Rapid recovery after intrathecal dexamethasone in <scp>FIRES</scp>

Febrile infection-related epilepsy syndrome (FIRES) is a rare and severe epileptic encephalopathy affecting previously healthy individuals, with high morbidity and mortality. This condition is defined by new-onset refractory status epilepticus following a nonspecific febrile illness, without identifiable structural, metabolic, or infectious causes, and frequently progresses to super-refractory status epilepticus (SRSE).1, 2 Diagnosis is clinical, requiring an extensive work-up.1, 2 Management involves escalation of antiseizure medications (ASMs), early ketogenic diet (KD), and immunotherapy, though responses are often limited.1-3 Intrathecal dexamethasone (IT-DEX) has emerged as a potential adjunctive option in refractory cases.4, 5 We report a previously healthy 15-year-old boy with generalized tonic–clonic seizures and fever after 5 days of asthenia, somnolence, and headache. Initial investigations (blood tests, lumbar puncture, cranial computed tomography, and brain and spinal magnetic resonance imaging) showed mild leukocytosis and elevated C-reactive protein. Video-electroencephalography (vEEG) demonstrated diffuse slowing with a sparse alpha rhythm. Empirical acyclovir, ceftriaxone, ciprofloxacin, and methylprednisolone were started for presumed infectious or autoimmune encephalitis. Within 24 h, he progressed to SRSE with respiratory failure, requiring pediatric intensive care admission. Extensive autoimmune, metabolic, infectious, immunologic, and paraneoplastic work-up was unremarkable, except for positive immunoglobulin M and immunoglobulin G (IgG) for Mycoplasma pneumoniae (recent infection) and IgG for Listeria monocytogenes. Whole-exome sequencing revealed no pathogenic variants. SRSE persisted despite continuous midazolam and multiple ASMs (levetiracetam, valproic acid, lacosamide, clobazam, perampanel, phenobarbital, and phenytoin), and invasive mechanical ventilation was required on day seven for worsening consciousness. After a 7-day course of high-dose intravenous methylprednisolone with taper, immunotherapy with intravenous immunoglobulin (2 g/kg over 3 days) and therapeutic plasma exchange (five sessions) was ineffective. The KD also failed to control seizures. On day 12, thiopental achieved burst suppression but caused hemodynamic instability requiring norepinephrine infusion and gastrointestinal intolerance. Following thiopental withdrawal, seizures recurred despite ketamine and cenobamate. With a working diagnosis of FIRES, anakinra (300 mg/day, subcutaneous) was initiated on day 21, yet seizures persisted. The KD was reintroduced on day 26 with good tolerance but limited effect. By day 37, SRSE persisted despite maximal therapy, prompting IT-DEX as a late rescue. Each dose was 12 mg (0.15 mg/kg) dexamethasone diluted in sterile saline to a total volume of 5 mL, instilled slowly after withdrawal of an equivalent volume of cerebrospinal fluid (CSF). IT-DEX was administered for three consecutive days, followed by three additional doses on alternate days. Seizures ceased after the second dose, allowing anesthetic weaning and extubation on day 39. IT-DEX was well tolerated, with no adverse effects despite the use of a preservative-containing formulation. The patient progressively recovered neurological function. CSF obtained before anakinra later showed markedly elevated interleukin-6 (IL-6). Given this IL-6 predominant profile and the limited response to IL-1 blockade, immunotherapy was switched from anakinra to monthly intravenous tocilizumab (8 mg/kg) to target persistent IL-6-driven inflammation despite seizure remission. He was transferred to the ward on day 53 on multiple ASMs. On day 57, a brief cluster of focal seizures occurred during a febrile urinary tract infection, with no further events. Cognitive screening with the Montreal Cognitive Assessment (score 21/30) demonstrated mild deficits in attention and calculation, prompting cognitive rehabilitation. On day 85, he was discharged seizure-free, ambulant, and on monthly tocilizumab and ASMs. The overall clinical and therapeutic course is summarized in Figure 1, with vEEG recordings in Figures S1–S5. Recent cohorts report around 15%–25% mortality and frequent long-term cognitive impairment and drug-resistant epilepsy.3, 6-9 Early recognition and escalation to immunotherapy are recommended, although responses remain inconsistent.1-3, 6, 7 The complexity of FIRES may preclude strict adherence to recommendations, as illustrated by delayed anakinra initiation in this case. IT-DEX has been used as a late rescue after failure of multiple immunotherapies and anesthetic regimens, with seizure improvement often occurring within a few doses and no reported adverse events.4, 5 This pattern is consistent with the temporal course observed in our patient, in whom seizures ceased after the second IT-DEX dose. The rapid seizure cessation supports direct intrathecal corticosteroid modulation of central nervous system inflammation and may more effectively downregulate pro-inflammatory cytokine cascades than systemic steroids alone.3, 4, 8, 9 In summary, IT-DEX may represent a biologically plausible adjunctive rescue therapy for super-refractory FIRES, offering rapid seizure control and neurological recovery. None of the authors has any conflict of interest to disclose. Written informed consent for publication of the clinical details and accompanying images included in this report was obtained from the patient's legal guardians. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Data S1 Data S2 Figures S1-S5 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. What is the main proposed mechanism of action of intrathecal dexamethasone in FIRES? What was the observed clinical response following intrathecal dexamethasone in this patient with FIRES? Which statement best reflects current understanding of FIRES management? Answers may be found in the Supporting information.