New-onset Refractory Status Epilepticus Research Articles

NORSE seasonality may vary geographically in adults.

The mechanisms causing new onset refractory status epilepticus (NORSE) are often unknown. Recently, a seasonal variation with NORSE peaking during the summer was described in a mixed cohort of adults and children why we here studied the seasonal variation in a Danish status epilepticus (SE) cohort. This retrospective cohort study comprised SE patients aged ≥18 diagnosed and treated 2008-2017 at the Odense University Hospital. Clinical characteristics and seasonality of patients fulfilling the diagnostic criteria for NORSE were compared with patients with refractory SE (RSE) due to other reasons and with the seasonal variation of autoantibodies associated with autoimmune encephalitis in the Danish autoimmune encephalitis register. In this cohort, 26 patients met NORSE criteria. As compared to RSE patients not fulfilling NORSE criteria (n = 152), NORSE patients were more likely to have symptoms of systemic inflammation (C-reactive protein concentrations ≥10 mg/L or fever ≥38°C) at admission; nine fulfilled the criteria for febrile infection related epilepsy syndrome (FIRES). In contrast to the even seasonal distribution of patients with RSE not fulfilling the NORSE criteria, admissions due to NORSE peaked during the winter (46.1%, p = 0.04 as compared to non-NORSE RSE); six out of nine FIRES episodes occurred in the winter season. The seasonal variation was not explained by a seasonal variation of the detection rates of autoantibodies associated with autoimmune encephalitis (incl. NMDAR, LGI1, CASPR2, GABAR, GFAP) in a Danish nationwide register (n = 259). In conclusion, we confirm the seasonality of NORSE in a Danish cohort, however, with a peak during winter suggesting a geographical variation not solely explained by autoimmune encephalitis associated with known autoantibodies. PLAIN LANGUAGE SUMMARY: The study investigated the seasonal patterns of new-onset refractory status epilepticus (NORSE), i.e. severe seizures that occur without an obvious cause and require very intensive treatment. In contrast to the previously observed peak frequency in summer, this Danish study found that NORSE cases peak in winter. Furthermore, the seasonal variation in NORSE cases was not found to be associated with autoimmune encephalitis caused by known autoantibodies. Together with the high rate of patients showing symptoms of systemic inflammation compared to other status epilepticus patients, the data suggest a link between misdirected immune system responses and NORSE. The study can therefore help in the further search for the currently unknown causes of NORSE.

Comparative analysis of patients with new onset refractory status epilepticus preceded by fever (febrile infection-related epilepsy syndrome) versus without prior fever: An interim analysis.

Febrile infection-related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status epilepticus. It is unclear whether FIRES and non-FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non-FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non-FIRES NORSE (median = 28 vs. 48 years old, p = .048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non-infection-related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein-1 alpha (MIP-1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non-FIRES NORSE are very similar conditions.

Powassan Virus Infection Presenting as Rapidly Progressive Encephalitis and New-onset Refractory Status Epilepticus (NORSE) (P10-13.009)

Powassan Virus Infection Presenting as Rapidly Progressive Encephalitis and New-onset Refractory Status Epilepticus (NORSE) (P10-13.009)

Responsive neurostimulation as a therapy for epilepsy following new-onset refractory status epilepticus: Case series and review of the literature

ObjectiveTo report clinical outcomes of patients who presented with new-onset refractory status epilepticus (NORSE), developed drug-resistant epilepsy (DRE), and were treated with responsive neurostimulation (RNS). MethodsWe performed a retrospective review of patients implanted with RNS at our institution and identified three who originally presented with NORSE. Through chart review, we retrieved objective and subjective information related to their presentation, workup, and outcomes including patient-reported seizure frequency. We reviewed electrocorticography (ECoG) data to estimate seizure burden at 3, 6, 12, and 24 months following RNS implantation. We performed a review of literature concerning neurostimulation in NORSE. ResultsUse of RNS to treat DRE following NORSE was associated with reduced seizure burden and informed care by differentiating epileptic from non-epileptic events. ConclusionsOur single-center experience of three cases suggests that RNS is a safe and potentially effective treatment for DRE following NORSE. SignificanceThis article reports outcomes of the largest case series of NORSE patients treated with RNS. Since patients with NORSE are at high risk of adverse neuropsychiatric and cognitive sequelae beyond seizures, a unique strength of RNS over other surgical options is the ability to distinguish ictal or peri-ictal from non-epileptic events.

Clinical outcomes among initial survivors of cryptogenic new-onset refractory status epilepsy (NORSE).

New-onset refractory status epilepticus (NORSE) is a rare but severe clinical syndrome. Despite rigorous evaluation, the underlying cause is unknown in 30%-50% of patients and treatment strategies are largely empirical. The aim of this study was to describe clinical outcomes in a cohort of well-phenotyped, thoroughly investigated patients who survived the initial phase of cryptogenic NORSE managed in specialist centers. Well-characterized cases of cryptogenic NORSE were identified through the EPIGEN and Critical Care EEG Monitoring Research Consortia (CCEMRC) during the period 2005-2019. Treating epileptologists reported on post-NORSE survival rates and sequelae in patients after discharge from hospital. Among survivors >6 months post-discharge, we report the rates and severity of active epilepsy, global disability, vocational, and global cognitive and mental health outcomes. We attempt to identify determinants of outcome. Among 48 patients who survived the acute phase of NORSE to the point of discharge from hospital, 9 had died at last follow-up, of whom 7 died within 6 months of discharge from the tertiary care center. The remaining 39 patients had high rates of active epilepsy as well as vocational, cognitive, and psychiatric comorbidities. The epilepsy was usually multifocal and typically drug resistant. Only a minority of patients had a good functional outcome. Therapeutic interventions were heterogenous during the acute phase of the illness. There was no clear relationship between the nature of treatment and clinical outcomes. Among survivors of cryptogenic NORSE, longer-term outcomes in most patients were life altering and often catastrophic. Treatment remains empirical and variable. There is a pressing need to understand the etiology of cryptogenic NORSE and to develop tailored treatment strategies.

Second-line immunotherapy in new onset refractory status epilepticus.

Several pieces of evidence suggest immune dysregulation could trigger the onset and modulate sequelae of new onset refractory status epilepticus (NORSE), including its subtype with prior fever known as febrile infection-related epilepsy syndrome (FIRES). Consensus-driven recommendations have been established to guide the initiation of first- and second-line immunotherapies in these patients. Here, we review the literature to date on second-line immunotherapy for NORSE/FIRES, presenting results from 28 case reports and series describing the use of anakinra, tocilizumab, or intrathecal dexamethasone in 75 patients with NORSE. Among them, 52 patients were managed with anakinra, 21 with tocilizumab, and eight with intrathecal dexamethasone. Most had elevated serum or cerebrospinal fluid cytokine levels at treatment initiation. Treatments were predominantly initiated during the acute phase of the disease (92%) and resulted, within the first 2 weeks, in seizure control for up to 73% of patients with anakinra, 70% with tocilizumab, and 50% with intrathecal dexamethasone. Cytokine levels decreased after treatment for most patients. Anakinra and intrathecal dexamethasone were mainly initiated in children with FIRES, whereas tocilizumab was more frequently prescribed for adults, with or without a prior febrile infection. There was no clear correlation between the response to treatment and the time to initiate the treatment. Most patients experienced long-term disability and drug-resistant post-NORSE epilepsy. Initiation of second-line immunotherapies during status epilepticus (SE) had no clear effect on the emergence of post-NORSE epilepsy or long-term functional outcomes. In a small number of cases, the initiation of anakinra or tocilizumab several years after SE onset resulted in a reduction of seizure frequency for 67% of patients. These data highlight the potential utility of anakinra, tocilizumab, and intrathecal dexamethasone in patients with NORSE. There continues to be interest in the utilization of early cytokine measurements to guide treatment selection and response. Prospective studies are necessary to understand the role of early immunomodulation and its associations with epilepsy and functional outcomes.

Successfully treated anti-GAD limbic encephalitis in a 15-year-old diabetic boy with intravenous immunoglobulin: case report

Introduction and importance: Limbic encephalitides (LE) have symptoms and signs of new-onset seizures accompanied by cognitive impairment and signal changes in the MRI of the limbic system in the brain. Numerous antibodies against the neurons and synapses have been detected so far. Of those, antiglutamic acid decarboxylase antibody (Anti-GAD Ab) impairs the gamma amino butyric acid, one of the primary mediators that naturally prevents abnormal neuronal activity causing seizure. Case presentation: The authors have reported a case of anti-GAD Ab LE in a diabetic male adolescent who responded dramatically to intravenous immunoglobulin and reviewed all similar pediatric cases for 15 years now. Clinical discussion: The symptoms in children suffering from anti-GAD LE in three categories, systemic, psychiatric, and neurological, are heterogeneous. The most common manifestations were seizures followed by altered mental status and behavioral changes, respectively. The two main clinical scenarios described in GAD65-mediated autoimmune epilepsy are (1) an acute/subacute onset of seizures alone or seizures (including new-onset refractory status epilepticus, NORSE) accompanied by some degrees of cognitive and psychiatric manifestations, including amnesia and mesiotemporal inflammatory involvement consistent with LE and (2) epilepsy without clinical or MRI evidence of active central nervous system inflammation. Conclusion: Although rare, the neurologist should consider the potential role of anti-GAD ab-associated encephalitis in the presence of diabetes mellitus.

Treatment of cryptogenic new-onset refractory status epilepticus (C-NORSE) with tocilizumab: A case report.

A 35-year-old woman with no prior history of epilepsy developed status epilepticus (SE), which was highly resistant to multiple antiseizure medications and sedatives. The etiology of SE was not identified despite extensive investigation, and the patient was diagnosed with cryptogenic new-onset refractory status epilepticus (C-NORSE). Although first-line immunotherapies such as high-dose corticosteroids and plasma exchange were ineffective, the patient manifested a resolution of SE after the administration of tocilizumab, which inhibits interleukin-6. Non-antibody-mediated inflammation has been hypothesized to be a probable pathophysiology of C-NORSE in recent studies, and tocilizumab may be a plausible second-line treatment.

Management strategies for refractory status epilepticus

Refractory status epilepticus (RSE) is defined as the persistence of either clinical or electrographic seizures despite the administration of appropriate doses of an initial benzodiazepine and suitable second-line antiepileptic drugs (AEDs). The Neurocritical Care Society and the American Epilepsy Society have proposed a treatment paradigm for the management of convulsive status epilepticus (CSE). The third-line therapy in refractory CSE may involve general anesthesia using intravenous midazolam, propofol, or other agents, while recent evidence supports the use of ketamine to manage RSE in both adults and children. However, although these treatment strategies are frequently employed in nonconvulsive status epilepticus (NCSE), the efficacy of AEDs and anesthetics in NCSE has not been thoroughly investigated. Recent evidence has demonstrated the safety and efficacy of newer AEDs, including levetiracetam and lacosamide, in the treatment of status epilepticus (SE) and RSE, which also encompasses NCSE. Use of multiple combinations of various intravenous AEDs can also be considered in NCSE before the administration of general anesthesia. In addition, AEDs alone exhibit limited effectiveness in managing SE for new-onset RSE (NORSE) and its subset, febrile infection-related epilepsy syndrome. Therefore, in cases of refractory status, it is imperative to explore treatment options beyond AEDs, including immunotherapy and the incorporation of a ketogenic diet. The present review suggests treatment approaches for RSE based on subgroups, including CSE, NCSE, and NORSE. A discussion of recent clinical studies on AEDs and anesthetics in the management of RSE, as well as proposed treatment methods for NORSE, is also provided.

Initial Management of Status Epilepticus

Status epilepticus(SE)is defined as a prolonged seizure and is a common neurological emergency with high morbidity and mortality rates. As uncontrolled SE causes irreversible neurological damage, prompt diagnosis and treatment are required. If anti-seizure medications and benzodiazepines, which are initial treatments for SE, are not effective and SE deteriorates to refractory, anesthetic drugs are needed to suppress seizure activity under electroencephalogram(EEG)monitoring. Continuous EEG monitoring is useful not only for evaluating the control of SE but also for diagnosing non-convulsive SE(NCSE)and psychogenic non-epileptic seizures. New-onset refractory status epilepticus is defined as refractory SE in a patient without active epilepsy and without a clear acute or active structural, toxic, or metabolic cause. Because autoimmune encephalitis is the most frequently identified cause, immunotherapy can be attempted in addition to antiepileptic treatment within 2 weeks. Although NCSE is the major cause of unconsciousness, diagnosis is difficult because of uncertain clinical symptoms. Continuous EEG monitoring over 24 h is crucial for diagnosis, although arterial spin labeling-magnetic resonance imaging is alternatively useful. Finally, the building of a multidisciplinary cooperation system is required for prompt diagnosis and intensive treatment for controlling SE.

Reply to the article entitled “International consensus recommendations for management of new onset refractory status epilepticus (NORSE) including febrile infection-related epilepsy syndrome (FIRES): Summary and clinical tools”. Doi: 10.1111/epi.17391

Reply to the article entitled “International consensus recommendations for management of new onset refractory status epilepticus (NORSE) including febrile infection-related epilepsy syndrome (FIRES): Summary and clinical tools”. Doi: 10.1111/epi.17391

A - 94 A Case of New Onset Refractory Status Epilepticus (NORSE) Associated with COVID-19.

New Onset Refractory Status Epilepticus (NORSE) is a rare condition of prolonged medication-refractory seizures potentially due to elevated inflammatory molecules in the brain. NORSE can be triggered by a viral infection and is a documented neurologic consequence of COVID-19. A 74-year-old, left-handed, Hispanic male was in his usual state of health until experiencing 1-2weeks of speech decline, which culminated in an episode of altered mental status (disorientation and mumbling speech). He presented to the Emergency Department with drowsiness and complaints of a "funny feeling" on the left side of his head. Upon arrival, he was found to be COVID-19 positive and hyperglycemic with normal CT, MRI, lumbar puncture, and bloodwork. An EEG showed "focal temporal activity" and he was diagnosed with non-convulsant status epilepticus. Hospitalization and medical sedation lasted 2months followed by 8months of inpatient rehabilitation. The patient was discharged shortly before presenting for neuropsychological evaluation. Neuropsychological evaluation showed weaknesses in learning and free recall, visuospatial skills (due to disorganization and poor attention to details), processing speed, and executive functioning. The patient reported elevated anxiety symptoms. Collateral report indicated severe declines in executive organizational abilities, as well as mild memory and divided attention declines. Results suggest frontal cortical and subcortical impairments affecting multiple areas of cognition and functional decline consistent with a diagnosis of major neurocognitive disorder. Similar to the literature, status epilepticus was attributed to inflammatory meningoencephalitis triggered by the prior COVID-19 infection. Interdisciplinary care was an integral factor in this case.

The role of neuronal antibodies in cryptogenic new onset refractory status epilepticus.

Most cases with new onset refractory status epilepticus (NORSE) remain cryptogenic despite extensive diagnostic workup. The aim of this study was to analyze the etiology and clinical features of NORSE and investigate known or potentially novel autoantibodies in cryptogenic NORSE (cNORSE). We retrospectively assessed the medical records of adults with status epilepticus at a Swiss tertiary referral center between 2010 and 2021. Demographic, diagnostic, therapeutic, and outcome parameters were characterized. We performed post hoc screening for known or potentially novel autoantibodies including immunohistochemistry (IHC) on rat brain with cerebrospinal fluid (CSF) and serum samples of cNORSE. Twenty patients with NORSE were identified. Etiologies included infections (n = 4), Creutzfeldt-Jakob disease (n = 1), CASPR2 autoimmune encephalitis (n = 1), and carotid artery stenosis with recurrent perfusion deficit (n = 1). Thirteen cases (65%) were cryptogenic despite detailed evaluation. A posteriori IHC for neuronal autoantibodies yielded negative results in all available serum (n = 11) and CSF (n = 9) samples of cNORSE. Our results suggest that neuronal antibodies are unlikely to play a major role in the pathogenesis of cNORSE. Future studies should rather focus on other-especially T-cell- and cytokine-mediated-mechanisms of autoinflammation in this devastating disease, which is far too poorly understood so far.

A case of new onset refractory status epilepticus in a U.S. traveler with Japanese encephalitis

New onset refractory status epilepticus (NORSE) is a rare but critical condition characterized by refractory status epilepticus (RSE) in an individual without prior history of epilepsy or known structural, toxic, or metabolic cause. Postinfectious immune activation is an important cause of NORSE. Early testing for autoimmune antibodies is strongly recommended (Wickstrom et al., 2022). We report a case of NORSE triggered by Japanese encephalitis (JE) in an unvaccinated US adult traveler. Her CSF later revealed positive anti-N-methyl-d-aspartate (NMDA)-receptor antibody. The patient responded well to first line immunotherapy with favorable functional outcome. This case highlights the diagnostic and treatment challenges in this rare presentation.

New-onset Refractory Status Epilepticus after BNT162b2 mRNA COVID-19 Vaccination

Increasing importance of vaccination during coronavirus disease 2019 (COVID-19) pandemic, several vaccines were developed. Messenger RNA (mRNA) vaccines including BNT162b2 (Pfizer, New York, NY, USA; BioNTech, Mainz, Germany), mRNA-1273 (Moderna, Cambridge, MA, USA) have been disclosed side effects such as thrombocytopenia, myocarditis and headache in general. In addition, adverse effects due to autoimmune responses induced by spike glycoproteins of mRNA vaccines are rarely reported such as the Guillain-Barre syndrome, autoimmune encephalitis and so on. Herein, we report a rare case of encephalitis with new-onset refractory status epilepticus after BNT162b2 mRNA COVID-19 vaccination improved with immune therapy.

Reversible Brain Atrophy in Cryptogenic New-onset Refractory Status Epilepticus.

Cryptogenic new-onset refractory status epilepticus (C-NORSE) is a neurologic emergency condition characterized by refractory status epilepticus (RSE) of unknown cause. Brain atrophy in a setting of C-NORSE is usually irreversible. A 33-year-old woman who was highly suspected of C-NORSE once showed mild frontotemporal atrophy on brain magnetic resonance imaging (MRI), but follow-up MRI revealed recovery of the brain atrophy. Her cognitive function also gradually improved, with a reduction in seizure frequency. Early initiation of intensive immunotherapy with anti-seizure medications may have minimized irreversible brain damage associated with RSE, resulting in a relatively good outcome.

ID: 217537 Novel Use of RNS as a Last Resort Therapy for New-Onset Refractory Status Epilepticus (NORSE)

New-onset refractory status epilepticus (NORSE) is a rare and morbid neurologic phenomenon. As its namesake implies, it involves the development of new-onset, unrelenting status epilepticus in a patient without clear seizure risk factors or triggers. Unfortunately, given the condition’s rarity, optimal treatment paradigms for NORSE patients remain unclear. In recent years, responsive neurostimulation (RNS) has emerged as a surgical option for patients with intractable seizures. Considering the promising data surrounding RNS, we offered it as a treatment option to a select few NORSE patients at our institution. Here we recapitulate our experience surgically managing NORSE by presenting a series of 3 NORSE patients treated with RNS.

Interleukin-1 in Febrile Infection-Related Epilepsy Syndrome

Febrile infection-related epilepsy syndrome (FIRES) characteristically affects previously healthy children, who experience a sudden and explosive onset of super-refractory status epilepticus preceded by febrile infection and accompanied by fulminant neurogenic inflammation. FIRES, however, can affect individuals of all ages and is a subcategory of new-onset refractory status epilepticus. This definition of FIRES excludes febrile status epilepticus in infants. FIRES is a rare type of epileptic encephalopathy with rapidly progressive onset of seizures and a devastating prognosis, as drug-resistant epilepsy often follows without a latency period. Although the exact pathogenesis of FIRES has not been elucidated, a functional deficiency in the endogenous interleukin-1 receptor antagonist has been implicated in a genetic predisposition to FIRES. Dysregulation of the interleukin-1β–interleukin-1 receptor 1 (IL-1β–IL-1R1) signaling pathway appears to be involved in the pathogenesis of FIRES. In this review, the authors summarize the definition of FIRES, IL-1β–IL-1R1 signaling, the nucleotide-binding oligomerization domain the NLRP3 inflammasome, and IL-1 targeted therapy for FIRES.

NEW ONSET REFRACTORY STATUS EPILEPTICUS (NORSE): A CASE REPORT

New-onset refractory status epilepticus (NORSE) is rare and potential life-threatening neurological state where one develops status epileptic us without apparent aetiology. In the following case report, we see the management of NORSE (new onset of refractory status epilepticus) through standard guidelines in a patient with a history of CAD (coronary artery disease) with the risk-benet ratio. The management had a major risk of respiratory depression and heart failure and/or heart block, been given the age factor and the medical history of the patient and no known aetiology. Initiation of benzodiazepines and antiepileptic medication had a major impact on the patient, where the risk of heart block was high. The recovery of the patient was thoroughly monitored for 7 complete days. upon no further complaints the patient was then discharged. But the patient was stabilized by rst managing the NORSE and then treating the cardiac conditions.

A practical approach to in-hospital management of new-onset refractory status epilepticus/febrile infection related epilepsy syndrome.

New-onset refractory status epilepticus (NORSE) is "a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other preexisting relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic, or metabolic cause." Febrile infection related epilepsy syndrome (FIRES) is "a subcategory of NORSE that requires a prior febrile infection, with fever starting between 2 weeks and 24 h before the onset of refractory status epilepticus, with or without fever at the onset of status epilepticus." These apply to all ages. Extensive testing of blood and CSF for infectious, rheumatologic, and metabolic conditions, neuroimaging, EEG, autoimmune/paraneoplastic antibody evaluations, malignancy screen, genetic testing, and CSF metagenomics may reveal the etiology in some patients, while a significant proportion of patients' disease remains unexplained, known as NORSE of unknown etiology or cryptogenic NORSE. Seizures are refractory and usually super-refractory (i.e., persist despite 24 h of anesthesia), requiring a prolonged intensive care unit stay, often (but not always) with fair to poor outcomes. Management of seizures in the initial 24-48 h should be like any case of refractory status epilepticus. However, based on the published consensus recommendations, the first-line immunotherapy should begin within 72 h using steroids, intravenous immunoglobulins, or plasmapheresis. If there is no improvement, the ketogenic diet and second-line immunotherapy should start within seven days. Rituximab is recommended as the second-line treatment if there is a strong suggestion or proof of an antibody-mediated disease, while anakinra or tocilizumab are recommended for cryptogenic cases. Intensive motor and cognitive rehab are usually necessary after a prolonged hospital stay. Many patients will have pharmacoresistant epilepsy at discharge, and some may need continued immunologic treatments and an epilepsy surgery evaluation. Extensive research is in progress now via multinational consortia relating to the specific type(s) of inflammation involved, whether age and prior febrile illness affect this, and whether measuring and following serum and/or CSF cytokines can help determine the best treatment.