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NORD gratefully acknowledges Nicolas Gaspard MD, PhD, Neurology Department and Comprehensive Epilepsy Center, Université Libre de Bruxelles – Hôpital Erasme, Bruxelles, Belgium and Lawrence J. Hirsch MD, Neurology Department and Comprehensive Epilepsy Center, Yale School of Medicine, for assistance in the preparation of this report.

Synonyms

  • Cryptogenic new-onset refractory status epilepticus (cryptogenic NORSE)
  • Presumed encephalitis with refractory status epilepticus

Related conditions

  • Febrile illness-related epilepsy syndrome (FIRES)
  • Idiopathic hemiconvulsion-hemiplegia and epilepsy syndrome (IHHES)
  • Devastating epilepsy in school-aged children (DESC)
  • Acute encephalitis with refractory, repetitive partial seizures (AERRPS)

General Discussion

New-onset refractory status epilepticus (NORSE) is defined as refractory status epilepticus without an obvious cause after initial investigations; “initial” typically refers to 1-2 days, which is adequate time to rule out strokes, brain masses, drug overdoses, and herpes encephalitis.  Refractory status epilepticus (SE) is a condition in which patients suddenly experience continuous seizures or a flurry of very frequent seizures (the definition of “SE”) that do not respond to standard anticonvulsant medications (the definition of “refractory”). Seizures are thought to be due to an excess of pro-inflammatory molecules in the brain, perhaps triggered by a simple viral infection, although no clear cause has ever been demonstrated. Affected individuals are most often treated for weeks in an intensive care unit because they require prolonged anesthesia with coma-inducing drugs to control their seizures. NORSE carries a high rate of complications and mortality, but a significant proportion of patients do eventually recover. Epilepsy (a life-long predisposition to unprovoked seizures) and cognitive issues are common among survivors although a small minority of them eventually return to a normal lifestyle.

Introduction

Refractory status epilepticus (SE) is defined as a continuous seizures or a flurry of very frequent seizures that do not respond to standard anticonvulsant medications. It most commonly complicates an acute brain injury (stroke, trauma, infection, etc.) or a serious medical illness. It may also occur in people with a chronic seizure disorder. In a significant minority of cases, however, refractory SE strikes out of the blue and no cause can be identified. These cases are known as cryptogenic new-onset  refractory SE, or NORSE.

Affected Populations

NORSE has been described mostly in young adults but it can occur at any age during adulthood. Similar conditions, called febrile illness-related epilepsy syndrome (FIRES) and idiopathic hemiconvulsion-hemiplegia and epilepsy syndrome (IHHES), have been described in school-aged children and infants, respectively. Some authors now believe that these different syndromes might be the expression of a common disease.

As NORSE is not always clearly reported per se in series of patients with SE, but often as either “unknown cause” or “possible brain infection”, it is difficult to provide an accurate estimate of its incidence. However, it is likely that it is responsible for at least 10 to 20% of cases of SE that do not respond to standard anticonvulsant medications. This proportion can reach 50 to 70% when considering only cases of SE that do not respond to a first trial of coma-inducing anesthetic (known as “super-refractory” or “malignant” SE) and/or last more than one week (“prolonged” SE).

Symptoms

The course of the syndrome often begins with a mild febrile illness, associated with malaise, fatigue and symptoms of upper respiratory tract or gastro-intestinal tract infection. Symptoms of meningeal inflammation, such as headache and photophobia, are uncommon. Behavioral and cognitive symptoms, such as apathy or agitation, amnesia, and sometimes hallucinations can be observed.

This initial phase lasts a few days to a week or two and is followed by the onset of seizures. Both partial complex (“staring episodes”) and generalized tonic-clonic (“grand mal”) seizures can occur. They are initially intermittent but become increasingly more frequent and the patient’s consciousness declines as he transitions into SE.

This full-blown phase usually last several weeks and in some cases can even last several months. During this phase, the patient remains comatose due to the effect of the seizures and anesthetic treatment and can develop any of the complications associated with prolonged unconsciousness and mechanical ventilation. The mortality rate reaches 30%.

Once SE is controlled and anesthetic treatment is discontinued, the patients progressively regain consciousness and can be discharged from the ICU and the hospital. At least one half of the surviving patients are left with long-term cognitive and functional disability and most will have epilepsy, requiring lifelong treatment with anticonvulsants. A small minority, however, will be able to resume their previously normal lifestyle.

Causes

The exact cause of NORSE is currently unknown.

One study in children with related conditions has found that genes involved in epilepsy with fever sensitivity (SCN1A and PCDH19) or in status epilepticus often initiated by fever (POLG) did not show any mutations. The data available so far, however, are very limited and further studies are required to fully explore the hypothesis of a genetic defect.

The frequent occurrence of a mild febrile illness in the days preceding seizures and the presence of inflammatory markers in the cerebrospinal fluid (CSF) of patients with NORSE suggest that it might be due to an excess of pro-inflammatory molecules in the brain, perhaps triggered by a viral infection. This hypothesis is supported by experimental evidence that inflammatory molecules are powerful triggers of seizures in animals and by the fact that well established autoimmune disorders affecting the brain can lead to refractory SE.

Finally, it is possible that a direct infection of the brain by an undetected and/or unknown pathogen can be responsible for some cases of NORSE.

Related Disorders

Refractory SE can also occur in patients with a known history of epilepsy or with an acute brain injury (trauma, stroke, etc.). These cases are easily identified and distinguished from NORSE on the basis of clinical history and/or brain imaging.

A clinical picture very similar to NORSE can also be the manifestation of brain infections, such as viral encephalitis, or autoimmune disorders, such as encephalitis associated with anti-neuronal antibodies (anti-NMDA receptor, anti-voltage-gated potassium channel complex, etc.). A thorough work-up will need to rule out these treatable conditions.

Several syndromes have been described in infants and children, which share many similarities with NORSE. These include febrile illness-related epilepsy syndrome (FIRES), idiopathic hemiconvulsion-hemiplegia and epilepsy syndrome (IHHES), devastating epilepsy in school-aged children (DESC), and acute encephalitis with refractory, repetitive partial seizures (AERRPS). All these syndromes have in common an acute onset, a prolonged course of refractory SE, and inflammatory features in the CSF.

Diagnosis

Diagnosis is usually made on clinical grounds in patients who developed refractory SE once most causes of SE have been carefully excluded. As there is currently no known cause to NORSE, no specific test is available.

Clinical Testing and Work-Up

The clinical work-up should aim at identifying treatable causes of refractory SE. Brain CT and MRI scans are required to rule out stroke and other conditions with a characteristic appearance on imaging. Cerebrospinal fluid studies and blood tests should be performed to rule out infectious and known inflammatory and autoimmune conditions. In selected cases, additional tests can be performed to identify other very rare causes of SE.

Electroencephalography and continuous electroencephalographic monitoring are often required to detect seizures, as they frequently become increasingly more subtle during the course of the disease.

Standard Therapies

Treatment

There is currently no known specific therapy for NORSE and studies are urgently needed to determine what the best treatment options are.

The treatment of SE initially consists of benzodiazepines (lorazepam, diazepam, or clonazepam), followed by a standard anticonvulsant medication, as in most cases of SE. Preference is given to drugs that are available in IV form (valproic acid, phenytoin, levetiracetam, phenobarbital and lacosamide).  

By definition, NORSE does not respond to these first two lines of treatment, and additional drugs are required. The two options are either to try additional anticonvulsant medications and/or to induce pharmacological coma with an anesthetic drug. In the former case, medications available in an IV formulation are often favored but others (e.g., topiramate, pregabalin) are sometimes used later as add-on therapy. In the latter case, choices include infusions of midazolam, propofol and barbiturates (pentobarbital in the USA and thiopental in Europe). Of the three, midazolam has the best safety profile but may be associated with a higher risk of recurrent seizures. Barbiturates are associated with more prolonged coma and need for mechanical ventilation, with a higher rate of complications. Propofol carries a small risk of propofol infusion related syndrome (PRIS), a potentially lethal syndrome of acidosis, kidney and heart failure.

Given the putative causal role of inflammation in NORSE, it is tempting to try approaches that modulate the immune system. These options include IV steroids, IV immunoglobulins, plasma exchange therapy (plasmapheresis) and some monoclonal antibodies against inflammatory cells (e.g., rituximab). The efficacy of these strategies is suggested by small case series and needs to be demonstrated in controlled trials.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov.  All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site. 

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com.
 
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

First Ever Registry of NORSE Patients

A much-needed registry of NORSE patients is now underway. The overall goals of this prospective observational registry of patients with cryptogenic NORSE is to define its cause, identify the key determinants of outcome, and determine best management strategies.

Inclusion criteria is SE refractory to first- and second-line therapy and no etiology found within the first three days despite extensive work-up in patients of age 5 and older.

The NORSE registry will be carried out by member centers of the Critical Care EEG Monitoring Research Consortium which currently is comprised of 41 medical centers, mostly in North America. Demographic, medical, and biological data (blood, serum CSF, brain biopsy if available) will be collected. 

The study has the potential to help define the cause of NORSE, determine which medications warrant further investigations, and help identify key determinants of complications and outcomes in patients with refractory status epilepticus.  

A detailed description of the registry is available from principal investigator Nicolas Gaspard.

References

Kilbride RD, Reynolds  AS, Szaflarski J P, Hirsch L J. Clinical Outcomes Following Prolonged Refractory Status Epilepticus (PRSE). Neurocrit Care. 2013;18:374–385.

Gall, CRE, Jumma O, Mohanraj R. Five cases of new onset refractory status epilepticus (NORSE) syndrome: Outcomes with early immunotherapy. Seizure.2013:22(3):217-20. doi:10.1016/j.seizure.2012.12.016

Li J, Saldivar C, Maganti RK. Plasma exchange in cryptogenic new onset refractory status epilepticus. Seizure. 2012;22:70-73. doi:10.1016/j.seizure.2012.09.011

Nabbout R, Vezzani A, Dulac O, Chiron C. Acute encephalopathy with inflammation-mediated status epilepticus. Lancet Neurol. 2011;10:99–108.

Costello D J, Kilbride RD, Cole  AJ. Cryptogenic New Onset Refractory Status Epilepticus (NORSE) in adults-Infectious or not? J. Neurol. Sci. 2009;277:26–31.

Holtkamp M. et al. A ‘malignant’ variant of status epilepticus. Arch Neurol.2005;62:1428–1431.

Wilder-Smith EPV, et al. The NORSE (new-onset refractory status epilepticus) syndrome: defining a disease entity. Ann. Acad. Med. Singap. 2005;34:417–420.

Van Lierde I I, Van Paesschen WW, Dupont PP, Maes AA, Sciot RR. De novo cryptogenic refractory multifocal febrile status epilepticus in the young adult: a review of six cases. Acta Neurol Belg. 2003;103:88–94.

Mayer SA, et al. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol.2002;59:205–210.

Resources

American Epilepsy Society

342 North Main Street
West Hartford, CT 06117-2507 
Phone #: 860-586-7505
e-mail: khucks@aesnet.org
Home page: http://www.aesnet.org

Child Neurology Foundation

201 Chicago Ave, #200
Minneapolis, MN 55415 USA
Phone #: 952-641-6100
800 #: 877-263-5430
e-mail: jstone@childneurologyfoundation.org
Home page: http://www.childneurologyfoundation.org

CURE: Citizens United for Research in Epilepsy

430 W. Erie
Suite Suite 210
Chicago, IL 60654 
Phone #: 312-765-7118
800 #: 800-765-7118
e-mail: info@CUREepilepsy.org
Home page: http://www.CUREepilepsy.org

Epilepsy Foundation

8301 Professional Place
Landover, MD 20785-7223 
Phone #: 866-330-2718
800 #: 800-332-1000
e-mail: ContactUs@efa.org
Home page: http://www.epilepsy.com

Genetic and Rare Diseases (GARD) Information Center

PO Box 8126
Gaithersburg, MD 20898-8126 
Phone #: 301-251-4925
800 #: 888-205-2311
Home page: http://rarediseases.info.nih.gov/GARD/

Intractable Childhood Epilepsy Alliance (ICE)

PO Box 365
250 Lewisville-Vienna Road
Lewisville, NC 27023 
Phone #: 336-918-9440
Home page: http://www.icepilepsy.org

This content was created through a partnership between the Epilepsy Foundation and American Epilepsy Society.

Authored By: 
Nicolas Gaspard MD, PhD
Lawrence J. Hirsch MD
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Authored Date: 
08/2015