Staged treatment response in status epilepticus: Lessons from the SENSE registry.

OBJECTIVES: Although in epilepsy patients the likelihood of becoming seizure-free decreases substantially with each unsuccessful treatment, to our knowledge this has been poorly investigated in status epilepticus (SE). We aimed to evaluate the proportion of SE cessation and functional outcome after successive treatment steps. METHODS: We conducted a post hoc analysis of a prospective, observational, multicenter cohort (Sustained Effort Network for treatment of Status Epilepticus [SENSE]), in which 1049 incident adult SE episodes were prospectively recorded at nine European centers. We analyzed 996 SE episodes without coma induction before the third treatment step. Rates of SE cessation, mortality (in ongoing SE or after SE control), and favorable functional outcome (assessed with modified Rankin scale) were evaluated after each step. RESULTS: SE was treated successfully in 838 patients (84.1%), 147 (14.8%) had a fatal outcome (36% of them died while still in SE), and 11 patients were transferred to palliative care while still in SE. Patients were treated with a median of three treatment steps (range 1-13), with 540 (54.2%) receiving more than two steps (refractory SE [RSE]) and 95 (9.5%) more than five steps. SE was controlled after the first two steps in 45%, with an additional 21% treated after the third, and 14% after the fourth step. Likelihood of SE cessation (p < 0.001), survival (p = 0.003), and reaching good functional outcome (p < 0.001) decreased significantly between the first two treatment lines and the third, especially in patients not experiencing generalized convulsive SE, but remained relatively stable afterwards. SIGNIFICANCE: The significant worsening of SE prognosis after the second step clinically supports the concept of RSE. However, and differing from findings in human epilepsy, RSE remains treatable in about one third of patients, even after several failed treatment steps. Clinical judgment remains essential to determine the aggressiveness and duration of SE treatment, and to avoid premature treatment cessation in patients with SE.

Sustained effort network for treatment of status epilepticus/European academy of neurology registry on adult refractory status epilepticus (SENSE-II/AROUSE).

BACKGROUND: Status Epilepticus (SE) is a common neurological emergency associated with a high rate of functional decline and mortality. Large randomized trials have addressed the early phases of treatment for convulsive SE. However, evidence regarding third-line anesthetic treatment and the treatment of nonconvulsive status epilepticus (NCSE) is scarce. One trial addressing management of refractory SE with deep general anesthesia was terminated early due to insufficient recruitment. Multicenter prospective registries, including the Sustained Effort Network for treatment of Status Epilepticus (SENSE), have shed some light on these questions, but many answers are still lacking, such as the influence exerted by distinct EEG patterns in NCSE on the outcome. We therefore initiated a new prospective multicenter observational registry to collect clinical and EEG data that combined may further help in clinical decision-making and defining SE. METHODS: Sustained effort network for treatment of status epilepticus/European Academy of Neurology Registry on refractory Status Epilepticus (SENSE-II/AROUSE) is a prospective, multicenter registry for patients treated for SE. The primary objectives are to document patient and SE characteristics, treatment modalities, EEG, neuroimaging data, and outcome of consecutive adults admitted for SE treatment in each of the participating centers and to identify factors associated with outcome and refractoriness. To reach sufficient statistical power for multivariate analysis, a cohort size of 3000 patients is targeted. DISCUSSION: The data collected for the registry will provide both valuable EEG data and information about specific treatment steps in different patient groups with SE. Eventually, the data will support clinical decision-making and may further guide the planning of clinical trials. Finally, it could help to redefine NCSE and its management. TRIAL REGISTRATION: NCT number: NCT05839418.

A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies.

Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P < 5 × 10-8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10-16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187-0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (>90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10-4, OR = 2.5, 95%CI = 1.499-4.157) and DRB1*04:01 allele (P = 8.3 × 10-5, OR = 2.4, 95%CI = 1.548-3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles.

Making SENSE of what we do - How to bring evidence to clinical practice.

Status epilepticus is a frequent neurological emergency. Several audits and registries have enhanced our knowledge regarding patient demography, etiology, treatment, and outcome. Several large registries have also contributed significantly to current treatment guidelines that emphasize the importance of instant and effective treatment onset. Large registries also document that deviation from these treatment guidelines is not the exception but the rule. Therefore, careful analysis of the treatment pathways as well as balanced intervention efforts are necessary to overcome the gap between knowledge and action. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.

Successful treatment of adult Dravet syndrome patients with cenobamate.

Dravet syndrome (DS) is a rare, drug-resistant, severe developmental and epileptic encephalopathy caused by pathogenic variants in the α subunit of the voltage-gated sodium channel gene SCN1A. Hyperexcitability in DS results from loss of function in inhibitory interneurons. Thus sodium channel blockers are usually contraindicated in patients with DS as they may lead to disease aggravation. Cenobamate (CNB) is a novel antiseizure medication (ASM) with promising rates of seizure freedom in patients with focal-onset, drug-resistant epilepsy. CNB blocks persistent sodium currents by promoting the inactive states of sodium channels. In a multi-center study, we analyzed retrospectively the effect of an add-on therapy of CNB in adult patients with DS. We report four adult patients with DS in whom the use of CNB resulted in a significant seizure reduction of more than 80%, with a follow-up of up to 542 days. CNB was the first drug in these patients that resulted in a long-lasting and significant seizure reduction. No severe adverse events occurred. We highlight CNB as an ASM that may lead to a clinically meaningful reduction of seizure frequency in adult patients with DS. It is unclear, however, if all patients with DS benefit, requiring further investigation and functional experiments.

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.

Cell injury and receptor expression in the epileptic human amygdala.

Neuropathological findings in the amygdala obtained from patients with mesial temporal lobe epilepsy (MTLE) indicate varying degrees of histopathological alterations, such as neuronal loss and gliosis. The mechanisms underlying cellular damage in the amygdala of patients with MTLE have not been fully elucidated. In the present study, we assess cellular damage, determine the receptor expression of major inhibitory and excitatory neurotransmitters, and evaluate the correlation between the expression of various receptors and cell damage in the basolateral complex and the centromedial areas in the amygdala specimens resected during brain surgery on 30 patients with medically intractable MTLE. Our data reveal an increased rate of cell damage and apoptosis as well as decreased expression levels of several GABAergic receptor subunits (GABAARα1, GABAARß3, and GABABR1) and GAD65 in the amygdalae obtained during epilepsy surgery compared to autopsy specimens. Analyses of the expression of glutamate excitatory receptor subunits (NR1, NR2B, mGluR1α, GluR1, and GluR2) reveal no significant differences between the epileptic amygdalae and autopsy control tissues. Furthermore, the increased occurrence of apoptotic cells in the amygdala is negatively correlated with the reduced expression of the studied GABAergic receptor subunits and GAD65 but is not correlated with the expression of excitatory receptors. The present data point to the importance of GABAergic neurotransmission in seizure-induced cell injury in the amygdala of patients with MTLE and suggest several GABA receptor subunits as potential druggable target structures to control epilepsy and its comorbid disorders, such as anxiety.

Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis.

We performed a genome-wide association study in 1,194 controls and 150 patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR, n = 96) or anti-leucine-rich glioma-inactivated1 (anti-LGI1, n = 54) autoimmune encephalitis. Anti-LGI1 encephalitis was highly associated with 27 single-nucleotide polymorphisms (SNPs) in the HLA-II region (leading SNP rs2858870 p = 1.22 × 10-17 , OR = 13.66 [7.50-24.87]). Potential associations, below genome-wide significance, were found with rs72961463 close to the doublecortin-like kinase 2 gene (DCLK2) and rs62110161 in a cluster of zinc-finger genes. HLA allele imputation identified association of anti-LGI1 encephalitis with HLA-II haplotypes encompassing DRB1*07:01, DQA1*02:01 and DQB1*02:02 (p < 2.2 × 10-16 ) and anti-NMDAR encephalitis with HLA-I allele B*07:02 (p = 0.039). No shared genetic risk factors between encephalitides were identified. Ann Neurol 2018;83:863-869.

Sustained Effort Network for treatment of Status Epilepticus (SENSE) - A multicenter prospective observational registry.

Status epilepticus (SE) is an important neurological emergency lacking adequate evidence for efficacy and safety of treatment beyond the application of benzodiazepines as first treatment step. To bridge the gap between the few pivotal trials and retrospective uncontrolled case series, we established a prospective multicenter registry recruiting patients in experienced centers in German-speaking countries. We could document 1179 episodes of 1049 patients over a period of 5 years. First data analysis showed that in the majority of the episodes, established treatment guidelines were not followed. Latency between status onset and different treatment steps were longer, and bolus doses lower than recommended. Moreover, a relevant proportion of the patients did not receive a benzodiazepine but levetiracetam as first treatment step. Although SE could be controlled in more than 90% of the episodes, lower bolus dose and longer treatment latency were associated with refractoriness of the SE in multivariate analysis. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures.

SENSE registry for status epilepticus.

Evidence is scarce regarding the treatment of status epilepticus (SE). Only a few large randomized controlled trials have been published. Therefore, we set up a multicenter registry to prospectively document treatment practice in several different large hospitals in German-speaking countries. Over a period of more than 4 years, we were able to document 1179 episodes of 1049 patients who were treated for SE in 1 of the 8 participating centers in Germany, Austria, and Switzerland. Median age was 70 years. The most frequent etiology was remote (32%), followed by acute (31%), or a mixture of acute and remote factors (10%). Semiology was generalized convulsive in 44%, focal motor in 27%, and nonconvulsive in 30%. Only a few patients did not have relevant comorbidities. Median latency between SE onset and first treatment was 1 hour (median). Three hundred ninety-three (32%) of the patients were treated within 30 minutes after onset. The first treatment step consisted of benzodiazepines in more than 80%, and in levetiracetam in 15%. Five hundred eleven patients (49%) were refractory (defined as ongoing SE after application of benzodiazepine and 1 intravenous anticonvulsant). Further analysis of these registry data may be important for hypothesis generation and trial design for treatment of status epilepticus.

Making SENSE--Sustained Effort Network for treatment of Status Epilepticus as a multicenter prospective registry.

BACKGROUND: Evidence regarding the different treatment options of status epilepticus (SE) in adults is scarce. Large randomized trials cover only one treatment at early stage and suggest the superiority of benzodiazepines over placebo, of intravenous lorazepam over intravenous diazepam or over intravenous phenytoin alone, and of intramuscular midazolam over intravenous lorazepam. However, many patients will not be treated successfully with the first treatment step. A large randomized trial covering the treatment of established status (ESETT) has just been funded recently by the NIH and will not start before 2015, with expected results in 2018; a trial on the treatment of refractory status with general anesthetics was terminated early due to insufficient recruitment. Therefore, a prospective multicenter observational registry was set up; this may help in clinical decision-making until results from randomized trials are available. METHODS/DESIGN: SENSE is a prospective, multicenter registry for patients treated for SE. The primary objective is to document patient characteristics, treatment modalities and in-house outcome of consecutive adults admitted for SE treatment in each of the participating centres and to identify predictors of outcome. Pre-treatment, treatment-related and outcome variables are documented systematically. To allow for meaningful multivariate analysis in the patient subgroups with refractory SE, a cohort size of 1000 patients is targeted. DISCUSSION: The results of the study will provide information about risks and benefits of specific treatment steps in different patient groups with SE at different points of time. Thus, it will support clinical decision-making and, furthermore, it will be helpful in the planning of treatment trials. TRIAL REGISTRATION: DRKS00000725.

Clinical Correlation of Altered Molecular Signatures in Epileptic Human Hippocampus and Amygdala.

Widespread alterations in the expression of various genes could contribute to the pathogenesis of epilepsy. The expression levels of various genes, including major inhibitory and excitatory receptors, ion channels, cell type-specific markers, and excitatory amino acid transporters, were assessed and compared between the human epileptic hippocampus and amygdala, and findings from autopsy controls. Moreover, the potential correlation between molecular alterations in epileptic brain tissues and the clinical characteristics of patients undergoing epilepsy surgery was evaluated. Our findings revealed significant and complex changes in the expression of several key regulatory genes in both the hippocampus and amygdala of patients with intractable epilepsy. The expression changes in various genes differed considerably between the epileptic hippocampus and amygdala. Different correlation patterns were observed between changes in gene expression and clinical characteristics, depending on whether the patients were considered as a whole or were subdivided. Altered molecular signatures in different groups of epileptic patients, defined within a given category, could be viewed as diagnostic biomarkers. Distinct patterns of molecular changes that distinguish these groups from each other appear to be associated with epilepsy-specific functional consequences.

Influence of a silastic ECoG grid on EEG/ECoG based source analysis.

The simultaneous evaluation of the local electrocorticogram (ECoG) and the more broadly distributed electroencephalogram (EEG) from humans undergoing evaluation for epilepsy surgery has been shown to further the understanding of how pathologies give rise to spontaneous seizures. However, a well-known problem is that the disruption of the conducting properties of the brain coverings can render simultaneous scalp and intracranial recordings unrepresentative of the habitual EEG. The ECoG electrodes for measuring the potential on the surface of the cortex are commonly embedded into one or more sheets of a silastic material. These highly resistive silastic sheets influence the volume conduction and might therefore also influence the scalp EEG and ECoG measurements. We carried out a computer simulation study to examine how the scalp EEG and the ECoG, as well as the source reconstruction therefrom, employing equivalent current dipole estimation methods, are affected by the insulating ECoG grids. The finite element method with high quality tetrahedral meshes, generated using a constrained Delaunay tetrahedralization meshing approach, was used to model the volume conductor that incorporates the very thin ECoG sheets. It is shown that the insulating silastic substrate of the ECoG grids can have a large impact on the scalp potential and on source reconstruction from scalp EEG data measured in the presence of the grids. The reconstruction errors are characterized with regard to the location of the source in the brain and the mislocalization tendency. In addition, we found a non-negligible influence of the insulating grids on ECoG based source analysis. We conclude, that the thin insulating ECoG sheets should be taken into account, when performing source analysis of simultaneously measured ECoG and scalp EEG data.

Concurrent recordings of slow DC-potentials and epileptiform discharges: Novel EEG amplifier and signal processing techniques.

Ionic currents within the brain generate voltage oscillations. These bioelectrical activities include ultra-low frequency electroencephalograms (DC-EEG, frequency less than 0.1 Hz) and conventional clinical electroencephalograms (AC-EEG, 0.5-70 Hz). Although AC-EEG is commonly used for diagnosing epilepsy, recent studies indicate that DC-EEG is an essential frequency component of EEG and can provide valuable information for analyzing epileptiform discharges. During conventional EEG recordings, DC-EEG is censored by applying high-pass filtering to i) obliterate slow-wave artifacts, ii) eliminate the bioelectrodes' half-cell potential asymmetrical changes in ultralow-low frequency, and iii) prevent instrument saturation. Spreading depression (SD), which is the most prolonged fluctuation in DC-EEG, may be associated with epileptiform discharges. However, recording of SD signals from the scalp's surface can be challenging due to the filtering effect and non-neuronal slow shift potentials. In this study, we describe a novel technique to extend the frequency bandwidth of surface EEG to record SD signals. The method includes novel instrumentation, appropriate bioelectrodes, and efficient signal-processing techniques. To evaluate the accuracy of our approach, we performed a simultaneous surface recording of DC- and AC-EEG from epileptic patients during long-term video EEG monitoring, which provide a promising tool for diagnosis of epilepsy. DATA AVAILABILITY STATEMENT: The data presented in this study are available on request.

Natural History and Developmental Trajectories of Individuals With Disease-Causing Variants in STXBP1.

BACKGROUND AND OBJECTIVES: Pathogenic variants in STXBP1 are among the major genetic causes of neurodevelopmental disorders. Despite the increasing number of individuals diagnosed without a history of epilepsy, little is known about the natural history and developmental trajectories in this subgroup and endpoints for future therapeutic studies are limited to seizure control. METHODS: We performed a cross-sectional retrospective study using standardized questionnaires for clinicians and caregivers of individuals with STXBP1-related disorders capturing medical histories, genetic findings, and developmental outcomes. Motor and language function were assessed using Gross Motor Function Classification System (GMFCS) scores and a speech impairment score and were compared within and across clinically defined subgroups. RESULTS: We collected data of 71 individuals with STXBP1-related disorders, including 44 previously unreported individuals. Median age at inclusion was 5.3 years (interquartile range 3.5-9.3) with the oldest individual aged 43.8 years. Epilepsy was absent in 18/71 (25%) of individuals. The range of developmental outcomes was broad, including 2 individuals presenting with close to age-appropriate motor development. Twenty-nine of 61 individuals (48%) were able to walk unassisted, and 24/69 (35%) were able to speak single words. Individuals without epilepsy presented with a similar onset and spectrum of phenotypic features but had lower GMFCS scores (median 3 vs 4, p < 0.01) than individuals with epilepsy. Individuals with epileptic spasms were less likely to walk unassisted than individuals with other seizure types (6% vs 58%, p < 0.01). Individuals with early epilepsy onset had higher speech impairment scores (p = 0.02) than individuals with later epilepsy onset. DISCUSSION: We expand the spectrum of STXBP1-related disorders and provide clinical features and developmental trajectories in individuals with and without a history of epilepsy. Individuals with epilepsy, in particular epileptic spasms, and neonatal or early-onset presented with less favorable motor and language functional outcomes compared with individuals without epilepsy. These findings identify children at risk for severe disease and can serve as comparator for future interventional studies in STXBP1-related disorders.

Dacrystic seizures: demographic, semiologic, and etiologic insights from a multicenter study in long-term video-EEG monitoring units.

PURPOSE: To provide an estimate of the frequency of dacrystic seizures in video-electroencephalography (EEG) long-term monitoring units of tertiary referral epilepsy centers and to describe the clinical presentation of dacrystic seizures in relationship to the underlying etiology. METHODS: We screened clinical records and video-EEG reports for the diagnosis of dacrystic seizures of all patients admitted for video-EEG long-term monitoring at five epilepsy referral centers in the United States and Germany. Patients with a potential diagnosis of dacrystic seizures were identified, and their clinical charts and video-EEG recordings were reviewed. We included only patients with: (1) stereotyped lacrimation, sobbing, grimacing, yelling, or sad facial expression; (2) long-term video-EEG recordings (at least 12 h); and (3) at least one brain magnetic resonance imaging (MRI) study. KEY FINDINGS: Nine patients (four female) with dacrystic seizures were identified. Dacrystic seizures were identified in 0.06-0.53% of the patients admitted for long-term video-EEG monitoring depending on the specific center. Considering our study population as a whole, the frequency was 0.13%. The presence of dacrystic seizures without other accompanying clinical features was found in only one patient. Gelastic seizures accompanied dacrystic seizures in five cases, and a hypothalamic hamartoma was found in all of these five patients. The underlying etiology in the four patients with dacrystic seizures without gelastic seizures was left mesial temporal sclerosis (three patients) and a frontal glioblastoma (one patient). All patients had a difficult-to-control epilepsy as demonstrated by the following: (1) at least three different antiepileptic drugs were tried in each patient, (2) epilepsy was well controlled with antiepileptic drugs in only two patients, (3) six patients were considered for epilepsy surgery and three of them underwent a surgical/radiosurgical or radioablative procedure. Regarding outcome, antiepileptic drugs alone achieved seizure freedom in two patients and did not change seizure frequency in another patient. Radiosurgery led to moderately good seizure control in one patient and did not improve seizure control in another patient. Three patients were or are being considered for epilepsy surgery on last follow-up. One patient remains seizure free 3 years after epilepsy surgery. SIGNIFICANCE: Dacrystic seizures are a rare but clinically relevant finding during video-EEG monitoring. Our data show that when the patient has dacrystic and gelastic seizures, the cause is a hypothalamic hamartoma. In contrast, when dacrystic seizures are not accompanied by gelastic seizures the underlying lesion is most commonly located in the temporal cortex.

Modern technology calls for a modern approach to classification of epileptic seizures and the epilepsies.

In the last 10-15 years the ILAE Commission on Classification and Terminology has been presenting proposals to modernize the current ILAE Classification of Epileptic Seizures and Epilepsies. These proposals were discussed extensively in a series of articles published recently in Epilepsia and Epilepsy Currents. There is almost universal consensus that the availability of new diagnostic techniques as also of a modern understanding of epilepsy calls for a complete revision of the Classification of Epileptic Seizures and Epilepsies. Unfortunately, however, the Commission is still not prepared to take a bold step ahead and completely revisit our approach to classification of epileptic seizures and epilepsies. In this manuscript we critically analyze the current proposals of the Commission and make suggestions for a classification system that reflects modern diagnostic techniques and our current understanding of epilepsy.

Treatment of status epilepticus in a large community hospital.

BACKGROUND: Status epilepticus (SE) is a neurological emergency usually requiring immediate medical treatment. Due to the lack of adequate studies, treatment guidelines and their application vary between countries and institutions. We intended to analyze current treatment of SE in a German community hospital. METHODS: We retrospectively identified patients from a large community hospital in northern Germany who had been diagnosed with SE between August 2008 and December 2010. Their charts were reviewed regarding sociodemographic variables, treatment and outcome. RESULTS: We studied the first SE episode in 172 patients with a median age of 69 years (range 18-90 years). The etiology was acute symptomatic in 30 patients, progressive symptomatic in 22 patients and remote symptomatic in 120 patients. Presentation was generalized convulsive in 60 patients, non-convulsive in 72 patients and simple motor/aura in 40 patients. Median latency from onset to treatment start was 0.75 h (range 0.2-336 h). Initial treatment had a success rate (SR) of 40%. Second line treatment had a success rate of 54%. In patients whose seizures were refractory to the first two drugs, success rates were between 31% and 55%, with only a minority of the patients receiving established drugs such as phenytoin or barbiturates. Multivariate analysis revealed non-convulsive semiology as the only factor significantly associated with refractoriness. SE could be terminated in 95% of the patients and in-hospital mortality was 10%. Benzodiazepines and phenytoin had the most severe side effects. CONCLUSIONS: Status epilepticus can be terminated successfully and with low in-hospital mortality in the vast majority of the patients treated in a large community hospital. The success rate of each treatment step is between 30% and 55% regardless of the substances used.

New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES) of unknown aetiology: A comparison of the incomparable?

PURPOSE: The discussion is ongoing whether new-onset refractory status epilepticus (NORSE) in adults and febrile infection-related epilepsy syndrome (FIRES) in children are one syndrome if the aetiology is unknown. In this study we will compare an adult cohort with NORSE and a paediatric cohort with FIRES in order to determine if they are similar or different. METHODS: We retrospectively compared 18 adults with NORSE versus 48 children with FIRES, both cohorts without identifiable cause despite extensive investigations. We analyzed demographic and clinical data using Mann-Whitney-U and χ2- tests. RESULTS: NORSE affected more women (78% vs. 42%; P = 0.009) than in FIRES. Median acute hospital stay was longer in FIRES (35 days [interquartile range, IQR=36] vs. 20 days [IQR=19]; P<0.001). FIRES was treated more frequently with coma therapy (82% vs. 28%; P<0.001) and with a higher median number of antiseizure medicines (7 [IQR=5] vs. 4 [IQR=2]; P<0.001). Children with FIRES showed a higher cerebrospinal fluid (CSF) cell count (10 cells/µl; P = 0.002) but a lower CSF protein level than adults with NORSE (48 mg/dl; P = 0.028). Immunotherapy was administered more frequently in FIRES (73% vs. 22%; P<0.001) than in NORSE. Group differences in number of antiseizure medicines after hospital stay (P = 0.229) and in overall mortality (P = 0.327) were not significant. CONCLUSION: In our explorative comparison, differences prevailed. NORSE and FIRES should be compared prospectively in age-matched cohorts.

Refractory Status Epilepticus: Risk Factors and Analysis of Intubation in the Multicenter SENSE Registry.

BACKGROUND AND OBJECTIVES: Refractory status epilepticus (RSE) bears significant morbidity and mortality. Therapy escalation and in some cases intubation are recommended. Most existing studies are retrospective and focus on intensive care units. We aimed to describe routine-care management and analyze determinants of RSE development and outcomes in a large multicenter cohort. METHODS: We performed post hoc analysis of an observational, cohort study, which prospectively registered all consecutive adults with SE at 9 centers from 3 central European countries. Only incident episodes were included. Ongoing SE despite 2 antiseizure medications was defined as RSE. Patients intubated during first-line or second-line treatments were excluded. Variables investigated included demographics, severity (Status Epilepticus Severity Score), etiology, and guideline-compliant treatment (defined as fixed minimum doses). Outcome parameters included survival and mRS at baseline, and discharge (good: 0-2, or absence of worsening compared with prehospitalization). RESULTS: Among 1,179 SE episodes from 1,049 adults, 996 patients were eligible (median age: 70 years, 52% female), of which 545 (54.7%) developed RSE. RSE was associated with higher baseline mRS (p < 0.001) and treatment deviation from guidelines (p < 0.001, OR 0.09; 95% CI 0.06-0.1). Good outcomes were observed in 52.7% of refractory patients, correlating with lower status epilepticus severity (p < 0.001), absence of acute etiology (p < 0.001, OR 0.5; 95% CI 0.3-0.7), adequate first-line benzodiazepine dose (p < 0.001, OR 2.5; 95% CI 1.6-4.0), shorter durations of SE and hospitalization (both p < 0.001), and lack of intubation (p < 0.001, OR 0.4; 95% CI 0.3-0.6). Most (71.7%) refractory patients were not intubated. Intubation was associated with younger age (p = 0.006), more severe consciousness disturbances (p < 0.001, OR 3.2; 95% CI 2.1-4.8), more severe SE types (p < 0.001), higher severity score (p = 0.009), acute etiologies (p = 0.01, OR 1.6; 95% CI 1.1-2.4), more antiseizure medications (p < 0.001), initial treatment after shorter latency (p = 0.01), worse outcomes (p < 0.001, OR 0.4; 95% CI 0.4-0.6), and longer hospitalizations (p < 0.001). DISCUSSION: Variables associated with RSE were identified, some potentially preventable. More than 70% of RSE were treated without intubation, suggesting that focal RSE without deep impairment of consciousness, in older patients, may be successfully treated outside ICUs. TRIAL REGISTRATION INFORMATION: Original cohort study registered at the German Clinical Trials Register (DRKS00000725).