Decoding NORSE Diagnosis: A Comprehensive Guide to New-Onset Refractory Status Epilepticus

New-onset refractory status epilepticus (NORSE) presents a significant clinical challenge in the field of neurology. Characterized by its sudden onset and resistance to conventional treatments, NORSE carries a substantial mortality rate, ranging from 16% to 27% in adult populations, and often leads to debilitating long-term neurological consequences. A perplexing aspect of Norse Diagnosis is that in approximately half of all cases, the underlying cause remains elusive even after thorough investigations. Currently, a definitive consensus on optimal treatment strategies for NORSE patients is lacking. However, prompt intervention aimed at halting seizure activity, initiating continuous anesthetic infusions, and exploring immunotherapeutic approaches are recognized as critical steps in mitigating morbidity and improving survival rates in NORSE. This article delves into the complexities of NORSE diagnosis, exploring evaluation methodologies, available treatment modalities, and emphasizing the collaborative role of the healthcare team in effectively managing this critical condition.

Understanding the Landscape of Status Epilepticus and NORSE

The International League Against Epilepsy (ILAE) defines status epilepticus (SE) as a state of ongoing seizure activity, either clinically apparent or detectable via electroencephalography, or recurrent seizures without regaining baseline neurological function for a duration of 5 minutes or longer.[1] When seizure activity persists despite the administration of adequate doses of a benzodiazepine followed by a second-line intravenous (IV) antiepileptic drug, the condition is classified as refractory status epilepticus (RSE).[2] In cases where RSE continues or recurs even after 24 hours or more of IV anesthetic agent administration, including recurrences upon withdrawal of these agents, it is termed super-refractory status epilepticus (SRSE).[3] RSE is observed in a significant portion of SE cases, with reported occurrences ranging from 9% to 43% and an in-hospital mortality rate between 15% and 33%.[4, 5] Progression to SRSE occurs in approximately 4% to 12% of SE patients, dramatically increasing in-hospital mortality to as high as 40% to 54%.[6, 7, 8]

The term new-onset refractory status epilepticus (NORSE) emerged in 2005, introduced by Wilder-Smith and colleagues to describe SRSE cases in individuals without a prior history of epilepsy and lacking an identifiable cause after initial diagnostic evaluations.[9] By 2018, international experts established a consensus definition for NORSE and related conditions, aiming to standardize terminology for better clinical management and research. NORSE is now defined as “a clinical syndrome, not a specific disease, in a patient without pre-existing epilepsy or other relevant neurological disorder, presenting with new-onset refractory status epilepticus without a clear acute symptomatic cause.” Febrile infection-related epilepsy syndrome (FIRES), a closely related entity, is considered a NORSE subset associated with a preceding febrile infection, where fever onset occurs between 2 weeks and 24 hours before RSE onset.[10] Notably, fever may or may not be present before the onset of RSE in NORSE patients, distinguishing it from the defining febrile element in FIRES.

Etiological Factors in NORSE Diagnosis

Identifying the underlying cause of NORSE is crucial for targeted treatment strategies, yet it remains elusive in a significant number of cases. A comprehensive retrospective study analyzing 130 NORSE cases found that an etiology could not be determined in 52% of patients, categorizing these as “cryptogenic NORSE” or “NORSE of unknown etiology.”[11] Among cases where a cause was identified, autoimmune and paraneoplastic encephalitis were the most frequent, followed by infections.

Non-Paraneoplastic Autoimmune Encephalitis: This category includes autoimmune disorders where the body’s immune system mistakenly attacks brain cells, leading to encephalitis and seizures. Commonly detected antibodies include anti-NMDA (N-methyl-D-aspartate) receptor, anti-VGKC (voltage-gated potassium complex) antibodies like anti-LGI1 and anti-Caspr2. Less frequent but notable antibodies are Anti-GABA, Anti-glycine, Anti-GAD65, Anti-striational, and those associated with steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT).
Paraneoplastic Autoimmune Encephalitis: In these instances, the encephalitis is triggered by the body’s immune response to cancer. Anti-NMDA receptor-associated encephalitis is the most prevalent in this group, particularly affecting young women, with about 50% of cases linked to germ cell tumors such as ovarian teratomas. Other associated antibodies include anti-Hu (linked to small cell lung cancer and neuroblastoma), anti-CRMP5 (small cell lung cancer), anti-Ma2 (germ cell tumor of the testis), anti-amphiphysin (breast cancer, small cell lung cancer), and anti-VGCC (small cell lung cancer, thymoma).
Infections: Viral infections are significant triggers for NORSE. Herpes simplex virus type 1 (HSV-1) is the most commonly identified infectious agent. Other implicated viruses include Enterovirus, Epstein Barr virus (EBV), Varicella zoster virus (VZV), Cytomegalovirus (CMV), as well as bacterial agents like Bartonella henselae and Mycoplasma pneumoniae, and arboviruses such as West Nile virus.
Genetic Conditions: Rare genetic conditions, including mitochondrial disorders like POLG mutations, have also been associated with NORSE, highlighting the complex and multifaceted nature of its etiology.[12, 13]

Epidemiology and Risk Factors in NORSE Diagnosis

NORSE and FIRES are considered rare neurological conditions, with epidemiological data primarily derived from case series. They have been reported across all age groups, from previously healthy young adults and school-aged children to older adults aged 60 and above. Interestingly, adult females appear to be more affected than males, while in pediatric cases, boys are more frequently affected than girls.[11, 14]

The absence of a consistent NORSE definition in the past may have led to underdiagnosis, making it difficult to accurately estimate its incidence. Current estimates suggest that NORSE accounts for approximately 20% of all RSE cases.[15] Both NORSE and FIRES show no known ethnic or racial predilections and can occur in any population group.[14]

Pathophysiological Mechanisms Underlying NORSE Diagnosis

An immune-mediated inflammatory process is strongly implicated in the pathophysiology of FIRES.[16] Research by Sakuma et al. revealed a significant surge in proinflammatory cytokines and chemokines within the cerebrospinal fluid (CSF) of children with FIRES compared to those with other inflammatory neurological conditions.[17] This inflammatory cascade, potentially triggered by the activation of T cells, glial cells, and blood-brain barrier cells, may contribute to epileptogenesis.[18] However, other mechanisms, such as mitochondrial dysfunction or synaptic plasticity alterations, may also play crucial roles in seizure propagation in NORSE and FIRES.[15]

Recent hypotheses suggest a genetic predisposition to developing FIRES or NORSE, linked to allelic variations in human leukocyte antigen subtypes and the IL1 pathway.[19, 20] Given that FIRES is considered a subtype of NORSE, a similar autoimmune inflammatory mechanism is considered a likely underlying factor in NORSE. Further research is essential to fully elucidate the precise pathophysiological mechanisms in both NORSE and FIRES.

Clinical Presentation: History and Physical Examination in NORSE Diagnosis

NORSE and FIRES share clinical similarities and can manifest in previously healthy individuals. Prodromal symptoms are common, occurring in about 60% of NORSE patients, typically 1 to 14 days before seizure onset.[11] These early symptoms can include confusion, fatigue, headache, mild fever, behavioral changes, mild gastroenteritis, upper respiratory infections, and memory issues.[11, 21, 22] While fever is a defining feature of FIRES, it is absent in up to one-third of NORSE cases.[11] Notably, fever may resolve in approximately 50% of patients before the first seizure episode.[14]

Initially, seizures are often brief and infrequent, gradually increasing in frequency over hours to days, eventually progressing to status epilepticus. In severe cases, children can experience over 100 seizures daily. Focal motor seizures are the most common type, which may generalize into bilateral tonic-clonic seizures. Other seizure types observed include myoclonic seizures affecting facial muscles and focal seizures with impaired awareness. The pre-SE seizure phase can last from days to weeks before evolving into refractory status epilepticus.[9, 14, 23, 24, 25]

Once SE develops and becomes refractory to initial treatments, intensive care unit (ICU) admission is necessary for advanced management. Cryptogenic NORSE cases often exhibit similar clinical features and disease progression to autoimmune encephalitis-related NORSE but may present with longer seizure duration, greater severity, increased respiratory involvement requiring mechanical ventilation, and potentially worse outcomes.[11, 22]

Diagnostic Evaluation: Unraveling NORSE Diagnosis

Effective NORSE diagnosis hinges on a systematic and comprehensive evaluation to identify potential underlying etiologies and guide appropriate management. For patients presenting with status epilepticus, initial laboratory assessments are essential, including a complete blood count, comprehensive metabolic panel, creatine kinase, C-reactive protein, erythrocyte sedimentation rate, and levels of calcium, magnesium, and phosphorus. Urine and blood toxicology screens for substances like alcohol, amphetamines, cocaine, opioids, benzodiazepines, heavy metals, synthetic cannabinoids, and bath salts should be performed upon admission.[26] If RSE develops and the initial workup is non-diagnostic, further investigations focused on autoimmune and less common infectious causes are warranted.

Laboratory Investigations in NORSE Diagnosis

Lumbar puncture (LP) is a critical step if the initial evaluation fails to reveal a clear etiology. Routine CSF analysis should include cell count, protein and glucose levels, lactate, inflammatory markers (oligoclonal bands and IgG index), Gram stain, bacterial culture, and cytology. Additional CSF studies may include fungal stains and cultures for M. tuberculosis, polymerase chain reaction (PCR) for HSV-1/2, EBV, VZV, HIV-1/2, Chlamydia pneumoniae, Mycoplasma pneumoniae, and VDRL in select cases where the cause remains unknown.[26] Mild CSF pleocytosis (≤ 10 cells/μl) with elevated protein and normal glucose is observed in approximately two-thirds of NORSE cases, with no significant differences in CSF findings between cryptogenic and etiology-identified cases.[11] HSV PCR is highly sensitive and specific for HSV meningitis/encephalitis, but can be negative if LP is performed within 24 hours of neurological symptom onset.

Both CSF and serum should be tested for autoimmune antibodies, including 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 including ANA, ANCA, Anti-Ro, Anti-La, antithyroid antibodies, and anti-Scl-70 should be considered. Viral serologies for HSV-1/2, VZV, EBV, enterovirus, and HIV-1/2 are recommended for all NORSE patients.[26] In immunocompromised individuals, serologies for IgG Cryptococcus species, IgM and IgG Histoplasma capsulatum, and IgG Toxoplasma gondii should be added. Stool samples should be tested for adenovirus and enterovirus. To screen for underlying malignancy in suspected paraneoplastic NORSE, scrotal ultrasound, pelvic MRI, chest/abdomen/pelvis CT scans, and whole-body PET-CT are recommended.

Neuroimaging in NORSE Diagnosis

Brain MRI with contrast, including venography and angiography, is essential for all NORSE and FIRES patients to assess for structural or focal brain abnormalities. MRI abnormalities are detected in approximately 60% of NORSE cases.[11] The most common findings are hyperintensities on T2/FLAIR sequences in limbic and neocortical structures, often bilaterally. Other regions like the claustrum, basal ganglia/thalami, and peri-insular cortex may also show abnormal T2/FLAIR hyperintensity.[27, 28]

Electroencephalography (EEG) in NORSE Diagnosis

Continuous EEG monitoring (cEEG) is mandatory to characterize seizure type and frequency, rule out non-convulsive status epilepticus (NCSE), and monitor treatment response. Neurocritical Care Society guidelines recommend initiating cEEG within one hour of SE onset for all patients.[2] EEG patterns in NORSE can include periodic or epileptiform discharges, commonly lateralized or focal, generalized periodic discharges, and multifocal discharges.[14, 27]

Focal onset seizures are frequently observed, followed by bilateral independent, generalized, and multifocal seizures. Seizures typically start as brief, infrequent events with focal fast beta activity, progressing to SE characterized by rhythmic spike and wave complexes or beta-delta activity.[29] In some cases, EEG patterns can suggest specific diagnoses. For instance, approximately one-third of anti-NMDA receptor encephalitis cases show an “extreme-delta brush” pattern, featuring beta bursts superimposed on delta waves.[30]

Therapeutic Strategies: Management and Treatment of NORSE

Status epilepticus represents a neurological emergency requiring immediate seizure cessation to prevent permanent neurological damage. Initial management should adhere to established guidelines.[2, 31, 32]

Cardiocirculatory Stabilization and Airway Management: Patient stabilization begins with assessing and supporting cardiocirculatory function. Airway patency and safety are paramount, ensuring adequate oxygenation through supplemental oxygen or, if necessary, rapid sequence intubation and mechanical ventilation.
Benzodiazepines: Intravenous (IV) benzodiazepines are the first-line agents for emergent seizure termination. Prehospital benzodiazepine administration has shown efficacy in terminating seizures in 43% to 59% of SE cases, reducing the need for respiratory support upon hospital arrival and subsequent ICU admissions. Intramuscular (IM) midazolam has demonstrated superiority over IV lorazepam in patients without IV access.[33] However, IM midazolam, IV lorazepam, IV diazepam, and IV phenobarbital are all recommended as initial options for seizures lasting 5 minutes or longer, with comparable efficacy.[31]
Acyclovir: In cases with suspected HSV encephalitis (acute febrile encephalopathy, new-onset seizures, asymmetric medial temporal lobe involvement, and lymphocytic pleocytosis with red blood cells in CSF), IV acyclovir should be initiated early, pending CSF HSV-PCR results. Early acyclovir administration has been shown to reduce mortality and morbidity in HSV encephalitis.
Second-Line Antiepileptic Drugs: For benzodiazepine-refractory SE, a second-line antiepileptic agent should be promptly administered at appropriate doses. Randomized controlled trials have demonstrated similar safety and efficacy for IV levetiracetam, IV fosphenytoin, and IV sodium valproate in established SE.[34] It’s important to note that the effectiveness of each subsequent antiepileptic drug diminishes after the first agent.
Additional Antiepileptic Agents: If seizures persist after a second-line agent, another antiepileptic drug should be tried before resorting to IV anesthetic agents. IV phenytoin/fosphenytoin, phenobarbital, valproate, levetiracetam, and lacosamide have all been shown effective in treating established SE, with no clear preference among them.[32] These agents can be used individually or in combination.

For patients progressing to refractory SE (by definition, failing first and second-line therapies), continuous IV anesthetic agents are necessary to achieve seizure control.

Continuous IV Anesthetic Infusion: Current guidelines recommend continuous IV anesthetic infusions to induce seizure suppression or burst suppression coma for 24-48 hours before attempting to wean.[2] Commonly used agents include:
- Midazolam: Loading dose of 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: Loading dose of 0.5-4 mg/kg followed by maintenance infusion at 0.3 to 5 mg/kg/hr.

IV midazolam and propofol are often preferred over longer-acting agents like pentobarbital due to the association of long-acting agents with prolonged mechanical ventilation and cardiovascular complications.[35, 36] However, high doses and prolonged propofol use can lead to propofol infusion syndrome, increasing mortality and complications compared to midazolam and ketamine.

Given the refractory nature of NORSE/FIRES, and their often poor response to antiepileptic medications, continuous IV anesthetic agents should be initiated promptly. Approximately one-third of NORSE patients require multiple anesthetic agents, often for extended periods, to achieve seizure suppression.[11, 16] Since no specific therapy exists for NORSE/FIRES, immunotherapy is recommended early in the course, given that autoimmune/paraneoplastic etiologies are implicated in nearly half of cases.[15, 37] First-line immunotherapy includes steroids, IV immunoglobulins, and plasmapheresis. Second-line options include tacrolimus, rituximab, cyclophosphamide, and anakinra. Immunotherapy has shown greater effectiveness in improving outcomes and seizure control in adults compared to children.[22, 38] Current immunotherapy recommendations are largely based on expert opinion and case series data, as randomized controlled trials are lacking.

Immunotherapy Regimens:
- IV methylprednisolone: 1 gm/day for 3 to 5 days, ideally started within the first week of RSE onset if no clear etiology is identified and NORSE suspicion is high.
- Alternatives: IV immunoglobulin (0.4 gm/day for 3 to 5 days) or plasmapheresis (3 to 5 sessions on alternate days) may be considered as first-line treatments based on patient characteristics and clinical context.[15, 39]
- Second-line immunotherapy (for failure to wean anesthetics or prolonged RSE): 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 human Interleukin-1 receptor antagonist, has shown promise in reducing seizure frequency and achieving remission in case reports.[40, 41]
Other Therapeutic Options: Hypothermia, cannabidiol, and ketogenic diet are less studied options that have been attempted in NORSE patients with variable results and require further validation.[42, 43, 44]

Differential Diagnosis in NORSE

While the etiology of NORSE often remains unknown, autoimmune/paraneoplastic encephalitis is the most frequently identified cause.[11, 45] Therefore, a detailed history and clinical examination are crucial, as specific clinical features can suggest an underlying etiology, potentially leading to early immunotherapy and influencing outcomes.

Prognosis and Long-Term Outcomes in NORSE

NORSE and FIRES are severe neurological conditions associated with significant long-term morbidity and mortality. Many patients become unresponsive to multiple anesthetic agents and progress to SRSE. Mortality rates are reported as 12% in children and 16% to 27% in adults.[11, 14, 50, 51]

Most survivors develop multidrug-resistant epilepsy and experience significant cognitive and functional impairments. Factors associated with worse outcomes include prolonged ICU stay, medical complications, duration of barbiturate-induced coma, and the use of multiple anesthetic agents in both children and adults.[11, 13, 14, 25, 52]

Complications of NORSE and its Management

Prolonged use of multiple IV anesthetic agents in NORSE management increases the risk of various complications, including cardiovascular (hypotension, arrhythmias), gastrointestinal (liver dysfunction, ileus, gastric ulcers), infectious (pneumonia, UTI), hematological (anemia, thrombocytopenia, pulmonary embolism), and electrolyte abnormalities. The severity and risk of these complications correlate with the duration of RSE and the number of anesthetic agents used.[11]

Consultations in NORSE Management

Effective NORSE management requires a multidisciplinary approach involving:

Neurologist
Anesthesiologist
Intensivist

Deterrence and Patient Education for NORSE

NORSE is a distinct clinical entity with high mortality and long-term morbidity. Current understanding of its etiology, diagnosis, and treatment is based largely on expert opinion and retrospective case series. Comprehensive support and education should be provided to families regarding potential neurological sequelae in NORSE survivors, including refractory epilepsy and cognitive/functional impairments.

Raising awareness about NORSE and its management among medical professionals is crucial. Educational initiatives at institutional and national levels can improve early recognition and management, ultimately enhancing patient outcomes. NORSE is often underrecognized outside specialized academic centers, highlighting the need for improved professional education.

Enhancing Healthcare Team Outcomes in NORSE

Managing NORSE effectively necessitates a collaborative, interprofessional healthcare team approach. Early treatment initiation, including aggressive immunotherapy, is vital for reducing morbidity and mortality. Open and clear communication with the patient’s family is essential throughout the disease course, addressing the diagnostic uncertainty, treatment options, and potential outcomes. Palliative care services should be involved early to support families and facilitate discussions about care goals. Encouraging families to participate in national NORSE registries, such as the NORSE Institute registry, is crucial for advancing clinical research, understanding NORSE causes, identifying optimal treatments, and improving patient outcomes.

An interprofessional team comprising clinicians, specialists, nursing staff, and pharmacists, working collaboratively with open communication, is essential to achieve the best possible care standards and outcomes for patients with NORSE.

Review Questions

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References

(Note: References are present in the original article and are included in this rewritten version as per instructions.)

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Disclosure: Kunal Bhatia declares no relevant financial relationships with ineligible companies.

Disclosure: Orlando De Jesus declares no relevant financial relationships with ineligible companies.