NORSE: Cryptogenic New-Onset Refractory Status Epilepticus

Shivani Ghoshal, MD; and Lawrence J. Hirsch, MD

Department of Neurology

Yale University School of Medicine

New Haven, Connecticut

Disclosures:

Dr. Hirsch reports research support to Yale University for investigator-initiated studies from Eisai Inc, Lundbeck, Sunovion Pharmaceuticals Inc, and Upsher-Smith Laboratories, Inc, all of whom market or plant to market medications for epilepsy/seizures. He also reports consultation frees for advising from Marinus Pharmaceuticals, Inc, Sun Pharmaceutical Industries Ltd., Sunovion Pharmaceuticals Inc,and Upsher-Smith Laboratories, Inc., all of whom market or plan to market medications for epilepsy/seizures.

Introduction

Status epilepticus (SE) is a common neurological emergency that requires prompt recognition, management, and work-up. Just over one-third of SE cases are refractory to appropriate first- and second-line treatment.¹ A portion of these refractory cases occur in healthy patients with no prior significant medical disease or history of epilepsy. Despite standard initial evaluations including imaging and lumbar puncture, their etiology remains unclear after the first couple days.

This review focuses on this last understudied group of patients, who have the condition known as NORSE: cryptogenic new-onset refractory status epilepticus. We will focus on practical approaches to work-up and management for the >3000 patients with this syndrome in the United States each year.

Case

A 22-year-old right-handed male high school teacher with no significant past medical or seizure history presented to another hospital following a convulsive seizure, as well as 5 focal seizures. On initial exam, he was afebrile, lethargic, disoriented, and had anomia, but normal cranial nerve, motor and reflex examinations. In the week preceding his presentation, the patient had headaches, intermittent fever, nausea, and vomiting.

Magnetic resonance imaging (MRI) brain with and without contrast was unremarkable. Cerebrospinal fluid findings (CSF) studies showed a glucose of 74 mg/dL (normal), protein of 24 mg/dL (normal), no xanthochromia, 1 red blood cell, and 13 white blood cells, all lymphocytes. Acyclovir was started and phenytoin was loaded. He continued to have focal seizures with impaired awareness despite addition of levetiracetam and valproate, and was transferred to our center, where continuous electroencephalogram (EEG) monitoring was begun.

The patient rapidly developed refractory nonconvulsive status epilepticus. He was intubated and started on a midazolam infusion. He continued to have intermittent seizures, almost all nonconvulsive, despite high dose midazolam (up to 2.5 mg/kg/h). Propofol infusion was added and led to seizure control, but seizures returned during the propofol taper. Treatments utilized over the next 3 to 4 weeks included pentobarbital and ketamine infusions, steroids, antibiotics, and later phenobarbital to aid with weaning off pentobarbital.

The patient achieved seizure control after 33 days, and remained in the ICU for 66 days. His course was complicated by severe acidosis and rhabdomyolysis during his high-dose midazolam and ketamine infusions (resembling propofol-infusion syndrome, but with no recent use of propofol), a collapsed lung, and a brief cardiac arrest. His pancreatic enzymes were elevated on admission, and remained so. His spine MRI showed extensive abnormal signal. He underwent tracheostomy and percutaneous gastrostomy placement, and was discharged to an acute rehabilitation facility fully alert.

Multiple lab investigations, including a work-up for autoimmune and paraneoplastic encephalitis, were all negative, except serologies for mycoplasma pneumonia returned IgM+/IgG+, later becoming IgM-/IgG+, suggesting recent infection. He completed a course of doxycycline. His pancreatitis and myelitis were felt to be secondary to mycoplasma.

At one-year follow-up, he completely returned to his cognitive and behavioral baseline, including his upbeat, charismatic personality. At 4 years out, he remains with normal cognition, a moderate spastic paraparesis, and only rare, brief focal seizures (about 1 per year). Three years after NORSE, he was accepted into graduate school at multiple institutions, including an Ivy League school. He does voluntary motivational speaking as well.

Definitions^1-3

1. Status epilepticus (SE) – Any 1 of the following:
   1. Convulsive seizure with impaired consciousness lasting >5 minutes

   2. ≥2 seizures without full recovery in between

   3. Nonconvulsive or electrographic seizure activity lasting 10 minutes⁴

   4. Electrographic seizure activity occupying >50% of any hour.

2. Refractory status epilepticus (RSE): persistent SE that fails to respond to at least 2 appropriate parenteral medications.
3. NORSE: no prior epilepsy, and new onset of RSE without an obvious cause after the first 48 hours of evaluation (adequate time to rule out strokes, brain masses, drug overdoses, and common viral encephalitides such as herpes simplex virus-1).1,2

Related syndromes:

There are multiple related names and syndromes, most commonly FIRES (febrile infection-related epilepsy syndrome).⁵ This typically refers to children with a recent febrile illness (within 2 weeks), followed by NORSE, and most commonly followed by chronic epilepsy. We view FIRES as a subcategory of NORSE.

Epidemiology:

We estimate the following annual incidences in the United States, though these are likely to be underestimates:

Status epilepticus: ~45,000 cases.

Calculation: ~14/100,000 per year,⁶ with US population = 325 million

Refractory SE (any etiology): 37% of SE³ = ~17,000

NORSE (cryptogenic RSE): 130/675 RSE cases in Gaspard et al² = 19% of RSE

= ~3200 cases in the US each year.

NORSE in the literature:

Much of what is known regarding NORSE comes from retrospective case studies.^2,7-10 The largest included 130 patients2; of these patients, 60% presented with some prodrome up to 2 weeks prior to admission, with confusion in 45% and fever in 34%. MRI brain scans were normal in 38% of cases. In the remaining cases, the abnormalities were most often seen on fluid-attenuated inversion recovery images, within the limbic or neocortical areas. 65% of patients had CSF pleocytosis, usually mild (median 5 lymphocytes), though this did not necessarily indicate an infectious or inflammatory cause. CSF abnormalities occurred as frequently in cryptogenic cases as those with causes eventually identified (Table). Retrospective reviews have shown SE itself can be associated with a CSF pleocytosis of 6 to 28 lymphocytes/mL in up to 30% of patients, despite negative laboratory and radiologic testing for established causes.¹¹

Table. NORSE Diagnostic Checklist

Within first 24 hours:

• Initiate institution status epilepticus protocol
• Obtain thorough history, especially regarding immunosuppression, medications and supplements, recent travel to endemic areas, accidental or occupational exposure to animals, insects, pathogens, drugs or toxins
• Consider treatment for possible HSV encephalitis
• Triage for appropriate cardiopulmonary support
• MRI brain with and without contrast; consider MRA and MRV head
• Initiate continuous EEG, regardless of cessation of convulsive activity
• Serologic/imaging tests (see below)

At 48 hours:

• Assess returned testing, initiate appropriate treatments
• If patient continues to have refractory status epilepticus or coma, transfer to higher level of care for appropriate further treatment of NORSE at a center with experience in these cases, including continuous video/EEG monitoring.

At 72 hours:

• Consider initiation of 5-day course of high dose parental corticosteroids. Transfer to higher level of care for consideration of IVIG, plasmapheresis, or further immunomodulatory therapy if no clear diagnosis, if still having seizures, if no continuous EEG monitoring available, or if still comatose.

*This is not a complete list of tests to be done, but is a sample of suggested tests. Table adapted from http://www.norseinstitute.org/ , with permission. Please see that website for the full table, as well as other helpful tables including a sample status epilepticus protocol, zoonotic/geographic tips, diagnostic clues to specific organisms or syndromes, and list of medications, drugs and toxins that can cause status epilepticus.

Recommendations for work-up

Each patient with cryptogenic refractory status should undergo rigorous systemic and CSF infectious work-ups for viral, bacterial, and atypical agents. Systemic metabolic and general autoimmune panels should be sent, as well as further work-up for autoimmune or paraneoplastic causes. Of the 130 NORSE patients from the Gaspard et al 2015 study, 48% of patients were ultimately found to have autoimmune or paraneoplastic encephalitis.² Among these, anti-NMDA antibodies (12%) and anti-voltage-gated potassium channel antibodies (6%) were the most frequent. 52% of patients from this study remained cryptogenic despite extensive investigation.

Other retrospective case studies have similarly noted a percentage of NORSE patients with an underlying autoimmune or paraneoplastic etiology.^7-10

We have included a sample checklist of recommended (for most patients) and optional (to be used in specific settings) testing for NORSE patients (Table); a more thorough list that will be updated periodically can be found at www.norseinstitute.org.

Management

The general management of SE has been recently and extensively reviewed elsewhere.^1,3,12 With regard to NORSE in particular, the body of literature is small, but findings are suggestive of the importance of early immunotherapy, even in patients without clearly identified antibodies.2 Li et al describe successful cessation of seizures by using plasma exchange in a small number of NORSE cases refractory to multiple anticonvulsants and general anesthetics.¹⁰ Khawaja et al reported improved outcomes in patients treated with immune therapies (intravenous steroids, immune globulins, plasmapheresis, or a combination).⁹ It is possible that patients with NORSE that remain cryptogenic have an underlying occult auto-immune or other immunologic condition (not yet defined); in addition, it could be that inflammatory mechanisms are occurring at the seizure focus due to ongoing seizures, creating further epileptogenicity.^12,13 Until further evidence accumulates, we recommend fairly early use of immune therapies in most or all cases of NORSE.

Outcomes

Most NORSE cases progress to super-refractory status epilepticus (SRSE), meaning persistent seizures after >24 hours of treatment, usually including anesthetics. SRSE has a mortality rate of 35% and high morbidity—in part due to the systemic effects of RSE, and in part due to prolonged ICU stays, anti-seizure and anesthetic medications.^1,12,13 In one study, all patients with prolonged SRSE developed measurable brain atrophy, with atrophy more notable in younger patients with prolonged hospitalization and longer duration of anesthetic treatment.¹⁴

However, not all patients with NORSE have a poor outcome, as demonstrated in our case. In 2013, Kilbride et al reviewed the outcomes of 63 patients in prolonged SRSE (>7 days of RSE) of any etiology.⁸ Of the 63 patients included, two-thirds survived to discharge. Of the survivors, 22% achieved good recovery (modified Rankin score 0-3) in follow-up, outcomes ranging from no disability to moderate disability. In the recent Gaspard multicenter review of patients with NORSE, 62% of the 130 patients had severe disability at hospital discharge (mRS score of 4-6), but many patients improved on longer-term follow up. Among the surviving patients, 72% had a good outcome at a median of 9 months, and 41% (26/63) had no significant disability (mRS 0-1).² The 2016 retrospective study by Hocker et al showed no correlation of development of cerebral atrophy with functional outcome¹⁴; thus, cerebral atrophy should not be used as a prognosticating factor for functional recovery. While NORSE has significant morbidity and mortality, good outcome remains possible, as shown in our case, where despite 1 month of iatrogenic coma, 2 months in the ICU, and many medical complications, he returned to baseline cognitively. We believe good outcome remains possible in many (but certainly not all) patients, especially with early recognition, aggressive treatment of seizures, and probably with use of immune therapy regardless of diagnostic testing results, at least while we await further and better investigations.

Conclusion

NORSE patients are previously healthy patients who present in refractory status epilepticus with unknown etiology despite appropriate initial investigation, including imaging and lumbar puncture. There is increasing evidence that a large proportion of these cases have a component of autoimmune encephalitis. Increased awareness of NORSE is imperative for determining the prevalence, etiologies, and best treatments for NORSE patients. There are ongoing prospective, multicenter studies investigating the role of the immune system, infections, and genetics, and tracking treatments and outcomes.

For further information or to help with further efforts to increase awareness and research into NORSE:

Websites:

• http://www.norseinstitute.org/ [primary website dedicated to NORSE]
• http://www.epilepsy.com/article/2015/10/norse-new-onset-refractory-status-epilepticus [summary and podcast]
• https://rarediseases.org/rare-diseases/new-onset-refractory-status-epilepticus-norse/ [brief summary of NORSE]

Suggested reviews/key papers:

• Status epilepticus treatment: refs 1, 3 and 12.
• Autoimmune epilepsy and NORSE: refs 2 and 15.

1. Grover EH, Nazzal Y, Hirsch LJ. Treatment of Convulsive Status Epilepticus. Curr Treat Options Neurol. 2016;18(3):11.

2. Gaspard N, Foreman BP, Alvarez V, Cabrera Kang C et al. New-onset Refractory Status Epilepticus: Etiology, Clinical Features, and Outcome. Neurology. 2015;85(18):1604-13.

3. Hocker SE. Status Epilepticus. Continuum (Minneap Minn). 2015 Oct;21(5):1362-83.

4. Trinka E, Cock H, Hesdorffer D, Rossetti AO, Scheffer IE, Shinnar S, Shorvon, S, Lowenstein DH. A definition and classification of status epilepticus—Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015;56(10):1515-23

5. Van Baalen A, Vezzani A, Hausler M, Kluger G. Febrile Infection-Related Epilepsy Syndrome: Clinical Review and Hypotheses of Epileptogenesis. Neuropediatrics. 2016[Epub ahead of print]

6. Betjemann JP, Josephson SA, Lowenstein DH, Burke JF. Trends in Status Epilepticus-Related Hospitalizations and Mortality: Redefined in US Practice Over Time. JAMA Neurol. 2015;72(6):650-5.

7. Wilder-Smith EPV, Lim ECH, Teoh HL, Sharma VK, Tan JJH, Chan BPL, et al. The NORSE (new-onset refractory status epilepticus) syndrome: defining a disease entity. Ann Acad Med Singap. 2005 ;34(7):417-20.

8. Kilbride RD, Reynolds AS, Szaflarski JP, Hirsch LJ. Clinical outcomes following prolonged refractory status epilepticus (PRSE). Neurocrit Care. 2013;18(3):374-85.8.

9. Khawaja AM, DeWolfe JL, Miller DW, Szaflarski JP. New-onset refractory status epilepticus (NORSE) – The potential role for immunotherapy. Epilepsy Behav. 2015; 47:17-23.

10. Li J, Saldivar C, Maganti RK. Plasma Exchange in Cryptogenic New Onset Refractory Status Epilepticus. Seizure. 2013;22(1):70-3.

11. Barry E, Hauser WA. Pleocytosis after status epilepticus. Arch Neurol. 1994 Feb;51(2):190-3.

12. Trinka E, Brigo F, Shorvon S. Recent Advances in Status Epilepticus. Curr Opin Neurol. 2016;29(2):189-98.

13. Hocker, S. Systemic Complications of Status Epilepticus – An Update. Epilepsy Behav. 2015;49:83-7.

14. Hocker S, Nagarajan E, Rabinstein AA, Hanson D, Britton W. Progressive Brain Atrophy in Super-refractory Status Epilepticus. JAMA Neurol. 2016.

.15. Gaspard N. Autoimmune Epilepsy. Continuum (Minneap Minn). 2016;22(1 Epilepsy):227-45.