A Novel Limited-Dose C5 Inhibitor Add-On as Rescue Therapy for Refractory NMOSD Attacks: A Practical Alternative to Conventional Multi-Dose Regimens

A Novel Limited-Dose C5 Inhibitor Add-On as Rescue Therapy for Refractory NMOSD Attacks: A Practical Alternative to Conventional Multi-Dose Regimens | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Novel Limited-Dose C5 Inhibitor Add-On as Rescue Therapy for Refractory NMOSD Attacks: A Practical Alternative to Conventional Multi-Dose Regimens Dianjia Gao, Lei Cui, Miaoxin Yu, Qing Sun, Jinsong Jiao, Yu Wang, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8755894/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract This study evaluated the efficacy and safety of limited-dose eculizumab as rescue therapy for acute neuromyelitis optica spectrum disorder (NMOSD) attacks refractory to first-line treatment. Eight patients (six aquaporin-4 antibody seropositive and two seronegative) with incomplete responses to intravenous methylprednisolone with or without plasma exchange received one to four weekly doses of eculizumab (900 mg). Six patients with severe attacks (median nadir Expanded Disability Status Scale/Visual Outcome Scale: 9.0/11.5) showed only minimal improvement after conventional therapy. The remaining two, although not meeting severe criteria, also responded poorly. Add-on limited-dose eculizumab produced substantial neurological recovery: in myelitis, median Expanded Disability Status Scale improved from 8.5 to 3.5 at three months; in optic neuritis, median Visual Outcome Scale improved from 8.5 to 5.0. The proportion achieving marked-to-moderate improvement rose from 14.3% at one month to 85.7% at three months. Both seronegative patients responded favorably. Treatment was well tolerated, with no serious adverse events. These findings indicate that limited-dose eculizumab is an effective and safe option for accelerating recovery in refractory acute NMOSD attacks and may serve as a practical bridging strategy to long-term immunosuppression. neuromyelitis optica spectrum disorder acute attack refractory eculizumab complement inhibition rescue therapy limited-dose therapy Figures Figure 1 Figure 2 Figure 3 Introduction Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disorder of the central nervous system (CNS) that predominantly affects the optic nerves and spinal cord [ 1 ]. The disease is characterized by frequent relapses and rapid progression, leading to substantial disability in up to 50–60% of untreated patients within five years [ 2 , 3 ]. Attacks are primarily driven by AQP4-IgG–mediated complement activation, resulting in astrocyte injury, demyelination, and neuronal loss [ 4 ]. In some patients, even a single attack can cause irreversible neurological damage [ 5 , 6 ], highlighting the importance of prompt and effective management of acute episodes alongside long-term relapse prevention. High-dose intravenous methylprednisolone (IVMP) and plasma exchange (PLEX) remain the cornerstone of acute-phase therapy [ 7 ]. While these interventions can rapidly control inflammation and remove pathogenic factors, some patients still experience incomplete or delayed neurological recovery [ 8 , 9 ], indicating that current approaches may be insufficient to fully prevent acute attack–related disability. Such limitations underscore the ongoing need for strategies that can further optimize short-term outcomes when combined with standard therapy. Complement component 5 (C5) inhibition selectively blocks complement activation triggered by pathogenic antibodies, thereby reducing downstream CNS injury [ 10 ]. Eculizumab (ECU), the first complement C5 inhibitor approved for AQP4-IgG–seropositive NMOSD, was shown in the phase III PREVENT trial and its open-label extension to reduce the risk of relapse by 94%; notably, 100% of patients receiving ECU monotherapy remained relapse-free for up to 144 weeks [ 11 , 12 ], with accumulating evidence supporting its efficacy in relapse prevention during remission [ 11 , 13 ]. Mechanistically, ECU rapidly blocks peripheral C5 cleavage into C5a and C5b, preventing pro-inflammatory signaling and membrane attack complex–mediated cytolysis [ 14 ]. This pharmacodynamic profile provides a strong rationale for its use during acute NMOSD attacks, where rapid suppression of complement-mediated injury may prevent irreversible damage. Although a few studies have explored acute-phase ECU administration [ 15 – 19 ], available evidence is limited, and standardized guidance on timing, dosing, or integration with conventional immunotherapies is lacking. Its high cost and requirement for sustained intravenous access further limit practicality. We hypothesize that a limited-dose, add-on regimen of ECU could bridge this gap, offering a targeted, effective, and more economically feasible strategy for rescuing refractory attacks. Therefore, this retrospective case series evaluates the efficacy and safety of a novel limited-dose add-on ECU strategy for acute attacks in refractory NMOSD, aiming to generate preliminary clinical evidence and inform future approaches to acute-phase management. Materials and methods Patients and inclusion criteria This single-center, retrospective case series included patients with acute NMOSD attacks admitted to the Department of Neurology, China-Japan Friendship Hospital, between June 2024 and July 2025. Eligible patients met the following criteria: (1) diagnosis of NMOSD, with or without AQP4-IgG, according to the 2015 International Panel for NMO Diagnosis criteria [ 20 ]; (2) admission during an acute attack; (3) receipt of standard acute-phase therapy with IVMP, with or without PLEX; and (4) administration of a limited-dose of ECU (1–4 doses) as a rescue intervention due to incomplete response to conventional therapy. Patients with severe comorbidities, active infections, or other conditions affecting immune status were excluded. Baseline demographic and clinical characteristics, including age, sex, serum AQP4-IgG status, coexistence with other autoimmune disorders, disease duration, prior relapse history, type of acute attack (optic neuritis, myelitis, or others), and concomitant immunotherapies were collected from medical records. Serum AQP4-IgG was measured by an independent laboratory using a cell-based assay. In AQP4-IgG seronegative patients, both myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) and glial fibrillary acidic protein antibodies (GFAP-IgG) were also negative. Treatments All patients received IVMP (500–1000 mg/day for at least 5 days) as first-line therapy. PLEX (3–5 sessions) was performed in cases of poor or incomplete response or severe neurological deficits, with treatment intensity tailored to clinical severity. Severe disabling attacks were defined as a nadir EDSS ≥ 6 or VOS ≥ 5[ 21 , 22 ]. ECU was administered as an add-on limited-dose regimen (900 mg per dose, delivered via 1–4 weekly intravenous infusions) in patients demonstrating insufficient recovery following IVMP ± PLEX. Dosing and timing were individualized. Because ACYW135 meningococcal vaccination was not available during hospitalization, all patients received prophylactic antibiotics during ECU and were vaccinated after discharge. One patient with deep vein thrombosis and pulmonary embolism received an inferior vena cava filter and full-dose anticoagulation, enabling safe ECU administration without PLEX. Concomitant maintenance immunotherapies (oral corticosteroids or other immunosuppressants) were continued or initiated as clinically indicated. Clinical evaluations Clinical data were retrospectively extracted from the hospital electronic medical system. Neurological function was assessed using the EDSS for patients with transverse myelitis (TM) or symptomatic brain lesions, and the VOS for those with optic neuritis (ON). Visual acuity was graded from 1 to 7 per eye based on VOS criteria: 0—20/20; 1—scotoma but better than 20/30; 2—20/30–20/59; 3—20/60–20/199; 4—20/200–20/800; 5—counting fingers only; 6—light perception; 7—no light perception. EDSS and VOS scores were documented at baseline (pre-attack), attack nadir, after IVMP ± PLEX (pre-ECU), as well as at 1 and 3 months after the last ECU dose, representing short- and long-term outcomes, respectively. Treatment response to ECU was assessed based on changes in EDSS or VOS scores. Patients achieving a ≥ 30% reduction at 1 or 3 months post-ECU were classified as having marked-to-moderate improvement (MMI), reflecting complete-to-moderate resolution of attack-related symptoms. Those with < 30% reduction was considered to have mild-to-no improvement (MNI). Patients with pre-ECU EDSS or VOS scores < 3 were not formally evaluated using MMI/MNI criteria due to minimal baseline deficits. All assessments were conducted by experienced neurologists following standardized procedures to ensure consistency and reliability. Neuroimaging and Functional Assessments MRI was performed during the acute phase using a 3.0T scanner (Signa HDX, GE Healthcare, Fairfield, CT, USA). Spinal cord imaging included sagittal, axial, and fat-suppressed sequences covering cervical, thoracic, and lumbar segments; lesions were assessed for location, longitudinal extent, and enhancement on T1-, T2-, and contrast-enhanced sequences. Orbital MRI included axial, sagittal, and coronal planes with fat suppression, with gadolinium-enhanced scans in selected cases. Lesion characteristics, location, and enhancement were documented for each optic nerve segment. Visual fields were tested using automated perimetry (Octopus 900, Haag-Streit AG, Köniz, Switzerland) following standard 30 − 2 protocols, and changes were recorded over time. Safety and Adverse Events Safety monitoring was conducted throughout ECU, IVMP, and PLEX therapy. All adverse events (AEs) occurring during hospitalization and follow-up were documented, including infections, hypersensitivity or infusion-related reactions, thromboembolic events, and other clinically significant complications. Laboratory monitoring was performed before and after ECU administration, including complete blood counts, liver and renal function tests, coagulation profiles, and infectious disease screening. Any abnormal results were recorded and evaluated for potential treatment-related causality. Special attention was given to signs or symptoms suggestive of meningococcal infection or other opportunistic infections, and appropriate prophylactic measures were implemented as indicated. Statistical analysis Statistical analyses were conducted using SPSS (version 26.0). Due to the small sample size and the ordinal nature of the functional scores (EDSS and VOS), non-parametric tests were employed. Continuous variables are presented as medians with interquartile ranges (IQRs). The Wilcoxon signed-rank test was used to compare pre- and post-treatment assessments. A two-sided p-value of less than 0.05 was considered statistically significant. For multiple comparisons, the Bonferroni correction was applied. One patient with unilateral ON did not experience a decline in visual acuity during the acute attack and was therefore excluded from the VOS-based response analysis. Results Baseline Clinical Characteristics The baseline characteristics of the eight patients with acute NMOSD attacks are summarized in Table 1 . The median age at attack onset was 57 years (IQR, 47.5–66.5; range, 34–73), and all patients were female. Six patients were AQP4-IgG seropositive, while two were seronegative. Coexisting autoimmune disorders were present in one patient, including Sjögren’s syndrome. The phenotypes of the acute attacks treated with ECU included three cases of TM and five cases of ON, with four patients having bilateral ON. Five patients experienced their first attack, and three had a history of ≥ 2 prior relapses. The median total disease duration prior to ECU treatment was 21.5 days (IQR, 20.5–27; range, 19–47). Among the three TM patients, two had thoracic longitudinally extensive lesions, while one had a short-segment lesion involving C1–C2. Orbital MRI was performed on four ON patients, all of whom demonstrated T2 hyperintense lesions with gadolinium enhancement. Table 1 Baseline Characteristics and Acute-Phase Treatment of NMOSD Patients Receiving limited-dose Eculizumab Case Age at ECU/Sex ECU-treated attack AQP4-IgG MRI at attack Pre-ISTs therapy Prior acute therapies Response to prior acute therapy Attack-to-ECU interval (days) No. of ECU doses ISTs post-ECU/duration (days) AEs 1 61/F TM + LETM MMF IVMP+PLEX MNI 21 1 INE/14 not report 2 73/F TM + LETM NA IVMP MNI 22 4 SAT/8 not report 3 56/F TM + Short-segment lesion MMF IVMP MNI 21 1 SAT/11 not report 4 34/F UON + NA INE IVMP limited* 20 2 INE/10 not report 5 46/F BON + Long-segment optic nerve enhancement NA IVMP MNI 47 1 INE/7 not report 6 72/F BON + Long-segment optic nerve enhancement NA IVMP+PLEX MNI 26 1 GC/9 not report 7 49/F BON - Long-segment optic nerve enhancement NA IVMP+PLEX MNI 19 1 MMF/11 Anti-HBc seroconversion 8 58/F BON - Long-segment optic nerve enhancement NA IVMP+PLEX MMI 28 2 MMF/8 not report * Patient with unilateral ON relapse, mainly visual field deficits without marked acuity loss; minimal subjective improvement after IVMP, not formally scored by MMI/MNI. Abbreviations: AE, adverse event; Anti-HBc, anti-hepatitis B core antibody; AQP4-IgG, aquaporin-4 antibody; BON, bilateral optic neuritis; ECU, eculizumab; F, female;GC, glucocorticoids; INE, inebilizumab; IST, immunosuppressive therapy; IVMP, intravenous methylprednisolone; LETM, longitudinal extensive transverse myelitis; MMF, mycophenolate mofetil; MMI, marked-to-moderate improvement; MNI, mild-to-no improvement; MRI, magnetic resonance imaging; NA, not available; NMOSD, neuromyelitis optica spectrum disorders; PLEX, plasma exchange; SAT, satralizumab; TM, transverse myelitis; UON, unilateral optic neuritis. Response to Conventional Immunotherapy (IVMP ± PLEX) A comprehensive timeline of all medications administered during and following the acute attack is provided in Fig. 1 . As outlined in Table 1 , all eight patients received high-dose IVMP as first-line therapy at the onset of the attack. Three patients additionally underwent five sessions of PLEX, while one patient received three sessions. Despite these interventions, six patients showed MNI, as detailed in Table 1 and Fig. 2 A, including three patients with TM and three with bilateral optic neuritis ON. Median EDSS scores improved modestly from 9.0 at nadir to 8.5 after IVMP ± PLEX, while median VOS scores in ON patients showed minimal change, from 11.5 to 8.5. These findings highlighting the limited efficacy of conventional immunotherapy in this cohort. One 73-year-old TM patient presented with concomitant lower extremity deep vein thrombosis and pulmonary embolism at admission. Following inferior vena cava filter placement and therapeutic anticoagulation, the patient received IVMP only; after three courses, both lower limbs remained plegic with persistent bladder and bowel dysfunction, and PLEX was not pursued due to contraindications. Among the remaining patients, one with TM exhibited left-hand weakness (Medical Research Council [MRC] grade IV−) accompanied by pain and numbness in the upper limb; IVMP improved motor strength to MRC V−, but sensory symptoms persisted. Another patient with unilateral ON relapse presented predominantly with visual field deficits without marked visual acuity loss; IVMP resulted in only minimal recovery of visual fields. limited-dose Eculizumab Therapy and Outcomes All eight patients received limited-dose ECU therapy (Table 1 and Fig. 1 ). Among the TM patients, two received ECU immediately during or following IVMP: one severe case received four weekly doses, while the other, with primarily residual sensory symptoms, received a single dose. A third severe TM patient received one dose of ECU immediately following IVMP combined with PLEX. For ON patients, three received 1–2 doses of ECU immediately after IVMP + PLEX, whereas the remaining two, whose visual improvement was minimal two weeks after IVMP alone, received 1–2 doses of ECU as a rescue intervention. Neurological outcomes were evaluated at 1 and 3 months post-ECU administration. In TM patients, median EDSS scores improved from 8.5 pre-ECU to 7.5 at 1 month and 3.5 at 3 months. For ON patients, median VOS scores improved from 8.5 pre-ECU to 8.0 at 1 month and 5.0 at 3 months. The proportion of patients achieving MMI was 14.3% at 1 month and 85.7% at 3 months (Fig. 2 A). As shown in Fig. 2 B, the reduction in EDSS/VOS scores from pre-ECU to 3 months post-ECU was significantly greater than that from attack nadir to post-IVMP/PLEX ( P = 0.015). One patient with unilateral ON and predominant visual field deficits showed minimal response to IVMP but reported subjective improvement in blurred vision after two ECU doses. Automated perimetry revealed substantial improvement in visual fields in representative ON cases (Fig. 3 ). Following limited-dose ECU therapy, all patients were transitioned to long-term sequential immunotherapy, with specific agents and intervals detailed in Table 1 . One AQP4-IgG seropositive patient, constrained by financial limitations, continued oral glucocorticosteroids alone. The two AQP4-IgG seronegative ON patients received mycophenolate mofetil, as no approved therapies were available for this subgroup. Throughout the transition to sequential immunotherapy, oral glucocorticosteroids were tapered gradually in all patients, and no relapses occurred during the conversion period. Safety and Adverse Events No allergic or infusion-related reactions occurred during ECU, IVMP, or PLEX administration, and no acute infections were documented during hospitalization or follow-up. One TM patient presented with concomitant lower extremity deep vein thrombosis and pulmonary embolism at admission. After inferior vena cava filter placement and full-dose low-molecular-weight heparin anticoagulation, the patient received IVMP combined with four ECU infusions without adverse impact on thrombosis management. Another patient with bilateral ON, without a prior history of chronic hepatitis B infection, was negative for hepatitis B core antibody (anti-HBc) at admission but tested positive after receiving IVMP + PLEX + one ECU infusion. Hepatitis B surface antigen and other viral markers remained negative, and the patient exhibited no clinical hepatitis. The patient was not given B-cell–depleting therapy; instead, mycophenolate mofetil was initiated. No other treatment-related AEs were identified in the remaining patients. Laboratory monitoring (complete blood counts, liver/renal function, coagulation, infectious disease screening) showed no clinically significant changes attributable to therapy. Discussion Despite the well-established efficacy of C5 inhibitors in preventing relapses during the remission phase of AQP4-IgG seropositive NMOSD [ 23 ], data on their use during acute attacks remain limited, and no standardized guidance exists for acute-phase administration. High-dose IVMP and PLEX, the current first-line therapies, are effective in many cases [ 7 ], yet a subset of patients demonstrates incomplete or delayed neurological recovery, leaving residual deficits [ 24 ]. Historically, clinicians often relied on natural recovery or transitioned patients directly to maintenance immunotherapy, as rapidly acting rescue options were lacking. Our study provides preliminary evidence that limited-dose ECU (1–4 weekly infusions) as an add-on therapy can accelerate neurological recovery during acute NMOSD attacks. Mechanistically, C5 inhibition rapidly interrupts complement-mediated neural injury by blocking membrane attack complex formation, thereby directly halting the key pathogenic pathway of antibody-mediated damage [ 11 ]. While previous studies have predominantly employed longer ECU regimens (multi-dose) for acute-phase recovery [ 15 – 19 ], as systematically compared in Table 2 , our findings demonstrate that even a reduced dosing regimen can lead to meaningful functional improvements in patients inadequately responsive to conventional therapies. Notably, all patients in our cohort successfully transitioned to conventional or other targeted maintenance ISTs, whereas patients in earlier reports largely continued on long-term ECU therapy. This key difference underscores the potential of our approach to alleviate the significant economic and logistical burdens associated with chronic complement inhibition, thereby enhancing treatment accessibility without compromising efficacy. These results support the use of limited-dose ECU as a feasible, low-burden acute-phase rescue therapy that effectively bridges traditional immunotherapies and long-term targeted treatments, offering valuable guidance for real-world management of acute NMOSD attacks. Table 2 Comparative Summary of Eculizumab Use in Acute NMOSD Across Studies Current Study Qingqing Zhuang, 2025 [ 15 ] Mitsuru, 2024 [ 16 ] San-Galli, 2023 [ 17 ] Chatterton, 2022 [ 18 ] Soni, 2025 [ 19 ] Study Design Case series (n = 8) Case series(n = 9) Cases series (n = 5) Cases report (n = 2) Case report (n = 1) Case report (n = 1) Gender/Age 8 F/34-73y 7 F,2 M/25-69y 4 F, 1 M/50-93y 2 F/30-41y F/46y F/10y AQP4-IgG (+/-) 6/2 9/0 5/0 2/0 + + ECU-treated attack 3 TM, 4 BON, 1 UON 2 TM, 2BON, 5UON 1 TM, 1 BS + TM, 2 BON, 1 UON 1 APS + TM, 1 BON + TM+BS UON TM Pre-ISTs therapy MMF: 2, INE: 1, none: 5 MMF: 2, SAT: 1, none: 6 GC: 3, none: 2 MMF: 1, none: 1 none none Acute Treatment IVMP: 4, IVMP+PLEX: 4 IVMP: 7 IVMP+PLEX: 1, IVMP + + IVIG: 1 IVMP+PLEX: 4, IVMP+PLEX +IVIG: 1 IVMP+PLEX: 2 IVMP+PLEX IVMP+PLEX ECU Regimen, doses 1 ~ 4 3 ~ 4 > 4 > 4 > 4 > 4 Time to 1st ECU, days 19 ~ 47 3 ~ 21 30 ~ 61 21, 32 12 16 Primary Efficacy (MMI) 6 4 1 1 1 1 Maintenance Therapy INE: 3, SAT: 2, GC + MMF: 2, GC: 1 MMF: 1, INE: 5, SAT: 1, GC: 1 ECU: 3, TAC: 2 ECU: 2 ECU RTX, ECU Safety Events 1 Anti-HBc seroconversion 1 UTI, 1 PNA Not reported Not reported Not reported Not reported Abbreviations: APS, area postrema syndrome; Anti-HBc,anti-hepatitis B core antibody; AQP4-IgG, aquaporin-4 antibody; BON, bilateral optic neuritis; BS,brainstem syndrome; ECU, eculizumab; F,female; GC, glucocorticoids; INE, inebilizumab; IST, immunosuppressive therapy; IVIG, intravenous immunoglobulin; IVMP, intravenous methylprednisolone; M,male; MMF, mycophenolate mofetil; MMI, marked-to-moderate improvement;NMOSD, neuromyelitis optica spectrum disorders; PNA, Pneumonia; UTI, urinary tract infection; PLEX, plasma exchange; RTX, rituximab; SAT, satralizumab; TAC, tacrolimus; TM, transverse myelitis; UON, unilateral optic neuritis Beyond single-agent use, our findings indicate that synergistic benefits can be achieved by combining ECU with conventional acute-phase therapies without strictly adhering to phase III dosing schedules [ 11 ]. In this context, IVMP and ECU exert their effects at distinct levels of the inflammatory cascade. IVMP broadly dampens immune activation by reducing antibody production, downregulating complement expression, and limiting inflammatory cell recruitment [ 25 ], whereas ECU directly blocks terminal complement activation and membrane attack complex formation [ 26 ]. Acting in concert, they disrupt the full spectrum of antibody-driven injury from both upstream and downstream pathways, enabling rapid control of acute inflammation. Clinically, this was exemplified in our series: four patients treated with IVMP plus ECU demonstrated neurological improvement. Notably, one severe TM case unresponsive to three days of IVMP subsequently improved after four ECU infusions, further underscoring the synergistic effect of this approach. A similar rationale applies to PLEX, which provides rapid clearance of circulating pathogenic antibodies [ 27 ], inflammatory mediators [ 28 ], and activated complement components [ 29 ], but its effects are transient and often followed by rebound. Building on this, our findings suggest that administering 1–2 ECU doses immediately after PLEX can prolong complement inhibition, creating a short- plus long-acting strategy that both mitigates acute injury and bridges the vulnerable period before maintenance immunotherapy takes effect. In our cohort, four patients, including one with severe TM and three with severe ON, received IVMP + PLEX followed by 1–2 ECU doses and achieved favorable recovery within 1–3 months. Importantly, because PLEX non-selectively removes plasma proteins, ECU should not be given beforehand to avoid drug loss. Based on these observations, we propose a stepwise regimen of IVMP and PLEX, followed by 1–2 ECU doses, as a rational approach for severe acute attacks. This sequence maximizes early neurological recovery while preventing therapeutic dead-ends in which ECU alone proves insufficient and subsequent PLEX cannot be promptly applied. Interestingly, two AQP4-IgG seronegative patients in our cohort also responded favorably to limited-dose ECU. Approximately 30% of NMOSD patients are seronegative for AQP4-IgG, and this subgroup may harbor other pathogenic antibodies, such as AQP1-IgG and MOG-IgG [ 30 , 31 ], or yet unidentified autoantibodies. Alternatively, negative findings can reflect technical limitations, assay sensitivity, or timing of testing, meaning that a single negative result does not definitively rule out antibody-mediated pathology. For instance, in our cohort, one patient with bilateral ON had not undergone testing for AQP4-IgG or other demyelinating antibodies at the local hospital and received high-dose corticosteroid therapy during the acute attack, which could have influenced subsequent antibody detection. Despite this, the patient achieved substantial neurological recovery following ECU treatment. Taken together, these observations suggest that limited-dose ECU may offer a valuable rescue option even in patients testing negative for AQP4-IgG. More importantly, our findings contribute novel evidence supporting the use of ECU in seronegative NMOSD, a population largely underrepresented in existing studies. This highlights both the therapeutic potential of complement inhibition in seronegative patients and the need for further systematic investigation in this subgroup. Sequential therapy following ECU requires careful management to prevent disease rebound, as severe relapses have been reported 2–3 months after switching to RTX or SAT [ 32 ]. This risk may result from ECU’s pharmacokinetics, with near-complete clearance after five half-lives (approximately 6–10 weeks) creating a therapeutic gap, reduced efficacy of CDC-mediated B cell depletion due to complement suppression, and persistence of upstream pathogenic antibodies and immune cells that can trigger acute inflammatory surges once complement is reactivated. In our cohort, five of six AQP4-IgG seropositive patients transitioned from limited-dose ECU to INE (ADCC-mediated) or SAT (IgG2, generally complement-independent) with gradual steroid tapering, and none experienced relapse. These findings illustrate a practical strategy for safely bridging complement inhibition to other targeted therapies by considering mechanisms of action, potential drug interactions, pharmacokinetics, and appropriate steroid support. In terms of safety, limited-dose ECU combined with conventional acute-phase immunotherapy was generally well tolerated in our cohort, consistent with findings from phase III studies in the remission phase. However, one patient with bilateral ON, who had no prior history of chronic hepatitis B infection, developed anti-HBc seroconversion following treatment. This case highlights an important consideration for sequential biologic therapy. Even when transitioning between agents over a short interval, it is crucial to re-assess the infectious disease baseline, including screening for hepatitis B, hepatitis C, and tuberculosis, to minimize the risk of infection activation and ensure patient safety. This study has several limitations. It is a single-center, retrospective analysis with a small sample size, limiting generalizability. There was no randomized control group, and all patients received conventional therapy in combination with ECU, making it impossible to attribute improvements solely to ECU. Delayed effects from prior IVMP or PLEX may have contributed. Nevertheless, limited-dose ECU appears to accelerate neurological recovery in this refractory population, particularly in severe attacks, suggesting its potential as a rescue therapy in the acute NMOSD setting. In conclusion, our novel limited-dose, add-on regimen of eculizumab for acute NMOSD attacks was generally well tolerated and facilitated rapid, clinically meaningful neurological and visual recovery, even in patients refractory to conventional first-line therapies. We further demonstrate that a carefully planned transition to alternative maintenance biologics after ECU is feasible and can mitigate rebound risk. These results address the current limitations of acute-phase NMOSD treatment by providing a practical and effective therapeutic option, offering valuable real-world evidence to guide management, and laying a foundation for future prospective studies aimed at optimizing treatment strategies and improving patient outcomes. Declarations Availability of data and materials: All datasets utilized and/or analyzed during the current study are provided within the article. Further information regarding additional data can be obtained upon request from the corresponding authors. Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author contributions: GDJ, ZWH prepared the materials, collected, and analyzed the data and drafted the manuscript; CL, YMX, JJS, SQ, WY, PDT prepared the materials, collected, and analyzed the data; PDT, ZWH revised the manuscript. All authors read and approved the final manuscript. Funding sources: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgements: Not applicable. Clinical trial number: Not applicable. Human Ethics and Consent to Participate declarations: Accordance with the Declaration of Helsinki,the study was approved by the Institutional Review Board of China–Japan Friendship Hospital (Approval No. 2024-KY-242).Informed consent to participate was obtained from all of the participants in the study. Consent for Publication: The participants have provided written informed consent for their personal or clinical details and any identifiable images to be published in this study. 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Monoclonal antibody therapies for aquaporin-4-immunoglobulin G-positive neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease. Saudi J Ophthalmol. 2023;38(1):2–12. 10.4103/sjopt.sjopt_102_23 . Given KS, Acker EG, Macklin WB, Carlin D, Owens GP, Bennett JL. Complement inhibition rapidly blocks lesion extension and facilitates remyelination in neuromyelitis optica. Acta Neuropathol Commun. 2025;13(1):129. 10.1186/s40478-025-02019-7 . Zhuang Q, Huang W, ZhangBao J, et al. Eculizumab for the acute attack of neuromyelitis optica spectrum disorder. Front Immunol. 2025;16:1645401. 10.3389/fimmu.2025.1645401 . Published 2025 Sep 25. Watanabe M, Masaki K, Tanaka E, Matsushita T, Isobe N. The Efficacy of Eculizumab in the Acute Phase of Neuromyelitis Optica Spectrum Disorder: A Case Series Study. Cureus. 2024;16(11):e73205. 10.7759/cureus.73205 . San-Galli A, Chaumont H, Bourgeois Q, Roge J, Lobjois Q, Cabre P. Eculizumab as rescue therapy in a context of dramatic NMOSD attack: Report of two cases. Rev Neurol (Paris). 2024;180(10):995–7. 10.1016/j.neurol.2024.09.001 . Chatterton S, Parratt JDE, Ng K. Eculizumab for acute relapse of neuromyelitis optica spectrum disorder: Case report. Front Neurol. 2022;13:951423. 10.3389/fneur.2022.951423 . Soni RH, Garcia M, Oak E, Applbaum EJ, Rajagopalan L, Krupp LB, O'Neill KA. Acute eculizumab treatment in a pediatric patient with AQP4-IgG+ NMOSD. Mult Scler. 2025;31(5):612–4. 10.1177/13524585241283650 . Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, de Seze J, Fujihara K, Greenberg B, Jacob A, Jarius S, Lana-Peixoto M, Levy M, Simon JH, Tenembaum S, Traboulsee AL, Waters P, Wellik KE, Weinshenker BG. International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177–89. 10.1212/WNL.0000000000001729 . Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444–52. 10.1212/wnl.33.11.1444 . Zhang W, Jiao Y, Cui L, et al. Therapeutic efficacy and safety of plasmapheresis in elderly patients with neuromyelitis optica spectrum disorder: a single-center observational study. Ther Adv Neurol Disord. 2023;16:17562864231162420. 10.1177/17562864231162420 . Published 2023 Mar 23. Paul F, Marignier R, Palace J, Arrambide G, Asgari N, Bennett JL, Cree BAC, De Sèze J, Fujihara K, Kim HJ, Hornby R, Huda S, Kissani N, Kleiter I, Kuwabara S, Lana-Peixoto M, Law L, Leite MI, Pandit L, Pittock SJ, Quan C, Ramanathan S, Rotstein D, Saiz A, Sato DK, Vaknin-Dembinsky A. International Delphi Consensus on the Management of AQP4-IgG+ NMOSD: Recommendations for Eculizumab, Inebilizumab, and Satralizumab. Neurol Neuroimmunol Neuroinflamm. 2023;10(4):e200124. 10.1212/NXI.0000000000200124 . Kleiter I, Gahlen A, Borisow N, Fischer K, Wernecke KD, Wegner B, Hellwig K, Pache F, Ruprecht K, Havla J, Krumbholz M, Kümpfel T, Aktas O, Hartung HP, Ringelstein M, Geis C, Kleinschnitz C, Berthele A, Hemmer B, Angstwurm K, Stellmann JP, Schuster S, Stangel M, Lauda F, Tumani H, Mayer C, Zeltner L, Ziemann U, Linker R, Schwab M, Marziniak M, Then Bergh F, Hofstadt-van Oy U, Neuhaus O, Winkelmann A, Marouf W, Faiss J, Wildemann B, Paul F, Jarius S, Trebst C. Neuromyelitis Optica Study Group. Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses. Ann Neurol. 2016;79(2):206–16. 10.1002/ana.24554 . Wang S, Xue M, Wang J, Wu R, Shao Y, Luo K, Liu J, Zhu M. Effects of intravenous pulse methylprednisolone in neuromyelitis optica during the acute phase. Ann Clin Transl Neurol. 2024;11(10):2731–44. 10.1002/acn3.52188 . Parker CJ, Kar S, Kirkpatrick P, Eculizumab. Nat Rev Drug Discov. 2007;6(7):515–6. 10.1038/nrd2369 . Jarius S, Paul F, Weinshenker BG, Levy M, Kim HJ, Wildemann B. Neuromyelitis optica. Nat Rev Dis Primers. 2020;6(1):85. 10.1038/s41572-020-0214-9 . Zhang W, Cui L, Jiao J, Zhang Y, Ma C, Peng D, Jin M. Decreased NETosis-related regulators in neuromyelitis optica spectrum disorders after plasma exchange. Int Immunopharmacol. 2024;142(Pt B):113234. 10.1016/j.intimp.2024.113234 . Wu Y, Zhong L, Geng J. Neuromyelitis optica spectrum disorder: Pathogenesis, treatment, and experimental models. Mult Scler Relat Disord. 2019;27:412–8. 10.1016/j.msard.2018.12.002 . Pandit L, Asgari N, Apiwattanakul M, Palace J, Paul F, Leite MI, Kleiter I, Chitnis T, GJCF International Clinical Consortium. & Biorepository for Neuromyelitis Optica. Demographic and clinical features of neuromyelitis optica: A review. Mult Scler. 2015;21(7):845–53. 10.1177/1352458515572406 . Mader S, Brimberg L. Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease. Cells. 2019;8(2):90. 10.3390/cells8020090 . Maillart E, Dubessy AL, Shor N, Piljan M, Decombe R, Lubetzki C, Stankoff B, Marignier R, Beigneux Y. Severe Relapse After Switching From Eculizumab to Satralizumab in Neuromyelitis Optica Spectrum Disorder. Neurology. 2025;104(5):e213399. 10.1212/WNL.0000000000213399 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 23 Mar, 2026 Reviews received at journal 22 Mar, 2026 Reviews received at journal 12 Mar, 2026 Reviewers agreed at journal 04 Mar, 2026 Reviewers agreed at journal 26 Feb, 2026 Reviewers agreed at journal 25 Feb, 2026 Reviewers invited by journal 25 Feb, 2026 Editor assigned by journal 25 Feb, 2026 Editor invited by journal 17 Feb, 2026 Submission checks completed at journal 17 Feb, 2026 First submitted to journal 17 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8755894","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":598836784,"identity":"6716ebdd-1004-4ec2-ab6f-099208e3891a","order_by":0,"name":"Dianjia Gao","email":"","orcid":"","institution":"China-Japan Friendship Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dianjia","middleName":"","lastName":"Gao","suffix":""},{"id":598836794,"identity":"96207ce3-00ec-4960-bb7c-953c2a0c5fb3","order_by":1,"name":"Lei Cui","email":"","orcid":"","institution":"China-Japan Friendship Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Cui","suffix":""},{"id":598836796,"identity":"4f581197-fb4d-4650-963b-68964d64c41b","order_by":2,"name":"Miaoxin Yu","email":"","orcid":"","institution":"China-Japan Friendship Hospital","correspondingAuthor":false,"prefix":"","firstName":"Miaoxin","middleName":"","lastName":"Yu","suffix":""},{"id":598836797,"identity":"f86bd025-1fbe-4754-9274-bf8102a2916f","order_by":3,"name":"Qing Sun","email":"","orcid":"","institution":"China-Japan Friendship Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qing","middleName":"","lastName":"Sun","suffix":""},{"id":598836798,"identity":"41dcd000-d226-45ec-8d89-38e98025a2f0","order_by":4,"name":"Jinsong Jiao","email":"","orcid":"","institution":"China-Japan Friendship Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jinsong","middleName":"","lastName":"Jiao","suffix":""},{"id":598836799,"identity":"6a02626e-3930-4947-84f0-cf854a1865cb","order_by":5,"name":"Yu Wang","email":"","orcid":"","institution":"China-Japan Friendship Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Wang","suffix":""},{"id":598836800,"identity":"3edf6d78-89bd-4619-8ab2-484f29871ef7","order_by":6,"name":"Dantao Peng","email":"","orcid":"","institution":"China-Japan Friendship Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dantao","middleName":"","lastName":"Peng","suffix":""},{"id":598836801,"identity":"a8009eea-5565-498a-b5e0-17d8db557cb0","order_by":7,"name":"Weihe Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtElEQVRIiWNgGAWjYLCCxAYGOTb29gOkaTHm4zmTQIIWxgaGxHkSDgbEqZZv4DF88HCHTXqbBEMCw4+KbcRYwGNskHgmLbdNuvEAY8+Z24S1MDPwbpNIbDuc2yZzIIGZsY0ILWwMvNt/JLb9T2eTSDAgTgsP0BaGxLYDCcRrkWDg/wx0WLJhGzCQDxLlF/kGtsSPP9vs5OXb2w8++FFBhBYG+QcI9gEi1I+CUTAKRsEoIAYAABgROAlkImdxAAAAAElFTkSuQmCC","orcid":"","institution":"China-Japan Friendship Hospital","correspondingAuthor":true,"prefix":"","firstName":"Weihe","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2026-02-01 11:53:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8755894/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8755894/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104168919,"identity":"b1fe2c80-c4c0-42c6-84c8-597059627bc3","added_by":"auto","created_at":"2026-03-08 14:36:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":81137,"visible":true,"origin":"","legend":"\u003cp\u003eTimeline of medications administered during and after acute NMOSD attacks.\u003c/p\u003e\n\u003cp\u003eAbbreviations: AQP4-IgG, aquaporin-4 antibody; GC, glucocorticoids; INE, inebilizumab; IVMP, intravenous methylprednisolone; MMF, mycophenolate mofetil; PLEX, plasma exchange; SAT, satralizumab.\u003c/p\u003e","description":"","filename":"Figure1..png","url":"https://assets-eu.researchsquare.com/files/rs-8755894/v1/60e220a634d95094994ca214.png"},{"id":104168917,"identity":"5494cb87-c45d-4734-b97f-4b39e85e88bd","added_by":"auto","created_at":"2026-03-08 14:36:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":96208,"visible":true,"origin":"","legend":"\u003cp\u003e(\u003cstrong\u003eA\u003c/strong\u003e) EDSS and VOS scores at key time points: baseline, attack nadir, post-IVMP ± PLEX (pre-ECU), and at 1- and 3-month follow-up after ECU therapy. (\u003cstrong\u003eB\u003c/strong\u003e) Comparison of the average reduction in EDSS/VOS scores across three intervals: from nadir to pre-ECU, from pre-ECU to 1-month post-ECU, and from pre-ECU to 3 months post-ECU.\u003c/p\u003e\n\u003cp\u003eAbbreviations: ECU, eculizumab; EDSS, expanded disability status scale; VOS, visual outcome scale.\u003c/p\u003e","description":"","filename":"Figure2..png","url":"https://assets-eu.researchsquare.com/files/rs-8755894/v1/11c1162667d814245cb0cb16.png"},{"id":104168918,"identity":"1619b523-ad82-4f4e-b669-c84a29d493f4","added_by":"auto","created_at":"2026-03-08 14:36:04","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":678166,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative visual field and acuity improvements following limited-dose ECU in two patients with ON. \u003cstrong\u003e(A)\u003c/strong\u003eCase 5: AQP4-IgG seropositive patient with bilateral optic neuritis. Localized defect on visual field of the right eye persisted following initial treatment with IVMP. After one dose of ECU, follow-up at 34 days showed a reduction in the size and density of the defect. Continued improvement was observed at the 50-day follow-up.\u003cstrong\u003e (B)\u003c/strong\u003e Case 7: AQP4-IgG seronegative patient with bilateral optic neuritis refractory to IVMP and PLEX. Visual fields of both eyes demonstrated persistent deficits post-IVMP/PLEX. After one add-on dose of ECU, modest improvement was observed at 7 days. Marked and progressive restoration of the visual field was evident at the 36-day follow-up, which correlated with a significant improvement in CVA.\u003c/p\u003e\n\u003cp\u003eAbbreviations: CF, counting fingers; CVA, corrected visual acuity; ECU, eculizumab; HM, hand motion; IVMP, intravenous methylprednisolone; PLEX, plasma exchange.\u003c/p\u003e","description":"","filename":"figure3..png","url":"https://assets-eu.researchsquare.com/files/rs-8755894/v1/15d1e976d582a5bce4e8761d.png"},{"id":105033474,"identity":"a3224d2b-2d63-412d-ad71-5f426a6f9b3d","added_by":"auto","created_at":"2026-03-20 07:17:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1756829,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8755894/v1/5c7b115a-8682-4f93-ba8b-e8bb88a5b077.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Novel Limited-Dose C5 Inhibitor Add-On as Rescue Therapy for Refractory NMOSD Attacks: A Practical Alternative to Conventional Multi-Dose Regimens","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disorder of the central nervous system (CNS) that predominantly affects the optic nerves and spinal cord [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The disease is characterized by frequent relapses and rapid progression, leading to substantial disability in up to 50\u0026ndash;60% of untreated patients within five years [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Attacks are primarily driven by AQP4-IgG\u0026ndash;mediated complement activation, resulting in astrocyte injury, demyelination, and neuronal loss [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In some patients, even a single attack can cause irreversible neurological damage [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], highlighting the importance of prompt and effective management of acute episodes alongside long-term relapse prevention. High-dose intravenous methylprednisolone (IVMP) and plasma exchange (PLEX) remain the cornerstone of acute-phase therapy [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. While these interventions can rapidly control inflammation and remove pathogenic factors, some patients still experience incomplete or delayed neurological recovery [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], indicating that current approaches may be insufficient to fully prevent acute attack\u0026ndash;related disability. Such limitations underscore the ongoing need for strategies that can further optimize short-term outcomes when combined with standard therapy.\u003c/p\u003e \u003cp\u003eComplement component 5 (C5) inhibition selectively blocks complement activation triggered by pathogenic antibodies, thereby reducing downstream CNS injury [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Eculizumab (ECU), the first complement C5 inhibitor approved for AQP4-IgG\u0026ndash;seropositive NMOSD, was shown in the phase III PREVENT trial and its open-label extension to reduce the risk of relapse by 94%; notably, 100% of patients receiving ECU monotherapy remained relapse-free for up to 144 weeks [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], with accumulating evidence supporting its efficacy in relapse prevention during remission [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Mechanistically, ECU rapidly blocks peripheral C5 cleavage into C5a and C5b, preventing pro-inflammatory signaling and membrane attack complex\u0026ndash;mediated cytolysis [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This pharmacodynamic profile provides a strong rationale for its use during acute NMOSD attacks, where rapid suppression of complement-mediated injury may prevent irreversible damage.\u003c/p\u003e \u003cp\u003eAlthough a few studies have explored acute-phase ECU administration [\u003cspan additionalcitationids=\"CR16 CR17 CR18\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], available evidence is limited, and standardized guidance on timing, dosing, or integration with conventional immunotherapies is lacking. Its high cost and requirement for sustained intravenous access further limit practicality. We hypothesize that a limited-dose, add-on regimen of ECU could bridge this gap, offering a targeted, effective, and more economically feasible strategy for rescuing refractory attacks. Therefore, this retrospective case series evaluates the efficacy and safety of a novel limited-dose add-on ECU strategy for acute attacks in refractory NMOSD, aiming to generate preliminary clinical evidence and inform future approaches to acute-phase management.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients and inclusion criteria\u003c/h2\u003e \u003cp\u003eThis single-center, retrospective case series included patients with acute NMOSD attacks admitted to the Department of Neurology, China-Japan Friendship Hospital, between June 2024 and July 2025. Eligible patients met the following criteria: (1) diagnosis of NMOSD, with or without AQP4-IgG, according to the 2015 International Panel for NMO Diagnosis criteria [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]; (2) admission during an acute attack; (3) receipt of standard acute-phase therapy with IVMP, with or without PLEX; and (4) administration of a limited-dose of ECU (1\u0026ndash;4 doses) as a rescue intervention due to incomplete response to conventional therapy. Patients with severe comorbidities, active infections, or other conditions affecting immune status were excluded. Baseline demographic and clinical characteristics, including age, sex, serum AQP4-IgG status, coexistence with other autoimmune disorders, disease duration, prior relapse history, type of acute attack (optic neuritis, myelitis, or others), and concomitant immunotherapies were collected from medical records. Serum AQP4-IgG was measured by an independent laboratory using a cell-based assay. In AQP4-IgG seronegative patients, both myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) and glial fibrillary acidic protein antibodies (GFAP-IgG) were also negative.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTreatments\u003c/h3\u003e\n\u003cp\u003eAll patients received IVMP (500\u0026ndash;1000 mg/day for at least 5 days) as first-line therapy. PLEX (3\u0026ndash;5 sessions) was performed in cases of poor or incomplete response or severe neurological deficits, with treatment intensity tailored to clinical severity. Severe disabling attacks were defined as a nadir EDSS\u0026thinsp;\u0026ge;\u0026thinsp;6 or VOS\u0026thinsp;\u0026ge;\u0026thinsp;5[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. ECU was administered as an add-on limited-dose regimen (900 mg per dose, delivered via 1\u0026ndash;4 weekly intravenous infusions) in patients demonstrating insufficient recovery following IVMP\u0026thinsp;\u0026plusmn;\u0026thinsp;PLEX. Dosing and timing were individualized. Because ACYW135 meningococcal vaccination was not available during hospitalization, all patients received prophylactic antibiotics during ECU and were vaccinated after discharge.\u003c/p\u003e \u003cp\u003eOne patient with deep vein thrombosis and pulmonary embolism received an inferior vena cava filter and full-dose anticoagulation, enabling safe ECU administration without PLEX. Concomitant maintenance immunotherapies (oral corticosteroids or other immunosuppressants) were continued or initiated as clinically indicated.\u003c/p\u003e\n\u003ch3\u003eClinical evaluations\u003c/h3\u003e\n\u003cp\u003eClinical data were retrospectively extracted from the hospital electronic medical system. Neurological function was assessed using the EDSS for patients with transverse myelitis (TM) or symptomatic brain lesions, and the VOS for those with optic neuritis (ON). Visual acuity was graded from 1 to 7 per eye based on VOS criteria: 0\u0026mdash;20/20; 1\u0026mdash;scotoma but better than 20/30; 2\u0026mdash;20/30\u0026ndash;20/59; 3\u0026mdash;20/60\u0026ndash;20/199; 4\u0026mdash;20/200\u0026ndash;20/800; 5\u0026mdash;counting fingers only; 6\u0026mdash;light perception; 7\u0026mdash;no light perception. EDSS and VOS scores were documented at baseline (pre-attack), attack nadir, after IVMP\u0026thinsp;\u0026plusmn;\u0026thinsp;PLEX (pre-ECU), as well as at 1 and 3 months after the last ECU dose, representing short- and long-term outcomes, respectively.\u003c/p\u003e \u003cp\u003eTreatment response to ECU was assessed based on changes in EDSS or VOS scores. Patients achieving a\u0026thinsp;\u0026ge;\u0026thinsp;30% reduction at 1 or 3 months post-ECU were classified as having marked-to-moderate improvement (MMI), reflecting complete-to-moderate resolution of attack-related symptoms. Those with \u0026lt;\u0026thinsp;30% reduction was considered to have mild-to-no improvement (MNI). Patients with pre-ECU EDSS or VOS scores\u0026thinsp;\u0026lt;\u0026thinsp;3 were not formally evaluated using MMI/MNI criteria due to minimal baseline deficits. All assessments were conducted by experienced neurologists following standardized procedures to ensure consistency and reliability.\u003c/p\u003e\n\u003ch3\u003eNeuroimaging and Functional Assessments\u003c/h3\u003e\n\u003cp\u003eMRI was performed during the acute phase using a 3.0T scanner (Signa HDX, GE Healthcare, Fairfield, CT, USA). Spinal cord imaging included sagittal, axial, and fat-suppressed sequences covering cervical, thoracic, and lumbar segments; lesions were assessed for location, longitudinal extent, and enhancement on T1-, T2-, and contrast-enhanced sequences. Orbital MRI included axial, sagittal, and coronal planes with fat suppression, with gadolinium-enhanced scans in selected cases. Lesion characteristics, location, and enhancement were documented for each optic nerve segment.\u003c/p\u003e \u003cp\u003eVisual fields were tested using automated perimetry (Octopus 900, Haag-Streit AG, K\u0026ouml;niz, Switzerland) following standard 30\u0026thinsp;\u0026minus;\u0026thinsp;2 protocols, and changes were recorded over time.\u003c/p\u003e\n\u003ch3\u003eSafety and Adverse Events\u003c/h3\u003e\n\u003cp\u003eSafety monitoring was conducted throughout ECU, IVMP, and PLEX therapy. All adverse events (AEs) occurring during hospitalization and follow-up were documented, including infections, hypersensitivity or infusion-related reactions, thromboembolic events, and other clinically significant complications. Laboratory monitoring was performed before and after ECU administration, including complete blood counts, liver and renal function tests, coagulation profiles, and infectious disease screening. Any abnormal results were recorded and evaluated for potential treatment-related causality. Special attention was given to signs or symptoms suggestive of meningococcal infection or other opportunistic infections, and appropriate prophylactic measures were implemented as indicated.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were conducted using SPSS (version 26.0). Due to the small sample size and the ordinal nature of the functional scores (EDSS and VOS), non-parametric tests were employed. Continuous variables are presented as medians with interquartile ranges (IQRs). The Wilcoxon signed-rank test was used to compare pre- and post-treatment assessments. A two-sided p-value of less than 0.05 was considered statistically significant. For multiple comparisons, the Bonferroni correction was applied. One patient with unilateral ON did not experience a decline in visual acuity during the acute attack and was therefore excluded from the VOS-based response analysis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eBaseline Clinical Characteristics\u003c/h2\u003e \u003cp\u003eThe baseline characteristics of the eight patients with acute NMOSD attacks are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age at attack onset was 57 years (IQR, 47.5\u0026ndash;66.5; range, 34\u0026ndash;73), and all patients were female. Six patients were AQP4-IgG seropositive, while two were seronegative. Coexisting autoimmune disorders were present in one patient, including Sj\u0026ouml;gren\u0026rsquo;s syndrome. The phenotypes of the acute attacks treated with ECU included three cases of TM and five cases of ON, with four patients having bilateral ON. Five patients experienced their first attack, and three had a history of \u0026ge;\u0026thinsp;2 prior relapses. The median total disease duration prior to ECU treatment was 21.5 days (IQR, 20.5\u0026ndash;27; range, 19\u0026ndash;47). Among the three TM patients, two had thoracic longitudinally extensive lesions, while one had a short-segment lesion involving C1\u0026ndash;C2. Orbital MRI was performed on four ON patients, all of whom demonstrated T2 hyperintense lesions with gadolinium enhancement.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Characteristics and Acute-Phase Treatment of NMOSD Patients Receiving limited-dose Eculizumab\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge at ECU/Sex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eECU-treated attack\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAQP4-IgG\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMRI at attack\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePre-ISTs therapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePrior acute therapies\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eResponse to prior acute therapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAttack-to-ECU interval\u003c/p\u003e \u003cp\u003e(days)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNo. of ECU doses\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eISTs post-ECU/duration (days)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eAEs\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLETM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIVMP+PLEX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMNI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eINE/14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003enot report\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLETM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIVMP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMNI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eSAT/8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003enot report\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eShort-segment lesion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIVMP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMNI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eSAT/11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003enot report\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUON\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIVMP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003elimited*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eINE/10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003enot report\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBON\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLong-segment optic nerve enhancement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIVMP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMNI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eINE/7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003enot report\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBON\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLong-segment optic nerve enhancement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIVMP+PLEX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMNI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eGC/9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003enot report\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBON\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLong-segment optic nerve enhancement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIVMP+PLEX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMNI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eMMF/11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eAnti-HBc seroconversion\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBON\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLong-segment optic nerve enhancement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIVMP+PLEX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eMMF/8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003enot report\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e* Patient with unilateral ON relapse, mainly visual field deficits without marked acuity loss; minimal subjective improvement after IVMP, not formally scored by MMI/MNI.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003eAbbreviations: AE, adverse event; Anti-HBc, anti-hepatitis B core antibody; AQP4-IgG, aquaporin-4 antibody; BON, bilateral optic neuritis; ECU, eculizumab; F, female;GC, glucocorticoids; INE, inebilizumab; IST, immunosuppressive therapy; IVMP, intravenous methylprednisolone; LETM, longitudinal extensive transverse myelitis; MMF, mycophenolate mofetil; MMI, marked-to-moderate improvement; MNI, mild-to-no improvement; MRI, magnetic resonance imaging; NA, not available; NMOSD, neuromyelitis optica spectrum disorders; PLEX, plasma exchange; SAT, satralizumab; TM, transverse myelitis; UON, unilateral optic neuritis.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eResponse to Conventional Immunotherapy (IVMP\u0026thinsp;\u0026plusmn;\u0026thinsp;PLEX)\u003c/h2\u003e \u003cp\u003eA comprehensive timeline of all medications administered during and following the acute attack is provided in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. As outlined in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, all eight patients received high-dose IVMP as first-line therapy at the onset of the attack. Three patients additionally underwent five sessions of PLEX, while one patient received three sessions. Despite these interventions, six patients showed MNI, as detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, including three patients with TM and three with bilateral optic neuritis ON. Median EDSS scores improved modestly from 9.0 at nadir to 8.5 after IVMP\u0026thinsp;\u0026plusmn;\u0026thinsp;PLEX, while median VOS scores in ON patients showed minimal change, from 11.5 to 8.5. These findings highlighting the limited efficacy of conventional immunotherapy in this cohort.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOne 73-year-old TM patient presented with concomitant lower extremity deep vein thrombosis and pulmonary embolism at admission. Following inferior vena cava filter placement and therapeutic anticoagulation, the patient received IVMP only; after three courses, both lower limbs remained plegic with persistent bladder and bowel dysfunction, and PLEX was not pursued due to contraindications. Among the remaining patients, one with TM exhibited left-hand weakness (Medical Research Council [MRC] grade IV\u0026minus;) accompanied by pain and numbness in the upper limb; IVMP improved motor strength to MRC V\u0026minus;, but sensory symptoms persisted. Another patient with unilateral ON relapse presented predominantly with visual field deficits without marked visual acuity loss; IVMP resulted in only minimal recovery of visual fields.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003elimited-dose Eculizumab Therapy and Outcomes\u003c/h2\u003e \u003cp\u003eAll eight patients received limited-dose ECU therapy (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Among the TM patients, two received ECU immediately during or following IVMP: one severe case received four weekly doses, while the other, with primarily residual sensory symptoms, received a single dose. A third severe TM patient received one dose of ECU immediately following IVMP combined with PLEX. For ON patients, three received 1\u0026ndash;2 doses of ECU immediately after IVMP\u0026thinsp;+\u0026thinsp;PLEX, whereas the remaining two, whose visual improvement was minimal two weeks after IVMP alone, received 1\u0026ndash;2 doses of ECU as a rescue intervention.\u003c/p\u003e \u003cp\u003eNeurological outcomes were evaluated at 1 and 3 months post-ECU administration. In TM patients, median EDSS scores improved from 8.5 pre-ECU to 7.5 at 1 month and 3.5 at 3 months. For ON patients, median VOS scores improved from 8.5 pre-ECU to 8.0 at 1 month and 5.0 at 3 months. The proportion of patients achieving MMI was 14.3% at 1 month and 85.7% at 3 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB, the reduction in EDSS/VOS scores from pre-ECU to 3 months post-ECU was significantly greater than that from attack nadir to post-IVMP/PLEX (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015). One patient with unilateral ON and predominant visual field deficits showed minimal response to IVMP but reported subjective improvement in blurred vision after two ECU doses. Automated perimetry revealed substantial improvement in visual fields in representative ON cases (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFollowing limited-dose ECU therapy, all patients were transitioned to long-term sequential immunotherapy, with specific agents and intervals detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. One AQP4-IgG seropositive patient, constrained by financial limitations, continued oral glucocorticosteroids alone. The two AQP4-IgG seronegative ON patients received mycophenolate mofetil, as no approved therapies were available for this subgroup. Throughout the transition to sequential immunotherapy, oral glucocorticosteroids were tapered gradually in all patients, and no relapses occurred during the conversion period.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSafety and Adverse Events\u003c/h2\u003e \u003cp\u003eNo allergic or infusion-related reactions occurred during ECU, IVMP, or PLEX administration, and no acute infections were documented during hospitalization or follow-up.\u003c/p\u003e \u003cp\u003eOne TM patient presented with concomitant lower extremity deep vein thrombosis and pulmonary embolism at admission. After inferior vena cava filter placement and full-dose low-molecular-weight heparin anticoagulation, the patient received IVMP combined with four ECU infusions without adverse impact on thrombosis management. Another patient with bilateral ON, without a prior history of chronic hepatitis B infection, was negative for hepatitis B core antibody (anti-HBc) at admission but tested positive after receiving IVMP\u0026thinsp;+\u0026thinsp;PLEX\u0026thinsp;+\u0026thinsp;one ECU infusion. Hepatitis B surface antigen and other viral markers remained negative, and the patient exhibited no clinical hepatitis. The patient was not given B-cell\u0026ndash;depleting therapy; instead, mycophenolate mofetil was initiated.\u003c/p\u003e \u003cp\u003eNo other treatment-related AEs were identified in the remaining patients. Laboratory monitoring (complete blood counts, liver/renal function, coagulation, infectious disease screening) showed no clinically significant changes attributable to therapy.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eDespite the well-established efficacy of C5 inhibitors in preventing relapses during the remission phase of AQP4-IgG seropositive NMOSD [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], data on their use during acute attacks remain limited, and no standardized guidance exists for acute-phase administration. High-dose IVMP and PLEX, the current first-line therapies, are effective in many cases [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], yet a subset of patients demonstrates incomplete or delayed neurological recovery, leaving residual deficits [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Historically, clinicians often relied on natural recovery or transitioned patients directly to maintenance immunotherapy, as rapidly acting rescue options were lacking.\u003c/p\u003e \u003cp\u003eOur study provides preliminary evidence that limited-dose ECU (1\u0026ndash;4 weekly infusions) as an add-on therapy can accelerate neurological recovery during acute NMOSD attacks. Mechanistically, C5 inhibition rapidly interrupts complement-mediated neural injury by blocking membrane attack complex formation, thereby directly halting the key pathogenic pathway of antibody-mediated damage [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. While previous studies have predominantly employed longer ECU regimens (multi-dose) for acute-phase recovery [\u003cspan additionalcitationids=\"CR16 CR17 CR18\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], as systematically compared in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, our findings demonstrate that even a reduced dosing regimen can lead to meaningful functional improvements in patients inadequately responsive to conventional therapies. Notably, all patients in our cohort successfully transitioned to conventional or other targeted maintenance ISTs, whereas patients in earlier reports largely continued on long-term ECU therapy. This key difference underscores the potential of our approach to alleviate the significant economic and logistical burdens associated with chronic complement inhibition, thereby enhancing treatment accessibility without compromising efficacy. These results support the use of limited-dose ECU as a feasible, low-burden acute-phase rescue therapy that effectively bridges traditional immunotherapies and long-term targeted treatments, offering valuable guidance for real-world management of acute NMOSD attacks.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eComparative Summary of Eculizumab Use in Acute NMOSD Across Studies\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCurrent Study\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eQingqing Zhuang, 2025 [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMitsuru,\u003c/p\u003e \u003cp\u003e2024 [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSan-Galli,\u003c/p\u003e \u003cp\u003e2023 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eChatterton,\u003c/p\u003e \u003cp\u003e2022 [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSoni,\u003c/p\u003e \u003cp\u003e2025 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStudy Design\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCase series (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase series(n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCases series (n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCases report (n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCase report (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCase report (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender/Age\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 F/34-73y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 F,2 M/25-69y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 F, 1 M/50-93y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 F/30-41y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eF/46y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eF/10y\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAQP4-IgG (+/-)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9/0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5/0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2/0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECU-treated attack\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 TM, 4 BON, 1 UON\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 TM, 2BON, 5UON\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 TM, 1 BS\u0026thinsp;+\u0026thinsp;TM, 2 BON, 1 UON\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 APS\u0026thinsp;+\u0026thinsp;TM,\u003c/p\u003e \u003cp\u003e1 BON\u0026thinsp;+\u0026thinsp;TM+BS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eUON\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eTM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePre-ISTs therapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMMF: 2, INE: 1, none: 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMMF: 2, SAT: 1, none: 6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGC: 3, none: 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMMF: 1, none: 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAcute Treatment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIVMP: 4,\u003c/p\u003e \u003cp\u003eIVMP+PLEX: 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVMP: 7\u003c/p\u003e \u003cp\u003eIVMP+PLEX: 1, IVMP\u0026thinsp;+\u0026thinsp;+\u0026thinsp;IVIG: 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIVMP+PLEX: 4, IVMP+PLEX +IVIG: 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIVMP+PLEX: 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIVMP+PLEX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIVMP+PLEX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECU Regimen, doses\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u0026thinsp;~\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u0026thinsp;~\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTime to 1st ECU, days\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u0026thinsp;~\u0026thinsp;47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u0026thinsp;~\u0026thinsp;21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30\u0026thinsp;~\u0026thinsp;61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21, 32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrimary Efficacy (MMI)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaintenance Therapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eINE: 3, SAT: 2, GC\u0026thinsp;+\u0026thinsp;MMF: 2, GC: 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMMF: 1, INE: 5, SAT: 1, GC: 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eECU: 3, TAC: 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eECU: 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eECU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRTX, ECU\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSafety Events\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 Anti-HBc seroconversion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 UTI, 1 PNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNot reported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNot reported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNot reported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNot reported\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAbbreviations: APS, area postrema syndrome; Anti-HBc,anti-hepatitis B core antibody; AQP4-IgG, aquaporin-4 antibody; BON, bilateral optic neuritis; BS,brainstem syndrome; ECU, eculizumab; F,female; GC, glucocorticoids; INE, inebilizumab; IST, immunosuppressive therapy; IVIG, intravenous immunoglobulin; IVMP, intravenous methylprednisolone; M,male; MMF, mycophenolate mofetil; MMI, marked-to-moderate improvement;NMOSD, neuromyelitis optica spectrum disorders; PNA, Pneumonia; UTI, urinary tract infection; PLEX, plasma exchange; RTX, rituximab; SAT, satralizumab; TAC, tacrolimus; TM, transverse myelitis; UON, unilateral optic neuritis\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBeyond single-agent use, our findings indicate that synergistic benefits can be achieved by combining ECU with conventional acute-phase therapies without strictly adhering to phase III dosing schedules [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In this context, IVMP and ECU exert their effects at distinct levels of the inflammatory cascade. IVMP broadly dampens immune activation by reducing antibody production, downregulating complement expression, and limiting inflammatory cell recruitment [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], whereas ECU directly blocks terminal complement activation and membrane attack complex formation [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Acting in concert, they disrupt the full spectrum of antibody-driven injury from both upstream and downstream pathways, enabling rapid control of acute inflammation. Clinically, this was exemplified in our series: four patients treated with IVMP plus ECU demonstrated neurological improvement. Notably, one severe TM case unresponsive to three days of IVMP subsequently improved after four ECU infusions, further underscoring the synergistic effect of this approach.\u003c/p\u003e \u003cp\u003eA similar rationale applies to PLEX, which provides rapid clearance of circulating pathogenic antibodies [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], inflammatory mediators [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], and activated complement components [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], but its effects are transient and often followed by rebound. Building on this, our findings suggest that administering 1\u0026ndash;2 ECU doses immediately after PLEX can prolong complement inhibition, creating a short- plus long-acting strategy that both mitigates acute injury and bridges the vulnerable period before maintenance immunotherapy takes effect. In our cohort, four patients, including one with severe TM and three with severe ON, received IVMP\u0026thinsp;+\u0026thinsp;PLEX followed by 1\u0026ndash;2 ECU doses and achieved favorable recovery within 1\u0026ndash;3 months. Importantly, because PLEX non-selectively removes plasma proteins, ECU should not be given beforehand to avoid drug loss. Based on these observations, we propose a stepwise regimen of IVMP and PLEX, followed by 1\u0026ndash;2 ECU doses, as a rational approach for severe acute attacks. This sequence maximizes early neurological recovery while preventing therapeutic dead-ends in which ECU alone proves insufficient and subsequent PLEX cannot be promptly applied.\u003c/p\u003e \u003cp\u003eInterestingly, two AQP4-IgG seronegative patients in our cohort also responded favorably to limited-dose ECU. Approximately 30% of NMOSD patients are seronegative for AQP4-IgG, and this subgroup may harbor other pathogenic antibodies, such as AQP1-IgG and MOG-IgG [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], or yet unidentified autoantibodies. Alternatively, negative findings can reflect technical limitations, assay sensitivity, or timing of testing, meaning that a single negative result does not definitively rule out antibody-mediated pathology. For instance, in our cohort, one patient with bilateral ON had not undergone testing for AQP4-IgG or other demyelinating antibodies at the local hospital and received high-dose corticosteroid therapy during the acute attack, which could have influenced subsequent antibody detection. Despite this, the patient achieved substantial neurological recovery following ECU treatment. Taken together, these observations suggest that limited-dose ECU may offer a valuable rescue option even in patients testing negative for AQP4-IgG. More importantly, our findings contribute novel evidence supporting the use of ECU in seronegative NMOSD, a population largely underrepresented in existing studies. This highlights both the therapeutic potential of complement inhibition in seronegative patients and the need for further systematic investigation in this subgroup.\u003c/p\u003e \u003cp\u003eSequential therapy following ECU requires careful management to prevent disease rebound, as severe relapses have been reported 2\u0026ndash;3 months after switching to RTX or SAT [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. This risk may result from ECU\u0026rsquo;s pharmacokinetics, with near-complete clearance after five half-lives (approximately 6\u0026ndash;10 weeks) creating a therapeutic gap, reduced efficacy of CDC-mediated B cell depletion due to complement suppression, and persistence of upstream pathogenic antibodies and immune cells that can trigger acute inflammatory surges once complement is reactivated. In our cohort, five of six AQP4-IgG seropositive patients transitioned from limited-dose ECU to INE (ADCC-mediated) or SAT (IgG2, generally complement-independent) with gradual steroid tapering, and none experienced relapse. These findings illustrate a practical strategy for safely bridging complement inhibition to other targeted therapies by considering mechanisms of action, potential drug interactions, pharmacokinetics, and appropriate steroid support.\u003c/p\u003e \u003cp\u003eIn terms of safety, limited-dose ECU combined with conventional acute-phase immunotherapy was generally well tolerated in our cohort, consistent with findings from phase III studies in the remission phase. However, one patient with bilateral ON, who had no prior history of chronic hepatitis B infection, developed anti-HBc seroconversion following treatment. This case highlights an important consideration for sequential biologic therapy. Even when transitioning between agents over a short interval, it is crucial to re-assess the infectious disease baseline, including screening for hepatitis B, hepatitis C, and tuberculosis, to minimize the risk of infection activation and ensure patient safety.\u003c/p\u003e \u003cp\u003eThis study has several limitations. It is a single-center, retrospective analysis with a small sample size, limiting generalizability. There was no randomized control group, and all patients received conventional therapy in combination with ECU, making it impossible to attribute improvements solely to ECU. Delayed effects from prior IVMP or PLEX may have contributed. Nevertheless, limited-dose ECU appears to accelerate neurological recovery in this refractory population, particularly in severe attacks, suggesting its potential as a rescue therapy in the acute NMOSD setting.\u003c/p\u003e \u003cp\u003eIn conclusion, our novel limited-dose, add-on regimen of eculizumab for acute NMOSD attacks was generally well tolerated and facilitated rapid, clinically meaningful neurological and visual recovery, even in patients refractory to conventional first-line therapies. We further demonstrate that a carefully planned transition to alternative maintenance biologics after ECU is feasible and can mitigate rebound risk. These results address the current limitations of acute-phase NMOSD treatment by providing a practical and effective therapeutic option, offering valuable real-world evidence to guide management, and laying a foundation for future prospective studies aimed at optimizing treatment strategies and improving patient outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eAll datasets utilized and/or analyzed during the current study are provided within the article. Further information regarding additional data can be obtained upon request from the corresponding authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e GDJ, ZWH prepared the materials, collected, and analyzed the data and drafted the manuscript; CL, YMX, JJS, SQ, WY, PDT prepared the materials, collected, and analyzed the data; PDT, ZWH revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding sources:\u003c/strong\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman Ethics and Consent to Participate declarations:\u003c/strong\u003e Accordance with the Declaration of Helsinki,the study was approved by the Institutional Review Board of China\u0026ndash;Japan Friendship Hospital (Approval No. 2024-KY-242).Informed consent to participate was obtained from all of the participants in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication:\u003c/strong\u003eThe participants have provided written informed consent for their personal or clinical details and any identifiable images to be published in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u003c/strong\u003e not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eUzawa A, Oertel FC, Mori M, Paul F, Kuwabara S. 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Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease. Cells. 2019;8(2):90. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/cells8020090\u003c/span\u003e\u003cspan address=\"10.3390/cells8020090\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaillart E, Dubessy AL, Shor N, Piljan M, Decombe R, Lubetzki C, Stankoff B, Marignier R, Beigneux Y. Severe Relapse After Switching From Eculizumab to Satralizumab in Neuromyelitis Optica Spectrum Disorder. Neurology. 2025;104(5):e213399. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1212/WNL.0000000000213399\u003c/span\u003e\u003cspan address=\"10.1212/WNL.0000000000213399\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"neuromyelitis optica spectrum disorder, acute attack, refractory, eculizumab, complement inhibition, rescue therapy, limited-dose therapy","lastPublishedDoi":"10.21203/rs.3.rs-8755894/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8755894/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis study evaluated the efficacy and safety of limited-dose eculizumab as rescue therapy for acute neuromyelitis optica spectrum disorder (NMOSD) attacks refractory to first-line treatment. Eight patients (six aquaporin-4 antibody seropositive and two seronegative) with incomplete responses to intravenous methylprednisolone with or without plasma exchange received one to four weekly doses of eculizumab (900 mg). Six patients with severe attacks (median nadir Expanded Disability Status Scale/Visual Outcome Scale: 9.0/11.5) showed only minimal improvement after conventional therapy. The remaining two, although not meeting severe criteria, also responded poorly. Add-on limited-dose eculizumab produced substantial neurological recovery: in myelitis, median Expanded Disability Status Scale improved from 8.5 to 3.5 at three months; in optic neuritis, median Visual Outcome Scale improved from 8.5 to 5.0. The proportion achieving marked-to-moderate improvement rose from 14.3% at one month to 85.7% at three months. Both seronegative patients responded favorably. Treatment was well tolerated, with no serious adverse events. These findings indicate that limited-dose eculizumab is an effective and safe option for accelerating recovery in refractory acute NMOSD attacks and may serve as a practical bridging strategy to long-term immunosuppression.\u003c/p\u003e","manuscriptTitle":"A Novel Limited-Dose C5 Inhibitor Add-On as Rescue Therapy for Refractory NMOSD Attacks: A Practical Alternative to Conventional Multi-Dose Regimens","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-08 14:36:00","doi":"10.21203/rs.3.rs-8755894/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-23T11:25:25+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-22T22:32:26+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-12T12:56:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"80502363420473774914607967093422042511","date":"2026-03-04T13:27:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"55037850933844088923820923953388929139","date":"2026-02-26T22:58:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"129835801375168107873554844000674887301","date":"2026-02-26T01:10:02+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-25T23:54:56+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-25T23:53:25+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-17T18:34:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-17T16:36:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2026-02-17T16:28:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1cec2e8e-ce49-44b3-889f-dc2b105b806f","owner":[],"postedDate":"March 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-11T08:28:18+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-08 14:36:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8755894","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8755894","identity":"rs-8755894","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}