ABSTRACT
Objective
This study aimed to assess the efficacy and safety of using tocilizumab in children with febrile infection‐related epilepsy syndrome (FIRES) and explore tocilizumab‐related changes in interleukin (IL)‐6 levels.
Methods
Patients with FIRES admitted to the Intensive Care Unit (ICU) of Beijing Children's Hospital were retrospectively included and categorized into tocilizumab and control groups based on whether tocilizumab was administered to compare prognostic differences and drug safety. Patients in the tocilizumab group were further classified into response (characterized by ≥ 50% reduction in seizure frequency on electroencephalogram within one‐week post‐treatment) and no‐response groups for intergroup comparison of tocilizumab regimens and clinical outcomes. Serum and CSF IL‐6 levels were collected before and after the first tocilizumab dose to analyze the dynamics.
Results
Of 58 enrolled patients with FIRES, 23 received tocilizumab. The tocilizumab group showed higher rates of consciousness recovery and favorable Pediatric Cerebral Performance Category scores (p < 0.05). The incidence of post‐FIRES epilepsy was lower in the tocilizumab group (p < 0.001). The response group (9 patients) received earlier tocilizumab treatment, had shorter mechanical ventilation and ICU durations, and experienced higher consciousness recovery rates (p < 0.05). Serum IL‐6 levels increased post‐treatment (p = 0.003), while CSF IL‐6 levels showed a non‐significant decline (p = 0.080). There was no significant difference in the rates of combined infection, liver function impairment, and total cholesterol elevation between the tocilizumab and control groups (p > 0.05).
Interpretation
Early tocilizumab administration may improve outcomes in patients with FIRES, with a clinically acceptable safety profile.
Keywords: cytokines, febrile infection‐related epilepsy syndrome (FIRES), immunotherapy, safety, tocilizumab
1. Introduction
Febrile infection‐related epilepsy syndrome (FIRES), a rare and devastating neurological condition of unknown etiology, typically affects previously healthy school‐aged children. FIRES is a subcategory of new‐onset refractory status epilepticus (NORSE) characterized by a prior febrile infection. For a FIRES diagnosis, fever should precede the onset of refractory status epilepticus (SE) between 2 weeks and 24 h but may or may not still be present at SE onset [1]. The prognosis of patients with FIRES is generally poor, with a high risk of mortality. Even among survivors, cognitive impairments and refractory epilepsy are common outcomes [2, 3]. Emerging evidence implicates cytokine dysregulation, particularly interleukin (IL)‐6, which may play a significant role in the FIRES pathogenesis [4, 5].
Tocilizumab, a recombinant humanized monoclonal antibody that targets the IL‐6 receptor, has recently been used to treat conditions such as acute encephalopathy and refractory autoimmune encephalitis. A systematic review of 20 case reports and case series on the use of tocilizumab for treating NORSE, published between 2016 and 2023, reported an efficacy rate of 70% [6]. Additionally, the 2022 NORSE and FIRES consensus recommended tocilizumab for cases of FIRES with an inadequate response to first‐line immune treatment [7, 8]. However, due to the rarity of FIRES, data on the efficacy of tocilizumab treatment remain limited, and cohort studies have not been published to date. To address this gap, this retrospective study evaluates the efficacy and safety of tocilizumab in patients with FIRES, aiming to optimize therapeutic strategies.
2. Materials and Methods
This retrospective study was conducted on pediatric patients with FIRES who were treated between January 2017 and September 2024 in the Pediatric Intensive Care Unit (PICU) or Emergency Intensive Care Unit (EICU) at Beijing Children's Hospital, affiliated with Capital Medical University. This study was approved by the Institutional Review Board of Beijing Children's Hospital, Capital Medical University ([2024]‐E‐131‐R), and informed consent was not required.
2.1. Inclusion and Exclusion Criteria
Inclusion criteria were as follows: age between 29 days and 18 years; diagnosis with FIRES according to established criteria [1]; and exclusion of intracranial infections, paraneoplastic syndromes, autoimmune encephalitis, and genetic etiologies.
Exclusion criteria were as follows: hospitalization duration < 14 days; no requirement for invasive mechanical ventilation (MV); and incomplete clinical data.
2.2. Data Collection and Follow‐Up
Patients were identified from the hospital information system using the search term “febrile infection‐related epilepsy syndrome”. Baseline demographic and clinical data were recorded, including age, sex, and time from fever onset to first seizure. Additionally, results from brain magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, electroencephalogram (EEG), and continuous EEG were documented. The Pediatric Cerebral Performance Category (PCPC) [9] scores of patients at hospital discharge were also collected.
The timing, dosage, and treatment course of tocilizumab were documented. Additional therapeutic interventions, including antiseizure medications (ASMs), continuous intravenous anesthetic drugs (CIVADs), intravenous immunoglobulin (IVIG), corticosteroids, vagus nerve stimulation (VNS), and ketogenic diet (KD), were also recorded.
Serum and CSF IL‐6 levels were measured before and within 2 weeks after the first tocilizumab administration to evaluate post‐treatment changes. If a new infection arose, a preexisting infection worsened, or anakinra was administered between the initial tocilizumab dose and cytokine retesting, the IL‐6 data were excluded from analyses, as assessed by two clinical physicians.
Follow‐up assessments were conducted via outpatient visits or telephone interviews to evaluate consciousness recovery, PCPC scores, and the occurrence of post‐FIRES epilepsy.
2.3. Grouping of Participants
All study participants were categorized into the tocilizumab group or the control group based on whether they received tocilizumab treatment during intensive care unit (ICU) hospitalization.
The patients in the tocilizumab group were further categorized into the response group and no‐response group. This classification was based on whether the frequency of seizures decreased by ≥ 50% compared to pre‐treatment levels, as indicated by EEG within 1 week of the first dose of tocilizumab.
2.4. Definitions
Consciousness recovery was defined as the ability to follow commands. A favorable PCPC score was defined as a PCPC score of 1 to 3. The PCPC is a validated six‐point scale to categorize functional impairment (1 = normal, 2 = mild disability, 3 = moderate disability, 4 = severe disability, 5 = coma and vegetative state, and 6 = death) [9]. Post‐FIRES epilepsy was defined as the occurrence of at least one unprovoked post‐FIRES seizure after the patient's initial hospitalization for FIRES.
2.5. Measurement of Cytokine Concentrations
Serum cytokine IL‐6 levels were assessed using the 12 test kits for cytokines (magnetic particle luminescence) from Nanjing AtomLife Technology Co. Ltd. The results were returned within 2 working days after sample submission. CSF samples were stored at −20°C and retrieved within 24 h by personnel from Guangzhou KingMed Diagnostics Group Co. Ltd. IL‐6 detection was performed within 48 h, strictly following the instructions of the Aimplex kit (flow cytometry).
2.6. Evaluation of Adverse Events
Tocilizumab safety was assessed by comparing rates of infection, hepatic dysfunction, and increased total cholesterol levels between the tocilizumab and control groups. Laboratory results were evaluated in accordance with the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 [10].
2.7. Statistical Analysis
Data were managed in Excel, visualized using PowerPoint and GraphPad Prism 10, and analyzed with SPSS 27.0. Normally distributed continuous variables are expressed as the mean ± standard deviation and compared using t‐tests. Non‐normally distributed data are presented as the median (interquartile range, 25th–75th percentile) and analyzed with Mann–Whitney U tests. Paired data were evaluated with paired t‐tests or Wilcoxon signed‐rank tests based on normality. Categorical variables are reported as frequencies (%) and compared via chi‐squared tests. Statistical significance was defined as a two‐sided p value of < 0.05.
3. Results
3.1. Demographic and Baseline Characteristics
A total of 58 patients were included (Figure 1) with a mean age of 7.79 ± 3 years. Of these, 38 (65.52%) were male. The median time from fever onset to the first seizure was 4 (3.75, 5) days. Initial CSF analysis revealed a white blood cell count of 6 (3, 17.5) × 106/L and protein levels of 277.5 (211.25, 396.25) mg/L. Continuous EEG predominantly showed multifocal epileptiform discharges. Brain MRI abnormalities were observed in 44 patients, most commonly involving the frontal and temporal lobes, with 12 patients showing claustrum involvement. All patients received intravenous IVIG and corticosteroids. The other concomitant treatment measures are shown in Table 1.
FIGURE 1.
Flowchart showing the inclusion and exclusion of patients with FIRES.
TABLE 1.
Comparison of clinical characteristics between the tocilizumab and control groups.
| Indicator | Total (N = 58) | Tocilizumab group (N = 23) | Control group (N = 35) | p |
|---|---|---|---|---|
| Male, n (%) | 38 (65.52) | 12 (52.17) | 26 (74.29) | 0.083 |
| Age (years), mean ± SD | 7.79 ± 3 | 7.01 ± 2.8 | 8.31 ± 3.06 | 0.108 |
| Treatment measures during ICU stay | ||||
| ASMs, median (IQR) | 5 (4, 6) | 6 (4, 7) | 5 (4, 6) | 0.199 |
| CIVADs used, median (IQR) | 2 (1, 3) | 2 (1, 3) | 2 (1, 3) | 0.644 |
| High‐dose phenobarbital, n (%) | 26 (44.83) | 13 (56.52) | 13 (37.14) | 0.147 |
| Vasopressor drugs, n (%) | 14 (24.14) | 8 (34.78) | 6 (17.14) | 0.125 |
| Plasma exchange, n (%) | 15 (25.86) | 8 (34.78) | 7 (20) | 0.208 |
| Anakinra, n (%) | 4 (6.9) | 3 (13.04) | 1 (2.86) | 0.333 |
| KD, n (%) | 40 (68.97) | 18 (78.26) | 22 (62.86) | 0.215 |
| VNS, n (%) | 31 (53.45) | 15 (65.22) | 16 (45.71) | 0.145 |
| Magnesium sulfate, n (%) | 4 (6.9) | 2 (8.7) | 2 (5.71) | 1.000 |
| MV (days), median (IQR) | 24 (14.75, 38.25) | 26 (16, 43) | 21 (14, 30) | 0.159 |
| Duration of ICU hospitalization (days), median (IQR) | 31 (23.5, 48) | 38 (26, 51) | 30 (22, 46) | 0.198 |
| Duration of hospitalization (days), median (IQR) | 58.5 (39.75, 74.5) | 63 (48, 74) | 57 (37, 76) | 0.332 |
| Consciousness recovery at ICU discharge, n (%) | 15 (25.86) | 10 (43.48) | 5 (14.29) | 0.013 |
| At hospital discharge | ||||
| Death, n (%) | 3/58 (5.17) | 1/23 (4.35) | 2/35 (5.71) | 1.000 |
| Consciousness recovery, n (%) | 30/58 (51.72) | 16/23 (69.57) | 14/35 (40) | 0.028 |
| PCPC score ≤ 3, n (%) | 12/58 (20.69) | 7/23 (30.43) | 5/35 (14.29) | 0.249 |
3.2. Efficacy Analysis Comparing the Tocilizumab and Control Groups
A total of 23 (39.66%) patients were treated with tocilizumab and were classified into the tocilizumab group. SE remitted in 78.26% (18/23) of the patients following one or two doses of tocilizumab therapy. Two patients in the control group and one in the tocilizumab group died during hospitalization due to cerebral failure. The tocilizumab group demonstrated higher rates of consciousness recovery at ICU discharge (43.48% vs. 14.29%, p = 0.013) and hospital discharge (69.57% vs. 40%, p = 0.028) than the control group (Table 1).
The surviving patients were followed up. One patient in the control group was lost to follow‐up due to caregiver refusal and was excluded from subsequent prognostic evaluation. Two patients each from the control group and the tocilizumab group died between 7 days and 6 months after discharge, possibly due to accidental asphyxiation or cerebral failure secondary to intractable frequent seizures. One month after discharge, the tocilizumab group had higher rates of consciousness recovery (80.95% vs. 45.16%, p = 0.010) and favorable PCPC scores (52.38% vs. 16.13%, p = 0.005). The incidence of post‐FIRES epilepsy was significantly lower in the tocilizumab group (47.62% vs. 90.32%, p < 0.001). Six months after discharge, the proportion of patients with favorable PCPC scores in the tocilizumab group was higher than that in the control group (68.42% vs. 36.67%, p = 0.030) (Table 2).
TABLE 2.
Comparison of follow‐up data between the tocilizumab and control groups.
| Indicator | Total (N = 58) | Tocilizumab group (N = 23) | Control group (N = 35) | p |
|---|---|---|---|---|
| 1 month after discharge | ||||
| Death, n (%) | 5/57 (8.77) | 2/23 (8.7) | 3/34 (8.82) | 1.000 |
| Evaluation of surviving children | ||||
| Consciousness recovery, n (%) | 31/52 (59.62) | 17/21 (80.95) | 14/31 (45.16) | 0.010 |
| PCPC score ≤ 3, n (%) | 16/52 (30.77) | 11/21 (52.38) | 5/31 (16.13) | 0.005 |
| Post‐FIRES epilepsy, n (%) | 38/52 (73.08) | 10/21 (47.62) | 28/31 (90.32) | < 0.001 |
| 6 months after discharge a | ||||
| Death, n (%) | 7/56 (12.5) | 3/22 (13.64) | 4/34 (11.76) | 1.000 |
| Evaluation of surviving children | ||||
| Consciousness recovery, n (%) | 36/49 (73.47) | 16/19 (84.21) | 20/30 (66.67) | 0.175 |
| PCPC score ≤ 3, n (%) | 24/49 (48.98) | 13/19 (68.42) | 11/30 (36.67) | 0.030 |
| Post‐FIRES epilepsy, n (%) | 43/49 (87.76) | 15/19 (78.95) | 28/30 (93.33) | 0.294 |
| 1 year after discharge b | ||||
| Death, n (%) | 6/42 (14.29) | 2/11 (18.18) | 4/31 (12.9) | 1.000 |
| Evaluation of surviving children | ||||
| Consciousness recovery, n (%) | 23/36 (63.89) | 6/9 (66.67) | 17/27 (62.96) | 1.000 |
| PCPC score ≤ 3, n (%) | 18/36 (50) | 6/9 (66.67) | 12/27 (44.44) | 0.443 |
| Post‐FIRES epilepsy, n (%) | 35/36 (97.22) | 8/9 (88.89) | 27/27 (100) | 0.250 |
One patient in the tocilizumab group did not complete 6 months of post‐discharge follow‐up at the time of data analysis.
Twelve patients in the tocilizumab group and three patients in the control group did not complete 1 year post‐discharge follow‐up at the time of data analysis.
3.3. Comparisons Between the Response Group and No‐Response Group
Nine children (39.13%) in the tocilizumab group experienced a reduction of ≥ 50% in EEG seizure frequency within 1 week after receiving the first dose of tocilizumab and were classified into the response group. Compared with the no‐response group, the response group started tocilizumab earlier (7 [4.5, 12] vs. 14.5 [10, 20.25], p = 0.014), required fewer doses (1 [1, 1.5] vs. 2 [1.75, 3.25], p = 0.015), and had a shorter duration of MV (15 [11, 27.5] vs. 40.5 [24, 49.25], p = 0.005), ICU stay (31 [18, 36] vs. 45.5 [28.25, 54.5], p = 0.021), and total hospitalization (51 [40, 66] vs. 71.5 [58, 94.5], p = 0.041). Moreover, the proportion of patients with consciousness recovery at hospital discharge was higher in the response group than in the no‐response group (100% vs. 50%, p = 0.019) (Table 3). Additionally, no statistically significant differences were observed in follow‐up data between the response group and the no‐response group (Table 4).
TABLE 3.
Comparison of clinical characteristics between the response and no‐response groups.
| Indicator | Response group (N = 9) | No‐response group (N = 14) | p |
|---|---|---|---|
| Male, n (%) | 6 (66.67) | 6 (42.86) | 0.400 |
| Age (years), median (IQR) | 7.67 (5.08, 11) | 6.38 (4.15, 7.35) | 0.196 |
| CSF IL‐6 level (pg/mL), median (IQR) | 189.22 (43.1, 640.23) | 144.8 (16.45, 256.62) a | 0.342 |
| Serum IL‐6 level (pg/mL), median (IQR) | 13.53 (3.7, 40.17) b | 18.74 (9.68, 39.48) | 0.375 |
| Treatment measures during ICU stay | |||
| ASMs, median (IQR) | 5 (4, 6.5) | 6 (4, 7.25) | 0.402 |
| CIVADs used, median (IQR) | 2 (1, 2.5) | 2 (1.75, 3) | 0.284 |
| High‐dose phenobarbital, n (%) | 6 (66.67) | 7 (50) | 0.722 |
| Vasopressor drugs, n (%) | 2 (22.22) | 6 (42.86) | 0.400 |
| Plasma exchange, n (%) | 2 (22.22) | 6 (42.86) | 0.400 |
| Anakinra, n (%) | 2 (22.22) | 1 (7.14) | 0.538 |
| KD, n (%) | 5 (55.56) | 13 (92.86) | 0.056 |
| VNS, n (%) | 4 (44.44) | 11 (78.57) | 0.179 |
| Magnesium sulfate, n (%) | 0 (0) | 2 (14.29) | 0.502 |
| Time of tocilizumab initiation (days), median (IQR) | 7 (4.5, 12) | 14.5 (10, 20.25) | 0.014 |
| Initial dose of tocilizumab (mg/kg), median (IQR) | 8 (4.5, 11.84) | 8.09 (5.5, 9.38) | 0.899 |
| Total times of tocilizumab, median (IQR) | 1 (1, 1.5) | 2 (1.75, 3.25) | 0.015 |
| MV (days), median (IQR) | 15 (11, 27.5) | 40.5 (24, 49.25) | 0.005 |
| Duration of ICU hospitalization (days), median (IQR) | 31 (18, 36) | 45.5 (28.25, 54.5) | 0.021 |
| Total duration of hospitalization (days), median (IQR) | 51 (40, 66) | 71.5 (58, 94.5) | 0.041 |
| Consciousness recovery at ICU discharge, n (%) | 6 (66.67) | 4 (28.57) | 0.102 |
| At hospital discharge | |||
| Death, n (%) | 0/9 (0) | 1/14 (7.14) | 1.000 |
| Consciousness recovery, n (%) | 9/9 (100) | 7/14 (50) | 0.019 |
| PCPC score ≤ 3, n (%) | 5/9 (55.56) | 2/14 (14.29) | 0.066 |
Eleven patients.
Eight patients.
TABLE 4.
Comparison of follow‐up data between the response and no‐response groups.
| Indicator | Response group (N = 9) | No‐response group (N = 14) | p |
|---|---|---|---|
| 1 month after discharge | |||
| Death, n (%) | 0/9 (0) | 2/14 (14.29) | 0.502 |
| Evaluation of surviving children | |||
| Consciousness recovery, n (%) | 9/9 (100) | 8/12 (66.67) | 0.104 |
| PCPC score ≤ 3, n (%) | 7/9 (77.78) | 4/12 (33.33) | 0.080 |
| Post‐FIRES epilepsy, n (%) | 4/9 (44.44) | 6/12 (50) | 1.000 |
| 6 months after discharge a | |||
| Death, n (%) | 0/8 (0) | 3/14 (21.43) | 0.273 |
| Evaluation of surviving children | |||
| Consciousness recovery, n (%) | 8/8 (100) | 8/11 (72.73) | 0.228 |
| PCPC score ≤ 3, n (%) | 7/8 (87.5) | 6/11 (54.55) | 0.177 |
| Post‐FIRES epilepsy, n (%) | 7/8 (87.5) | 8/11 (72.73) | 0.603 |
| 1 year after discharge b | |||
| Death, n (%) | 0/3 (0) | 2/8 (25) | 1.000 |
| Evaluation of surviving children | |||
| Consciousness recovery, n (%) | 3/3 (100) | 3/6 (50) | 0.464 |
| PCPC score ≤ 3, n (%) | 3/3 (100) | 3/6 (50) | 0.464 |
| Post‐FIRES epilepsy, n (%) | 3/3 (100) | 5/6 (83.33) | 1.000 |
One patient in the response group did not complete 6 months of post‐discharge follow‐up at the time of data analysis.
Six patients in the response group and six patients in the no‐response group did not complete 1 year post‐discharge follow‐up at the time of data analysis.
3.4. IL‐6 Levels Before and After Tocilizumab Therapy
Six patients underwent repeat CSF IL‐6 testing, and one was excluded because of anakinra use (n = 5 analyzed). Fourteen patients underwent repeat serum IL‐6 testing, with 3 excluded (two due to infection exacerbation and one for anakinra use; n = 11 analyzed). Baseline CSF and serum IL‐6 levels were measured 10 (2.5, 17.5) and 6 (3, 13) days post‐onset, respectively.
Post‐tocilizumab CSF IL‐6 levels showed no significant change (276.82 [150.76, 708.94] vs. 49.5 [6.54, 89.83], p = 0.080), with 80% (4/5) of the patients achieving seizure reduction. Serum IL‐6 levels increased significantly (17.16 [9, 20.17] vs. 68.12 [50.74, 255.2], p = 0.003), with 81.82% (9/11) of patients showing seizure reduction (Figure 2).
FIGURE 2.
Trends in IL‐6 levels before and after tocilizumab treatment. (A) CSF IL‐6 dynamics; (B) serum IL‐6 dynamics. The red line represents patients who did not experience seizure reduction at retesting, whereas the black line indicates those who did experience seizure reduction at retesting.
3.5. Safety of Tocilizumab
No significant differences were observed in the rates of infection, hepatic dysfunction, or increased total cholesterol levels between the tocilizumab and control groups (Table 5). In the tocilizumab group, two patients developed neutropenia after treatment, which resolved within 3–5 days. Additionally, two patients experienced thrombocytopenia, which improved within 1–2 days. No hypertensive or allergic reactions were observed related to the tocilizumab infusion.
TABLE 5.
Safety outcomes.
| Indicator | Tocilizumab group (N = 23) | Control group (N = 35) | p |
|---|---|---|---|
| Bronchitis, n (%) | 0 (0) | 3 (8.57) | 0.403 |
| Pneumonia, n (%) | 23 (100) | 32 (91.43) | 0.403 |
| Urinary tract infection, n (%) | 5 (21.74) | 5 (14.29) | 0.704 |
| Gastroenteritis, n (%) | 2 (8.7) | 1 (2.86) | 0.707 |
| Sepsis, n (%) | 2 (8.7) | 4 (11.43) | 1.000 |
| Total cholesterol elevation | |||
| Total, n (%) | 19 (82.61) | 28 (80) | 1.000 |
| CTC grade 1, n (%) | 11 (47.83) | 23 (65.71) | |
| CTC grade 2, n (%) | 8 (34.78) | 5 (14.29) | |
| ALT elevation | |||
| Total, n (%) | 18 (78.26) | 24 (68.57) | 0.419 |
| CTC grade 1, n (%) | 9 (39.13) | 14 (40) | |
| CTC grade 2, n (%) | 1 (4.35) | 3 (8.57) | |
| CTC grade 3, n (%) | 8 (34.78) | 5 (8.62) | |
| CTC grade 4, n (%) | 0 (0) | 2 (5.71) | |
| AST elevation | |||
| Total, n (%) | 17 (73.91) | 27 (77.14) | 0.779 |
| CTC grade 1, n (%) | 9 (39.13) | 19 (54.29) | |
| CTC grade 2, n (%) | 2 (8.7) | 1 (2.86) | |
| CTC grade 3, n (%) | 6 (26.09) | 3 (8.57) | |
| CTC grade 4, n (%) | 0 (0) | 4 (11.43) | |
Note: Multiple occurrences of the same adverse event were counted only once per patient.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTC, common terminology criteria.
4. Discussion
While the exact pathogenesis of FIRES remains unclear, it likely involves severe neurogenic inflammation in the brain [11], with peripheral inflammation also contributing [12]. Genetic variations in the IL‐1 receptor antagonist gene in some patients with FIRES can lead to functional defects [13, 14], allowing IL‐1β‐driven inflammation to remain unchecked [14]. Cytokines such as IL‐1β can upregulate IL‐6 expression [15]. Increased IL‐6 levels could reduce long‐term potentiation and hippocampal neurogenesis while promoting glial proliferation, which may contribute to the development of epilepsy [16]. Elevated IL‐6 levels have been observed in both the CSF and serum of patients with NORSE. While CSF IL‐6 levels tend to be more elevated [4, 5], serum IL‐6 levels are more closely associated with prognosis [12]. These findings suggest that markedly elevated IL‐6 levels may play an important role in disease progression, making tocilizumab a potentially effective treatment option.
The findings of this study suggest that tocilizumab may have a therapeutic effect on FIRES and earlier initiation of therapy may lead to improved clinical outcomes. A previous study reported that approximately 86% of patients experienced cessation of SE after receiving one to two doses of tocilizumab [17]. Additionally, tocilizumab may facilitate consciousness recovery and neurological function improvement in patients with FIRES [18]. Our study further supports these findings, suggesting its potential role in FIRES therapy. Furthermore, subgroup analysis revealed earlier treatment initiation in the response group (median 7 days post‐onset), supporting the current international consensus recommending tocilizumab administration within 7 days [7, 8]. The response group also showed reduced MV duration and higher consciousness recovery rates, suggesting that early administration of tocilizumab may lead to a more favorable prognosis, which aligns with findings reported in previous studies [19]. Although the response group had relatively better PCPC scores and lower mortality rates than the no‐response group, no statistically significant difference was found, possibly due to the small sample size.
While tocilizumab appeared to reduce short‐term post‐FIRES epilepsy incidence, the 6‐month follow‐up revealed an increased rate (47.62% to 78.95%), approaching the 86% prevalence reported in NORSE systematic reviews [6]. The occurrence of post‐FIRES epilepsy may be associated with persistent release or reactivation of innate immunity‐related proinflammatory cytokines. Thus, the discontinuation of tocilizumab therapy in some patients following discharge from the hospital may have contributed to the subsequent development of post‐FIRES epilepsy in this cohort. The relationship between tocilizumab duration and post‐FIRES epilepsy prevention remains unclear and warrants further investigation.
In patients with FIRES treated with tocilizumab, serum IL‐6 levels may increase even as symptoms improve. Currently, only a limited number of reports document serum IL‐6 level changes before and after treatment in FIRES patients [17, 18, 20, 21, 22, 23]. Notably, four patients demonstrated increased serum IL‐6 levels alongside clinical symptom amelioration following tocilizumab treatment [18, 20, 21, 22], which aligns with our findings. This phenomenon may be attributed to tocilizumab binding to IL‐6 receptors, which inhibits receptor‐mediated clearance and leads to an accumulation of IL‐6 in the serum [24]. Therefore, further tocilizumab use should be based mainly on clinical manifestations rather than serum IL‐6 levels. Current reports on CSF IL‐6 alterations in FIRES patients following tocilizumab treatment include five patients [17, 18, 21, 22, 25]. In one case, CSF IL‐6 levels transiently increased following tocilizumab treatment but declined rapidly [21]. A mild elevation was observed in another case [18], while no IL‐6 elevation was detected in the remaining patients [17, 22, 25]. Upon re‐evaluation, all five patients exhibited symptomatic improvement [17, 18, 21, 22, 25]. In our study, CSF IL‐6 levels decreased in four patients, three of whom demonstrated seizure reduction. However, owing to the limited sample size, the relationship between CSF IL‐6 dynamics and clinical prognosis requires further investigation. The discordant CSF‐serum IL‐6 responses may involve the dynamics of the blood–brain barrier and complex intracranial cytokine networks [16, 21], necessitating further study.
The comparable adverse event rates between the tocilizumab and control groups suggested acceptable safety, although infection monitoring remains imperative given the drug's mechanism.
The limitations of this study include its relatively small sample size and single‐center retrospective design. Cytokine testing was not performed in some patients, and the dosage and treatment duration of tocilizumab were not fully standardized. Additionally, approximately 50% of patients in the tocilizumab group were discharged within 1 year at the time of follow‐up, which may have influenced some outcomes.
Author Contributions
S.Q., Q.W., and Y.H. contributed to the conception and design of the study; Y.H., J.W., C.F., Z.L., J.L., and K.L. contributed to the acquisition and analysis of data; Y.H., S.Q., and Q.W. contributed to drafting the text or preparing the figures.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
We are grateful to thank the Wiley Editing Services for English Language Editing and Review Services. This study was funded by the Beijing Municipal Science and Technology Commission (no. Z211100002921063).
Funding: This work was supported by Beijing Municipal Science and Technology Commission, Adminitrative Commission of Zhongguancun Science Park (No. Z211100002921063).
Suyun Qian and Quan Wang are co‐senior authors.
Funding Statement
This work was funded by Beijing Municipal Science and Technology Commission, Adminitrative Commission of Zhongguancun Science Park grant Z211100002921063.
Contributor Information
Quan Wang, Email: wq_bch@163.com.
Suyun Qian, Email: syqian2020@163.com.
Data Availability Statement
Data are available to share upon reasonable request to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data are available to share upon reasonable request to the corresponding author.