.53-0.61], p < 0.01). After accounting for circadian variation and spike rate, we observed significant population trends in elevated theta and beta band power and theta and alpha connectivity features at the cycle peaks (sign test, p < 0.05). In the period directly after stimulation we observe a decreased association between cycle phase and EEG features compared to background recordings (AUC: 0.58 [0.55-0.64]).
CONCLUSIONS
Our findings suggest that seizure-correlated dIEA cycles are not solely due to epileptiform discharges but are associated with background measures of brain state; and that neurostimulation may temporarily interrupt these cycles. These results may help elucidate mechanisms underlying seizure generation, provide new biomarkers for seizure risk, and facilitate monitoring, treating, and managing epilepsy with implantable devices.
Topics: Humans; Electroencephalography; Epilepsy; Seizures; Brain
PubMed: 37979654
DOI: 10.1016/j.brs.2023.11.005 -
Neurological Sciences : Official... Sep 2023
Topics: Humans; Claustrum; Seizures; Drug Resistant Epilepsy; Epileptic Syndromes; Status Epilepticus
PubMed: 37273001
DOI: 10.1007/s10072-023-06887-6 -
The Journal of Clinical Investigation Jul 2023Mutations in HNRNPH2 cause an X-linked neurodevelopmental disorder with features that include developmental delay, motor function deficits, and seizures. More than 90%...
Mutations in HNRNPH2 cause an X-linked neurodevelopmental disorder with features that include developmental delay, motor function deficits, and seizures. More than 90% of patients with hnRNPH2 have a missense mutation within or adjacent to the nuclear localization signal (NLS) of hnRNPH2. Here, we report that hnRNPH2 NLS mutations caused reduced interaction with the nuclear transport receptor Kapβ2 and resulted in modest cytoplasmic accumulation of hnRNPH2. We generated 2 knockin mouse models with human-equivalent mutations in Hnrnph2 as well as Hnrnph2-KO mice. Knockin mice recapitulated clinical features of the human disorder, including reduced survival in male mice, impaired motor and cognitive functions, and increased susceptibility to audiogenic seizures. In contrast, 2 independent lines of Hnrnph2-KO mice showed no detectable phenotypes. Notably, KO mice had upregulated expression of Hnrnph1, a paralog of Hnrnph2, whereas knockin mice failed to upregulate Hnrnph1. Thus, genetic compensation by Hnrnph1 may counteract the loss of hnRNPH2. These findings suggest that HNRNPH2-related disorder may be driven by a toxic gain of function or a complex loss of HNRNPH2 function with impaired compensation by HNRNPH1. The knockin mice described here are an important resource for preclinical studies to assess the therapeutic benefit of gene replacement or knockdown of mutant hnRNPH2.
Topics: Animals; Humans; Male; Mice; Disease Models, Animal; Mutation; Mutation, Missense; Neurodevelopmental Disorders; Seizures
PubMed: 37463454
DOI: 10.1172/JCI160309 -
Neurobiology of Disease Nov 2023Epilepsies are multifaceted neurological disorders characterized by abnormal brain activity, e.g. caused by imbalanced synaptic excitation and inhibition. The neural...
Epilepsies are multifaceted neurological disorders characterized by abnormal brain activity, e.g. caused by imbalanced synaptic excitation and inhibition. The neural extracellular matrix (ECM) is dynamically modulated by physiological and pathophysiological activity and critically involved in controlling the brain's excitability. We used different epilepsy models, i.e. mice lacking the presynaptic scaffolding protein Bassoon at excitatory, inhibitory or all synapse types as genetic models for rapidly generalizing early-onset epilepsy, and intra-hippocampal kainate injection, a model for acquired temporal lobe epilepsy, to study the relationship between epileptic seizures and ECM composition. Electroencephalogram recordings revealed Bassoon deletion at excitatory or inhibitory synapses having diverse effects on epilepsy-related phenotypes. While constitutive Bsn mutants and to a lesser extent GABAergic neuron-specific knockouts (BsncKO) displayed severe epilepsy with more and stronger seizures than kainate-injected animals, mutants lacking Bassoon solely in excitatory forebrain neurons (BsncKO) showed only mild impairments. By semiquantitative immunoblotting and immunohistochemistry we show model-specific patterns of neural ECM remodeling, and we also demonstrate significant upregulation of the ECM receptor CD44 in null and BsncKO mutants. ECM-associated WFA-binding chondroitin sulfates were strongly augmented in seizure models. Strikingly, Brevican, Neurocan, Aggrecan and link proteins Hapln1 and Hapln4 levels reliably predicted seizure properties across models, suggesting a link between ECM state and epileptic phenotype.
Topics: Mice; Animals; Kainic Acid; Extracellular Matrix; Epilepsy; Neurons; Seizures
PubMed: 37838005
DOI: 10.1016/j.nbd.2023.106324 -
Epilepsy & Behavior : E&B Nov 2023To trace (i) changes in Australian Pregnancy Register (APR) records concerning antiseizure medications (ASMs) prescribed for women with epilepsy (WWE) over the course of...
OBJECTIVES
To trace (i) changes in Australian Pregnancy Register (APR) records concerning antiseizure medications (ASMs) prescribed for women with epilepsy (WWE) over the course of 24 years and correlate the changes with (ii) rates of occurrence of pregnancies involving foetal malformations, (iii) the body organs involved in the malformations, and (iv) freedom from epileptic seizures.
RESULTS
Use of valproate and carbamazepine decreased progressively, use of lamotrigine remained relatively static, and the use of levetiracetam increased progressively, whereas the use of topiramate first increased and then fell again, associated with a temporary increase in malformation-associated pregnancy rate. More serious malformations, such as spina bifida, became less frequent, whereas more trivial ones tended to increase, whereas epileptic seizure freedom rates improved.
CONCLUSIONS
The increasing use of newer ASMs in pregnant women has been associated with overall advantages in relation to the frequency and severity of foetal malformation and with advantages in relation to freedom from epileptic seizures.
Topics: Female; Pregnancy; Humans; Australia; Epilepsy; Anticonvulsants; Seizures; Lamotrigine; Valproic Acid; Pregnancy Complications
PubMed: 37839246
DOI: 10.1016/j.yebeh.2023.109482 -
Seizure Nov 2023This study aimed to characterize the Swedish cohort of surgically treated patients with TSC and explore differences in preoperative investigation and outcome over time.
PURPOSE
This study aimed to characterize the Swedish cohort of surgically treated patients with TSC and explore differences in preoperative investigation and outcome over time.
METHODS
Data on patient and seizure characteristics were retrieved from the Swedish National Epilepsy Surgery Register. Two-year follow-up results were compared between the years 1997-2010 and 2011-2018. Preoperative investigations were re-evaluated.
RESULTS
Eighteen tuberectomies and seven callosotomies were identified. Seizure freedom after tuberectomy was achieved in 11 % (1/9) 1997-2010 and 56 % (5/9) 2011-2018. The number of tuberectomies increased each decade. Patients operated on in 1997-2010 had higher seizure frequency (median 175 seizures/month vs. 102) and incidence of infantile spasms (4/9 vs. 1/9, none after 2011). There was a trend towards surgery at a younger age (median 86 months 1997-2010 vs. 48 months 2011-2018). None with >200 seizure/month, SEGA, or history of infantile spasms achieved seizure freedom. Two patients underwent anterior callosotomy (1992 and 1994) and became free of drop attacks. Five callosotomies were performed between 2011 and 2013, one patient became free of drop attacks. Two complications with new neurological deficits were reported. The median age at surgery was higher in the callosotomy group (14 years) than in the tuberectomy group (5 years).
CONCLUSION
Seizure freedom after tuberectomy in patients with TSC has increased over time in our cohort. Signs of a heavier disease burden were more frequently observed 1997-2010 and associated with worse outcomes. Callosotomy operations were prevalent at the beginning of the 2010s.
Topics: Humans; Adolescent; Child; Spasms, Infantile; Sweden; Tuberous Sclerosis; Treatment Outcome; Electroencephalography; Epilepsy; Seizures; Registries; Syncope; Retrospective Studies
PubMed: 37757549
DOI: 10.1016/j.seizure.2023.09.016 -
Transient targeting of hypothalamic orexin neurons alleviates seizures in a mouse model of epilepsy.Nature Communications Feb 2024Lateral hypothalamic (LH) hypocretin/orexin neurons (HONs) control brain-wide electrical excitation. Abnormally high excitation produces epileptic seizures, which affect...
Lateral hypothalamic (LH) hypocretin/orexin neurons (HONs) control brain-wide electrical excitation. Abnormally high excitation produces epileptic seizures, which affect millions of people and need better treatments. HON population activity spikes from minute to minute, but the role of this in seizures is unknown. Here, we describe correlative and causal links between HON activity spikes and seizures. Applying temporally-targeted HON recordings and optogenetic silencing to a male mouse model of acute epilepsy, we found that pre-seizure HON activity predicts and controls the electrophysiology and behavioral pathology of subsequent seizures. No such links were detected for HON activity during seizures. Having thus defined the time window where HONs influence seizures, we targeted it with LH deep brain stimulation (DBS), which inhibited HON population activity, and produced seizure protection. Collectively, these results uncover a feature of brain activity linked to seizures, and demonstrate a proof-of-concept treatment that controls this feature and alleviates epilepsy.
Topics: Mice; Animals; Male; Humans; Orexins; Seizures; Epilepsy; Neurons; Hypothalamus
PubMed: 38341419
DOI: 10.1038/s41467-024-45515-5 -
British Journal of Hospital Medicine... Oct 2023The National Confidential Enquiry into Patient Outcome and Death reviewed the quality of care provided to adults who presented to hospital following an epileptic...
The National Confidential Enquiry into Patient Outcome and Death reviewed the quality of care provided to adults who presented to hospital following an epileptic seizure. Clinical and organisational changes are highlighted that aim to improve patient care and outcomes.
Topics: Adult; Humans; Epilepsy; Hospitals; Seizures
PubMed: 37906066
DOI: 10.12968/hmed.2023.0283