A NORSE With No Name

Commentary

New-Onset Refractory Status Epilepticus: Etiology, Clinical Features, and Outcome.

Gaspard N, Foreman BP, Alvarez V, Cabrera Kang C, Probasco JC, Jongeling AC, Meyers E, Espinera A, Haas KF, Schmitt SE, Gerard EE, Gofton T, Kaplan PW, Lee JW, Legros B, Szaflarski JP, Westover BM, LaRoche SM, Hirsch LJ; for the Critical Care EEG Monitoring Research Consortium (CCEMRC). Neurology 2015;85:1604–1613. doi:10.1212/WNL.0000000000001940.

OBJECTIVES: The aims of this study were to determine the etiology, clinical features, and predictors of outcome of new-onset refractory status epilepticus. METHODS: Retrospective review of patients with refractory status epilepticus without etiology identified within 48 hours of admission between January 1, 2008, and December 31, 2013, in 13 academic medical centers. The primary outcome measure was poor functional outcome at discharge (defined as a score >3 on the modified Rankin Scale). RESULTS: Of 130 cases, 67 (52%) remained cryptogenic. The most common identified etiologies were autoimmune (19%) and paraneoplastic (18%) encephalitis. Full data were available in 125 cases (62 cryptogenic). Poor outcome occurred in 77 of 125 cases (62%), and 28 (22%) died. Predictors of poor outcome included duration of status epilepticus, use of anesthetics, and medical complications. Among the 63 patients with available follow-up data (median 9 months), functional status improved in 36 (57%); 79% had good or fair outcome at last follow-up, but epilepsy developed in 37% with most survivors (92%) remaining on antiseizure medications. Immune therapies were used less frequently in cryptogenic cases, despite a comparable prevalence of inflammatory CSF changes. CONCLUSIONS: Autoimmune encephalitis is the most commonly identified cause of new-onset refractory status epilepticus, but half remain cryptogenic. Outcome at discharge is poor but improves during follow-up. Epilepsy develops in most cases. The role of anesthetics and immune therapies warrants further investigation.

Cases of refractory status epilepticus (RSE), defined as persistent status despite treatment with first- and second-line antiseizure therapy, and super-refractory status epilepticus, in which refractory status persists or recurs after more than 24 hours, are commonly encountered in neurocritical care units. Often the etiology of RSE is apparent, with common underlying causes including stroke, hypoxic-ischemic injury, traumatic brain injury, infection, or exacerbation of underlying epilepsy. The outcome of RSE in these cases is often tied to the underlying etiology.

Regularly encountered in clinical practice, but somewhat less frequently reported in the literature, are cases of RSE without apparent etiology that begin abruptly in otherwise healthy, often young, people who have no prior history of epilepsy. Understanding of this syndrome has been hampered by lack of uniform terminology. A variety of names have been applied, including “refractory de novo status epilepticus,” “acute encephalitis with refractory repetitive partial seizures,” “fever-induced refractory epileptic encephalopathy syndrome (FIRES),” and others, which may all be describing the same syndrome (1). Some authors have argued that FIRES describes a different, pediatric syndrome that often lacks evidence of antibody production and may not respond to immunotherapy (2, 3).

The term “new-onset refractory status epilepticus (NORSE)” was coined in 2005 by Wilder-Smith and colleagues to describe healthy adults who developed RSE with no clear cause (4). Common features include development of RSE after an apparently mild febrile illness, often in young women, and frequently accompanied by early CSF pleocytosis. The initial reports described high morbidity and mortality in this condition. By definition, the cause of RSE was unidentified, and there was no prior history of epilepsy. To meet most definitions of NORSE, the investigation to exclude known causes must be extensive (5). However, discovery of new autoimmune causes of RSE has created a moving target for the definition of these “cryptogenic” cases.

A few small case series of NORSE have been reported, with many suggesting that early immunotherapy might produce favorable outcomes, but much about the clinical course and response to treatment remains unknown (5, 6). In a letter to the editor, Wilder-Smith et al. suggested that a multicenter effort would be needed to improve our understanding of the syndrome (7).

The present report by Gaspard and colleagues leverages the larger patient numbers available from the joint efforts of 13 academic medical centers that participate in the Critical Care EEG Monitoring Research Consortium. This effort, which retrospectively identified 130 cases fulfilling their criteria for NORSE among 675 cases of RSE, represents the largest case series to date addressing this topic. The goal was to describe a large cohort of patients with NORSE, including underlying etiology if known, clinical features, response to treatment, and prognosis.

Definitions of NORSE have varied and are critical to shaping the boundaries of the syndrome. The Gaspard study included adult patients with RSE in whom no cause had been identified in the first 48 hours. Although an etiology was ultimately identified in nearly half of the subjects, the 48-hour criterion seems an appropriate operational cutoff, as it excludes many of the readily identified causes of RSE, while targeting an early time window in which decision making about treatment—including immunotherapy—often must occur before results of immunologic testing are known. Only patients with at least 24 hours of video-EEG monitoring and who were studied for autoimmune or paraneoplastic processes were included, though the extent and intensity of antibody searches varied. Data on clinical features, etiology, and outcome were gathered using defined criteria.

Overall, an etiology was ultimately identified in 47% of patients. The most common cause was autoimmune (40%), followed by paraneoplastic (30%) or infectious (16%) processes. The most commonly identified specific etiology was anti-NMDA receptor antibodies, followed by anti-voltage-gated potassium-channel complex antibodies. Herpes viruses (excluding herpes simplex virus 1, which was typically identified in the first 48 hours) were the most frequently diagnosed infectious causes.

The clinical features of this group would not be surprising to epileptologists who have treated such patients. Most patients had a prodrome that began on average 6 days before admission, consisting of, in descending order of frequency, confusion, fever, fatigue, headache, gastrointestinal or respiratory infection, and behavioral changes. The vast majority (90%) had experienced seizures before admission. Most patients (88%) had seizures recorded on continuous EEG monitoring, with unilateral seizures more common than bilateral independent onsets, followed by generalized and multifocal patterns. Other diagnostic tests were commonly abnormal, with abnormal MRI scans in 62%—not only isolated to limbic regions (19%) but also in neocortical (22%) or both neocortical and limbic regions (16%). CSF pleocytosis, with or without elevated CSF protein, was common (62%).

In keeping with the refractory nature of the status epilepticus (SE), patients received a median of five antiepileptic drugs (AEDs), and three-quarters were treated with continuous anesthetic agents. Those with known and those with cryptogenic etiology were equally likely to be treated with anesthetics; however, those with an identified cause were somewhat more likely to receive immunotherapy in this retrospective study.

A majority of patients (77 of 125 cases; 62%) had poor outcome (modified Rankin Scale, 0–3) at hospital discharge, and 22% died in hospital. However, longer-term, 9-month follow-up, available in two-thirds of survivors, showed continued improvements in a majority, with good or fair outcomes in 79% of the surviving group. Longer duration or greater severity of SE was associated with poorer outcomes, but good to fair outcomes were still seen in a substantial minority of patients in RSE for more than a week (23%) or even a month (14%), suggesting that prolonged treatment of these patients is not futile. Whether use of anesthetic agents affects outcome in SE has been controversial. In this cohort, use and number of anesthetic agents were associated with poor outcome and increased mortality, but not after controlling for duration and severity of SE and burden of complications, suggesting that anesthetic use may simply be an indicator of more severe SE.

The descriptive findings and associations with outcome described by Gaspard et al. provide a clearer, but still incomplete, picture of NORSE syndrome. Cases of RSE that appeared cryptogenic in the first 48 hours ultimately had an etiology identified nearly half of the time, yet half remained unexplained. Similarities in the clinical features and lab findings between patients with autoimmune causes and those without known etiology and the steady progress in discovery of new autoantibodies suggest that we may identify an autoimmune etiology in more of these cases in the future. The study design did not allow for a clear understanding of the role of early immunotherapy in NORSE. Because the response of autoimmune epilepsy in general appears better with early immunotherapy, the role of early immunotherapy in NORSE should be a focus of future research.

Those of a certain age may remember the song “A Horse With No Name” by America that improbably bumped Neil Young's “Heart of Gold” from the #1 spot on the US pop charts in 1972. The song, set in the desert, was panned by critics because of inane lyrics such as “the heat was hot” and “there were plants and birds and rocks and things….” Likewise, despite the knowledge gained from large case series such as the present one, we often still can't be much more eloquent in defining etiology in many cases of new-onset refractory status epilepticus. There are viruses and autoantibodies and paraneoplastic causes and things, but in many instances, we are still left with a NORSE with no name.