Abstracts

Rationale: Febrile-Infection related Epilepsy Syndrome (FIRES) is an epileptic encephalopathy seen in children with refractory status epilepticus after febrile illness. Immune-modulating therapies are often trialed with little success. The current hypothesis for pathogenesis is that a non-specific febrile illness causes release of intrathecal inflammatory molecules in genetically predisposed hosts and anti-inflammatory mediators fail to resolve inflammation. The innate immune system is activated giving rise to a neuro-inflammatory cascade with release of cytokines, chemokines and danger signals.  A hyper-excitable state develops. There is activation of gene transcription in neuroglia. Recurrent seizures amplify neuro-inflammation.Another disorder of unbalanced inflammatory response is hemophagocytic lymphohistiocytosis (HLH). HLH can be genetic or secondary to malignancy, autoinflammatory, infectious or metabolic conditions. HLH occurs when natural killer cells (NKC) and T regulatory lymphocytes are unable to regulate cytotoxic T lymphocytes (CTL). Hyper-activated CTL secrete interferon-γ, stimulating macrophages and monocytes which are responsible for secreting neopterin. Hemophagocytosis ensues, culminating in an overwhelming cytokine storm. Secondary HLH (sHLH) can occur through acquired defects in cytotoxicity leading to reduced NKC function or after hyper-activation of the innate immunity via excessive stimulation of toll-like receptors. We describe the co-occurrence of HLH in patients with FIRES and hypothesize a potential pathophysiological mechanism of secondary systemic and neurological inflammation.     Methods: We identified 5 patients with FIRES from a neurocritical care database who were assessed for HLH. All patients had extensive testing yielding no diagnosis. Patients were assessed for HLH using the 2004 Histocyte Society Criteria. The presence of ≥ 5 criteria was considered diagnostic for HLH. Other features analyzed included: rash, transaminitis, cholestasis and hemodynamic instability during HLH screen. We used Wilcoxon rank sum test to compare median cerebrospinal (CSF) neopterin for patients with FIRES to published median CSF neopterin values in the following pediatric patients with: Acute disorders (n=30), Chronic progressive disorders (n=17), Febrile exacerbation of chronic static disorders (n=6) and Chronic static disorders (n=105). The p-values were adjusted for the number of comparisons using the Sidak method. Data analysis was performed using Stata 14 (College Station, TX). Results: Patient characteristics are summarized in Table 1. The time to screen for HLH ranged from 20-29 days after admission (mean 23.4, SD 3.6). Three patients met ≥5 criteria for sHLH. Two patients met 3 and 4 criteria. No patient had a genetic mutation associated with HLH. CSF neopterin ranged from 122-300 nmol/dL (median 260, IQR 188-297). CSF neopterin was found to be higher in FIRES patients compared to reported values for acute disorders (p=0.0187), chronic progressive disorders (p=0.0036) and chronic static disorders (p=0.0008). Outcomes six months after FIRES/HLH diagnosis were variable. All patients have medically refractory epilepsy. One patient was treated with chemotherapy for sHLH with CNS involvement and improved. Conclusions: We describe a possible association of FIRES and sHLH. We hypothesize that in FIRES patients, HLH occurs due to excessive and prolonged central nervous system innate immune activation. Activated interferon-γ pathways produce marked elevation of CSF neopterin. By reporting on the co-occurrence of sHLH we come closer to understanding pathophysiological mechanisms potentially responsible for acute epileptogenesis in FIRES. Funding: None