New-onset refractory status epilepticus (NORSE) is a life-threatening condition in which a healthy person without a previous history of seizures begins having seizures (new-onset) and within several days the seizure activity progresses to status epilepticus (SE). SE describes a state in which a person has one prolonged seizure or a cluster of seizures without recovery time in between the seizures. When the cause of SE cannot initially be identified and it cannot be controlled with standard anti-seizure medicine (refractory), the condition is called NORSE. SE leads to a comatose state, either directly due to the seizure activity or due to anesthesia therapy used try to stop the seizure activity. In NORSE, SE may last days, weeks, or months. NORSE can affect people of all ages, but is more common in young adults and children.

After initial testing fails to find a cause for the refractory SE, more extensive testing is performed. In just under half of the cases of NORSE, a probable or possible cause is eventually found. When the cause cannot be found, cryptogenic NORSE is diagnosed. Cryptogenic is the medical term for unknown cause. In many cases of cryptogenic NORSE, the person had a fever between 24 hours and two weeks before seizures began. These cases are classified as a sub-type of NORSEcalled Febrile Infection-Related Epilepsy Syndrome (FIRES). Despite the fever, no known infection has been found to cause FIRES, and the fever may or may not be present when the seizures begin. There is currently no evidence that cryptogenic NORSE, including FIRES, is hereditary.

If an underlying cause for NORSE is found, the treatment depends on the cause. There is no standard treatment for cryptogenic NORSE, including FIRES. Cryptogenic NORSE does not respond to standard treatment of SE and requires additional treatment with other anti-seizure medicines and/or medically inducing a coma using anesthesia to control seizures. Anesthesia therapy may not be completely effective in stopping seizure activity (super-refractory SE). NORSE can cause significant brain damage and between 20-30% of people do not survive. In some cases, people with NORSE have made a full recovery, but in most cases survivors will have life long epilepsy as well as mental and physical disabilities.

Of note, FIRES previously was considered a separate condition that occurred only in children, while NORSE was described only in adults. However, FIRES is now considered a sub-type of cryptogenic NORSE (distinguished only by a preceding fever), and both can apply to people of any age.

Some researchers believe cryptogenic NORSE, including FIRES, may be an inflammatory disorder. Others suggest that an unidentified brain infection may cause some cases. Currently there is no evidence that NORSE runs in families (hereditary), but researchers suspect changes in certain genes may increase a person's risk for developing NORSE. However no associated genetic changes have yet been found.

The seizures that begin in people with NORSE are typically either focal impaired awareness seizures or tonic-clonic seizures (more commonly known as grand mal seizures). The seizures become very prolonged or frequent over time and transition to status epilepticus (SE) over a few days. SE may consist of one long seizure or a cluster of seizures presenting one right after the other (no periods of normal brain activity between seizures). SE causes progressive loss of consciousness and is not controlled by anti-seizure medications (refractory SE). The seizure activity may continue or begin again during anesthesia therapy, or may begin again after being weaned off anesthesia therapy (super-refractory SE). In people with cryptogenic NORSE, SE lasts for days, weeks, or even several months (prolonged SE) before it finally stops or is able to be controlled with treatment. The prolonged, refractory/super-refractory SE is often referred to as the acute phase of cryptogenic NORSE/FIRES.

Complications associated with anesthesia therapy, including complications associated with being on a "breathing machine" (mechanical ventilation) and extended unconsciousness (coma), may develop and can be fatal.

While the duration of SE varies from person to person, it eventually does stop and consciousness is regained. Most people with cryptogenic NORSE, including FIRES, will enter a chronic phase and may face mental and physical disabilities as well as life-long epilepsy. However, some people have fully recovered.

If initial testing does not find a cause, further, more extensive testing will be performed to rule out rare causes of new-onset refractory SE, such as known inflammatory and autoimmune diseases, rare genetic disorders including metabolic disorders, and less common viral infections. The NORSE Institute provides a suggested Diagnostic Checklist.

When extensive testing does not find a cause, the condition is called cryptogenic NORSE. FIRES is a sub-type of cryptogenic NORSE. People with FIRES have a fever a day to two weeks before the seizures begin. Even though a fever may or may not be present at the time seizure activity begins, FIRES has not been found to be caused by any known infection.

NORSE does not respond to standard treatment of status epilepticus (SE). Standard treatment would normally involve benzodiazepines followed by a standard anti-seizure medicine such as valproic acid, phenytoin, levetiracetam, phenobarbital, or lacosamide (preferably given intravenously). NORSE requires additional treatment with other anti-seizure medicines, medically inducing a coma with an anesthetic drug, and/or trying alternative therapies to control seizures.

Since some researchers suggest cryptogenic NORSE may be caused by an inflammatory process, immune therapies are sometimes tried to shorten the length of SE and minimize brain damage. Although there are reports of positive outcomes with immune therapies, not everyone responds and there have been no controlled studies to determine the effectiveness. First-line immune therapies that may be used include steroids, intravenous immunoglobulins (IVIG), plasmapheresis. Second line therapies include tacrolimus, rituximab, cyclophosphamide, and anakinra. Other alternative treatments that are considered to also be anti-inflammatory include the ketogenic diet (an established treatment for drug‐resistant epilepsy), cannabidiol (FDA approved for two refractory seizure syndromes, Dravet syndrome and Lennox-Gastaut syndrome), and lowering a person's body temperature (therapeutic hypothermia). These treatments have been used with some success in individual cases and small groups of cases, but again without controlled studies to determine their overall effectiveness.

Many survivors of cryptogenic NORSE, including those with FIRES, are left with long-term mental and/or physical disabilities and lifelong epilepsy. This is referred to as the chronic phase of NORSE. Mental disabilities range from mild to severe and may include lower IQ, memory problems, learning disabilities, difficulties with language, difficulties controlling emotions, and behavior problems. Physical disabilities include difficulties controlling movement. In a majority of cases, the epilepsy continues to be difficult to control (refractory). Some people may die in the chronic phase due to having a severe seizure. In some cases, people with NORSE make a full recovery and are able to resume their previous lifestyle.