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Disease Profile

New-onset refractory status epilepticus

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Adult

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ICD-10

G41.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

New onset refractory status epilepticus; De novo cryptogenic refractory multifocal febrile status epilepticus; NORSE

Categories

Nervous System Diseases

Summary

New-onset refractory status epilepticus (NORSE) occurs when a person without a previous history of seizures, experiences status epilepticus (SE) without a clear cause. SE describes a state in which a person has one prolonged seizure, or a cluster of seizures without recovery time in between.[1][2][3] The symptoms of NORSE typically begin with a mild fever and general symptoms of illness. People with NORSE may also experience behavioral and cognitive symptoms. SE associated with NORSE can last days, weeks, or months and may lead to a comatose state.[1][2] A likely cause is identified in about half of all people with NORSE. The most common causes of NORSE include autoimmune disorders, paraneoplastic disorders, and viral encephalitis.[1][2][3] Studies indicate that changes in certain genes, including the SCN2A and IL1RN gene(s) may increase the risk to develop NORSE.[1] When the cause cannot be found, cryptogenic NORSE is diagnosed. Most people with cryptogenic NORSE experience a fever prior to seizure development. These cases are classified as a sub-type of NORSE, called Febrile Infection-Related Epilepsy Syndrome (FIRES).[1][2][3][4]

A diagnosis of NORSE is suspected in people who develop SE that does not respond to typical treatment and that does not have an obvious cause. A diagnostic work-up may include brain imaging, cerebrospinal fluid studies, and blood tests. Electroencephalography (EEG) is used to monitor seizures throughout the illness.[1] There is no standard treatment for NORSE. If an underlying cause of NORSE is known, it should be treated appropriately. SE associated with NORSE does not respond to at least two typical lines of anti-seizure treatment. Additional treatment with other anti-seizure medications and/or medically inducing a coma using anesthesia may be suggested.[1][2][3]

Symptoms

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]

Cause

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); however, studies indicate that changes in certain genes, including the SCN2A and IL1RN gene(s) may increase the risk to develop NORSE.[1]

Diagnosis

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]

Treatment

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 antiseizure 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]

Organizations

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

    Organizations Providing General Support

      Learn more

      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

            References

            1. Gaspard N, Hirsch LJ. New-Onset Refractory Status Epilepticus (NORSE) and Febrile Infection-Related Epilepsy Syndrome (FIRES). National Organization for Rare Disorders (NORD). 2020; 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. https://www.norseinstitute.org/definitions-1. Accessed 12/29/2020.
            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.

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