NORD gratefully acknowledges Nicolas Gaspard, MD, PhD, Neurology Department and Comprehensive Epilepsy Center, Université Libre de Bruxelles – Hôpital Erasme, Bruxelles, Belgium and Lawrence J. Hirsch, MD, Neurology Department and Comprehensive Epilepsy Center, Yale University School of Medicine, for assistance in the preparation of this report.
Definitions and Summary
New-onset refractory status epilepticus (NORSE) is defined as a condition, not a specific diagnosis, with new onset of refractory status epilepticus without a clear acute or active structural, toxic or metabolic cause in a patient without active epilepsy. Status epilepticus (SE) is a condition in which patients suddenly experience a prolonged seizure or a flurry of very frequent seizures. Status epilepticus that persists despite at least 2 standard anticonvulsant medications is termed refractory status epilepticus (RSE). Most of the common causes of RSE can be identified within 24-72 hours of presentation. Febrile Infection-Related Epilepsy Syndrome (FIRES) is a subcategory of NORSE that requires a prior febrile infection starting between 2 weeks and 24 hours prior to onset of refractory status epilepticus, with or without fever at onset of status epilepticus.
In up to half of the cases of NORSE, a possible or probable cause is ultimately found, most often autoimmune or paraneoplastic encephalitis, with infectious causes less common. In the remaining half, no cause is identified despite an extensive work-up. These cases are referred to as cryptogenic NORSE or NORSE of unknown etiology. In cryptogenic cases, and possibly in other cases, seizures are thought to be caused or exacerbated by an excess of pro-inflammatory molecules in the brain, perhaps triggered by a typical minor infection in a susceptible individual, although no clear cause—or even risk factor--has been demonstrated. Affected individuals are most often treated for weeks in an intensive care unit because they require prolonged anesthesia with coma-inducing drugs to control their seizures. NORSE carries a high rate of complications and mortality, but a significant proportion of patients do eventually recover. Epilepsy (a life-long predisposition to unprovoked seizures), cognitive and psychological issues are common among survivors although a minority of them eventually return to a normal lifestyle.
Status epilepticus (SE) is defined as a prolonged seizure or a cluster of seizures without recovery in between. Status epilepticus that persists despite administration of at least 2 appropriately selected and dosed parenteral medications including a benzodiazepine is termed refractory status epilepticus (RSE). Most of the causes of RSE can be identified within 24-72 hours of presentation, as it commonly due to an obvious acute brain injury (stroke, trauma, infection, etc.) or serious acute medical illness. It may also occur in people with a chronic seizure disorder. In a substantial minority of cases, however, RSE strikes out of the blue without a clear acute or active structural, toxic or metabolic cause, in a healthy patient without active epilepsy. These cases are known as new-onset refractory status epilepticus, or NORSE. 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, however, no cause is identified despite an extensive work-up. These cases are referred to as cryptogenic NORSE or NORSE of unknown etiology.
Febrile Infection-Related Epilepsy Syndrome (FIRES) is a subtype of NORSE preceded by a febrile infection, with fever starting between 2 weeks and 24 hours prior to onset of refractory status epilepticus. Fever may or may not be present at the time of onset of status epilepticus. The syndrome has been mostly described in school-aged children but occurs in adults as well. Previously, the term FIRES was only used in the pediatric population while NORSE was mainly used in adults. According to recently proposed definitions, FIRES is now considered a subtype of NORSE and both conditions now have no age limits. Children can have NORSE and adults can have FIRES. Everyone with FIRES also has NORSE, by definition. The distinguishing feature of FIRES is the preceding fever. Although the term NORSE includes the subcategory of FIRES, both terms are used here because the recent integration of the two disorders is still being disseminated in the literature and public.
In two-thirds of NORSE cases, the course of the syndrome begins with a mild febrile illness, associated with malaise, fatigue and symptoms of upper respiratory tract or gastro-intestinal tract infection. Symptoms of meningeal inflammation, such as headache and photophobia, are uncommon. Behavioral and cognitive symptoms, such as apathy or agitation, amnesia, and sometimes hallucinations can be observed. The presence of hallucinations may suggest an autoimmune etiology, especially anti-NMDA receptor encephalitis.
This initial phase lasts a few days to a week or two and is followed by the progressive onset of seizures. Both focal seizures with impaired awareness (previously known as complex partial seizures, and typically described as staring episodes) and bilateral tonic-clonic seizures (often referred to as “grand mal” in non-medical terms) can occur. They are initially intermittent but become increasingly more frequent and the patient’s consciousness declines as he/she transitions into status epilepticus.
This acute phase usually lasts days to several weeks and in some cases can even last several months. During this phase, the patient remains comatose due to the effect of the seizures and anesthetic treatment and can develop any of the complications associated with prolonged unconsciousness and mechanical ventilation. The mortality rate reaches 30% and is higher in adults.
Once SE is controlled and anesthetic treatment is discontinued, the patients progressively regain consciousness and can be discharged from the ICU and the hospital. At least one half of the surviving patients are left with long-term cognitive and functional disability and many will have epilepsy, requiring prolonged (or lifelong) treatment with anticonvulsants. A small minority, however, will be able to resume their previously normal lifestyle.
The infantile hemiconvulsion‐hemiplegia and epilepsy syndrome (IHHE) is a specific syndrome that also qualifies as NORSE. IHHE occurs in a patient <2 years old, presenting as NORSE with unilateral motor seizures, high‐grade fever persisting at the time of onset of refractory status epilepticus, and unilaterally abnormal acute imaging, followed by hemiparesis lasting at least 24 hours, and excluding definite infectious encephalitis.
The most common causes of NORSE and FIRES are autoimmune/paraneoplastic disorders, such as encephalitis associated with anti-neuronal antibodies (anti-NMDA receptor, anti-voltage-gated potassium channel complex, etc.), followed by viral encephalitis. Genetic epilepsy syndromes associated with sensitivity to fever do not represent a major cause of NORSE and FIRES, as suggested by one study in children that did not find mutations in the SCN1A (Dravet syndrome), PCDH19 or POLG1 (Alpers syndrome) genes. The data available so far, however, are very limited and further studies are required to fully explore the hypothesis of a genetic predisposition.
As the term “cryptogenic” implies, the cause of cryptogenic NORSE and FIRES is currently unknown. The frequent occurrence of a mild febrile illness in the days preceding seizures and the presence of inflammatory markers in the cerebrospinal fluid (CSF) (though usually only mild) of patients with NORSE and FIRES suggest that it might be due to an excess of pro-inflammatory molecules in the brain, perhaps triggered by a viral infection. This hypothesis is supported by experimental evidence that inflammatory molecules are powerful triggers of seizures in animals and by the fact that well established autoimmune disorders affecting the brain can lead to refractory SE. Furthermore, there is some evidence that immune-suppressing medications may be helpful, at least in some cases (more clearly shown in adults). Finally, it is possible that a direct infection of the brain by an undetected and/or unknown pathogen can be responsible for some cases of NORSE and FIRES.
NORSE and FIRES can occur at any age but preferentially affect young adults and school-age children, with a second peak occurring around age 65. In adults, females are more likely to be affected than males, but probably not in children. The idiopathic hemiconvulsion-hemiplegia and epilepsy syndrome (IHHE) is a related syndrome in infants, presenting as NORSE with unilateral motor seizures, high-grade fever, and unilaterally abnormal acute imaging, followed by hemiparesis.
As NORSE and FIRES are not always clearly reported per se in series of patients with SE, but often as either “unknown cause” or “possible brain infection”, it is difficult to provide an accurate estimate of their incidence. However, it is likely that it is responsible for at least 10 to 20% of cases of refractory SE. This proportion can reach 50 to 70% when considering only cases of SE that persist or recur despite appropriate anesthetic treatment; or recur after withdrawal of anesthesia (known as “super-refractory” SE) and/or that persists for at least 7 days (known as “prolonged” RSE).
In the United States, SE occurs in 14 individuals/100,000 per year. Refractory SE represents approximately a third of all SE cases and NORSE represents approximately 20% of all RSE cases. Thus it can be estimated that ~3200 cases of NORSE, including FIRES, occur each year in the United States.
The diagnosis of NORSE or FIRES, as a clinical presentation, is usually made on clinical grounds in patients who developed refractory SE once obvious causes of SE have been excluded. The diagnosis of cryptogenic NORSE or FIRES can only be made once uncommon causes of SE have been carefully excluded (see Clinical Testing and Work-Up section below). As there is currently no known cause to cryptogenic NORSE and FIRES, no specific test is available.
Clinical Testing and Work-Up
The clinical work-up 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 and FIRES, brain MRI can reveal bilateral claustrum hyperintensity. Cerebrospinal fluid studies and blood tests should be performed to rule out infectious and known metabolic, infectious, inflammatory and autoimmune conditions. In selected cases, additional tests can be performed to identify other very rare causes of SE (a suggested diagnostic checklist can be found on http://www.norseinstitute.org/definitions/). Electroencephalography (EEG) and continuous EEG monitoring are usually required to detect seizures, as they frequently become increasingly subtler clinically, then undetectable, during the course of the disease.
The treatment of SE initially consists of benzodiazepines (lorazepam, diazepam, or clonazepam), followed by a standard anticonvulsant medication, as in most cases of SE. Preference is given to drugs that are available in IV form (valproic acid, phenytoin, levetiracetam, phenobarbital and lacosamide).
By definition, NORSE and FIRES do not respond to these first two lines of treatment, and additional drugs are required. The two options are either to try additional anticonvulsant medications and/or to induce pharmacological coma with an anesthetic drug. In the former case, medications available in an IV formulation are often favored but others (e.g., topiramate, pregabalin) are sometimes used later as add-on therapy. In the latter case, choices include infusions of midazolam, propofol and barbiturates (pentobarbital in the USA and thiopental in Europe). Of the three, midazolam has the best safety profile but may be associated with a higher risk of recurrent seizures. Barbiturates are associated with more prolonged coma and 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 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 FIRES and studies are urgently needed to determine the best treatment options.
Given the putative causal role of inflammation in cryptogenic NORSE and FIRES, 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 brexanolone (neuroactive steroid), anakinra (recombinant Il-1 receptor antagonist) and cannabinoids, have been used in FIRES in case reports. The ketogenic diet, a therapy for chronic drug-resistant epilepsy, has shown some efficacy in pediatric cases of FIRES, and more recently in adults with NORSE.
A prospective multi-center clinical registry of patients with NORSE or FIRES and biobanking of CSF, serum and DNA samples is currently ongoing through the Critical Care EEG Monitoring Research Consortium (http://www.norseinstitute.org/norse-registry-2/), with funding from the NORSE Institute.
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