Early Successful Treatment in a Child with Febrile Infection-Related Epilepsy Syndrome
Article information
Febrile infection-related epilepsy syndrome (FIRES) is an extremely rare and dramatic type of epileptic encephalopathy, with an estimated incidence of 1 in 1 million children [1-3]. It mostly affects previously healthy children, between 3 and 15 years of age, with a median age of around 6 years old and a slight predominance in males [1-3]. The term “FIRES” was proposed in 2010, and it is currently classified as a sub-type of new-onset refractory status epilepticus (NORSE) [1,3]. NORSE typically affects adults, may not be preceded by fever, and has an identifiable cause in about 50% of cases, including a specific viral infection or an autoimmune syndrome [2,4]. In FIRES, infectious, structural, toxic, and metabolic studies are usually normal, making it difficult to identify an etiology for this catastrophic condition [2,5].
FIRES is characterized by recurrent seizures or refractory status epilepticus preceded by febrile infection, such as a common upper respiratory tract infection or gastrointestinal infection [2,3]. Seizures typically begin after a period of low-grade fever, occurring 24 hours to 2 weeks before, with or without fever at the onset of the status epilepticus [1,4,6]. The clinical course is typically biphasic [1]. In the acute phase, seizures are brief at first, gradually increasing in frequency, and refractory status epilepticus is established within hours to days [1]. The chronic phase follows when status epilepticus stops, without a silent period between the two phases [1,5]. In this phase, seizures mostly occur every 2 to 4 weeks and patients show memory decline, speech impairment, functional disability, and emotional instability [1].
A continuous electroencephalogram (cEEG) should be performed as soon as possible to identify non-convulsive status epilepticus [1]. In FIRES, seizures are typically focal to bilateral tonic-clonic, with eye and head deviation and chewing movements, and epileptic foci are often frontal and temporal [1,2].
There are no specific treatment guidelines for FIRES [7-9]. However, FIRES has recently been categorized as an immune-inflammatory-mediated epileptic encephalopathy, since intrathecal overproduction of pro-inflammatory cytokines with known pro-convulsive activity has been reported [2,10]. In fact, anesthetic drugs are frequently required in combination with anti-seizure medications for seizure control, and other treatment strategies have been increasingly used, including a ketogenic diet (KD), intravenous (IV) steroids, intravenous immunoglobulin (IVIG), plasmapheresis, and immunomodulatory agents (anakinra, tocilizumab, rituximab, tacrolimus, and cyclophosphamide) [1,2,4,8].
Despite treatment, clinical outcomes are disappointing and the general mortality rate is up to 20% to 25% [5,8]. Refractory epilepsy during long-term follow-up may be present in 90% of cases and severe intellectual disability in up to 38% [1,5,8]. Fortunately, children with FIRES only experience status epilepticus once [1]. We report a clinical case of a child with FIRES, in which a prompt, aggressive, and combined treatment approach led to a favorable outcome.
A previously healthy 6-year-old boy, with an unremarkable family history, was admitted to the pediatric emergency department due to repeated episodes of impaired consciousness, fixed gaze, perioral cyanosis, and drooling, with no involuntary movements. He had a recent history of low-grade fever and neck pain for three days, being apyretic for 24 hours. He had no other symptoms. Trauma and toxic ingestion were not reported. Non-contrast enhanced brain computed tomography was normal, and a cerebrospinal fluid (CSF) study disclosed mild pleocytosis (37 leucocytes/μL), a protein level of 0.54 g/L, and normal glucose. Worsening of the neurological status was observed, with no recovered consciousness between seizures, despite IV diazepam. Midazolam was started, and he was admitted to the pediatric intensive care unit (PICU), requiring invasive mechanical ventilation. IV acyclovir and empirical antibiotic therapy with ceftriaxone and clindamycin were started. The initial EEG, under midazolam perfusion, showed no epileptiform activity.
On the third day of his PICU stay, clinical improvement was observed and he was transferred to the pediatric ward. However, the seizures became increasingly frequent and long, despite levetiracetam and valproic acid administration, and 3 days later he developed status epilepticus and was readmitted to the PICU, with the diagnosis of FIRES. At this time, the cEEG showed criteria for status epilepticus, with temporal and frontal activity. He maintained clinical and electrographic seizures (mostly focal but sometimes generalized), without a complete recovery of normal behavior between them. Multiple anti-seizure medications were tried, in variable combinations: levetiracetam (up to 30 mg/kg per day), valproic acid (up to 40 mg/kg per day), lacosamide (up to 5 mg/kg per day), perampanel (4 mg once a day), and phenytoin (up to 10 mg/kg per day). Midazolam and ketamine infusions and propofol boluses were also administered.
Considering the diagnosis of FIRES, an additional treatment strategy was implemented (Table 1): methylprednisolone (30 mg/kg per day; for 5 days, starting on day 6), plasmapheresis (five sessions on alternate days; starting on day 8), enteric KD (starting on day 10), IVIG (2 g/kg divided between days 17 and 18), subcutaneous anakinra (4 mg/kg per day; starting on day 17), IV pyridoxine (50 mg twice a day; starting on day 17), and cannabidiol (20 mg/kg per day; starting on day 18). A barbiturate coma was also induced with thiopental for 48 hours (days 14 to 16). The patient was under invasive mechanical ventilation from days 10 to 25, and he completed 10 days of clindamycin, 15 days of acyclovir, 22 days of ceftriaxone, and 21 days of ciprofloxacin.
Timing of therapeutic strategies
An extensive etiological investigation disclosed normal results. Infectious causes were excluded. Oligoclonal bands were absent both in CSF and serum. Immunological studies were negative, including autoimmune encephalitis antibodies (antineuronal, anti-N-methyl-D-aspartate receptor, anti-aquaporin 4, anti-myelin oligodendrocyte glycoprotein, anti-voltage-gated potassium channel, anti-gamma aminobutyric acid-B, anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, anti-glutamic acid decarboxylase-65, and anti-dipeptidyl-peptidase-like-protein-6). Contrast-enhanced brain magnetic resonance imaging (MRI) was normal.
Clinical and electrographic seizures gradually ceased from day 18 and status epilepticus ended on day 22, with cEEG showing temporal and frontal sporadic epileptiform discharges. He was transferred to the pediatric ward on day 30, under valproic acid, lacosamide, perampanel, phenytoin, cannabidiol, pyridoxine, anakinra, and KD. At this time, he had periods of emotional instability, with progressive improvement, and was discharged on day 43.
An improvement in mood stability was observed after cannabidiol discontinuation. After 12 months of follow-up, the patient is functional in daily activities, remains seizure-free, and is slowly weaning from anti-seizure medications (currently on valproic acid, lacosamide, and clobazam). The last EEG showed slow activity excess in posterior areas (probably in relation to cannabidiol) and no evidence of epileptiform activity. Contrast-enhanced brain MRI was repeated and was also normal. He was recently diagnosed with attention deficit hyperactivity disorder and has mild cognitive impairment. Table 1 summarizes the timing of our therapeutic approach.
In our case, early aggressive and combined treatment was performed, without progression to refractory epileptic encephalopathy in the chronic phase. This outcome is remarkably atypical in FIRES patients, and it may be related to the adopted treatment strategy, in which drugs with anti-inflammatory and immunomodulatory central nervous system effects were promptly used.
As a type of immune-inflammatory-mediated epileptic encephalopathy, in over 50% of FIRES patients, the CSF features mild inflammatory changes with pleocytosis, and protein levels may be increased, without evidence of an infection or a specific autoimmune antibody, as in our patient. [1] According to this pathophysiology, conventional anti-seizure medications are largely unsuccessful in the acute phase [2,4]. Continuous IV anesthetic drugs, such as barbiturates, can momentarily stop seizure activity, which can return as soon as they are discontinued [4]. Interestingly, the anti-inflammatory properties of KD and cannabidiol seem to play an important role in FIRES treatment in the acute and chronic phases [4,8]. Early administration of KD—within the 1st week—is recommended [8]. Ketone bodies, namely β-hydroxybutyrate, inhibit the proteolytic activity of caspase-1, reducing the release of biologically active interleukin 1β (IL-1β), exerting an anti-inflammatory effect [8]. Similarly, cannabidiol features anti-inflammatory component and has been efficaciously used in treatment of refractory epileptic syndromes [1,4]. Anakinra is a recombinant version of a human IL-1 receptor antagonist that exerts the biological actions of IL-1β [4,10]. In drug-resistant epilepsy, such as FIRES, an increased expression of IL-1β in microglia and astrocytes is observed [4,10]. Studies support anakinra as a potential immunomodulator for patients with FIRES that should be considered within the first 2 weeks of presentation if seizures remain refractory after empiric treatment with IV steroids and IVIG, as in our case [2,4,8,10].
FIRES is an extremely rare neurological emergency with a challenging treatment approach and a difficult prognosis. Guidelines are urgently needed and should be focused on the early use of drugs with anti-inflammatory and immunomodulatory central nervous system effects.
This study was approved by the Ethics Committee of São João Universitary Hospital Center (No. 116_2021). Written informed consent was obtained from legal representative of patient.
Notes
No potential conflict of interest relevant to this article was reported.
Author contribution
Conceptualization: NSG and MS. Writing-original draft: NSG, CM, and MS. Writing-review & editing: NSG, CM, JF, RS, and MS.