New Onset Refractory Status Epilepticus (NORSE)

Department of Emergency Medicine and Critical Care, Kauvery Hospital, Trichy-Cantonment, India

Background

Status epilepticus is a life-threatening emergency, especially if refractory. While immediate treatment of seizures is paramount, it is also important to establish the cause. Up to 20% of patients with refractory status epilepticus have a negative initial workup, these represent up to 60% of de novo refractory status epilepticus and most are previously healthy young adults and children. Such cases have been variously referred to as having new onset refractory status epilepticus (NORSE) or idiopathic catastrophic epileptic encephalopathy. They have also been classified as ‘possible encephalitis’, since some have a preceding febrile illness and the diagnosis of autoimmune and infective encephalitis does not require an identified pathogen or antibody. NORSE is thought to be rather rare. Here we discuss a patient presenting with NORSE.

Case Presentation

A 15-years-old boy was brought to our ER with an alleged history of RTA – a fall from a bike, following a seizure spell. He was initially managed at an outside hospital and was intubated; CT brain taken at the outside hospital was normal.

He was referred to us for further management as the patient continued to have recurrent seizures without regaining consciousness for a period of 2 h until he arrived at our ER.

His GCS was E1V1M2 on arrival. He was managed with anti-seizure medications as a bolus and continued as iv infusions, along with iv fluids. He was sedated paralyzed and continued with mechanical ventilation. MRI Brain plain and contrast with whole spine screening showed T2/flair Hyperintensities in B/L medial temporal lobe, thalamus and periventricular cortex, B/L posterior parietal cortex with diffusion restriction and mass effect suggestive of viral encephalitis.

His initial labs showed leucocytosis (WBC: 29,800), normal renal parameters, and negative COVID RT-PCR.

He was shifted to the neuro intensive care unit for further management. Fever spikes were noted following admission.

CSF analysis showed lymphocytic pleocytosis, protein, 51.3; glucose, 73; WBC, 25; DC-polymorphs, 25%; Lympho-75%.

Total RBC: 3500.

CSF bacterial, viral, and autoimmune workups were all negative, JE workup was also negative; another systemic workup was negative.

EEG has done on day 8 was suggestive of encephalopathy, so new onset refractory status epilepticus secondary to encephalopathy or MISC was considered.

Features against MISC were fever presentation after the illness started which is rare in MISC, and the not significantly high Ferritin and COVID IgG levels.

He was empirically treated with anti-meningitic antimicrobials, multiple anti-epileptic drugs, and other supportive medications.

He was pulsed with steroid injection methylprednisolone 1 g OD for 5 days. Seizures slowly settled; AED infusion Midazolam was tapered and stopped on day 10 of admission and put on enteral route.

Tracheostomy was done to facilitate weaning and was gradually weaned off from NIV.

He showed very minimal improvement in his sensorium; his repeat MRI showed encephalitic changes.

He was discharged on tracheostomy, with nursing and physiotherapy care after 2 months of hospitalisation. On discharge, his GCS was E4 Vt M5.

Discussion

NORSE

New onset refractory status epilepticus is a condition, not a specific diagnosis, without a clear, acute or active, structural, toxic, or metabolic cause in a healthy patient without active epilepsy.

FIRES

FIRES is a subcategory of NORSE that requires a prior febrile infection, with fever starting between 2 weeks and 24 h prior to the onset of refractory status epilepticus, with or without fever at the onset of status epilepticus.

Status Epilepticus (SE)

It is defined as a prolonged seizure (>5 min if convulsive, >10 min if not) or a cluster of seizures without recovery in between. Status epilepticus that persists despite administration of at least two appropriately selected and dosed parenteral medications is termed Refractory status epilepticus (RSE). Most of the causes of RSE can be identified within 2-3 days of presentation, as it is commonly due to stroke or serious acute medical illness. In half of the cases, a cause is ultimately identified, most often autoimmune or paraneoplastic, followed by infections (mostly viral, although mycoplasma is not rare). In the remaining half or more, no cause is identified despite an extensive work-up. These cases are referred to as cryptogenic NORSE or NORSE of unknown etiology.

Incidence of NORSE

In the US, NORSE occurs in 7% of SE in 1/100000/year and it can occur at any age but most commonly affect young adults and school age children with a second peak occurring around age 65, females are more commonly affected than males

Causes of NORSE

The most common causes of NORSE are autoimmune or paraneoplastic disorders including anti-neuronal antibodies (anti-NMDA receptor), voltage-gated potassium channel complex, followed by viral encephalitis. These data are still very limited and further studies are required to fully explore the hypothesis of a genetic predisposition. These are referred to as cryptogenic NORSE or NORSE of unknown origin.

Symptoms and signs

The course of the syndrome begins as a mild fever, malaise, fatigue, and upper respiratory tract or gastrointestinal infection. Two third of patients of NORSE sometimes hallucinate, apathy or agitation, and amnesia. Symptoms of meningeal inflammation such as headache and photophobia are uncommon.

Course

It starts as a complex partial seizure or grand mal seizure, intermittently and becomes increasingly more frequent, and the patient’s consciousness declines to status epilepticus. This acute phase lasts days to several weeks and may even last for several months. The mortality rate is up to 30% and is higher in adults than children, Once SE was controlled with antiepileptic drugs (AED) and continuous anaesthetic agents, they are subsequently discontinued once the seizure stops. The patients progressively regain consciousness and can be discharged from the hospital. But, half of the patients are left with long-time cognitive functional disorders and may have epilepsy lifelong, requiring AEDs.

Clinical testing and work up

The clinical workup should aim at identifying treatable causes of refractory SE. Brain CT and MRI scans are required to rule out stroke and other conditions with a characteristic appearance on imaging. In some cases of cryptogenic NORSE, brain MRI can reveal leptomeningeal enhancement, bilateral claustrum hyperintensity, or progressive mesial temporal lobe atrophy. Cerebrospinal fluid studies and blood tests should be performed to rule out infectious and inflammatory and autoimmune conditions. Kidney and liver function test, serum electrolytes to rule out metabolic conditions. Electroencephalography (EEG) and continuous EEG monitoring are usually required to detect and monitor and treat seizures.

Treatment

The treatment of SE initially consists of benzodiazepines (Lorazepam, Diazepam, or Clonazepam), followed by standard anti-seizure medication, as in most cases of SE. preference is given to drugs that are available in IV form (valproic acid, phenytoin, fosphenytoin, levetiracetam, Phenobarbital, llacosamide, and more recently brivaracetam).

The two options are either to try additional anti-seizure medications or to induce pharmacological coma with an anaesthetic drug. In the former case medications available in an IV formulation are often favoured but others (e.g. topiramate, pregabalin, clobazam, perampanel) are sometimes used later as add-on therapy via nasogastric tube.

Anesthetic agents utilized most commonly include infusions of midazolam, propofol, and barbiturates (pentobarbital in the USA and thiopental in Europe). Of the three, midazolam likely has the best safety profile but may be associated with a higher risk of recurrent seizures. Barbiturates are associated with more prolonged coma and the need for mechanical ventilation, with a higher rate of complications. propofol carries a small risk of propofol infusion-related syndrome (PRIS), a potentially lethal syndrome of metabolic acidosis, kidney and heart failure.

When an underlying cause is identified it should be appropriately treated.

There is currently no known specific therapy for cryptogenic NORSE and studies are urgently needed to determine the best treatment options.

Given the putative causal role of inflammation in cryptogenic NORSE, it is common to use approaches that modulate the immune system. These options include IV steroids, IV immunoglobulins, plasma exchange therapy (plasmapheresis), and some monoclonal antibodies against inflammatory cells (e.g. Rituximab). The efficacy of these strategies is suggested by small case series, though never investigated in controlled trials. Emerging therapies, such as anakinra (recombinant Il-1 receptor antagonist), tocilizumab (Il-6 receptor blocking humanized antibody), and cannabinoids have been used in NORSE, in case reports and small case series. The ketogenic diet, a therapy for chronic drug-resistant epilepsy, has shown some efficacy in both paediatric and more recently adult cases.

Conclusion

Status epilepticus is a medical emergency associated with significant mortality and morbidity. NORSE and FIRES are rare challenging presentation, comprehensive management includes early initiation of treatment, to prevent resistance to anti epileptics and extensive evaluation of etiology to treat the treatable causes, which includes autoimmune and paraneoplastic or metabolic causes these patients need to be treated in intensive care to continue second line drugs with ventilator support and EEG monitoring to prevent secondary brain insults.

New Onset Refractory Status Epilepticus (NORSE)