Neuromyelitis optica spectrum disorder (NMOSD) with aquaporin-4 immunoglobulin G positivity (AQP4-IgG) is a severe autoimmune disease of the central nervous system (CNS) characterized by inflammatory attacks targeting the optic nerves and spinal cord. Pathologically, these attacks are driven by the binding of pathogenic AQP4-IgG to astrocytes, which triggers a potent, complement-dependent cytotoxicity. The deposition of the C5b-9 membrane attack complex (MAC) on the astrocyte surface leads to widespread cell necrosis, breakdown of the blood-brain barrier, and subsequent inflammatory demyelination and neuronal damage [1]. Clinically, acute NMOSD attacks—presenting mainly as optic neuritis (ON) or longitudinally extensive transverse myelitis (LETM)—frequently result in profound and irreversible disability, such as blindness or paralysis, if not rapidly and effectively controlled [2].

The standard of treatment for acute attacks consists of high-dose intravenous corticosteroids (IVMP) and, for more severe cases, plasma exchange (PLEX) to remove pathogenic antibodies and other inflammatory mediators [3]. While these interventions are beneficial for many patients, a substantial subset of attacks prove refractory, with ongoing neurologic deterioration despite first-line therapy. Clinical data indicate that only about 21.6% of AQP4 positive patients achieve complete recovery following a relapse, highlighting a critical unmet need for more effective therapies capable of rapidly halting acute tissue injury [4]. In these fulminant cases, irreversible disability can accrue within days, underscoring the urgency for adjunctive treatments that can arrest the immunopathologic cascade.

In recent years, complement C5 inhibitors—eculizumab and its long-acting successor, ravulizumab—have emerged as transformative disease-modifying therapies for the prevention of relapses in AQP4-IgG NMOSD. By binding to complement component C5 and preventing its cleavage into the pro-inflammatory anaphylatoxin C5a and the MAC initiator C5b, these monoclonal antibodies abrogate the final common pathway of complement-mediated astrocyte destruction. Eculizumab was the first such agent approved for NMOSD after the pivotal PREVENT trial demonstrated a 94% relative reduction in adjudicated relapse risk compared to placebo [5]. More recently, ravulizumab, which was engineered for an extended dosing interval, demonstrated zero adjudicated relapses over a median of 73.5 weeks in the open-label CHAMPION-NMOSD trial, suggesting at least comparable efficacy with a more convenient dosing schedule every 8 weeks [5–7].

Given their profound success in relapse prevention and the centrality of complement to NMOSD pathogenesis and the gap of knowledge regarding effective treatments to prevent disability due to relapses, we propose that there is a compelling pathophysiological rationale to repurpose C5 inhibitors as acute therapies during severe attacks. This report critically examines the mechanistic justification, comparative pharmacology, and emerging clinical evidence for the use of eculizumab and ravulizumab as rescue therapies in acute AQP4-IgG NMOSD attacks.

We conducted a narrative review to assess the rationale and clinical evidence for terminal complement C5 inhibition during acute AQP4-IgG–positive NMOSD attacks. Searches were performed in MEDLINE (PubMed), Embase, and The Cochrane Library using controlled vocabulary and keywords for “neuromyelitis optica spectrum disorder”/NMOSD, “aquaporin-4,” “complement C5,” “eculizumab,” and “ravulizumab,” from inception until July 2025; no language restrictions were applied. Eligible reports enrolled AQP4-IgG–positive patients treated with eculizumab or ravulizumab during an acute attack, irrespective of concomitant steroids, plasma exchange, or IVIg; prevention-only studies without an acute-use component and studies confined to MOGAD or seronegative cohorts were excluded. Two reviewers independently screened records and extracted data on attack phenotype, timing from symptom onset to C5 inhibition, dosing, short-term outcomes, and safety; disagreements were resolved by consensus. While this review focuses on literature published from 2021 to 2025, any necessary inclusion of earlier works is clearly noted in the text with an (Author, Year) citation.

The pathophysiological justification for acute complement blockade

The rationale for using C5 inhibitors as an acute intervention is derived from the pathophysiology of NMOSD. The binding of AQP4-IgG to its target on astrocytes initiates the classical complement cascade, an inflammatory amplification system. This cascade culminates in the enzymatic cleavage of C5 into two highly active fragments: C5a and C5b. C5a is a potent anaphylatoxin that recruits and activates inflammatory cells, such as neutrophils, driving a robust inflammatory infiltrate into the CNS lesion. C5b, in turn, initiates the assembly of the terminal C5b-9 MAC, a pore-forming structure that inserts into the astrocyte membrane, causing osmotic dysregulation and rapid cell death [8]. Histopathological studies confirm this mechanism, revealing co-localization of AQP4-IgG, activated complement components, and astrocyte loss in NMOSD lesions (Lucchinetti et al., 2014) [9].

Administering a C5 inhibitor during an evolving attack directly targets this final, destructive pathway. By binding C5 with high affinity, eculizumab and ravulizumab prevent its cleavage, thereby blocking both the generation of the C5a and the formation of the C5b-9 complex. This mechanism positions C5 inhibition as a therapeutic circuit breaker, capable of instantly interrupting the final, irreversible step of tissue damage. This action is mechanistically distinct from and complementary to standard acute therapies. While corticosteroids broadly dampen systemic inflammation and reduce immune cell activation, they do not neutralize complement proteins that are already activated and fixed within the tissue (Weiler et al., 1982) [10]. PLEX, and immunoadsorption, are effective at removing circulating AQP4-IgG and other pathogenic factors, but this process takes time and cannot immediately stop the complement cascade already underway at the tissue level [11].

C5 inhibition, therefore, fills a critical therapeutic gap by directly and immediately mitigating the ongoing astrocytolysis and C5a-mediated inflammation that drive tissue destruction in acute NMOSD. This concept is supported by animal models where complement depletion or C5 inhibition abrogates AQP4-IgG–mediated lesion formation [11]. The urgency of such an intervention is underscored by clinical studies demonstrating that 96 hour delay in effective treatment for NMOSD optic neuritis significantly worsens final visual outcomes [12], reinforcing the principle that "time is tissue" (Dalmau, 2019) [13].

Pharmacology of acute C5 inhibition: Eculizumab vs. Ravulizumab

The suitability of C5 inhibitors for acute intervention is strongly supported by their pharmacokinetic (PK) and pharmacodynamic (PD) profiles, which allow for rapid (1 hour) and complete shutdown of the terminal complement system.

Eculizumab (soliris): Eculizumab is a humanized IgG2/4κ monoclonal antibody with a terminal half-life of approximately 11–17 days. The approved dosing for NMOSD prevention involves a 900 mg intravenous (IV) weekly induction for four weeks, followed by 1,200 mg every two weeks. For acute use, the most critical PD characteristic is its speed of onset [14,15]. Multiple analyses confirm that eculizumab achieves complete terminal complement inhibition within minutes to hours of the first infusion. A PK/PD analysis from the PREVENT trial showed that free C5 levels were suppressed to less than 0.5 µg/mL—the threshold for full blockade—in 96% of patients on day one [16]. This immediate pharmacologic action is ideal for an emergency therapy aimed at halting an ongoing attack.

Ravulizumab (ultomiris): Ravulizumab is a second-generation C5 inhibitor derived from eculizumab, engineered with four amino acid substitutions in its Fc region. These modifications enhance its recycling via the neonatal Fc receptor (FcRn), resulting in a dramatically extended half-life of approximately 50 days, which is 3-4 times longer than that of eculizumab. The approved dosing regimen reflects this, with a weight-based IV loading dose followed by maintenance infusions only every 8 weeks [17].

From a PD perspective, ravulizumab provides the same immediate and complete C5 inhibition as eculizumab. Therapeutic serum concentrations are achieved after the first infusion and are sustained throughout the entire 8-week dosing interval. Critically, analyses from the CHAMPION-NMOSD trial showed that every patient had free C5 levels suppressed below the 0.5 µg/mL threshold immediately after the initial dose, with no breakthrough complement activity detected at any point, even at the 8-week trough just before the next dose [18].

Both agents carry an increased risk of infection with encapsulated bacteria, most notably Neisseria meningitidis. Therefore, meningococcal vaccination is mandatory prior to or at the time of initiation. If treatment is urgent and vaccination is not complete, antibiotic prophylaxis is required.

Emerging clinical evidence for acute use of C5 inhibitors in NMOSD AQP4 positive

While no randomized controlled trials have yet been conducted, a growing body of case reports and small series provides compelling, albeit anecdotal, evidence for the efficacy and feasibility of using C5 inhibitors as salvage therapy in severe, refractory NMOSD attacks [19–25]. The growing body of evidence from case reports and small series highlights a crucial relationship between the timing of C5 complement inhibition and the clinical response in severe AQP4-IgG-positive NMOSD attacks. These reports consistently demonstrate that initiating complement inhibitors like eculizumab or ravulizumab can rapidly halt neurological deterioration, often within 24 to 48 hours, even in attacks refractory to standard therapies. This immediate stabilization is corroborated by biomarker data showing a significant decline in serum GFAP, a marker of the core astrocyte injury, shortly after treatment begins.

Across these reports, totaling over 20 patients, a consistent pattern emerges: the initiation of C5 inhibition in refractory attacks is temporally associated with the cessation of clinical worsening and, in many cases, the beginning of recovery. While authors rightly caution about potential confounding from the delayed effects of steroids or PLEX, the abrupt change in clinical trajectory following C5 blockade is compelling.

The accumulated evidence, though anecdotal, provides a strong proof-of-concept for the use of C5 inhibitors as a rescue therapy in acute NMOSD. The approach is mechanistically sound, pharmacologically feasible, and appears to have a manageable safety profile when appropriate prophylaxis is used. The consistent signal across all published cases is that C5 blockade can halt the progression of severe attacks that are refractory to standard-of-care treatments.

A key practical consideration is patient selection and timing. Based on current evidence, this intervention is most appropriate for patients with fulminant attacks who are at imminent risk of profound, permanent disability and who have demonstrated an insufficient response to an adequate trial of IVMP and PLEX. Poorer prognostic risk factors include: older age of onset, clinical severity (EDSS ≥ 2.5), delayed acute treatment (72-96 hrs), high anti-AQP4 antibody titers (≥1:100 or ≥1:320), clinical presentation (optic neuritis, longitudinally extensive transverse myelitis), male patients, and elevated levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) [12,26–32].The decision to escalate to a C5 inhibitor is typically made within the first one to two weeks of an attack, balancing the need to allow standard therapies time to work against the risk of irreversible tissue damage from prolonged, uncontrolled complement activation.

The emergence of this strategy creates a new paradigm for "neuro-immunologic emergency" care in NMOSD. However, the high cost and logistical hurdles of obtaining these drugs on an emergency basis remain significant barriers. For this approach to become more widespread, institutions managing NMOSD patients may need to develop pre-established protocols for rapid drug access, pharmacy coordination, and on-call specialist consultation to minimize delays once a refractory attack is identified.

Looking forward, systematic investigation is crucial. While a randomized controlled trial of standard care plus a C5 inhibitor versus standard care plus placebo would be the gold standard, the rarity of NMOSD and the ethical challenges of withholding a potentially effective rescue therapy in a catastrophic attack make such a trial difficult to conduct. A prospective, multi-center registry to collect standardized data on outcomes of patients treated acutely with C5 inhibitors versus matched historical or concurrent controls is a more feasible and essential next step. Such studies are needed to formally define efficacy, optimal timing, and patient selection criteria.

The advent of C5 inhibitors has revolutionized the prevention of relapses in AQP4-IgG NMOSD, and emerging evidence suggests these therapies may hold similar promise for the management of acute attacks. By directly targeting the final common pathway of complement-mediated astrocyte destruction, eculizumab and ravulizumab offer a mechanism-driven, rapidly-acting strategy to halt ongoing tissue injury in severe ON and LETM. The case reports and series published to date, while limited, consistently show that acute C5 blockade can stabilize or improve neurologic outcomes in patients who are failing standard care, with a manageable safety profile under vigilant prophylaxis.

While the evidence is not yet from controlled trials, the strong pathophysiological rationale and the consistent pattern of positive outcomes lend significant credence to this approach. In severe, refractory NMOSD attacks that threaten permanent disability, complement C5 inhibition represents a vital adjunctive therapy to quell the immune assault and preserve neurological function. This strategy is not a replacement for standard care but rather a powerful tool to be used in synergy with it. Continued investigation and clinical experience are needed to refine its place in the treatment algorithm, but for patients facing severe NMOSD relapses, acute complement blockade offers a new possibility.