Understanding NORSE & FIRES
New Onset Refractory Status Epilepticus (NORSE) and its sub-type, febrile infection-related epilepsy syndrome, (FIRES) are rare, severe neurological conditions. Understanding their complexity helps guide treatment and support for patients and families facing these challenges.
What is NORSE?
In everyday language, NORSE refers to the unstoppable seizures that strike suddenly from out of the blue in healthy people without epilepsy.
In medical terms, NORSE stands for New Onset Refractory Status Epilepticus where status epilepticus refers to prolonged seizures lasting five minutes or more that are a neurological emergency. Refractory refers to those seizures being resistant to anti-seizure drugs. And new onset refers to these prolonged seizures erupting suddenly, without readily identifiable cause rather than resulting from an ongoing condition. One place to get reliable, peer-reviewed articles read by medical professionals is NIH's National Library of Medicine website, Pubmed: https://pubmed.ncbi.nlm.nih.gov/
NORSE is defined as a clinical presentation, not a diagnosis. NORSE refers to the unexplained, unending seizures we see, not what is causing the seizures. Often there seems to be a delay in doctors telling you that the case is NORSE. That’s because they must first rule out frequent causes for these seizures like a brain injury, a tumor or a toxin.
If a cause is identified, doctors should tell you what the cause is, and what it means for the patient's prognosis. The most commonly identified cause is autoimmune encephalitis in which a person's immune system mistakenly attacks its own organs (in NORSE, the brain and central nervous system).
But in over half the cases of NORSE, no cause for the illness is ever found despite weeks of extensive testing. These cases are referred to as cryptogenic NORSE or c-NORSE. Although immune dysfunction is suspected in NORSE cases in general, the specific mechanisms of that dysregulation are still not fully understood.
A report about NORSE written by Drs Gaspard and Hirsch filed with the National Organization for Rare Disorders (NORD) can be found here.
What is FIRES?
NORSE is the umbrella term for the syndrome, and FIRES sits under that umbrella. Febrile Infection-Related Epilepsy Syndrome or FIRES is a subtype of NORSE in which patients experience a fever between two weeks and twenty-four hours before the seizures start.
The fever is what distinguishes FIRES from overall NORSE, but FIRES is still considered a case of NORSE. Doctors used to think FIRES affected only children; they now know FIRES can affect both children and adults because adults, like the children, have had fever prior to the seizures.
Symptoms
In about two-thirds of the cases of NORSE, patients experience what is called a "prodromal phase" or the early, non-specific symptoms prior to the full presentation of NORSE. These non-specific symptoms can include:
Mild febrile illness (fever, malaise, fatigue, feeling unwell)
Upper respiratory or gastrointestinal symptoms (cough, sore throat, runny nose, diarrhea, nausea)
Confusion, subtle behavioral changes, irritability, or memory problems
Headache (occasionally)
In FIRES, fever between 2 weeks and 24 hours before the prolonged seizures
It is important to note that these symptoms are common to many illnesses like the seasonal flu or Covid. So there is no way that family, friends, or even physicians could have predicted or prevented NORSE by observing these early symptoms.
Many times, the symptoms are so mild that they are not noted by others until the patient is unresponsive and seizing in the ICU, and family and friends are racking their brains to understand what led to this condition.
NORSE Requires urgent, specialised medical care
NORSE is a life-threatening syndrome that requires immediate intervention from critical care and epilepsy specialists experienced in its management. Rapid access to appropriate treatment in the hospital's Intensive Care Unit (ICU) is essential. Time is brain.
Treatment often involves administering drugs to put the patient in a medically-induced coma to stop the seizures, which may last for weeks or even months. NORSE carries a significant risk of death and long-term complications. Many survivors develop epilepsy and require intensive cognitive, psychological, and physical rehabilitation after leaving intensive care.
While full recovery is not common, it does occur. Hope and realistic assessments are critical. Families should insist upon frequent, candid discussions with the entire medical team to assess their loved one's condition and obtain the best treatment available.
Treatments
Each case is different because of the different age, sex, and underlying cause of the seizures which is often unknown. Rapid response by a multidisciplinary medical team is vital. Treatment protocols have been published (see resources) and there are ways to access timely advice from global experts associated with the NORSE Institute.
You can encourage the presiding physician of your loved one to take advantage of these resources (see resources). They are available only physician-to--physician, they are not.
Resources
Time-Sensitive Resources for Healthcare Professionals
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NORSE Institute Medical & Scientific Advisory Board (MSAB)
Presiding clinicians can get insights to their acute case from the MSAB by sending a de-identified patient summary and their questions to the contact page via their center’s professional email. Case discussion will occur via group email.
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International Case Conference
An active, acute NORSE/FIRES case is presented online to an international audience, usually every second Friday of the month at 9am ET. These brainstorming sessions are organized by Eyal Muscal, MD (Baylor/TCH) and Marios Kaliakatsos, MD (GOSH). To present your case on the program, or to confirm schedule/time, email: Divya.Thomas@bcm.edu
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Cytokine Analysis from NORSE/FIRES Biorepository
For patients in the acute phase, cytokine results from donated bio samples can be reported back promptly which may guide treatment. Yale handles the consent process with the families and covers the cost of shipping.
Other terms for NORSE & FIRES
The term NORSE is a relatively new one, the first reference to NORSE in a medical journal was in 2005. Since then researchers have used various terms to describe this syndrome (a condition characterized by a set of associated symptoms):
super-refractory status epilepticus,
autoimmune encephalitis,
de novo refractory status epilepticus or presumed encephalitis with refractory status epilepticus.
The terms devastating epileptic encephalopathy in school-aged children (DESC),
acute encephalitis with refractory, repetitive partial seizures (AERRPS); and
infantile hemiconvulsion-hemiplegia and epilepsy syndrome (IHHES) have been used to describe pediatric illnesses similar to FIRES.
The common element in all these terms is the cascades of seizures that seem to come from out of the blue in healthy people with no history of epilepsy, and the refractory nature of these seizures they do not respond to traditional anti-epileptic drugs.
You can listen to an interview of Dr. Nicolas Gaspard about the nuanced changes in the conceptualization of NORSE reflected in the newly-proposed consensus definitions. We are grateful to Dr. Joseph Sirven, Editor-in-Chief of the Epilepsy Foundation's website, epilepsy.com, for conducting this interview as part of his Hallway Conversations series.
Incidence and Cause: Why did this happen?
Families and friends, there is nothing that you did or didn't do that caused NORSE to happen.
No one knows why NORSE strikes some people and not others. As of now, there is no established biological marker like a missing or defective gene that distinguishes NORSE as a specific disease.
Recent genetic analyses (whole genome sequencing and autoimmune and metagenomic sequencing of biosamples from the NORSE/FIRES biorepository) found no single genetic marker for NORSE. There are no reports of NORSE affecting more than one person in a family.
There is no established patient profile other than, ironically, that it usually occurs in healthy young adults and children with no history of seizures. But people of all ages can have NORSE.
Some scientists believe that NORSE is a syndrome resulting from a number of different, yet unidentified factors, with all of them having a combined effect. And although inflammation and immune dysfunction are seen to play pivotal roles in NORSE, exactly how they are involved is not yet entirely understood. In cases where a cause has been identified, autoimmune encephalitis, where the patient's immune system mistakenly attacks the brain and spinal cord, is often identified. But again, more than half the cases of NORSE have no identifiable cause which frustrates everyone since identifying the cause of an illness is the first step in finding the right treatment.
NORSE is a rare disorder. The incidence has been estimated to be ~3200 cases in the US each year, or 1 in 1 million people. Because the terms NORSE and FIRES are relatively new and refer to a presentation as opposed to a formal diagnosis, cases may not be recognized or documented.
Thus, NORSE is likely to be underreported and misdiagnosed.
Investigators think NORSE is of "heterogeneic etiology" which is a complicated way to say that the unique, dramatic presentation of NORSE is likely the result of a number of different causes: most likely polygenetic, that is, a combination of different genes, plus an environmental trigger that could be an innoculous as the common cold. It is this "perfect storm" of these things coming together at one terrible point in time (and no time ever before in that person's life) that make it difficult to find the exact cause and therefore, the best treatment for each case.
NORSE is not a specific diagnosis
The proposed consensus definition defines NORSE as a “clinical presentation.” This assessment of NORSE is arrived at by a process of observations of the patient, extensive medical testing and elimination of other causes.
This process of elimination takes time for tests to be administered, sent to laboratories (often off premises) and then the wait for results. The frustrating thing is that even if or when doctors conclude that the patient has NORSE, the precise cause of NORSE may not ever be identified which prevents identifying the best treatment to address that specific cause. And a treatment protocol for cryptogenic NORSE (cases without identifiable cause) is just forming now, which focuses on immune-modifying treatments.
Many hospitals have their own protocol for treating refractory status epilepticus (seemingly unstoppable seizures.) Peer-reviewed treatment protocols for NORSE in particular, have been published and are available on our website for your doctors to review. We also post the treatment protocol for prolonged seizures developed at Yale-New Haven Hospital.
As a disclaimer, it should be clear that each patient requires treatment unique to that patient. These protocols developed by doctors who have experience treating NORSE are offered only as a starting reference point other centers may wish to consider. As NORSE is rare, what experience there is should be shared.
In the acute phase of NORSE, it is important that your loved one receive treatment from critical care and epilepsy specialists with experience in NORSE. Most often, that is in a tertiary care center, level 4, medical center with EEG monitoring. If you do not have access to that level of care, the doctors caring for your patient can still access advice from NORSE experts to guide their treatment.
Your loved one's presiding doctors can request timely advice and timely biosample results that can inform treatment. That information is accessible through our Professional portal, (please add hyperlink.) This is a doctor-to-doctor resource, not available to families. But families can encourage the doctors caring for their loved ones to pursue this information which is free of charge.
Request Periodic Medical Conferences
A patient with NORSE symptoms will most likely be seen by a number of doctors: neurologists, specialists in critical care, epilepsy, nephrology and cardiology as the seizures, the anti-seizure and anesthetic drugs and the prolonged immobility can cause negative effects on the body.
Try to identify the one or two doctors who lead the case to help you integrate and interpret this information. Ask for a medical conference with this lead doctor and other doctors key to the case to assess what is currently known and expected to happen. Understand that early in the case, the doctors are still struggling to identify the cause of the illness to determine the best treatment. That identification process is largely a process of elimination that takes time. Keep a daily record of your own observations and questions to ask at the conference.
The condition of your loved one will likely change over time. Request additional medical conferences to be informed of the patient’s current condition and planned course of treatment.
Consider Involving a Palliative Care Team
A palliative care team can help support communication among the medical teams and between the doctors and the family. There are misconceptions on the part of both the public and doctors about palliative care.
Many times a palliative care team or a palliative care approach is not called in until death is imminent. As a result, palliative care is often erroneously associated exclusively with end of life care. Palliative care is relevant when illness is life-threatening and life-altering for survivors.
The World Health Organization’s definition of palliative care is “an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual.” It “intends neither to hasten or postpone death “and is applicable early in the course of illness, in conjunction with other therapies that are intended to prolong life, such as chemotherapy or radiation therapy, and includes those investigations needed to better understand and manage distressing clinical complications.” Read full definition here https://www.who.int/news-room/fact-sheets/detail/palliative-care
Full recovery from NORSE is possible. Requesting palliative care services does not negate that hope. Morbidity and mortality are also possible. Early involvement of a palliative care team can help doctors and families be on the same page regarding the patient’s current condition, and what to hope and plan for given the expected outcomes. It can be upsetting to hear that doctors are uncertain of the cause and the possible outcomes for a patient.
NORSE is full of uncertainty for both families and doctors. You can read about the differing perspectives on communication here. https://www.statnews.com/2016/11/22/palliative-care-rare-disease-norse/ Frequent and frank discussion of what is known and what remains uncertain may help doctors and families plan together for the best course of action for the patient.
NORSE Glossary of Terms
The following are terms that may come up in your conversations with medical staff that you should know. (The NORSE Institute is grateful to Erica Sieg, PsyD, Northwestern University Feinberg School of Medicine for providing this content.)
Terms often used in medical conferences
Acquired brain injury vs Traumatic Brain Injury: Acquired brain injury is an umbrella term for any type of injury to a person’s brain. Traumatic brain injury is a specific type of acquired brain injury that refers to some force external to the person that causes injury such as a car accident, fall, assault, gun shot etc. that damages the brain. Some examples of acquired non-traumatic brain injury (that occur from within a person) include stroke, brain tumors, encephalitis, and NORSE and FIRES among others.
Breakthrough Seizures: Sudden unexpected seizures in someone who previously had achieved reliable seizure control with medications.
Cognition: Broad term for mental abilities (“thinking”) related to information processing such as attention, processing speed, working memory, language, visual spatial, problem solving, planning, and memory.
Comorbidities: Additional illnesses or all the illnesses present in a person, not just the primary one being discussed. For example, someone may have epilepsy and also have comorbidities of depression, anxiety, or cognitive impairment. Comorbidities can be physical, cognitive, or psychiatric.
Electroencephalography (EEG) Monitoring: the most common way to monitor brain functioning for seizure activity. It does not hurt and is not dangerous as it is only a recording device for brain waves. It does not transmit, shock, or produce any kind of electrical current. Electrodes (small metal recording devices) are placed on the surface of the scalp and secured with a safe glue or tape. Once in place, electrodes measure the electrical activity in the brain through the skull. The electrodes send the information by attached wires to a computer to be recorded and analyzed by doctors.
Epilepsy: Epilepsy is a disease characterized by an enduring predisposition to generate epileptic seizures. A seizure is one event (see below) and epilepsy is the disease involving recurrent, unprovoked seizures.
Function: What someone can do; how well they can perform or complete tasks.
Neurobehavior: Behavioral, emotional, or personality changes associated with changes in brain structure or function. Examples are aggression, irritability, apathy, crying, sadness, hallucinations, eating more/less, sleeping more/less, repeating the same activity multiple times, or not engaging in normal activities.
Neuroimaging: Any procedure that provides visual information about the structure of the brain. This includes brain scans such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET) scan or single-photon emission computerized tomography (SPECT) among others.
Neurologic state: The state of a person’s central nervous system which includes the brain and spinal cord. When a change in this system occurs, immediate medical intervention is needed because the central nervous system regulates important aspects of the body’s internal environment like breathing and heart rate, processes all sensory information such as sight and sound, and is responsible for conscious awareness, voluntary body movement, thinking, learning, and feeling.
Seizure: Abnormal excessive or synchronous neuronal activity in the brain. In other words, an episode when the cells of the brain are too active or start acting together in ways that are atypical. This interrupts normal brain functioning and produces the associated symptoms of changes in awareness, thinking, moving, speaking, or feeling (the brain’s normal processes). Most seizures do not last longer than 2 minutes.
Status Epilepticus (“Status”): A medical emergency defined as a continuous seizure lasting more than 5 minutes, or two or more seizures without full recovery of consciousness between any of them. Essentially, this is when seizures last too long or don’t stop. This is dangerous because it can cause significant brain damage or even death.
Listen to Recordings from our Family & Scientific Conferences
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