What is New Onset Refractory Status Epilepticus?
The International League Against Epilepsy (ILAE) describes ‘status epilepticus’ (SE) as either nonstop seizure activity or repeated seizures without a return to normal that lasts for 5 minutes or longer. If someone still has seizures despite proper doses of initial medication (like a benzodiazepine) and a second, approved intravenous (IV) ‘antiepileptic’ medicine (which helps control seizures), they are said to have ‘refractory status epilepticus’ (RSE). ‘Super refractory status epilepticus’ (SRSE) is a type of RSE where the seizures continue or happen again even after IV anesthetics have been used for over 24 hours. This can include cases where seizures occur once anesthetics are stopped. About 9% to 43% of all SE cases lead to RSE with a hospital death rate between 15% and 33%. It’s been noted that about 4% to 12% of patients with SE will eventually progress to SRSE, with the hospital death rate reaching up to 40% to 54%.
The term ‘new-onset refractory status epilepticus’ (NORSE) was first used in 2005 to describe cases of severe, drug-resistant SE in patients who had no previous history of epilepsy and couldn’t be initially linked to an identifiable cause. In 2018, a group of experts proposed to define NORSE as a condition where SE is a new development in someone who doesn’t have epilepsy or another underlying neurological disorder, and there’s no clear acute or obvious cause, such as strokes, toxicity or metabolic disorders. A related condition known as ‘febrile infection-related epilepsy syndrome’ (FIRES) is considered a type of NORSE but is linked to a prior fever-related infection. FIRES is identified when fever starts from 2 weeks to 24 hours before the onset of RSE. In contrast, patients with NORSE may or may not get a fever before the start of RSE.
What Causes New Onset Refractory Status Epilepticus?
In a major look back at 130 cases of a rare disease called NORSE, medical professionals couldn’t determine the exact cause for over half the patients, despite thorough testing. They referred to these as “NORSE of unknown cause”. The most common known causes though included diseases where the immune system attacks the brain (autoimmune and paraneoplastic encephalitis), and infections.
Autoimmune encephalitis not linked to cancer saw the detection of certain antibodies like those against NMDA recepter, VGKC complex, LGI1, and, less commonly, Caspr2. Certain other immune system proteins (anti-GABA, anti-glycine, anti-GAD65, anti-striational) associated with conditions like thyroid-related brain inflammation also turned up in NORSE patients.
For folks with brain inflammation due to cancer (paraneoplastic autoimmune encephalitis), the anti-NMDA receptor is most commonly involved. Mostly young women get this and it’s often tied to tumors in the ovaries. There are other immune system proteins connected with different types of cancers that have also been found to cause NORSE.
Looking at infections, the Herpes simplex virus type 1 (HSV-1) was the most common infection causing NORSE. There were also cases in which the Enterovirus, Epstein Barr virus (EBV), Varicella zoster virus (VZV), Cytomegalovirus (CMV), Bartonella henselae, Mycoplasma pneumoniae, and arboviruses like West Nile virus were involved.
Some rarer genetic conditions, such as POLG131 which causes problems with the part of the cell that produces energy (mitochondria), have also been linked to NORSE.
Risk Factors and Frequency for New Onset Refractory Status Epilepticus
NORSE and its variant, FIRES, are uncommon disorders mostly known through individual case studies. These conditions have been recorded in healthy young adults and school-aged children, though they also affect adults who are 60 years and older. In adults, women tend to be more commonly affected than men, but in children, boys are affected more frequently than girls.
Due to prior uncertainty in defining NORSE, there might have been cases that weren’t correctly diagnosed, which makes it hard to accurately estimate its prevalence. However, it is believed that NORSE makes up about 20% of RSE cases. Both NORSE and FIRES can affect any age group, and they are not more common in any particular ethnic or racial group.
- NORSE and FIRES are relatively rare conditions.
- They affect healthy young adults, school-age children, and adults over 60.
- Among adults, it is more common in females while among children, boys are more frequently affected.
- The accurate estimate of NORSE is hard to determine due to previous unclear definitions.
- NORSE makes up about 20% of all RSE cases.
- Both NORSE and FIRES can affect any age group and are not linked to a particular ethnic or racial group.
Signs and Symptoms of New Onset Refractory Status Epilepticus
NORSE and FIRES are medical conditions that can occur in healthy adults or children and they have some similar traits. About 60% of people with NORSE have a period of illness, usually 1 to 14 days before seizures start. This period may involve symptoms such as confusion, tiredness, headache, low-grade fever, behavioral changes, mild stomach bug, upper respiratory infection, and memory issues. In about one third of NORSE cases, fever isn’t present, while in FIRES, fever is always present. In about half of the patients, the fever stops before the first seizure occurs.
At the beginning, seizures can be short and isolated, but they tend to increase in frequency within a few hours to days and eventually evolve into a state of continuous seizure, known as ‘status epilepticus’ or SE. For children, the number of seizures can reach over 100 per day. The most common type of seizure involves focal motor activities, which can spread and become generalized into bilateral tonic-clonic seizures. Other types of seizures may include rapid muscle jerks in the mouth and face muscles or focal seizures that come with impaired awareness. These seizures can last anywhere from a few days to weeks before progressing to SE.
Once the seizures progress into SE, they usually resist initial and secondary treatments, hence patients often need to be admitted to the intensive care unit (ICU) for more aggressive treatments. Patients with NORSE of unknown origin, termed “cryptogenic NORSE,” have been observed to show similar traits and disease course compared to patients with NORSE caused by autoimmune encephalitis, except the seizures tend to last longer and be more severe, often requiring mechanical ventilation and leading to worse outcomes.
Testing for New Onset Refractory Status Epilepticus
If you’re showing signs of Status Epilepticus (SE), a condition where seizures last too long or occur too close together without recovery in-between, doctors will conduct several laboratory tests. Tests can include a complete blood count, comprehensive metabolic profile, and assessments for things like inflammation markers, important minerals and potential drugs or toxins in your system. If no clear cause is found or symptoms progress to Refractory Status Epilepticus (RSE), a state where seizures don’t respond to initial treatment, further tests may focus on autoimmune or rare infectious causes.
One of these further tests your doctor might opt for is a lumbar puncture (also known as a spinal tap), especially if no clear cause can be identified from initial testing. This procedure involves collecting a sample of cerebrospinal fluid (CSF), which helps protect the brain and spinal cord. This fluid can be tested for a range of things like potential infection-causing organisms, glucose and lactate levels, and markers of inflammation. Test results, along with thorough examination of signs and symptoms can help doctors diagnose what’s causing your seizures.
Beyond lab tests, doctors look at your immune system and test for the presence of certain autoantibodies. Autoantibodies mistakenly see normal parts of your body as foreign and can attack them, potentially leading to conditions like SE. They’ll also test for certain viral infections.
If the cause can’t be identified, or if you have a weakened immune system, certain uncommon germs might be suspected. In these cases, doctors also test for infections from fungi like Cryptococcus and Histoplasma, and the parasite Toxoplasma gondii. Additionally, they might test stool specimens for certain viruses.
If there’s reason to suspect an underlying tumor (for instance associated with Paraneoplastic Syndrome, a condition that leads to an immune response against tumor cells), doctors might recommend imaging tests like an ultrasound, CT or an MRI scan or PET-CT scan, which gives wide pictures of the body’s tissues.
Doctors also use imaging like a brain MRI to identify structural or functional abnormalities in the brain that could explain the seizures. In many instances, these MRIs show specific changes in the levels of brightness or intensity in different areas of the brain.
Another incisive tool doctors use is a continuous electroencephalography (EEG). This is a non-invasive test that records electrical patterns in the brain which can be used to detect, among other things, the type and frequency of seizures, as well as to monitor the response to treatment. EEG patterns might also give clues on specific diagnosis in certain cases.
Treatment Options for New Onset Refractory Status Epilepticus
Status epilepticus is a serious brain disorder that requires immediate medical attention. It’s important to stop the seizures as soon as possible to avoid permanent brain damage. Here’s how doctors typically handle this medical emergency, according to the latest guidelines:
First, doctors stabilize the patient’s heart function. Making sure the patient’s airways are open and the patient can breathe is also a priority. Doctors might deliver extra oxygen through a nasal tube or other methods. If the patient’s breathing doesn’t improve, they might need a treatment called “rapid sequence intubation”.
When dealing with seizures, doctors will usually give a medicine called a benzodiazepine. This type of drug can stop seizures quickly and can be given in a hospital setting or even before someone arrives at the hospital. Tests have shown that this many cases of status epilepticus get better with benzodiazepines, and fewer people need help with their breathing or need more intensive care as a result.
If doctors suspect that a virus called HSV is causing encephalitis (brain swelling), they may start treatment with a medicine called acyclovir. This medicine has proven effective in reducing the impact of the disease if given early. For patients with status epilepticus that doesn’t improve with benzodiazepines, doctors may try other anti-seizure medications. However, the effectiveness of additional seizure medicines may decrease after the first one is given.
If a patient’s seizures are still happening despite using a second anti-seizure medicine, a third one is typically tried before moving on to stronger IV anesthetic agents. These medications work effectively in treating established status epilepticus, meaning a non-stop seizure.
In some severe cases, a patient’s seizures might not improve even with first and second-line therapies. This is known as refractory status epilepticus, and it requires even stronger medications called IV anesthetic agents for seizure control. Evidence suggests that two types of anesthetic agents (midazolam and propofol) are preferred, but long-term use can be linked to longer periods of needing a ventilator for breathing and heart complications.
One type of disease, called NORSE (or FIRES), often doesn’t respond well to seizure medicines, and so IV anesthetic agents need to be started quickly. Sometimes, multiple anesthetic agents are needed to control seizures. For such patients, doctors often recommend a type of treatment called immunotherapy, which can include several different types of drugs. While there isn’t specific treatment for patients with NORSE, immunotherapy has been shown to have positive effects, especially in adults.
Patients with NORSE or unclear cause of status epilepticus might receive a number of additional treatments. One is high-dose IV methylprednisolone, administered usually within the first week. Other treatments can include the use of other immunotherapies or the introduction of other therapeutic options, such as hypothermia, dietary changes, or a substance known as cannabidiol, although these options are still being studied and evaluated.
What else can New Onset Refractory Status Epilepticus be?
In many cases of NORSE (New-Onset Refractory Status Epilepticus), the root cause isn’t clear even after exhaustive medical tests. However, autoimmune or paraneoplastic encephalitis (brain inflammation due to cancer-linked autoimmune reactions) is often the most identifiable cause. Therefore, tracking a complete medical history and careful physical examination is essential for pinpointing any underlying disease for quick immunotherapy. This early treatment during the acute phase plays a critical role in patient outcomes and managing disability.
Anti-NMDA encephalitis, a type of brain inflammation that targets a specific set of nerve cells, is the most common autoimmune form of the disease. It often first appears in young adults, especially in women, as a feverish illness. Other signs that can follow soon include psychological changes like hallucinations, sleeping disruption, hyperactivity, memory problems, seizures, abnormal mouth-tongue movements, and failures in the body’s automatic functions. Compared to this, those with unknown-cause NORSE usually report early start of epileptic status, lengthy disease progression, absence of behavioral symptoms, depending on a ventilator, and more serious outcomes.
In cases of encephalitis associated with VGKC complex antibodies (typically LGI1 or, less often, Caspr2), patients can show symptoms similarly seen in limbic encephalitis. These include issues with cognition, confusion, behavioral changes, sleep disturbances, and seizures, and they might have abnormal blood sodium levels related to inappropriate antidiuretic hormone secretion. Uncontrollable facial and arm muscle contractions can occur in patients with LGI1 encephalitis and this is a distinct symptom of the disease.
When considering infectious causes, tests should be done promptly for atypical infections. HSV-1 infection might be indicated by symptoms such as fever, altered mental status, behavioral changes, multiple seizures (though rarely escalating to ongoing seizure status), one-sided paralysis or muscle weakness, uncoordinated movements, speech problems, with or without skin rashes along a nerve line. In contrast, weakness on one side of the body along with skin rash and symptoms of a previous feverish illness could suggest an infection due to enterovirus. Diseases caused by toxic-metabolic disturbances (like heavy metals like lead, aluminum, arsenic, or mercury) or drug toxicity should also be considered.
What to expect with New Onset Refractory Status Epilepticus
NORSE, or New-Onset Refractory Status Epilepticus, and FIRES, or Febrile Infection-Related Epilepsy Syndrome, in children are rare neurological conditions that can have serious and long-lasting health impacts. These conditions often do not respond well to multiple anesthetic drugs and can evolve into SRSE (Super-Refractory Status Epilepticus), a severe form of epilepsy that continues despite treatment. Mortality rates in children with these conditions have been seen at 12%, and between 16% and 27% in adults.
Many of the survivors of these conditions go on to develop epilepsy that is resistant to multiple drugs, and may also experience significant cognitive (brain function) and functional impairment (difficulty doing everyday tasks) over time. Factors such as a long stay in an Intensive Care Unit (ICU), medical complications, lengthy periods of coma induced by barbiturates (a type of drug used to relax muscles and control seizures), and the use of multiple anesthetic drugs could lead to worse health outcomes for both children and adults.
Possible Complications When Diagnosed with New Onset Refractory Status Epilepticus
Patients with NORSE often need several types of IV anesthesia for extended periods to reach a desired level of unconsciousness. However, this often comes with an increased risk of complications. These complications can include effects on the heart such as low blood pressure requiring medication to raise it and irregular heart rhythms. It can also lead to problems with the digestive system like liver issues, reduced intestinal activity, and stomach ulcers. Furthermore, infection risks like pneumonia and urinary tract infections are common. Other potential complications are blood-related issues such as anemia, low platelet count, or blood clots in the lungs. There can also be balance issues in the body’s salts and mineral levels such as low or high sodium levels, low phosphate levels, and severe decrease in body fluid pH. These complications are more likely and often more severe in situations of prolonged RSE duration requiring several IV anesthesia.
Common complications:
- Heart-related issues: low blood pressure, irregular heart rhythms
- Digestive problems: liver issues, reduced intestinal activity, stomach ulcers
- Infections: Pneumonia, urinary tract infections
- Blood-related issues: anemia, low platelet count, lung blood clots
- Abnormalities in body’s salts or minerals: low or high sodium, low phosphate, severe acidosis
Preventing New Onset Refractory Status Epilepticus
NORSE, which stands for New-Onset Refractory Status Epilepticus, is a unique health condition that carries high rates of death and ongoing health problems. The information we have about what causes it, how to detect it, and how to treat it mostly comes from experts’ advice and looking back at previous cases. The family members of people who have NORSE should be given support, including teaching them about possible issues that can happen in the brain after having NORSE, such as hard-to-treat seizures, and challenges with physical activities and thinking abilities.
It’s important to increase understanding about this disease and the treatment options among healthcare professionals. This includes arranging meetings on an institution-based and nationwide scale to discuss the condition. Most doctors who specialize in brain disorders and critical medical care aren’t very familiar with NORSE, unless they work at top-level health education institutions. Therefore, improving training for healthcare professionals can lead to quicker identification and management of the disease, which will better the health results for patients suffering from NORSE.
