What is the diagnosis for New-Onset Refractory Status Epilepticus (NORSE) with negative autoimmune workup?

From the Guidelines

For NORSE (New-Onset Refractory Status Epilepticus) with negative autoimmune workup, I recommend an aggressive treatment approach starting with first-line antiseizure medications (ASMs) such as levetiracetam (60 mg/kg loading dose, then 30-60 mg/kg/day), valproate (40 mg/kg loading dose, then 30-60 mg/kg/day), or lacosamide (200-400 mg loading dose, then 200-400 mg/day), as suggested by recent guidelines 1. If seizures persist, proceed to anesthetic agents like midazolam (0.2 mg/kg loading dose, then 0.05-2 mg/kg/hr), propofol (1-5 mg/kg/hr), or ketamine (1-5 mg/kg/hr). Despite negative autoimmune panels, empiric immunotherapy should be considered, including methylprednisolone (1 g/day for 3-5 days), followed by IVIG (2 g/kg over 2-5 days) and/or plasmapheresis (5-7 exchanges), as supported by best practice recommendations for autoimmune encephalitis diagnosis and acute management 1. Rituximab (375 mg/m² weekly for 4 weeks) or cyclophosphamide may be needed for refractory cases. Continuous EEG monitoring is essential to guide therapy, as EEG can provide evidence of focal or multifocal brain abnormality when MRI is negative, which would support encephalitis over metabolic encephalopathy 1. The rationale for immunotherapy despite negative workup is that autoimmune encephalitis can present with normal initial testing, and early immunomodulation may improve outcomes. Cryptogenic NORSE often has an underlying autoimmune etiology that standard testing might miss. A ketogenic diet (4:1 ratio) may provide additional benefit as an adjunctive therapy in these challenging cases. Key considerations in the diagnosis and management of NORSE include:

• Evaluating the likelihood of autoimmune encephalitis relative to the patient’s clinical picture
• Performing brain MRI and/or EEG to look for focal or multifocal brain abnormality
• Considering brain FDG-PET when there is a high clinical suspicion of autoimmune encephalitis and other paraclinical studies are uninformative
• Starting acute immunotherapy with high dose corticosteroids, or IVIG or PLEX if steroids are not preferred or contraindicated, as recommended by recent guidelines 1. It is crucial to prioritize the patient's morbidity, mortality, and quality of life when making treatment decisions, and to consider the potential benefits and risks of each treatment option. In the absence of strong evidence, a firm decision on the side of caution is necessary, prioritizing aggressive treatment and empiric immunotherapy to improve outcomes in patients with NORSE and negative autoimmune workup.

From the Research

Diagnosis of New-Onset Refractory Status Epilepticus (NORSE) with Negative Autoimmune Workup

• The diagnosis of NORSE is based on the occurrence of refractory status epilepticus (RSE) in a patient without active epilepsy, and without a clear acute or active structural, toxic or metabolic cause 2.
• A standardized diagnostic algorithm is provided, and autoimmune encephalitis is the most frequent identified cause 2.
• In the absence of specific diagnosis, immunotherapy could be tried in addition to antiepileptic treatment 2, 3, 4.
• Histopathological findings have rarely been described in NORSE, but evidence of vasculitis, necrotizing vasculopathy, and lymphocytic infiltration in limbic structures have been reported 5.

Clinical Features and Investigations

• NORSE mainly affects school-age children and young adults, and a prodromal phase with flu-like symptoms precedes the SE onset in two thirds of cases 2.
• Status epilepticus usually starts with repeated focal seizures with secondary bilateralization, and most cases evolve to super RSE (SRSE) with unfavorable outcome 2.
• No specific imaging or laboratory abnormalities have been identified so far that allows an early diagnosis, and half of adult cases remain of unknown etiology 2.

Treatment and Prognosis

• Early immunotherapy has been associated with good outcomes in NORSE, and multicentre collaboration is required to establish the diagnostic criteria and appropriate management of patients presenting with NORSE 3.
• A pooled analysis of available case series showed a statistically significant effect of immunotherapy, with favorable outcomes in 42% of the patients who received any immunotherapy compared with 20% in those who did not 4.
• The use of immunotherapy in NORSE is currently based on Class IV evidence, and prospective multicenter studies are necessary to assess the true efficacy of immunotherapy in NORSE 4.