Febrile Seizures: Evaluation and Treatment

Febrile Infection–Related Epilepsy Syndrome

Febrile infection–related epilepsy syndrome (FIRES) is presented under several names in the literature including idiopathic catastrophic epileptic encephalopathy [66], devastating encephalopathy in school-age children [67], new-onset refractory status epilepticus [68], as well as fever-induced refractory epileptic encephalopathy syndrome [69] and fever-induced refractory epileptic encephalopathy in school-age children [70]. All describe rare catastrophic epilepsy presenting in otherwise healthy children during or days following a febrile illness. While febrile illness precedes the epilepsy in 96% of cases, up to 50% of patients may not have fever at the time they present [41,65]. While age of onset is typically in early childhood, presentation in adulthood also occurs. Initial seizures are often focal, presenting as forced lateral head or eye deviation, oral or manual automatisms, and clonic movements of the face and extremities. Seizures will inevitably progress to status epilepticus with ictal onset often multifocal predominating in the perisylvian regions [41]. MRI is often normal at onset or shows only subtle swelling of the mesial temporal structures. Over months, MRI often shows T2-hyperintensity and atrophy of the mesial temporal structures, though as many as 50% of MRIs may remain normal [71].

The evaluation for cause in FIRES is often unrewarding. Inflammatory markers are typically absent from both serum and CSF. CSF may show minimal pleocytosis with negative oligoclonal bands and absence of common receptor antibodies. Treatment is equally unrewarding with patients typically failing conventional antiepileptic drugs and continuous infusions titrated to burst suppression. Immunomodulatory therapies are mostly ineffective as well. The most useful therapy reported has been the keto-genic diet with efficacy in up to 50% of patients [72]. Recently, therapeutic hypothermia has also been reported to be effective in 2 cases [73]. For the majority of patients, therapy will remain ineffective and seizures will continue for weeks to months with gradual resolution, though seizures often continue intermittently following the end of status epilepticus. Prognosis is poor for seizure control and neurocognitive recovery with mortality of 30% reported [41].

Case 3 Conclusion

The epilepsy gene panel ordered returns with the result of a disease-causing mutation in the PCDH19 gene. The child is diagnosed with PCDH19-associated epilepsy and is treated with phenobarbital. For the first years of life, she presents on average once per year with a cluster of seizures in the setting of febrile illness which is often managed with short durations of scheduled benzodiazepines. Seizures slow by age 6. She has mild delays in speech and receives some accommodations through her school system. By age 10, she has been seizure-free for several years. She is able to be weaned off medications without recurrence of seizures.

Summary

Febrile seizures are a common manifestation in early childhood and very often a benign occurrence. For simple febrile seizures, minimal evaluation is necessary and treatment typically not warranted beyond reassurance and education of caregivers. For complex febrile seizures, additional evaluation in rare cases may suggest an underlying seizure tendency, though most follow a typical benign course of febrile seizures. In some cases, as needed benzodiazepines used for prolonged or recurrent febrile seizures may be of value. There are well described epilepsy syndromes for which febrile seizures may be the initial manifestation and it is paramount that providers recognize the signs and symptoms of these syndromes in order to appropriately counsel families and initiate treatment or referral when warranted. Providers should have a high index of suspicion for these syndromes when they encounter children that repeatedly present with prolonged febrile seizures, clusters of febrile seizures, or febrile seizures in addition to afebrile seizure events. Early referral, diagnosis, and treatment has the potential to alter outcome in some of these syndromes, thus the importance of becoming familiar with these diagnoses.

Corresponding author: Anup D. Patel, MD, Nationwide Children's Hospital, Columbus, OH 43205, anup.patel@nationwidechildrens.org.

Financial disclosures: Dr. Patel disclosed that he has consulted for GW Pharmaceuticals and Supernus and is on the Scientific Advisory Board for UCB Pharma.