Continuing Education Activity

New-onset refractory status epilepticus (NORSE) is an uncommon clinical entity with a mortality rate of 16-27% in adults and significant long-term neurological sequelae. Approximately 50% of patients with NORSE have an unknown etiology despite an extensive workup. There is a lack of consensus regarding the best treatment options available for managing patients with NORSE. However, immediate cessation of seizure activity, early institution of continuous infusion of anesthetic agents, and immunotherapies can play an important role in reducing morbidity and mortality in NORSE. This activity reviews the evaluation and treatment options available and highlights the healthcare team's role in managing patients with this condition.

Objectives:

• Describe the etiology of new-onset refractory status epilepticus.
• Explain the pathophysiology of new-onset refractory status epilepticus.
• Outline the typical presentation of a patient with new-onset refractory status epilepticus.
• Summarize the treatment considerations for patients with new-onset refractory status epilepticus.

Introduction

The International League Against Epilepsy (ILAE) defines status epilepticus (SE) as continuous clinical and/or electrographic seizure activity, or recurrent seizure activity without recovery to baseline, lasting for ≥ 5 mins.[1] If the seizure activity continues despite treatment with adequate doses of an initial benzodiazepine and an acceptable second-line intravenous (IV) antiepileptic medication, the patient is considered to have progressed into refractory status epilepticus (RSE).[2] Super refractory status epilepticus (SRSE) is defined as RSE that continues or recurs despite the use of IV anesthetic agents for ≥ 24 hours, including those cases that recur upon withdrawal or cessation of anesthetic agents.[3] RSE is seen in approximately 9% to 43% of all SE cases, with a reported in-hospital mortality of 15% to 33%.[4][5] It has been observed that approximately 4% to 12% of patients with SE eventually progress to SRSE, with in-hospital mortality reported to be as high as 40% to 54%.[6][7][8]

The term new-onset refractory status epilepticus (NORSE) was first used by Wilder-Smith et al. in 2005 to describe cases of SRSE with no associated past medical history of epilepsy and with no identifiable cause despite initial evaluation.[9] In 2018 an international group of experts proposed a consensus definition of NORSE and related conditions to allow a more standardized terminology to improve patient management and clinical research. NORSE is defined as a “clinical presentation characterized by new onset of refractory status epilepticus, in a patient without active epilepsy or other preexisting relevant neurological disorder (acute strokes, brain masses, drug overdoses, etc.), and without a clear acute or active structural, toxic or metabolic cause.” A closely related condition, febrile infection-related epilepsy syndrome (FIRES), has been defined as a subset of NORSE, associated with a prior febrile infection, with fever starting between 2 weeks to 24 hours before the onset of RSE.[10] In contrast, patients with NORSE may or may not be associated with fever before the start of RSE.

Etiology

In a large retrospective review, consisting of 130 NORSE cases, an etiology was not identified in 52% of cases despite an extensive evaluation. These cases were termed as “cryptogenic NORSE” or “NORSE of unknown etiology.”[11] The most common etiologies included autoimmune and paraneoplastic encephalitis followed by infections.

• Non-paraneoplastic autoimmune encephalitis - The most frequently detected antibodies include anti-NMDA (N-methyl-D-aspartate) receptor, anti-VGKC (voltage-gated potassium complex), anti-LGI1, and less commonly anti-Caspr2. Other autoimmune antibodies that have been found in patients with NORSE include - Anti-GABA, Anti-glycine, Anti-GAD65, Anti-striational, and steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT). 
• Paraneoplastic autoimmune encephalitis - Anti NMDA receptor-associated encephalitis is the most common in this category. Young females are predominantly affected, and 50% of cases are associated with germ cell tumors like ovarian teratoma. Other antibodies that have been identified include anti-Hu (small cell lung cancer, neuroblastoma), anti-CRMP5 (small cell lung cancer), anti-Ma2 (germ cell tumor of testis), anti-amphiphysin (breast cancer, small cell lung cancer), and anti-VGCC (small cell lung cancer, thymoma).  
• Infections - Herpes simplex virus type 1 (HSV-1) is the most common etiology identified in NORSE amongst infectious agents. Enterovirus, Epstein Barr virus (EBV), Varicella zoster virus (VZV), Cytomegalovirus (CMV), Bartonella henselae, Mycoplasma pneumoniae, and arboviruses (West Nile virus) have also been detected in patients with NORSE. 
• Some of the rare genetic conditions (POLG131), including mitochondrial defects, have also been associated with NORSE.[12][13]

Epidemiology

NORSE and its subtype FIRES are relatively uncommon disorders, with most epidemiological data coming from case series. NORSE and FIRES have been reported in previously healthy young adults and school-aged children. However, adults ≥ 60 years have also been affected. It has been observed that females are affected more than males amongst adults, whereas boys are more frequently affected than girls in the pediatric population.[11][14]

Due to the lack of a clear definition of NORSE previously, it is possible that some of the cases were not diagnosed as NORSE. Hence, an accurate incidence of NORSE cannot be estimated reliably. However, it is estimated that NORSE represents approximately 20% of cases of RSE.[15] Both NORSE and FIRES can occur in any age group with no ethnic or racial predilection.[14]

Pathophysiology

An immune-mediated inflammatory process has been postulated as the underlying pathophysiology in FIRES.[16] In a study by Sakuma et al., the authors observed a marked overproduction of proinflammatory cytokines and chemokines in the cerebrospinal fluid (CSF) of children with FIRES, compared to CSF specimens from patients with other inflammatory neurological conditions.[17] The upregulation of these inflammatory mediators could be secondary to activation of T cells, glial cells, and cells of the blood-brain barrier and perhaps have a role in epileptogenesis.[18] However, additional mechanisms such as mitochondrial dysfunction or synaptic plasticity may also play a key role in seizure propagation.[15]

Recently, a personal predisposition towards developing FIRES or NORSE has been hypothesized based on allelic variations in human leukocyte antigen subtypes and IL1 pathway.[19][20] The fact that FIRES is a subtype of NORSE, a similar autoimmune inflammatory mechanism has been considered as the most likely mechanism in patients with NORSE. Further research studies are required to understand the exact underlying pathophysiological mechanism in patients with NORSE and FIRES.

History and Physical

NORSE and its subtype FIRES can develop in previously healthy adults or children and share some common clinical characteristics. Approximately 60% of patients with NORSE experience a prodromal illness, typically 1 to 14 days before the onset of seizure or SE.[11] Prodromal symptoms may include confusion, fatigue, headache, mild febrile illness, behavioral changes, mild gastroenteritis, upper respiratory tract infection, and memory complaints.[11][21][22] Fever is absent in up to 1/3 cases of NORSE, but, by definition, it is universally present in FIRES.[11] There is complete cessation of fever in approximately 50% of patients before the first seizure episode.[14]

At the onset, seizures are usually brief and isolated with a propensity to gradually increase in number within a few hours to days and eventually evolve into SE. The number of seizures can be up ≥ 100/day in children. Focal motor seizures are the most common seizure type seen, which may spread and generalize into bilateral tonic-clonic seizures. Other seizure types may include myoclonic seizures affecting the oro-facial muscles or focal seizures associated with impaired awareness. Seizures can last anywhere from a few days to weeks before progressing to SE.[9][14][23][24][25] 

Once the seizures evolve into SE, they remain refractory to the first and second-line treatment options, requiring admission to the intensive care unit (ICU) for further aggressive treatment options. Patients with unknown etiology or “cryptogenic NORSE” have been observed to have similar clinical features and disease course compared to patients with NORSE caused by autoimmune encephalitis but with a longer duration and severity of seizures associated with respiratory involvement requiring mechanical ventilation and worse outcomes.[11][22]

Evaluation

Patients who present with SE should undergo an initial laboratory workup, including a complete blood count, comprehensive metabolic profile, creatine kinase, C-reactive protein, erythrocyte sedimentation rate, calcium, magnesium, and phosphorus levels. Urine and blood toxicology screen (alcohol, amphetamine, cocaine, fentanyl, benzodiazepines, heavy metals, synthetic cannabinoids, ecstasy, and bath salts) should be sent on admission.[26] For patients who progress to RSE and the initial workup fails to elucidate an etiology, additional laboratory investigations should then be considered to focus on autoimmune and uncommon infectious etiologies. 

Laboratory

A lumbar puncture should be performed if no clear etiology can be found on initial testing. Routine CSF studies, including cell count, protein, glucose, lactate, markers of inflammation (oligoclonal bands and IgG index), gram stain, bacteria culture, and cytology should be sent. Additional CSF studies should include fungal stain and cultures for M. tuberculosis, polymerase chain reaction (PCR) for HSV-1/2, Epstein Barr virus (EBV), Varicella zoster virus (VZV), HIV-1/2, Chlamydia pneumoniae, Mycoplasma pneumoniae, and VDRL in selected cases when the etiology remains unknown.[26] In approximately 2/3 of NORSE cases, mild CSF pleocytosis (≤ 10 cells/μl) with elevated protein and normal glucose can be seen, with no significant difference in CSF findings between cryptogenic cases and cases with identifiable etiology.[11] HSV PCR has high sensitivity (98 %) and specificity (99 %) and is positive early in the course of HSV meningitis/encephalitis. However, HSV PCR can be negative when LP is performed less than 24 hours from the onset of neurological symptoms.

Both CSF and serum should be tested for autoimmune anti-NMDA receptor, anti-VGKC (LGI1 and Caspr2), anti-AMPA, anti-GABA, and paraneoplastic antibodies (Anti-Hu, anti-CRMP5, anti-amphiphysin, anti-VGCC). An autoimmune panel (ANA, ANCA, Anti Ro, Anti La, Antithyroid antibodies, anti-Scl-70) should be sent for further testing. Viral serologies, most commonly HSV-1/2, VZV, EBV, enterovirus, and HIV-1/2, should be ordered in all patients with NORSE.[26] For immunocompromised patients, serologies should be sent for IgG Cryptococcus species, IgM and IgG Histoplasma capsulatum, and IgG Toxoplasma gondii. Stool specimens should be investigated for adenovirus and enterovirus. A scrotal ultrasound, pelvis magnetic resonance imaging (MRI), chest/abdomen/pelvis computed tomographic (CT) scan, and whole-body PET-CT are recommended to screen for an underlying malignancy in patients with suspicion for a paraneoplastic process. 

Neuroimaging

All patients with NORSE and FIRES should have a brain MRI with contrast, including venography and angiography, to evaluate structural or focal abnormalities. In approximately 60% of NORSE cases, symmetrical or asymmetrical abnormalities can be seen on the brain MRI.[11] The most common findings observed include hyperintensity on T2/FLAIR sequences within the limbic and neocortical structures, often bilaterally. Other brain regions like the claustrum, basal ganglia/thalami, and peri-insular cortex can show abnormal T2/FLAIR hyperintensity.[27][28]

Electroencephalography (EEG)

All patients should have continuous EEG monitoring (cEEG) to assess seizure type and frequency, rule out non-convulsive status epilepticus (NCSE) and monitor therapy response. The neurocritical care society guidelines recommend initiating cEEG in all patients within 1 hour of onset of SE.[2] EEG may demonstrate periodic or epileptiform discharges, which are most commonly lateralized or focal, generalized periodic discharges, and multifocal discharges.[14][27] 

The most common seizure noted in one series was focal onset followed by bilateral independent, generalized, and multifocal seizures. Seizures are brief and infrequent at the onset, associated with focal fast beta activity with a gradual evolution to SE characterized by rhythmic spike and wave complexes or beta-delta activity.[29] Some EEG patterns may provide clues to a specific diagnosis in a few cases. In 1/3 of the anti-NMDA receptor encephalitis cases, EEG monitoring may show a specific extreme-delta brush pattern characterized by beta bursts overriding delta waves.[30]

Treatment / Management

Status epilepticus is a neurological emergency that requires the immediate cessation of seizure activity to prevent permanent neurological injury. Initial management should be following the currently available guidelines.[2][31][32]

• Patients should be stabilized first with regards to their cardiocirculatory function.
• Airway patency and safety should be ensured. Supplemental O2 through a nasal cannula or other non-invasive methods should be considered to ensure oxygenation before advancing to intubation and mechanical ventilation.
• Rapid sequence intubation should be performed in patients with impaired oxygenation or ventilation despite conservative measures. 
• Intravenous (IV) benzodiazepines are the agents of choice for aborting seizures emergently. The use of benzodiazepines in the prehospital setting has been shown to terminate seizures in 43% to 59% cases with SE, en-route to the hospital, with less need for respiratory support on arrival to the emergency department and need for ICU subsequently. Intramuscular (IM) midazolam has been observed to be superior and more efficacious than IV lorazepam in patients without IV access.[33] However, IM midazolam, IV lorazepam, IV diazepam, and IV phenobarbital have been recommended as initial drugs of choice for aborting seizures lasting at least 5 minutes, with similar efficacy.[31]
• IV acyclovir should be started early during the course of illness in patients with suspicion for HSV encephalitis (acute febrile encephalopathy, new-onset seizures, asymmetric medial temporal lobe involvement, and lymphocytic pleocytosis with RBCs on CSF analysis), pending HSV-PCR results in CSF. It has been shown to reduce mortality and morbidity when started early in the course of illness.
• In patients with benzodiazepine refractory SE, a second-line antiepileptic agent should be attempted immediately at appropriate doses. In a randomized control trial, IV levetiracetam, IV fosphenytoin, and IV sodium valproate were shown to have similar safety and efficacy in established SE patients.[34] The effectiveness of each subsequent antiepileptic added in aborting status epilepticus decreases after initiating the first antiepileptic agent
• If seizures continue despite treatment with a second-line agent, another anti-epileptic agent should be used before progressing to IV anesthetic agents. IV phenytoin/fosphenytoin, phenobarbital, valproate, levetiracetam, and lacosamide; have been noted to be effective in the treatment of established SE with no preference over each other.[32] Hence one of these agents, either as single or in combination, can be used for treatment.

By definition, patients who fail to respond to first and second-line therapies progress to refractory SE and require treatment with continuous IV anesthetic agents to achieve seizure control.

• Current guidelines recommend using continuous IV infusion of anesthetic agents for seizure suppression or burst suppression coma for 24-48 hours before attempting to wean.[2]
• Midazolam: Load with 0.2 mg/kg IV followed by continuous infusion at 0.05 to 2 mg/kg/hr.
• Propofol: 2 mg/kg IV bolus followed by maintenance infusion at 20 to 250 mcg/kg/min.
• Pentobarbital: 5 mg/kg IV bolus, continuous infusion at 1 to 10 mg/kg/hr.
• Ketamine: Load with 0.5-4 mg/kg followed by maintenance infusion at 0.3 to 5 mg/kg/hr.
• IV midazolam and propofol are preferred over longer-acting agents like pentobarbital as long-acting agents are associated with a prolonged need for mechanical ventilation and cardiovascular complications.[35][36] However, higher doses and prolonged treatment of propofol have been associated with propofol infusion syndrome leading to higher mortality and complications than midazolam and ketamine. 

Patients with NORSE (or FIRES) often have a poor response to antiepileptic medications, and continuous IV anesthetic agents should be started without further delay, given the disease process's refractory nature. Multiple anesthetic agents are required in approximately 1/3 of patients with NORSE to achieve seizure suppression, and often for prolonged periods.[11][16] Since no specific therapy exists for patients with NORSE/FIRES, experts recommend using immunotherapies as soon as possible since nearly half of the cases are associated with an autoimmune/paraneoplastic etiology.[15][37] First-line immunotherapy agents include steroids, IV immunoglobulins, and plasmapheresis. Second-line options include tacrolimus, rituximab, cyclophosphamide, and anakinra. Immunotherapy has been shown to improve outcomes and control seizures more effectively in adults as compared to children.[22][38] There are currently no randomized controlled trials or prospective studies to guide immunotherapy in such patients, and recommendations are mostly based on expert opinion and experience from case series.

• Once the initial workup fails to elucidate a cause for RSE, and there is a high suspicion for NORSE, IV methylprednisolone should be started ideally within the first week at a dose of 1 gm/day for 3 to 5 days.
• Alternatively, other first-line treatment options (IV immunoglobulin 0.4 gm/day for 3 to 5 days or plasmapheresis for 3 to 5 sessions on alternate days) can be used depending on patient characteristics and clinical context.[15][39] 
• If there is no response to first-line therapies, i.e., failure to wean anesthetic agents due to high risk of seizure recurrence or prolonged RSE, the following second-line immunotherapies can then be considered: IV rituximab 375 mg/m^2 weekly for four doses, or IV cyclophosphamide 500-1000 mg/m^2 monthly for 3 to 6 months.
• Anakinra, a recombinant version of the human Interleukin-1 receptor antagonist, has been observed to reduce the seizure frequency and achieve remission in two case reports.[40][41]
• Other therapeutic options (hypothermia, cannabidiol, ketogenic diet), although less studied, have also been attempted in NORSE patients with mixed results and need to be validated.[42][43][44]

Differential Diagnosis

In most of the cases of NORSE, an etiology remains unknown despite an extensive workup. However, autoimmune/paraneoplastic encephalitis remains the most common identifiable etiology in NORSE.[11][45] Therefore, a detailed history and clinical examination should be sought as certain clinical features can point towards a specific underlying etiology leading to early immunotherapy during the acute phase, ultimately influencing outcomes and disability.

• Anti-NMDA encephalitis is the most common autoimmune encephalitis and should be ruled out early. It usually starts as a febrile illness in young adults, common in females.[46] This is soon followed by psychiatric disturbances like hallucinations (behavioral changes in children), sleep disturbances, hyperactivity, memory complaints, epileptic seizures, oro-lingual dyskinesias, and autonomic failure.[47] As compared to anti-NMDA encephalitis, patients with cryptogenic NORSE are more frequently associated with early onset of SE, prolonged disease course, absence of behavioral symptoms, ventilator dependence, and worse outcomes.[22]
• Encephalitis with anti-VGKC complex antibodies (LGI1 or, more rarely, Caspr2) can present with limbic encephalitis (cognitive impairment, confusion, behavioral disturbances, sleep disturbances, and seizures) and abnormalities in serum sodium levels associated with the syndrome of inappropriate antidiuretic hormone secretion.[48] Facio-brachial dystonic seizures can occur in patients with anti-LGI1 encephalitis and is a pathognomonic feature of the disease.[49]
• Amongst infectious causes, patients should be screened for uncommon infections as early as possible. HSV-1 infection can present with an acute illness consisting of fever, alteration in mentation, behavioral changes, multiple seizures (though uncommon to progress to RSE), focal neurological deficits (hemiparesis, ataxia, aphasia), without or without dermatomal rashes. Whereas lower motor neuron type weakness with rash and prodromal febrile illness can suggest an underlying enterovirus related infection.[11][13]
• Systemic reversible causes like toxic-metabolic disturbances (heavy metals including lead, aluminum arsenic, mercury) and drug toxicity should be considered in the differential and evaluated appropriately.

Prognosis

NORSE (and FIRES in children) is an uncommon neurological condition associated with significant long-term morbidity and mortality. Most patients remain unresponsive to multiple anesthetic agents and evolve into SRSE. A 12% mortality rate has been seen in children and 16% to 27% in adults.[11][14][50][51] 

Most of the survivors eventually develop multidrug-resistant epilepsy on long-term follow-up and significant cognitive and functional impairment. Prolonged ICU stay, medical complications, duration of barbiturate induced coma, and use of multiple anesthetic agents have been associated with worse outcomes both in children and adults.[11][13][14][25][52]

Complications

Patients with NORSE often require multiple IV anesthetic agents for prolonged periods to achieve burst suppression coma. Inadvertently, this is often associated with greater risk of complications including cardiovascular (hypotension requiring the use of vasopressors, cardiac arrhythmias), gastrointestinal (liver dysfunction, ileus, gastric ulcers), infectious (pneumonia, urinary tract infection), hematological (anemia, thrombocytopenia, pulmonary embolism), electrolyte abnormalities (hypo or hypernatremia, hypophosphatemia, severe acidosis), and worse outcomes. The severity and risk of complications have been associated with a prolonged RSE duration and the need for multiple IV anesthetic agents.[11]

Consultations

The following personnel should be consulted:

• Neurologist
• Anesthesiologist
• Intensivist

Deterrence and Patient Education

NORSE is a distinct clinical disorder with significant mortality and long-term morbidity. Existing evidence regarding the etiology, diagnostic workup, and treatment options is based on expert opinion and retrospective case series. Support should be offered to family members to provide education regarding possible neurological sequelae among NORSE survivors, including refractory epilepsy, functional and cognitive impairments.

General awareness about the nature of the disease and treatment options available should be promoted amongst medical professionals by organizing meetings at both the institutional and national levels. NORSE is not a well recognized clinical entity amongst general neurologists or medical intensive care physicians, except in specialized tertiary level academic health institutions. Hence, improving professional education will result in early recognition and management of the disease, improving patient outcomes.

Enhancing Healthcare Team Outcomes

NORSE is relatively an uncommon clinical entity with no clear etiology in the majority of the cases. It is associated with significant mortality and long-term neurological sequelae, requiring a multidisciplinary approach for management. Although no prospective long-term studies are comparing the efficacy of different treatment options in NORSE, physicians should recognize such patients and initiate treatment early during the disease course to improve patient outcomes.

Physicians and other health care team members, including nurses and pharmacists, should focus on the early institution of treatment, including the use of aggressive immunotherapies to reduce morbidity and mortality. Clear communication with an emphasis on discussing the uncertain nature of the diagnosis, treatment options available, and possible outcomes; should be maintained with the patient’s family throughout the course of the disease. Palliative care services can be consulted early during the hospital course to offer support to the family members and facilitate care discussion goals should the need arise. They can play an essential role in building a strong relationship between the patient’s family and the health care teams. Physicians should encourage families to participate in the national registry for NORSE patients (www.norseinstitute.org/norse-registry-2) to promote clinical research with an aim to understand possible causes of NORSE, identify best treatment options and hence improve patient outcomes.

Overall, an interprofessional healthcare team approach to managing NORSE will yield the best patient outcomes. This team is comprised of clinicians, specialists, nursing staff, and pharmacists, working collaboratively with open communication lines to achieve the best possible care standard. [Level 5]