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Addressing FIRES, NORSE, and Treatments at AES 2020

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This year's Pediatric State of the Art Symposium: febrile infection-related epilepsy syndrome (FIRES) and new‐onset refractory status epilepticus (NORSE): Current Concepts and Challenges was presented by Drs. Riviello, Muscal, Payne, Lai, Farias-Moeller, and Koh.

NORSE is a clinical condition of refractory status epilepticus (RSE) without a clear acute or active structural, toxic or metabolic cause, presenting in a patient without active epilepsy or other preexisting relevant neurological disorder. FIRES is considered a category of NORSE, with a prior febrile infection starting between 24 hours and two weeks prior to the onset of RSE, with or without fever at the onset of status epilepticus.

Infectious and autoimmune screens are usually negative, and no causative microorganism or antibody has been identified. Growing evidence suggests a heterogeneous etiology resulting in fulminant nonantibody-mediated neuroinflammation. This is considered related to the activation of inflammasomes.

Inflammasomes are a group of intracellular sensors that detects a broad range of microbial motifs, endogenous danger signals, and environmental irritants that are formed to mediate host immune responses to microbial infection and cellular damage. The assembly of an inflammasome triggers proteolytic cleavage of dormant procaspase-1 into active caspase-1, which converts the cytokine precursors pro-IL-1b and pro-IL-18 into mature and biologically active IL-1b and IL- 18, followed by the induction of pyroptosis, a form of cell death. Among these inflammasomes, the NLRP3 has been under intensive investigation, given its possible involvement in several human diseases, including FIRES.

Cytokine-level elevation in cerebral spinal fluid (CSF) and serum, particularly IL-1b, IL8, and IL6, have been reported in patients with FIRES, and measuring cytokine levels can help confirm the diagnosis. For some children with FIRES, this aberrant neuroinflammation appears secondary to a functional deficiency in the endogenous interleukin-1 receptor antagonist.

Beta-hydroxybutyrate produced during starvation limits NLRP3 activation and could explain why the ketogenic diet may have anti-inflammatory potential.

FIRES typically present in healthy children with a prodrome of a vague upper-respiratory infection or GI symptoms with and without rash and fever lasting one to 14 days prior to the onset of seizures. The prodrome is followed by an acute phase of focal and multifocal seizures, myoclonic seizures, tonic seizures, and nonconvulsive status epilepticus. Seizures dominate the clinical picture within 24 hours and are frequent and refractory. When suspected, further cytokine evaluation in serum and CSF, as well as anti-thyroid peroxidase antibody and neopterin, may be useful. Cytokine measurements may help guide clinical decisions of immunosuppressive or immunomodulatory medications. However, the lack of cytokine measurement should not preclude the administration of such therapy when clinical suspicion is high.

A complex and prolonged stay in the ICU often requires a medically induced coma that can lead to autonomic instability, encephalopathy, multi-organ dysfunction, and complications of prolonged immobility. 

The acute phase is often followed by a chronic phase of epileptic encephalopathy, drug-resistant epilepsy, permanent neurological deficits, cognitive impairment, and behavioral disturbances. Death was reported in 12% of cases, and about 50% of children have severe morbidity, with tracheostomy in 33% and gastrostomy in 57%.

Reports indicate that only 43% of cases are correctly diagnosed within the first two weeks. Subtle presenting signs require a high index of suspicion. Typical seizure semiology may include masticatory movements, head version, autonomic changes, clonic seizures involving face and limbs, myoclonic seizures, and tonic seizures that could occur numerous times a day. Interictal EEG features can reveal delta brush-like activity with slow waves with superimposed fast activity. Most patients have normal brain scans in the acute phase (61%), and about 25% of the patients reported in the literature had abnormalities in the temporal lobes. Changes in the basal ganglia and rarely in thalami or brainstem have been described, as well as diffuse cerebral edema in a minority of patients during the acute phase. The chronic phase of the disease was characterized by atrophic changes and evidence of mesial temporal sclerosis

Following management with anti-epileptic drugs and anesthetic treatment for RSE therapy for autoimmune encephalitides such as IV methylprednisolone and IVIG should be considered within the initial days of presentation.

Failure of the above therapies should prompt specific therapies shown to be beneficial in literature reports, including early initiation of a ketogenic diet, followed by anakinra and tocilizumab. The ketogenic diet was reported to be effective in FIRES and NORSE and is typically used within the first two weeks of presentation. Its use in the early acute phase was reported as a good outcome determinant. 

Anakinra works by blocking the biological activity of IL-1 a/b by binding to the IL-1 receptor. Anakinra has a short half-life of approximately six hours, allowing for easy titration. The median duration of therapy for anakinra was reported at 83 days. Early administration was associated with more than 50% seizure reduction in one week following therapy, shorter duration of mechanical ventilation, ICU, and hospital length of stay.

Tocilizumab is a monoclonal antibody that does not penetrate the CSF well but can target the innate immune system by blocking membrane-bound and soluble IL-6 receptors to dampen multiple signaling cascades. This therapy proved to be effective in adults with NORSE who remained refractory to conventional immunotherapy and in multiple case reports of children with RSE.

Considering the significant mortality and morbidity of NORSE and FIRES syndromes, prompt recognition and diagnosis are essential for initiating effective therapies that became available. Close collaboration between neurologists, pediatric intensivists, and rheumatologists is necessary for the complex management that ensures the best possible outcomes. Research into this unique and often devastating diagnosis is accelerating, and whether the acronym FIRES should relate to “febrile infection” or “febrile illness” remains to be debated.

Arie Weinstock, MD is a pediatric epileptologist and Robert Glover, MD is an adult epileptologist at the Comprehensive Epilepsy Program of the University at Buffalo. 

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