生酮饮食疗法在成人发热性感染相关性癫痫综合征（FIRES）中的应用：五例患者的病例系列及临床疗效分析

《Infection and Drug Resistance》：Ketogenic Diet Therapy for Adult Febrile Infection-Related Epilepsy Syndrome (FIRES): A Case Series of Five Patients and Clinical Efficacy Analysis

成人类发热性癫痫综合征（FIRES）是一种罕见且预后不良的疾病，以反复发作的难治性癫痫持续状态（RSE）为特征。本研究回顾性分析了5例接受生酮饮食（KD）治疗的成人FIRES患者，结果显示所有患者均于2-3天达到酮症，3-4天后癫痫发作显著减少，出院时改良Rankin量表（mRS）评分2-4分，3个月随访全部达到2分。常见副作用如腹泻、低白蛋白血症等均得到控制。提示KD对FIRES治疗有效且安全，但需更多大样本研究验证其长期疗效。

　　
Febrile Infection-Related Epilepsy Syndrome (FIRES) represents a rare but severe neurological disorder characterized by refractory status epilepticus (SE) triggered by a febrile infection within the prior two weeks. This condition is particularly devastating in adults, with high mortality rates and significant neurological deficits. A recent case series from Shanxi Bethune Hospital provides critical insights into the therapeutic potential of ketogenic diet (KD) in adult FIRES management.

The study documented five adult patients (median age 32, range 25–34) presenting with RSE following febrile prodromes. All patients demonstrated progressive neurological deterioration, with median mRS scores of 4 at admission. Neuroimaging revealed abnormalities in 60% of cases, including multifocal cortical and subcortical lesions, while EEG showed persistent slowing and epileptiform discharges. Standard therapies such as antiepileptic drugs (ASMs), anesthetics, and immunotherapy (corticosteroids, IVIG) failed to control seizures in this cohort.

The pivotal intervention involved KD initiation at a median of 33 days post-onset (range 10–50 days). This regimen achieved ketosis within 2 days (range 2–3) and induced measurable seizure reduction after 3 days (range 3–4). Remarkably, all patients achieved seizure freedom by discharge with mRS scores improving to 2 (40%) or 4 (60%). The median treatment duration was 123 days (range 30–141), followed by successful transition to regular diets without interruptions.

Key observations include:
1. **Treatment Timing**: KD initiation between 10–50 days post-onset demonstrated efficacy, challenging the conventional 7-day window proposed for pediatric cases. This suggests potential flexibility in adult populations.
2. **Mechanism of Action**: The study aligns with existing evidence that KD's antiseizure effects derive from ketone-mediated optimization of neuronal energy metabolism, anti-inflammatory modulation, and ion channel stabilization. Notably, ketosis induction occurred independently of these mechanisms, as patients showed clinical improvement before reaching target ketone levels.
3. **Adverse Effects Profile**: Adults exhibited distinct metabolic challenges, with 100% developing hypoalbuminemia (median onset 9 days), 80% anemia, and 60% diarrhea. These complications were manageable through supportive care, highlighting the need for personalized nutritional monitoring in adult patients.
4. **Immunotherapy Synergy**: One patient required adjunctive tocilizumab 97 days after KD initiation to overcome medication tapering resistance, suggesting sequential therapeutic interactions between KD and immunomodulation.

Neuroimaging findings revealed dynamic changes, with 60% showing abnormal MRI signals localized to frontal lobes, basal ganglia, and insula. Follow-up scans demonstrated partial regression of these lesions, particularly in patients with longer KD duration. However, the absence of standardized follow-up protocols limits definitive conclusions about imaging-time correlations.

This case series fills a critical gap in adult FIRES treatment literature. Prior studies focused predominantly on pediatric populations, with only three isolated adult reports available globally. The observed 100% seizure control rate, though limited by small sample size, provides preliminary evidence supporting KD as a viable therapeutic option. However, the study also identifies knowledge gaps:
- The optimal KD initiation window remains unclear, with current data showing efficacy beyond the 7-day mark.
- Adverse effect management strategies require further refinement, particularly for protein depletion and lipid imbalances.
- Long-term cognitive outcomes remain unassessed, necessitating extended follow-up periods.

The findings reinforce the 2022 International Consensus on NORSE management by validating KD as a first-line adjunct therapy when conventional approaches fail. However, they also highlight the importance of:
1. Developing age-specific KD protocols accounting for adults' higher protein requirements and different catabolic baseline.
2. Establishing standardized monitoring protocols for ketosis depth (β-hydroxybutyrate levels) and neurological progression.
3. Exploring combination therapies with immunomodulators like tocilizumab, which may address residual inflammatory processes unresponsive to KD alone.

The study underscores the urgent need for larger-scale prospective trials to validate these observations. Such research should prioritize:
- Multicenter collaboration to address regional variations in patient populations and treatment practices.
- Longitudinal neuropsychological assessments to quantify cognitive recovery trajectories.
- Metabolic biomarker tracking to better correlate KD efficacy with specific biochemical parameters.

In clinical practice, these findings suggest that KD should be considered as an early intervention (within first 50 days of onset) for refractory FIRES cases, particularly when neuroinflammation persists despite conventional immunotherapy. However, clinicians must balance potential benefits against age-related metabolic challenges, implementing rigorous supportive care to mitigate complications like hypoalbuminemia and anemia. The sequential activation observed in one patient— KD inducing initial seizure control followed by tocilizumab addressing residual inflammation—highlights the potential for synergistic therapeutic strategies in complex cases.

This study not only advances our understanding of KD's role in adult FIRES management but also identifies critical research directions. Future investigations should focus on optimizing KD parameters (energy density, fat-to-carb ratio adjustments) for adult patients, exploring mechanisms of action through multi-omics approaches, and developing predictive models for treatment response based on imaging biomarkers and inflammatory profiles. Until such studies are completed, the current evidence supports KD as a potentially life-saving intervention in appropriately selected adult FIRES patients, particularly when combined with targeted immunomodulation and meticulous metabolic management.