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

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 represents a condition of major public health magnitude.

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.

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 [13‐15]. 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 pro-inflammatory cytokines were increased in patients with cryptogenic NORSE and that these correlated with worse short- and 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.

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].

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 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 variable and some patients 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.

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.

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.

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 study of adult and pediatric NORSE patients performed by participating members of the Critical Care EEG Monitoring Research Consortium (CCEMRC), and a NORSE/FIRES 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/​).