Acute Brain Injury in New-Onset Refractory Status Epilepticus and Etiology-Defined Status Epilepticus

Stefano Meletti, MD, PhD1,2; Aurelie Hanin, PhD3,4; Giada Giovannini, MD, PhD1 et al

2026년04월27일

JAMA Neurol. Published online: April 27, 2026.

DOI:10.1001/jamaneurol.2026.0865

Abstract

Importance  Seizure-induced brain injury is central to the treatment urgency of new-onset refractory status epilepticus (NORSE). Identifying biomarkers that reflect ongoing neuronal damage could inform therapeutic timing and improve outcomes.

Objective  To quantify acute brain injury in patients with cryptogenic NORSE (cNORSE), etiology-defined status epilepticus (eSE), and chronic epilepsy.

Design, Setting, and Participants  This was an international cross-sectional study conducted between 2013 and 2025. Patients were enrolled at 36 hospitals in the US, 2 in Canada, and 1 in Italy, France, and Belgium. Patients with cNORSE and eSE for which biological samples were obtained during ongoing seizure activity were enrolled in the study. Comparison groups without status epilepticus comprised individuals with chronic epilepsy and healthy participants. None were excluded.

Exposures  Neurofilament light chain (NfL) and S100-beta (S100B) protein concentrations in serum and cerebrospinal fluid (CSF).

Main Outcomes and Measures  Degree of neuronal and glial damage, indexed by NfL and S100B levels, and their association with short-term functional outcomes.

Results  A total of 78 patients with cNORSE (mean [95% CI] age, 37 [30-41] years; 44 female [56%]) and 2 independent cohorts of 211 patients (mean [95% CI] age, 69 [66-71] years; 128 female [61%]) and 73 patients (mean [95% CI] age, 56 [45-65] years; 39 male [53%]) with eSE were included. NfL concentrations were markedly elevated in cNORSE—approximately 10-fold higher in CSF and 4-fold higher in serum—compared with the eSE cohorts (CSF: median [IQR], 6408 [1503-22 963] pg/mL compared with 694 [219-2389] pg/mL; serum: median [IQR], 231 [99-855] pg/mL compared with 55 [20-135] pg/mL; P <.001). Serum NfL levels were nearly 20-fold higher in cNORSE than in the cohort with epilepsy and in healthy controls (median [IQR], 11 [7-19 ] and 7 [5-14 ] pg/mL, respectively). Serum and CSF NfL levels were strongly correlated (Spearman ρ = 0.75; P < .001) and rose sharply between week 1 (median [IQR], 101 [51-137] pg/mL), week 2 (median [IQR], 197 [117-324] pg/mL), and week 3 (median [IQR], 598 [163-1000] pg/mL) after onset (P < .001). In contrast, S100B concentrations did not differ between groups and showed no consistent temporal pattern. NfL discriminated cNORSE from eSE (area under the receiver operating characteristic curve [AUROC], 0.79; 95% CI, 0.68-0.90) and from cohorts without status epilepticus (AUROC, 0.99; 95% CI, 0.78-1.00). Higher serum NfL was independently associated with poor functional outcome at discharge (Glasgow Outcome Scale extended score, 1-4; odds ratio, 1.01; 95% CI, 1.00-1.03; P = .03).

Conclusions and Relevance  Results of this cross-sectional study suggest that acute neuroaxonal injury, as reflected by elevated NfL levels, was substantially greater in cNORSE than in the cohorts with eSE and in controls without status epilepticus. The rapid early rise in NfL highlights a narrow therapeutic window, emphasizing the need for prompt, effective, and potentially neuroprotective interventions in cNORSE.

Key Points

Question  How extensive is brain damage during the acute phase of new-onset refractory status epilepticus (NORSE) as indexed by serum and cerebrospinal fluid levels of neurofilament light chain (NfL) and S100-beta proteins?

Findings  In this cross-sectional study including 78 patients with NORSE and 2 independent cohorts of 211 and 73 patients with etiology-defined status epilepticus, NORSE was associated with extraordinarily high and rapidly accumulating neuronal injury, disproportionate to astroglial damage, and exceeding that seen in etiology-defined status epilepticus.

Meaning  These findings highlight the diagnostic potential of NfL as a biomarker to guide clinical management of status epilepticus, and these results support early and aggressive therapeutic strategies to extinguish NORSE.

Figure 1.  Neurofilament Light Chain in the Different Patient Groups and Ages

Figure 2.  Serum Cerebrospinal Fluid (CSF) Correlations and Temporal Dynamics of Neurofilament Light Chain (NfL)

요약

·         중요성 : 발작에 의해 유발되는 뇌 손상은 신생 난치성 간질지속상태(new-onset refractory status epilepticus, NORSE)의 치료 긴급성을 규정하는 핵심 요소이다. 진행 중인 신경세포 손상을 반영하는 생체표지자를 규명하는 것은 치료 개입 시점의 결정 및 예후 개선에 기여할 수 있다.

·         목적 : 원인 불명 NORSE(cryptogenic NORSE, cNORSE), 원인 규명된 간질지속상태(etiology-defined status epilepticus, eSE), 그리고 만성 뇌전증 환자에서 급성 뇌 손상의 정도를 정량화하고자 하였다.

·         설계, 환경 및 참가자 :  

-연구 유형: 국제 다기관 단면연구

-연구 기간: 2013년~2025년

-참여 센터: 미국 36개 기관, 캐나다 2개 기관, 이탈리아, 프랑스, 벨기에 각 1개 기관

-대상자: 발작이 지속되는 동안 생물학적 검체 채취가 가능하였던 cNORSE 및 eSE 환자를 포함하였다. 간질지속상태가 없는 비교군으로는 만성 뇌전증 환자 및 건강 대조군을 포함하였으며, 별도의 제외 기준은 적용하지 않았다.

·         노출 : 혈청 및 뇌척수액에서 측정된 신경필라멘트 경쇄(neurofilament light chain, NfL)와 S100-베타(S100B) 단백질 농도.

·         주요 평가지표 : NfL 및 S100B 농도를 기반으로 한 신경세포 및 교세포 손상의 정도를 평가하였으며, 이들 생체표지자와 단기 기능적 예후 간의 연관성을 분석하였다.

 결과 : cNORSE 환자 78명과 eSE 환자 2개 독립 코호트(각각 211명, 73명)가 포함되었다. NfL 농도는 cNORSE에서 eSE 대비 유의하게 높았으며, 뇌척수액에서 약 10배, 혈청에서 약 4배 증가하였다(P < .001). 또한 혈청 NfL은 만성 뇌전증 및 건강 대조군에 비해 약 20배 높은 수준을 보였다.

혈청과 뇌척수액 NfL은 강한 상관관계를 보였고(ρ = 0.75; P < .001), 발병 후 1–3주 사이 급격한 상승을 나타냈다(P < .001). 반면 S100B는 군 간 차이나 시간적 변화 양상이 관찰되지 않았다.

NfL은 cNORSE와 eSE를 구분하는 데 유의한 판별력을 보였으며(AUROC 0.79), 간질지속상태가 없는 군과는 매우 높은 판별력을 나타냈다(AUROC 0.99). 높은 혈청 NfL은 퇴원 시 불량한 기능적 예후와 독립적으로 연관되었다(OR 1.01; P = .03).

·         결론 및 의의 : 본 단면 연구 결과, 상승된 NfL 농도로 반영되는 급성 신경축삭 손상은 cNORSE에서 eSE 및 간질지속상태가 없는 대조군에 비해 현저히 더 큰 것으로 나타났다. 발병 초기 NfL의 급격한 증가는 치료 가능 시간이 제한적임을 시사하며, cNORSE에서 신속하고 효과적이며 잠재적으로 신경보호적인 치료 개입의 필요성을 강조한다.