National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

New-onset refractory status epilepticus


Other Names:
New onset refractory status epilepticus; De novo cryptogenic refractory multifocal febrile status epilepticus; NORSE
Categories:
Subtypes:
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.[1][2][3] 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.[1][2] NORSE can affect people of all ages, but is more common in young adults and children.[1][2][3]

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 NORSE called 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.[1][2][3]

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.[1][2][3] Anesthesia therapy may not be completely effective in stopping seizure activity (super-refractory SE).[1][2][4] NORSE can cause significant brain damage and between 20-30% of people do not survive.[1][2] 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.[1][2][3]

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.[1][2][4]
Last updated: 9/6/2018
The majority of people with cryptogenic new-onset refractory status epilepticus (NORSE) develop a mild fever and symptoms of a viral illness (such as a cold or stomach flu) a day to two weeks before seizures begin and are classified as having FIRES, a sub-type of cryptogenic NORSE.[1][2][3][4] The fever may or may not be present when the seizures begin.[1][2][4] In some cases, a person may experience behavioral changes, difficulty thinking clearly, hallucinations, or headaches before seizures begin. In other cases there are no noticeable symptoms before seizure activity.[1]  

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).[1] 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).[1][2][4] 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.[1][2]

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.[1][3]

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.[1][3]

Last updated: 9/6/2018
The cause of status epilepticus (SE) can be found during initial tests in about 80% of cases. The remaining cases are classified as new-onset refractory status epilepticus (NORSE). Further, more extensive testing finds a cause in about 40% of NORSE cases, including autoimmune encephalitis paraneoplastic encephalitis, other known inflammatory or autoimmune diseases, rare genetic disorders including metabolic disorders, and uncommon viral infections. The cases that continue to have an unknown cause are classified as cryptogenic NORSE, which includes FIRES.[1][2]

Some researchers believe cryptogenic NORSE, including FIRES, may be an inflammatory disorder. Others suggest that an unidentified brain infection may cause some cases.[1][2] 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.[1][3]
Last updated: 9/6/2018
New-onset refractory status epilepticus (NORSE) is not a specific diagnosis but rather a clinical presentation or condition. Therefore a person has NORSE when they do not have a previous history of seizures, but developed seizures that progressed over a few days to status epilepticus (new-onset SE). In NORSE, the SE does not respond to anti-seizure medications (refractory SE) and it does not have a clear or obvious cause found during initial testing. Since there is no specific test to determine if a person has NORSE, other causes of the seizure activity must be ruled out (excluded).[1][2] Common causes ruled out in the initial testing include changes in the brain structure due to trauma or stroke, metabolic imbalances, alcohol or drug intoxication, central nervous system (CNS) infections, and alcohol withdrawal.[2] Tests may include imaging studies such as CT scan and MRI, various blood tests, and CSF studies.[1]

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.[1][2] 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.[1][2][4] 
Last updated: 9/6/2018
Treatment for NORSE (including FIRES) requires being cared for in an intensive care unit, at least until status epilepticus (SE) subsides and consciousness is regained. If an underlying cause of new-onset refractory status epilepticus (NORSE) is identified, treatment will include addressing the cause.[1] There is no standard treatment for cryptogenic NORSE (when the cause cannot be found).[1][2]

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.[1][2]

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.[1][2]
Last updated: 9/6/2018
New-onset refractory status epilepticus (NORSE) can cause significant brain damage and death.[1][2][3] Between 20-30% of people with cryptogenic NORSE, including those with FIRES, do not survive the prolonged, super-refractory status epilepticus (SE), also called the acute phase, most often due to complications of being in an extended medically-induced coma, having prolonged, uncontrollable seizure activity, and/or being on a "breathing machine" (ventilator).[1][5] 

Many survivors of cryptogenic NORSE, including those with FIRES, are left with long-term mental and/or physical disabilities and lifelong epilepsy.[1][2][3][5][6] 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.[5][6] In some cases, people with NORSE make a full recovery and are able to resume their previous lifestyle.[1][2][3][5]
Last updated: 9/6/2018

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

  • The Critical Care EEG Monitoring Research Consortium provides a list of members that treat NORSE. The list does not represent a complete list of doctors and facilities that can effectively treat NORSE, but is one place to start a search.

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

  • Orphanet lists European clinical trials, research studies, and patient registries enrolling people with this condition. 
  • The NORSE Institute provides information about ongoing and future research on NORSE and FIRES.

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss New-onset refractory status epilepticus. Click on the link to view a sample search on this topic.

Selected Full-Text Journal Articles

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  1. Gaspard N. New-Onset Refractory Status Epilepticus (NORSE) and Febrile Infection-Related Epilepsy Syndrome (FIRES). National Organization for Rare Disorders (NORD). 2018; https://rarediseases.org/rare-diseases/new-onset-refractory-status-epilepticus-norse/.
  2. Gaspard N, Hirsch LJ, Sculier C. New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): State of the art and perspectives. Epilepsia. April, 2018; 59(4):745-752. https://www.ncbi.nlm.nih.gov/pubmed/29476535.
  3. NORSE. The NORSE Institute. http://www.norseinstitute.org/. Accessed 9/6/2018.
  4. Hirsch LJ, Gaspard N, van Baalen A, et al. Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions. Epilepsia. April 2018; 59(4):739-744. https://www.ncbi.nlm.nih.gov/pubmed/29399791.
  5. Meletti S, Giovannini G, d’ Orsi G, et al. New-Onset Refractory Status Epilepticus with Claustrum Damage: Definition of the Clinical and Neuroimaging Features. Frontiers in Neurology. March 27, 2017; 8:111. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366956/.
  6. Hon KL, Leung AKC, Torres AR3. Febrile Infection-Related Epilepsy Syndrome (FIRES): An Overview of Treatment and Recent Patents.. Recent Pat Inflamm Allergy Drug Discov. May 8, 2018; [Epub ahead of print]:https://www.ncbi.nlm.nih.gov/pubmed/29745347.