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Département de Neurologie, Université Libre de Bruxelles, Hôpital Erasme, Brussels, BelgiumDivision of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Département de Neurologie, Université Libre de Bruxelles, Hôpital Erasme, Brussels, BelgiumComprehensive Epilepsy Center, Neurology Department, Yale University School of Medicine, New Haven, CT, USA
The NORSE definition provides standardized criteria for future multicenter research.
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Extensive patient-specific investigations are required to find rare causes of NORSE.
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The etiology is identified in approximatively 50% of adult cases.
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Recent immunotherapies and ketogenic diet are sometimes efficacious.
Abstract
Purpose
To summarize the clinical features, suggested work-up, treatment and prognosis of new-onset refractory status epilepticus (NORSE), a condition recently defined as the occurrence of refractory status epilepticus (RSE) in a patient without active epilepsy, and without a clear acute or active structural, toxic or metabolic cause; and of the related syndrome of febrile infection-related epilepsy syndrome (FIRES), also recently defined as a subgroup of NORSE preceded by a febrile illness between 2 weeks and 24 h prior to the onset of RSE.
Method
Narrative review of the medical literature about NORSE and FIRES.
Results
NORSE and FIRES mainly affect school-age children and young adults. A prodromal phase with flu-like symptoms precedes the SE onset in two third of NORSE cases, and by definition in all FIRES. Status epilepticus usually starts with repeated focal seizures with secondary bilateralization. Most cases evolve to super RSE (SRSE) and have unfavorable outcome, with short-term mortality of 12–27%, long-term disability and epilepsy. No specific imaging or laboratory abnormalities have been identified so far that allows an early diagnosis and half of adult cases remain of unknown etiology. A standardized diagnostic algorithm is provided and. Autoimmune encephalitis is the most frequent identified cause. In the absence of specific diagnosis, immunotherapy could be tried in addition to antiepileptic treatment.
Conclusions
This review presents the rare but devastating syndrome of NORSE, including the subcategory of FIRES. Early recognition with complete work-up is primordial to identify the underlying cause and promptly start appropriate treatment.
New-onset refractory status epilepticus in an adult with an atypical presentation of cat-scratch disease: successful treatment with high-dose corticosteroids.
Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES).
Febrile infection-related epilepsy syndrome (FIRES) with super-refractory status epilepticus revealing autoimmune encephalitis due to GABAAR antibodies.
] to describe cases of super refractory status epilepticus (SRSE) without a previous history of epilepsy and with no identifiable underlying cause. However, other definitions have been applied for the term in subsequent studies [
]. Similar conditions have also been described under various names in children, including severe refractory status epilepticus due to presumed encephalitis [
]. In the latter, the presence of a febrile episode prior to the onset of SE is by definition required. While fever often precedes the onset of seizures in adults with NORSE [
]. However, apart from age and fever, the two syndromes do in fact share many similarities (see below) and most authors now believe they are identical or at least belong to the same category of disease [
Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions.
Until recently, the lack of a standardized terminology was a limitation to clinical research. This motivated the introduction of consensus definitions [
Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions.
]. According to this recent proposal, NORSE is defined as a clinical presentation, in a patient without active epilepsy, with new onset of refractory status epilepticus (RSE) without a clear acute or active structural, toxic or metabolic cause [
Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions.
]. It includes cases with a known etiology, when it is not easily identified by the recommended initial investigations by imaging (including brain MRI) and lumbar puncture (including PCR for HSV-1), which are typically obtained within 72 h after admission. This definition allows ruling out usual causes of status epilepticus (SE) such as acute strokes, brain masses, drug overdoses, etc. On the other hand, cases due to viral infection of CNS (except HSV1 encephalitis) or auto-immune encephalitis are included [
Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions.
A definition of FIRES has also been proposed, defining it as a subgroup of NORSE preceded by a febrile illness between 2 weeks and 24 h prior to the onset of refractory status epilepticus, and removing any age criteria [
Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions.
An etiology is identified in approximatively 50% of adult cases of NORSE. The majority of cases with a known etiology are due to sporadic or paraneoplastic auto-immune encephalitis [
]. In case series of children with FIRES, the cause is almost always unknown but the lack of etiological diagnosis was likely an inclusion criteria for these studies, introducing a selection bias [
]. Further, those series are small and the diagnostic work-up is variable and often incomplete. Also, many published cases predates the description of encephalitis caused by more recently identified antibodies to neuronal surface antigens, such as anti-gamma-amino-hydroxybutyric acid [GABA](A) receptors [
NORSE and FIRES most frequently occurs in previously healthy young adults and school-aged children, although adults above 60 can also be affected. There is a female predominance in most adult series [
]. It is likely that many cases have been previously mislabeled as “possible” or “presumed” viral encephalitis as they often fulfill the diagnostic criteria for these entities [
3. Clinical features and prognosis of NORSE and FIRES
In adults, a non-specific mild illness with gastro-intestinal, upper respiratory or flu-like symptoms precedes the onset of seizures in two-third of cases [
] and the patient may be asymptomatic for a few days during the interval. Seizures are initially brief and infrequent, increasing within a few hours to days in frequency (up to hundreds per day) and evolving into SE, which usually requires ICU admission and anesthesia. The most frequent seizure type is focal seizure with secondary bilateralization [
The EEG shows various kinds of sporadic or periodic epileptiform discharges, which can be lateralized, bilateral independent or multifocal, often involving the temporal and frontal regions. Generalized discharges have also been reported [
Recently, a retrospective analysis suggested that FIRES was characterized by three EEG findings: beta-delta complexes resembling extreme delta brush, seizure onset with prolonged focal fast activity, followed by the gradual appearance of well-formed rhythmic spike or spike-and-wave complexes, and shifting ictal activity [
]. It is unclear if these findings are specific to these conditions, thus suggesting a specific pathogenic mechanism, or if they are merely the consequence of prolonged ictal activity.
Half to two-third of the cases of unknown etiology present mild CSF pleocytosis (less than 10 cells/μl) and slightly increased protein level [
], with neurological sequelae in most survivors. Long-term outcome is often poor with half to two-third of the survivors developing cognitive impairment and functional disability, including vegetative state, and only a small proportion of patients being able to resume their previous life [
Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES).
]. Drug-resistant epilepsy is the rule in most survivors. Factors associated with worse outcome include the duration of SE and the occurrence of medical complications [
]. Given the retrospective and observational design of these studies, it is unclear whether this association indicates an independent effect of anesthesia and its complications or is rather due to the variability in severity and refractoriness. Prospective randomized controlled studies are required to settle this question.
4. Known etiologies and clues to these etiologies
According to recent definitions, NORSE etiology is either unknown (previously called cryptogenic) or an unusual cause is identified after an extensive work-up. Close to 200 uncommon causes of SE have been reported in the literature [
] and can be divided in 4 categories: inflammatory and autoimmune encephalitis, uncommon infectious encephalitis, genetic disorders and toxic disorders. As indicated above, the most frequent identified cause is autoimmune encephalitis [
], including sporadic and paraneoplastic cases, highlighting the importance of a complete auto-immune workup which should be early set up in case of RSE without a straightforward cause. The most frequently identified antibodies target the N-methyl-D-aspartate (NMDA) receptor and the voltage-gated potassium channel (VGKC) complex. No antibody has been found in pediatric cohort except some anecdotal cases [
Febrile infection-related epilepsy syndrome (FIRES) with super-refractory status epilepticus revealing autoimmune encephalitis due to GABAAR antibodies.
Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES.
]. One study found anti-glutamate receptor (GluR) epsilon 2 antibodies in the CSF of a few FIRES cases but their role and significance remain unknown [
Some clinical features can suggest a specific underlying etiology (Table 1). For instance, paraneoplastic limbic encephalitis, which is exceptional in children but occurs more frequently in adults, is characterized by cognitive impairment, behavioral changes, sleep disturbances, and seizures. Status epilepticus is usually not a prominent manifestation [
] and often starts with febrile illness. Then patients develop psychiatric symptoms, manifesting in children as behavioral disturbances and tantrums. Children are more likely to present movement disorders, seizures and SE than adults. Rapid disintegration of speech and language, hyperactivity, and irritability are often seen, then progression to decreased responsiveness and severe catatonic stage, with typical oro-lingual dyskinesia and autonomic failure [
]. Encephalitis with anti- VGKC complex (LGI1 or, more rarely Caspr2) antibodies are associated with limbic encephalitis and a syndrome of inappropriate secretion of antidiuretic hormone (SIADH).Pathognomonic facio-brachial dystonic seizures can occur in anti-LGI1 encephalitis. Rare pediatric cases of SE associated with an unspecified anti-VGKC complex antibody have been reported [
]. No specific findings have been demonstrated in cryptogenic NORSE cases. They broadly have similar clinical course than patients with NORSE caused by auto-immune encephalitis, albeit with a longer SE duration [
]. A retrospective study compared the clinical features of 11 cryptogenic NORSE with anti-NMDA receptor encephalitis and revealed more frequent prodromal fever, symmetric brain MRI abnormalities, had less frequent involuntary movements, absent psychobehavioral symptoms, and had more severe SE with ventilatory support requirement [
5. Current hypothesis for cases with unknown etiology
Despite an extensive, albeit variable, workup, half of adult NORSE cases remain cryptogenic. However, their clinical features do not differ much from autoimmune cases, suggesting a similar etiology. It is possible that some cryptogenic cases correspond to autoimmune encephalitis associated with antibodies not yet identified. In particular, the prevalence of CSF abnormalities was similar in both cryptogenic cases and cases with an autoimmune or infectious etiology.
In children, elevated levels of pro-convulsant cytokines (interleukin-6, e.g.) have been documented in the CSF, suggesting an inflammatory cause [
]. Those cytokines could be the consequence of a viral infection, explaining the previous febrile illness, and could occur in the setting of a genetic predisposition [
In the absence of a specific diagnostic test, the diagnosis of NORSE and FIRES is made on clinical grounds after the initial workup rules out obvious causes of RSE, which usually takes 48–72 h.
Extensive investigations should then be performed to identify a rare cause of SE. These investigations should focus on autoimmune and uncommon infectious etiologies and take into account the specifics of each case. A diagnostic decision tree is available in Fig. 1 and on the NORSE institute website http://www.norseinstitute.org/definitions/.
Management of suspected viral encephalitis in children - association of british neurologists and british paediatric allergy, immunology and infection group national guidelines.
No validated tests are available to distinguish FIRES from a febrile RSE, a very different entity with good outcome. Theoretically, children with febrile SE present high fever at SE onset while children with FIRES had fever within the two previous weeks.
Association between FIRES cases and elevated cytokine levels in the CSF or predisposing genetic factors [
] should be confirmed they can be used. Similarly the occurrence of peculiar MRI changes in the claustrum should be further explored as candidate diagnostic tests [
Treatment with anti-seizure medications is often disappointing. At least 75% of patients require anesthetics in continuous infusion and prolonged burst-suppression coma is often unavoidable to stop the seizures. Status often resumes once the anesthetics are weaned off [
In adults, some studies have suggested better outcome with immunotherapies. This hypothesis is supported by the fact that half of NORSE cases are caused by auto-immune encephalitis. Early immune therapy is then recommended by experts, as delaying treatment may contributes to worse outcome, as in auto-immune and viral encephalitis [
]. These include first-line (steroids, intravenous immunoglobulins, and plasma exchange) and second-line therapies (e.g., tacrolimus, rituximab, cyclophosphamide, anakinra). However prospective controlled studies are lacking
In children, immunotherapies seem less effective [
Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES.
]. Multiple different therapeutic options have been reported in small case series and none seems to be superior, with the possible exception of the ketogenic diet [
Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES).
]. Nabbout et al highlighted the efficiency of this therapeutic diet on 8 children, with 7 them showing improvement after 1 to 4 days of ketonuria. This treatment is already known to be efficient in RSE in children of any cause and experts recommend to start it as soon as possible, once FIRES is suspected, e.g., from second day of super-refractory SE [
Cannabidiol (CBD) is a recent potential alternative therapy in epilepsy and has been shown to improve seizure frequency and duration in 6 out of 7 children, mainly in the chronic phase. However only on was seizure free and all had cognitive sequelae [
Anakinra, a recombinant version of human Interleukin(Il)-1 receptor antagonist, was successful in a single case of a 32-months-old girl with FIRES who received 5 mg/kg twice daily. The drug was well tolerated and effective, leading to a dramatic seizure reduction on 3 separate occasions in the same patient, however no long-term follow-up is available [
], ketamine, lidocaine, need to be validated by large and prospective studies. A suggested algorithm for the use of these therapies is presented in Fig. 2, with their suggested dosing.
Fig. 2NORSE treatment algorithm: Commonly used drugs in NORSE and FIRES with most frequently reported doses (expert opinion) [
Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the american epilepsy society.
New-onset refractory status epilepticus in an adult with an atypical presentation of cat-scratch disease: successful treatment with high-dose corticosteroids.
NORSE and FIRES are rare but devastating epileptic disorders, occurring in previously healthy patients. Uncommon but treatable etiologies, such as autoimmune encephalopathies, can be identified in some patients, especially adults, motivating extensive investigations. However a majority of cases remain without a known etiology and little is currently known about the underlying pathologic mechanism, although an inflammatory cause is suspected. Treatment is usually disappointing and outcome is often poor, although a minority of patients may resume their previous life. The ketogenic diet appears promising but requires larger prospective studies. The recent publication of consensus definitions will help future research, with the aims to understand the cause and to improve patient care.
Conflict of interest
The authors have no conflict of interest to declare.
References
Wilder-Smith E.P.V.
Lim E.C.H.
Teoh H.L.
Sharma V.K.
Tan J.J.H.
Chan B.P.L.
et al.
The NORSE (new-onset refractory status epilepticus) syndrome: defining a disease entity.
New-onset refractory status epilepticus in an adult with an atypical presentation of cat-scratch disease: successful treatment with high-dose corticosteroids.
Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES).
Febrile infection-related epilepsy syndrome (FIRES) with super-refractory status epilepticus revealing autoimmune encephalitis due to GABAAR antibodies.
Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions.
Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES.
Management of suspected viral encephalitis in children - association of british neurologists and british paediatric allergy, immunology and infection group national guidelines.
Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the american epilepsy society.
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