New-onset super-refractory status epilepticus

Abstract

Objective

To better understand the heterogeneous population of patients with new-onset refractory status epilepticus (NORSE), we studied the most severe cases in patients who presented with new-onset super-refractory status epilepticus (NOSRSE).

Methods

We report a retrospective case series of 26 adults admitted to the Columbia University Irving Medical Center neurologic intensive care unit (NICU) from February 2009 to February 2016 with NOSRSE. We evaluated demographics, diagnostic studies, and treatment course. Outcomes were modified Rankin Scale score (mRS) at hospital discharge and most recent follow-up visit (minimum of 2 months post discharge), NICU and hospital length of stay, and long-term antiepileptic drug use.

Results

Of the 252 patients with refractory status epilepticus, 27/252 had NORSE and 26/27 of those had NOSRSE. Age was bimodally distributed with peaks at 27 and 63 years. The majority (96%) had an infectious or psychiatric prodrome. Etiology was cryptogenic in 73%, autoimmune in 19%, and infectious in 8%. Seven patients (27%) underwent brain biopsy, autopsy, or both; 3 (12%) were diagnostic (herpes simplex encephalitis, candida encephalitis, and acute demyelinating encephalomyelitis). On discharge, 6 patients (23%) had good or fair outcome (mRS 0–3). Of the patients with long-term follow-up data (median 9 months, interquartile range 2–22 months), 12 patients (71%) had mRS 0–3.

Conclusion

Among our cohort, nearly all patients with NORSE had NOSRSE. The majority were cryptogenic with few antibody-positive cases identified. Neuropathology was diagnostic in 12% of cases. Although only 23% of patients had good or fair outcome on discharge, 71% met these criteria at follow-up.

New-onset refractory status epilepticus (NORSE) describes refractory status epilepticus (RSE) in patients with no seizure history. NORSE is a clinical syndrome, associated with over 20 distinct etiologies; up to 52% remain cryptogenic.¹ Many progress to super-refractory status epilepticus, which is associated with mortality rates up to 61%, poor functional outcomes, and high cost of admission.^1–5 We present a case series of patients with new-onset super-refractory status epilepticus (NOSRSE) to better understand this particularly fulminant subset of NORSE.

Methods

Patient cohort

We performed a retrospective chart review of patients admitted to the Columbia University Irving Medical Center (CUIMC) neurologic intensive care unit (NICU) for RSE from February 2009 to February 2016. We identified patients with NORSE using the First International NORSE and febrile infection–related epilepsy syndrome (FIRES) symposium criteria: new-onset RSE without clear acute or active structural, toxic, or metabolic cause in a patient without epilepsy or relevant neurologic disorder.³ Those with ongoing or recurrent seizures 24 hours after initiation of anesthetics met our criteria for NOSRSE.⁶

Standard protocol approvals, registrations, and patient consents

The CUIMC institutional review board approved this study (protocol IRB-AAAL4106).

Data collection

We retrospectively collected electronic medical record data including demographics (age, sex), clinical features (comorbidities, prodromal symptoms, baseline modified Rankin Scale [mRS] score), Status Epilepticus Severity Score), diagnostic results (laboratory, EEG, MRI, neuropathology), and treatments (antiepileptic drugs [AEDs], anesthetics, antimicrobials, immunomodulatory therapies).

Primary outcome was mRS at hospital discharge: good or fair outcome, defined as mRS 0–3; or poor outcome, defined as mRS 4–6. Secondary outcomes were mRS on follow-up (most recent clinical data, minimum 2 months postdischarge), NICU and hospital length of stay, and long-term AED use.

Results are displayed as median (interquartile range [IQR]) or number (percentage). Statistical analyses were performed using SPSS version 26.

Data availability

Anonymized data will be shared at the request of any qualified investigator.

Results

Patient cohort

Among 252 patients with RSE, 27 met criteria for NORSE and 26 of 27 patients had NOSRSE (figure). Age was bimodally distributed with peaks at 27 and 63 years (table 1). There was a female predominance. The most common comorbidity was an underlying autoimmune condition (23%), although most patients (42%) had no preexisting conditions. Twenty-five patients (96%) had an infectious or psychiatric prodrome prior to seizure onset. Thirteen patients (50%) were febrile between 24 hours and 2 weeks prior to the onset of NOSRSE, meeting criteria for FIRES.

Figure. Patient selection.

NORSE = new-onset refractory status epilepticus; NOSRSE = new-onset super-refractory status epilepticus.

Table 1.

Characteristics

Diagnostic studies

Common EEG findings were focal status epilepticus (38%) or multifocal or bitemporal status epilepticus (31%); 19% had extreme delta brush pattern (table 2). Brain MRIs were normal in 13 patients (50%); the most common abnormality was temporal/hippocampal T2 hyperintensity. Nineteen patients (73%) remained cryptogenic despite extensive work-up. Of the patients tested for the NMDA receptor antibody, 4 (15%) were positive. Twenty-two patients (85%) were tested for paraneoplastic antibodies. All CSF antibody testing was negative. Two patients (8%) had low serum titers of striated muscle antibody, which has no known association with encephalitis and was considered to be clinically insignificant. Seven patients (27%) underwent brain biopsy, autopsy, or both. Three patients (12%) had diagnostic neuropathology: 1 with herpes simplex virus (HSV) encephalitis (found on biopsy, confirmed on autopsy despite 3 negative CSF PCR tests), 1 with candida encephalitis on autopsy (despite negative CSF fungal cultures), and 1 with hemorrhagic necrotizing leukoencephalopathy on autopsy (thought to be acute demyelinating encephalomyelitis [ADEM] and unlikely secondary to RSE).

Table 2.

Diagnostic testing and treatment

Treatment course

All patients required multiple AEDs and at least 1 anesthetic agent, although most required more (table 2). Twenty-three patients (88%) received broad-spectrum antibiotics for meningoencephalitis; none received a full course. Twenty-four patients (92%) were started on acyclovir but stopped after CSF HSV PCR returned negative; 1 (4%) received a full 14-day course despite a negative PCR test. Twenty-one patients (81%) received immunotherapy; 15 patients (58%) received steroids (on median day 5 [IQR 3–8] after seizure onset), 11 patients (42%) received IV immunoglobulin (day 7 [IQR 4–27]), and 11 patients (42%) received plasmapheresis (day 9 [IQR 9–12]).

Primary outcome measures

On discharge, 6 patients (23%) had good or fair outcome (table 3). Six patients (23%) died; 3 (12%) never achieved seizure control (on day 36, 48, and 53 of ongoing NOSRSE). For all 3, family members withdrew life-sustaining therapy given ongoing NOSRSE and development of multiorgan system failure. Outcomes for those with known etiologies were poor; both patients with infectious encephalitis and the patient with ADEM died while admitted. All patients with NMDA encephalitis survived to discharge: 2 with mRS 4, 2 with mRS 5.

Table 3.

Outcomes

Secondary outcome measures

The median duration of NOSRSE was 17 days (IQR 11–46). Of the 20 patients who survived to hospital discharge, long-term outcomes were available in 17 (85%), with median follow-up at 9 months (IQR 2–22). Twelve of these patients (71%) had a good or fair outcome. Patients with mRS 0–3 on discharge had a shorter duration of NOSRSE compared to those with mRS 4–6 (11 days [IQR 10–13] vs 29 days [IQR 13–56]). Long-term outcomes were available for 3 patients with NMDA encephalitis (mRS 2, 4, 5). Most patients required long-term AEDs.

Discussion

In our population of 252 patients with RSE, 27 of 252 patients had NORSE and 26 of those 27 patients had NOSRSE. This series of 26 patients represents 10% of our entire cohort. The majority were cryptogenic with few antibody-positive cases identified. Neuropathology was diagnostic in several cryptogenic cases. Despite their severe course and poor short-term follow-up, the majority had good or fair long-term outcomes. It is striking, although not surprising, that nearly all of our patients with NORSE had NOSRSE. In a retrospective review by Gaspard et al.,¹ the duration of status epilepticus was longer in cryptogenic cases than in cases with a proven etiology, although the NORSE and NOSRSE cases were not clearly delineated.

Compared to the cohort of 130 patients with NORSE in the Gaspard et al.¹ review, our cohort had more frequent prodrome (96% vs 60%) and cases were more often cryptogenic (73% vs 52%). This was consistent with findings by Iizuka et al.⁷ that NORSE was more likely to be cryptogenic when it was highly resistant to AEDs. They also found that patients with cryptogenic NORSE more frequently had a prodrome (compared to NMDA encephalitis–related NORSE). The higher prevalence of cryptogenic cases in our cohort may explain more frequent prodrome. Interestingly, aside from NMDA antibodies, we identified no other pathogenic autoantibodies, although testing was variable—2 patients (8%) only had serum paraneoplastic testing; 4 patients (15%) had no paraneoplastic testing.

EEG findings included focal or multifocal status epilepticus and generalized periodic epileptiform discharges with similar distribution to that seen in the Gaspard cohort. Brain MRIs were normal in 50% of our patients, compared with 38% in the Gaspard et al.¹ cohort. Abnormalities were similar (diffusion restriction and temporal/hippocampal T2 hyperintensities).

Seven of our patients (27%) had neuropathology. While previous NORSE studies have exclusively found nonspecific changes on neuropathology (astrogliosis, inflammatory infiltrate, neuronal necrosis), neuropathology was diagnostic in 3 of our cases (12%).^1,5,8–10 Those with infections diagnosed on neuropathology had negative CSF testing and were not treated with appropriate antimicrobials; both died.

Despite a longer duration of RSE among our cohort compared to the Gaspard et al.¹ cohort (17 [IQR 11–46] vs 5 [IQR 2–16] days), the proportion of patients with good or fair outcomes at long-term follow-up was similar (71% vs 79%). This supports recent case series showing that even patients with extremely prolonged NORSE can recover.^1,11

Our study has several key limitations. As has been true in much of the NORSE literature, our study was small, single-center, and retrospective, with variability in diagnostic workup and management. Because we only studied patients on anesthetic medications, we did not capture patients who responded to antiepileptic medications alone. Thus, we lack a direct comparative group of non–super-refractory NORSE. Strengths include a relatively large cohort given the rarity of this syndrome, robust imaging, EEG and neuropathology samples, and long-term follow-up in most patients.

A prospective, multicenter study of NOSRSE is needed to help build on these findings and better understand this particularly fulminant syndrome.

Glossary

ADEM

acute demyelinating encephalomyelitis

AED

antiepileptic drug

CUIMC

Columbia University Irving Medical Center

FIRES

febrile infection–related epilepsy syndrome

HSV

herpes simplex virus

IQR

interquartile range

mRS

modified Rankin Scale

NICU

neurologic intensive care unit

NORSE

new-onset refractory status epilepticus

NOSRSE

new-onset super-refractory status epilepticus

RSE

refractory status epilepticus

Appendix. Authors

Study funding

No targeted funding reported.

Disclosure

E. Matthews reports no disclosures relevant to the manuscript. A. Alkhachroum is supported by the National Center for Advancing Translational Sciences of the NIH under the Miami CTSI KL2 Career Development Award UL1TR002736 N. Massad, R. Letchinger, and K. Doyle report no disclosures relevant to the manuscript. J. Claassen reports federal funding: NINDS R01 NS106014, R03 NS112760; foundation funding: DANA; and minority shares at iCE. K.T. Thakur reports K23 NIH/NINDS NS105935: Clinical impact of early pathogen identification in acute neurological infections. Go to Neurology.org/N for full disclosures.