October 20, 2020
Years published: 2014, 2016, 2018, 2020
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 of prolonged seizure activity or repeated seizures without full recovery in between. Status epilepticus that persists despite at least two standard anti-seizure 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 or more, 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 likely 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 (>5 minutes if convulsive, >10 minutes 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 24-72 hours of presentation, as it is commonly due to an obvious acute brain injury (stroke, trauma, etc.) or serious acute medical illness. RSE may also occur in people with epilepsy (also known as a 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 or more, 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 recent consensus 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 than children.
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 anti-seizure medications. 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 (the gene mostly associated with Dravet syndrome), PCDH19 or POLG1 (Alpers syndrome) genes. However, studies found genetic polymorphisms in the SCN2A gene (another gene involved in Dravet syndrome) and in the IL1RN gene (a gene coding for an immunomodulatory protein) in children with FIRES. These data are still 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 thus unknown. The frequent occurrence of a mild febrile illness in the days preceding seizures, the presence of inflammatory markers in the cerebrospinal fluid (CSF) (though usually only mild), and genetic polymorphisms in genes coding for immunomodulatory proteins 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 from uncontrolled case series that early immune-suppressing medications may be helpful, at least in some cases. 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 seen only in infants as discussed above.
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 persists or recurs despite appropriate anesthetic treatment or recurs after withdrawal of anesthesia (known as “super-refractory” SE), or that persists for at least 7 days (known as “prolonged” RSE).
In the United States, SE occurs in approximately 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 NORSE represents approximately 7% of cases of SE, or close to 1/100,000 per year. Thus it can be estimated that about 3,200 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 develop 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), which typically takes several weeks to complete.
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 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 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 evaluation can be found on the NORSE Institute website at 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 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, lacosamide, and, more recently, brivaracetam).
By definition, NORSE and FIRES do not respond to at least two lines of treatment, and additional drugs are required. The two options are either to try additional anti-seizure 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, 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 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 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 anakinra (recombinant Il-1 receptor antagonist), tocilizumab (Il-6 receptor blocking humanized antibody), and cannabinoids, have been used in NORSE and FIRES in case reports and small case series. The ketogenic diet, a therapy for chronic drug-resistant epilepsy, has shown some efficacy in both pediatric and, more recently, adult cases.
The NORSE Family Registry is collecting information about NORSE and FIRES patients in order to learn more about these conditions. The registry accepts information from families, patients and physicians and includes patients in the acute phase of NORSE or FIRES, those who have recovered (including years ago) or patients who have died. This registry is supported by the Robert N. Kohn NORSE Family Registry Memorial Fund and is maintained at Western University, London, Ontario, Canada in collaboration with the NORSE Institute.
A prospective, observational multi-center study of patients with NORSE (including FIRES) that includes the collection of biological samples is ongoing through the Critical Care EEG Monitoring Research Consortium with funding from the NORSE Institute.
More information about these registries is available here: http://www.norseinstitute.org/norse-registry-2/.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll Free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Additional information and resources for families/patients can be found at The NORSE Institute website: http://www.norseinstitute.org/
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