Intrathecal dexamethasone therapy for febrile infection-related epilepsy syndrome

Abstract

Objective: Increasing reports suggest a role for immunological mechanisms in febrile infection-related epilepsy syndrome (FIRES). The objective of this study was to elucidate the efficacy and safety of intrathecal dexamethasone therapy (IT-DEX).

Methods: We assessed six pediatric patients with FIRES who were administered add-on IT-DEX in the acute (n = 5) and chronic (n = 1) phases. We evaluated clinical courses and prognosis. We measured cytokines/chemokines in cerebrospinal fluid (CSF) from FIRES patients at several points, including pre- and post-IT-DEX, and compared them with control patients with chronic epilepsy (n = 12, for cytokines/chemokines) or with noninflammatory neurological disease (NIND, n = 13, for neopterin).

Results: Anesthesia was weaned after a median of 5.5 days from IT-DEX initiation (n = 6). There was a positive correlation between the duration from the disease onset to the introduction of IT-DEX and the length of ICU stay and the duration of mechanical ventilation. No patient experienced severe adverse events. Seizure spreading and background activities on electroencephalography were improved after IT-DEX in all patients. The levels of CXCL10, CXCL9, IFN-γ, and neopterin at pre-IT-DEX were significantly elevated compared to levels in epilepsy controls, and CXCL10 and neopterin were significantly decreased post-IT-DEX, but were still higher compared to patients with chronic epilepsy. IL-6, IL-8, and IL-1β were significantly elevated before IT-DEX compared to epilepsy controls, though there was no significant decrease post-treatment.

Interpretation: IT-DEX represents a therapeutic option for patients with FIRES that could shorten the duration of the critical stage of the disease. The effect of IT-DEX on FIRES might include cytokine-independent mechanisms.

Figure 1

The treatment course of the six patients with FIRES during intensive care. Intravenous antiepileptic drugs, immunotherapies, and ketogenic diet therapy are shown. Pink arrows represent discharge from ICU. AED, antiepileptic drugs; BT, barbiturate therapy; fPHT, fosphenytoin; KM, ketamine; MDL, midazolam; KD, ketogenic diet therapy; IVMP, intravenous methylprednisolone; IVIg, intravenous immunoglobulin.

Figure 2

CSF concentrations of cytokines, chemokines, and neopterin in the six patients with FIRES. Red squares show the administration of IT‐DEX. The x‐axis represents days from the onset of disease. The y‐axis represents CXCL10, CXCL9, IFN‐γ, neopterin, IL‐6, and IL‐8 concentrations presented in log scale (A–L). Patient 1 (A, C); Patient 2 (B, D); Patient 3 (E, G); Patient 4 (F, H); Patient 5 (I, K); and Patient 6 (J, L).

Figure 3

Proinflammatory cytokine/chemokine and neopterin concentrations in CSF from patients with FIRES and controls. (A): CSF neopterin levels were measured in samples from patients with FIRES and patients with noninflammatory neurological disease (NIND) using HPLC. FIRES, N = 6; NIND, N = 13. (B)–(G): CSF levels of (B) CXCL‐10, (C) CXCL‐9, (D) IFN‐γ, (E) IL‐1β, (F) IL‐6, and (G) IL‐8 measured using a multiplexed immunoassay in samples from patients with FIRES and epilepsy. FIRES, N = 6; Epilepsy, N = 12. Each dot represents the cytokine/chemokine or neopterin levels of each patient. Bars express the median and interquartile range.