Overview of new-onset refractory status epilepticus: current concepts, diagnosis, and management

New-onset refractory status epilepticus (NORSE) is a rare and devastating condition presenting with refractory status epilepticus and often evolving into super-refractory status epilepticus. The poor outcome with a significant mortality rate and a high rate of morbidity among survivors of NORSE warrants awareness and early identification of the condition so as to initiate appropriate investigations and management. Although the pathophysiological mechanisms are unknown, inflammatory mechanisms including activation of innate immunity are likely involved. Treatment should therefore include aggressive escalation of antiseizure medications followed by early initiation of a ketogenic diet and immunomodulation. First-line immunotherapy should be initiated within 72 h of seizure onset, with a ketogenic diet and second-line immunomodulation being started in the first week if seizures remain. This article aims to review current knowledge on NORSE and to highlight specific areas including recent consensus definitions and Delphi-based recommendations as well as open registries for future research.

New-onset refractory status epilepticus (NORSE) is a rare and acute condition with limited knowledge on its pathophysiological mechanisms, a generally poor outcome with a significant mortality, and a high rate of morbidity among survivors [1].Therefore, early recognition, transfer to an appropriate care-setting if needed, and initiation of appropriate treatment are of paramount importance.This article aims to review current knowledge on NORSE and to highlight specific areas that need to be considered.

NORSE is a major neurological problem
Refractory status epilepticus (RSE) is defined as a case of status epilepticus where seizures are not resolved by treatment with two antiseizure medications (ASM) including one benzodiazepine.NORSE is defined as an RSE that occurs in adults or children without active epilepsy and without a clear acute or active structural, toxic, or metabolic cause identified in the first few days [2].Importantly, a majority of cases of NORSE will evolve into a super-refractory status epilepticus (SRSE, defined as ongoing or recurrent seizures 24 h after initiation of anesthetics), and in some studies, nearly all cases do [3].Mortality in SRSE ranges from 30% to 50%, and half of the survivors have a poor functional outcome despite seizure control [1,4].Although mortality in NORSE studies is lower, at 12-27% [1,5], it clearly repre-sents a condition of major public health magnitude.

Does NORSE differ from other RSE?
The etiology for NORSE will vary as it is a clinical presentation and not a specific diagnosis.While active epilepsy or other preexisting relevant neurological disorders as well as acute or active structural, toxic, or metabolic causes preclude the diagnosis of NORSE, viral and autoimmune causes do not [2].Febrile infection-related epilepsy syndrome (FIRES) is a subgroup of NORSE where seizure onset is preceded by a febrile infection.FIRES can be seen in all age groups but is more prevalent among children [6].Whether FIRES is mechanistically different from NORSE without prior fever remains to be elucidated.
An important question is whether NORSE is fundamentally different from other forms of RSE or instead a part of the SE spectrum.It has been estimated that approximately 20% of RSE cases are NORSE [7] and there is an ongoing debate of whether these are part of the same entity [8].It is, however, possible that considering NORSE as a separate entity-apart from the advantages in communication with families and promoting understanding of the condition-may be useful as cases that remain unexplained (discussed below) might well represent a single disorder with a specific genetically determined immunological mechanism.

Etiologies and cryptogenic NORSE
In recent systematic reviews of etiologies in NORSE, the most commonly identified etiology in adults was autoimmune encephalitis (including both paraneoplastic and non-paraneoplastic antibodies; [9,10]).In pediatric cases, the most prevalently identified cause was infections.However, in about half of the cases, the etiology remained unexplained in spite of extensive evaluation [9].These latter cases, termed "cryptogenic NORSE" [2] may differ mechanistically from other etiologies and thus require other forms of treatment.Although immunological mechanisms have been implicated in cryptogenic NORSE, the underlying mechanisms have not been elucidated.
There are, however, several indications of a postinfectious process causing a cerebral inflammation as being at least part of the mechanisms.These include polymorphisms in cytokine-related genes found in FIRES [11,12] and increased cytokine levels in CSF (and to a lesser extent in serum) indicating an inflammatory activation [13][14][15].However, histopathological studies in NORSE have demonstrated neuronal cell loss and reactive gliosis rather than inflammatory cellular infiltrates [16].A recent study also demonstrated that levels of several innate immunity proinflammatory cytokines were increased in patients with cryptogenic NORSE and that these correlated with worse shortand long-term outcomes [17].The notion of innate immune mechanisms as part of the pathophysiology in NORSE is further supported by a plethora of reports of successful response to therapies targeting interleukin (IL)-1 or IL-6 receptor-mediated signaling (reviewed in [18]).This is mechanistically linked to seizures since proinflammatory cytokines such as IL-1b, IL-6, and tumor necrosis factor (TNF)-α lower the seizure threshold both in animal models and in human studies [19] and it has been suggested that inflammation and seizures act in a reciprocal way to reinforce a vicious cycle of hyperexcitability [20].It is thus possible that there is a specific autoinflammatory pathophysiological mechanism in cases with cryptogenic NORSE.This has important treatment implications as it suggests targeting specific aspects of the innate immune system such as blocking IL-1, IL-6, or the CXCL8 pathways.It is, however, important to point out that no controlled trials have been performed for cytokine inhibitors, or any other therapies, in NORSE.

Recommendations for management
As NORSE is both rare and occurs as an acute situation in a previously healthy individual, high-quality studies have been difficult to perform and the evidence therefore largely relies on case reports, case series, and limited observational studies.For this reason, an international consensus guideline using Delphi methodology was recently published with recommendations for diagnostic work-up, treatment, and future directions for research [18,21].Diagnostic and therapeutic flowcharts are available in several recent publications [21,22].
One general and important recommendation is that acute management of patients with NORSE should be carried out in a tertiary center with expertise in NORSE and with available multidisciplinary expertise in epileptology, rheumatology, and immunology as well as intensive care.In addition, management of adults should be carried out by neurointensivists in order to optimize care.As mentioned previously, an important finding from studies of SRSE is that mortality in NORSE is lower than in other causes of SRSE and prognosis is not dismal per se, even in long SE episodes [3].Treatment therefore needs to be carried out with adequate expertise, with patience, and with caution to avoid treatment-associated complications.A proposed algorithm for early identification and transfer of adult NORSE patients to institutions with adequate support has recently been published [23].

Diagnostic work-up
Early identification of NORSE and the etiology of the condition is important as early targeted interventions including immune therapy have the potential to improve outcome [24].A suggested diagnostic approach for NORSE was proposed in the international consensus recommendations [18].It is generally suggested to perform the same investigations in NORSE cases regardless of whether they also fulfill FIRES criteria.Underlying conditions may give clues to the etiology, so that in, e.g., patients with chronic autoimmune conditions, a primary autoimmune etiology should be suspected.Likewise, in patients with non-central nervous system (CNS) malignancies, a paraneoplastic etiology should be suspected and in particular in adults.
Infectious causes for NORSE are seen in approximately 20% of pediatric cases and approximately 10% of adult cases [9] and need to be ruled out as quickly as possible to enable initiation of appropriate therapies.Likewise, early testing for Clinical Epileptology 4 • 2023 299 autoimmune antibodies is of great importance.However, evaluation for paraneoplastic and autoimmune antibodies was performed in only 61% of patients in a recent systematic review of 1334 cases [9] and the majority of clinicians in a survey among neurointensivists in the United States did not test for antineuronal antibodies during the initial evaluation for NORSE [25].This is in spite of the fact that paraneoplastic encephalitis was identified in 18% of cases in a large retrospective cohort of adult NORSE patients [1].One reason for this may be that although diagnosing NORSE secondary to autoimmune encephalitis is important as treatment and prognosis may differ, it is often difficult in the early stage because antibody results have a latency.To address this problem, a clinical scoring system (the c-NORSE score) has been developed for use before antibody results are available.Although validated only in limited cohorts, it offers an easy tool with which to identify patients who are more likely to have cryptogenic NORSE and thus be less responsive to first-line immunotherapy [26].Evaluating inborn errors of metabolism (including mitochondrial disease) is important in younger children, but may also be warranted in cryptogenic cases in adolescents and adults, as penetrance in mitochondrial disorders is variableand somepatients may not manifest seizures until adulthood [27].
The initial testing for patients with NORSE should therefore, in addition to regular testing, also include (a) a comprehensive infectious evaluation including cultures, and viral and bacterial serology relevant in the geographical region and season, (b) a comprehensive rheumatologic evaluation, (c) autoimmune and paraneoplastic antibody panels, and (d) evaluation for inborn errors of metabolism, at least in young children [18].
Brain magnetic resonance imaging (MRI) should be performed during the first 48 h.It should be noted that early images may be normal but then progress to show abnormalities often involving the insula, temporal area, and basal ganglia [28].Malignancy screening should be considered in the diagnostic work-up for all patients with cryptogenic NORSE but is of particular importance in adults, as the prevalence of paraneoplastic etiologies is substantially lower in children [9].
The international consensus panel recommended that genetic testing should be considered early in young children and at some point in most patients with NORSE [18].However, it was performed in only 18% of the studies in the systematic review of NORSE etiologies [9].Reported gene abnormalities in NORSE include SCN1A, SCN2A, SCN10A, KCNT1, CACNA1A, cathepsin D, and PCHD19 as well as mitochondrial disorders associated with mutations in DNM1 and POLG1 (reviewed in [9,22]).However, no consistent reports of gene or allelic associations have been described in NORSE.
The utility of cytokine and chemokine analysis for diagnosis, for disease progression, and for guiding treatment choice is still unclear and cannot be directly translated into clinical practice yet.

Recommendations for treatment
The primary aim in NORSE treatment is to control the acute status epilepticus and this needs to include specific treatments for underlying etiologies.Treatment also includes long-term therapy after the acute phase has passed (acute phase defined as the period of time from seizure onset to end of status epilepticus or significantly fewer recurrent seizures), often including ASMs to control epilepsy but also possibly immunomodulation.

Treatment in the acute phase
Treatment of seizures in the acute phase of NORSE with ASMs and anesthetic drugs should follow the same principles as treatment of status epilepticus in other conditions during the initial 48 h.In general, the efficacy of ASMs in NORSE is generally low and no solid evidence exists to recommend a preferential use of specific drugs.Therefore, the basis for treatment in NORSE is an aggressive escalation of ASM regimens followed by early initiation of a ketogenic diet (KD) and immunomodulation.
The recommendation from the international consensus group is that first-line immunological treatment including corticosteroids, intravenous immunoglobulins, and possibly plasma exchange should be started during the first 72 h [18].However, although these may have a positive effect in some cases, they are more often not sufficient [1].In noninfectious NORSE with inadequate response to first-line immunological treatment in the initial week, KD and second-line immunological treatment should be started within 7 days of seizure onset provided that first-line treatment was initiated without delays.As immunotherapy may aggravate infections, adequate infectious diagnostic work-up is vital prior to commencing treatment.
A KD remains one of the most promising treatments and was the only treatment that shortened the acute phase in a retrospective study of children with NORSE.In a recent systematic review of KDs in pediatric SRSE, status epilepticus resolved in 60% of cases after a mean of 6.3 days of KD [29].Although it is used more often in pediatric cases and in NORSE cases also fulfilling FIRES criteria, the effectiveness of KD has also been demonstrated in RSE and SRSE in adults (reviewed in [30]).It should thus be considered early in all prolonged and severe cases, including in adults.Concerns of KD feasibility have been raised mainly for adults and include limited availability as well as lack of experience in its administration.However, a clear majority of the international consensus panel responded that they were able to start KD in the intensive care units at their institutions [18].If enteral KD is not possible, parenteral administration should be initiated, assuming local availability and expertise.
In addition to KD, escalation to secondline immunological treatment should be considered at 7 days if seizures remain.This treatment should be based on suspected etiology so that if a pathogenic antibody is identified or highly suspected, rituximab treatment should be initiated.By contrast, in cryptogenic NORSE without clinical features of autoimmune encephalitis, IL-1 blockers or IL-6 antagonists should be initiated.Risk-benefit discussions regarding these two agents should be conducted by a clinician comfortable with their use.It should also be noted that although there is no direct evidence to support this, second-line immunological treatment is considered to have the potential to improve outcome even when initiated late (several weeks) after seizure onset [18].The use of cannabidiol and hypothermia in the treatment of NORSE was considered in the international consensus guidelines to lack evidence and thus should not delay other treatments [18].
Recent case reports have also suggested that intrathecal administration of dexamethasone may be useful and have a higher efficacy in terminating seizures than systemic administration [31].This has only been demonstrated in small series of FIRES cases and thus needs further validation, but intrathecal steroids may have the potential to shorten the acute stage of the disease.Noninvasive and invasive neuromodulation methods are also feasible as treatment options for superrefractory status epilepticus, including NORSE.A recent systematic review of the use of neuromodulation techniques in the treatment of the acute phase of NORSE identified 20 patients (13 also FIRES and 17 were cryptogenic) who were treated with different forms of neuromodulation including electroconvulsive therapy (ECT), vagal nerve stimulation (VNS), and deep brain stimulation (DBS).In 17 of 20 patients, status epilepticus was resolved after neuromodulation (the remaining three patients died; [32]).A systematic review of responsive neurostimulation (RNS) in SRSE identified 10 cases (only one NORSE) of which seven exited SRSE after RNS placement and activation (time range: 1-27 days) whereas two patients died of SRSE complications [33].The small number of patients and the variability in modalities makes interpretation difficult, but early neuromodulation therapy may be of benefit.

Treatment in the postacute phase
The postacute and chronic phase of NORSE is frequently characterized by drug-resistant epilepsy and moderate-to-severe cognitive impairment [4].As in the acute phase, there is no evidence that clearly supports use of any specific ASM over others in the postacute phase of NORSE.
The efficacy of KD in the postacute phase has been demonstrated in a metaanalysis of pediatric FIRES cases, in which only treatment in the acute phase was clearly associated with a favorable longterm outcome [34].Sustained adherence to KD for a prolonged period may be challenging, but dietary treatment should be continued in the postacute phase if effective in the acute phase.Likewise, immunomodulation should be continued if initiated and perceived to be potentially effective during the acute phase.This may include slow tapering of steroids or anticytokine treatments, in particular if cytokine increases were seen in the acute phase of disease.The duration of immunomodulation in the postacute phase was recommended in the international NORSE consensus group to last for a minimum of 3 months [18].These recommendations also suggest that cytokine inhibition may have a therapeutic role in a severe or recurring postacute epilepsy situation even if it was not previously tried in the acute phase.Seizures in the postacute phase are often largely multifocal and may therefore not be amenable to or suitable for surgical intervention.However, in patients with focal onset seizures, an evaluation for epilepsy surgery should be considered.
Cognitive impairment and behavioral problems are a significant and likely underreported problem in survivors of NORSE (reviewed in [4]).All patients who are able to do so should therefore undergo neuropsychological evaluation, which should be periodically repeated.All patients should also be screened for mood and psychiatric disorders, as well as for sleep disorders.Furthermore, patients recovering from NORSE should undergo an intensive program of motor and cognitive rehabilitation.Postacute rehabilitation is thus essential and should be offered together with social service interventions in the long term to promote a return to social activities, school, or work and to promote quality of life as much as possible.

Outcome following NORSE
It is important to distinguish between short-term and long-term outcome extending beyond the early acute phase and with a multifaceted problem spectrum.However, although attention has increased lately, this field is not adequately studied.Mortality in NORSE is high at around 12% in children and 16-27% in adults [1,5].It is also well-known that a majority of survivors have long-term neurocognitive and functional disabilities including drug-resistant epilepsy (reviewed in [4]).In this systematic review, refractory epilepsy remained in 41% of adults and 58% of children, while only around a quarter of these patients were seizure free.However, while seizure status was assessed in over 90% of patients for whom data on the long-term outcomes were available, cognitive and functional outcomes were much less often reported.Likewise, psychiatric disorders were under-reported.Although data should be interpreted with caution given the methodological limitations, it is clear that moderate-to-severe cognitive disability, loss of functional independence, and psychiatric disorders are common in NORSE and represent a major public health problem of this disorder [4].The intensive care and extensive treatment needed for NORSE patients also carry a substantial risk of iatrogenic complications, and management is thus a trade-off between suppressing epileptic activity and the risk of treatment-related adverse effects.

Future perspectives and ongoing research
The research field in NORSE is very dynamic and follows several directions that have the potential to interact and further our understanding of the pathology and of adequate treatment.These include: (1) development of useful and relevant animal models that would offer a possibility of testing new treatments as candidates for clinical trials, (2) cytokine analysis as well as characterization of other inflammatory molecules in serum and/or CSF for usefulness in diagnostics and treatment effects, and (3) development of standardized common data elements including those for outcomes (and in particular for symptoms other than seizures).Collaborations to achieve larger cohorts are also ongoing and include a collaborative biorepository of samples from NORSE and FIRES patients at Yale, a prospective observational studyof adultand pediatric NORSE patients performed by participating members of the Critical Care EEG Monitoring Research Consortium (CCEMRC), and a NORSE/FIRES Clinical Epileptology 4 • 2023 301 family registry where patients or their medical team anywhere in the world can directly enter their data into the registry.These projects as well as other valuable tools may be found on the NORSE Institute website (https://www.norseinstitute.org/).

Practical conclusion 4 NORSE is a devastating condition present- ing with refractory status epilepticus (RSE) and often evolving to super-refractory sta- tus epilepticus. 4 Awareness and early identification of NORSE are essential to initiate appro- priate investigations and management. 4 Inflammatory mechanisms including ac- tivation of innate immunity are likely in- volved in the pathophysiology. 4 Treatment should therefore include ag- gressive escalation of antiseizure medi- cations followed by early initiation of a ketogenic diet (KD) and immunomodu- lation. First-line immunotherapy should be started within 72 h of seizure onset and KD and further immunomodulation started in the first week if seizures remain. 4 Treatment should be based on suspected etiology; if a pathogenic antibody is iden- tified or highly suspected, rituximab treat- ment should be initiated. 4 In cryptogenic NORSE without clinical fea- tures of autoimmune encephalitis, IL-1 blockers or IL-6 antagonists should be started. 4 Recent consensus definitions and Delphi- based recommendations offer clinical de- cision support, and open international biobanks and registries are available for patient inclusion. Corresponding address
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