New-onset refractory status epilepticus

Alternate names

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

Definition

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.

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

Signs and 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.
• The fever may or may not be present when the seizures begin.
• 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.
• 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.

Diagnosis

• 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.
• Since there is no specific test to determine if a person has NORSE, other causes of the seizure activity must be ruled out (excluded).
• 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.
• Tests may include imaging studies such as CT scan and MRI, various blood tests, and CSF studies.
• 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.
• 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.

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.
• There is no standard treatment for cryptogenic NORSE (when the cause cannot be found).
• 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.

NIH genetic and rare disease info

• NIH info on New-onset refractory status epilepticus

New-onset refractory status epilepticus is a rare disease.

New-onset refractory status epilepticus Resources
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