Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disease that involves inflammation and damage to the central nervous system (CNS), primarily affecting the optic nerves and spinal cord [1]. The diagnostic criteria for NMOSD include six core clinical characteristics involving distinct regions of the CNS: the spinal cord, causing longitudinally extensive transverse myelitis; the optic nerve, causing optic neuritis; the medulla, causing area postrema syndrome; the brainstem, causing brainstem syndromes; and the thalamus/hypothalamus, causing acute diencephalic syndromes [2]. Serologically, in ≥ 80% of cases, NMOSD is associated with pathogenic IgG autoantibodies against aquaporin-4 (AQP4-IgG), the most abundant water channel protein in the central nervous system (CNS) [3]. Persistent activation of the immune-inflammatory cascade leads to progressive astrocyte loss, resulting in impaired trophic support, subsequent demyelination, and irreversible axonal injury [4]. Histopathologically, NMOSD lesions demonstrate vasculocentric deposition of immunoglobulins and complement, with inflammatory infiltrates composed of macrophages, granulocytes, and lymphocytes [5]. Altered B-cell tolerance promotes the expansion of autoreactive clones responsible for AQP4-IgG production, while T-cell–mediated B-cell activation and interleukin (IL)-6–driven Th17 polarization further propagate inflammation through neutrophil recruitment [6–8]. Historically, disease-modifying treatment for NMOSD relied on broad, off-label immunosuppression, including corticosteroids, azathioprine, mycophenolate mofetil, and cyclophosphamide; although often effective, these agents are associated with significant long-term toxicity and variable efficacy [9]. Since 2005, accumulating evidence has supported the use of biologic therapies, particularly rituximab and tocilizumab, with rituximab progressively becoming a preferred option due to its demonstrated efficacy [10]. A major therapeutic shift occurred with the approval of targeted monoclonal antibodies, including eculizumab (2019), satralizumab (2021), inebilizumab (2022), and ravulizumab (2023). These agents act on key pathogenic pathways: satralizumab inhibits the IL-6 receptor; eculizumab and ravulizumab target complement component C5; and inebilizumab induces B-cell depletion via CD19, reflecting a transition toward mechanism-based and precision-targeted therapy in NMOSD [11].

Current treatment guidelines recommend that, in cases of inadequate response to a monoclonal antibody, therapy should be switched to an alternative agent with a different mechanism of action [12]. However, in aggressive cases of NMOSD with failure to multiple treatments, or in countries where access to approved therapies is limited, autologous hematopoietic stem cell transplantation (aHSCT) may be considered a therapeutic option [13].

This approach has been employed with acceptable outcomes across multiple case reports and cohort studies in refractory NMOSD. The European Society for Blood and Marrow Transplantation (EBMT) has endorsed aHSCT for refractory NMOSD; however, the current evidence supporting its use remains constrained by small sample sizes and limited follow-up durations [14].

In this context, reporting well-characterized cases of refractory NMOSD treated with aHSCT is of critical importance, as it contributes to the understanding of real-world therapeutic decision-making, particularly in resource-limited settings. Furthermore, such reports provide valuable insight into clinical outcomes, immunological behavior, and long-term disease control following immune reconstitution strategies, helping to refine patient selection and guide future research in this evolving field.

A 32-year-old woman with a history of hypothyroidism, systemic lupus erythematosus (SLE), and antiphospholipid syndrome (APS)—previously treated with cyclophosphamide, mycophenolate mofetil, and rituximab for lupus activity, including two episodes of lupus nephritis—presented in May 2022 with 1 week of nausea and hiccups, followed by lower-extremity weakness and a thoracic sensory level. She was diagnosed with thoracic myelitis with documented AQP4-IgG positivity (titer 1:10,000), consistent with NMOSD, and was treated with intravenous methylprednisolone followed by plasma exchange. Given prior exposure to cyclophosphamide and rituximab, treatment with satralizumab was initiated, with a favorable clinical response during the first year. However, in July 2023, she developed bilateral optic neuritis followed by cervical myelitis (Fig. 1), requiring intravenous methylprednisolone and five sessions of plasma exchange. In October 2023, she experienced further motor deterioration, with persistent contrast enhancement of the spinal cord lesion on imaging. In January 2024, satralizumab was discontinued due to treatment failure; at that time, no other approved therapies for NMOSD were available in Mexico, and the aHSCT protocol was initiated. In collaboration with the hematology service, hematopoietic stem cell mobilization and collection were performed, followed by conditioning with cyclophosphamide 2.0 g/m², rituximab 375 mg/m², and anti-thymocyte globulin 4.5 mg/kg. She subsequently underwent autologous hematopoietic stem cell transplantation with an infusion of 3.11 × 10⁶ CD34⁺ cells/kg. Early post-transplant complications included neutropenia and pneumonia on day +5, with favorable clinical response to treatment, allowing discharge on day +16. At 1-year follow-up, she developed a single episode of herpes zoster that responded appropriately to acyclovir, with no other infectious complications reported.

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Figure 1. Sagittal spinal MRI demonstrating disease evolution. (a) Extensive cervical myelitis at NMOSD onset. (b) Follow-up MRI performed approximately 18 months later showing a new longitudinally extensive thoracic spinal cord lesion, consistent with ongoing disease activity.

Regarding her autoimmune comorbidities, the patient has shown no evidence of SLE activity and is currently maintained on hydroxychloroquine as her sole rheumatologic therapy, representing a significant reduction in her previous immunosuppressive treatment burden. Her APS has been managed with warfarin and regular international normalized ratio (INR) monitoring throughout the follow-up period, with no thrombotic events reported to date. Thyroid function has remained stable on a fixed dose of levothyroxine, with no adjustments required during the follow-up period.

During follow-up, AQP4-IgG seropositivity persisted (titers 1:1,000) at both 1- and 2-year post-transplant evaluations, therefore, maintenance therapy with rituximab (1 g every 6 months) was initiated starting 1 year after transplantation. The patient has undergone rehabilitation and has remained free of clinical relapses at 2 years of follow-up, with recovery of ambulation and only mild residual weakness and dyschromatopsia. She continues under close neurological surveillance with ongoing serological monitoring of AQP4-IgG. A graphical summary of the patient’s clinical course and treatment history is presented in Figure 2.

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Figure 2. Longitudinal clinical course, key events, and treatment exposure from 2017 to 2026. EDSS: Expanded Disability Status Scale; SLE: systemic lupus erythematosus; APS: antiphospholipid syndrome; NMOSD: neuromyelitis optica spectrum disorder; AQP4: aquaporin-4; AQP4-IgG: aquaporin-4 immunoglobulin G antibody; ITP: immune thrombocytopenia; aHSCT: autologous hematopoietic stem cell transplantation.

We present a case of aggressive, treatment-refractory NMOSD in a patient with concomitant autoimmune comorbidities, SLE, and APS, who had previously been treated with rituximab and satralizumab before undergoing aHSCT. At 2 years of follow-up, she has demonstrated a favorable clinical response, although persistent AQP4-IgG seropositivity suggests an ongoing risk of disease reactivation.

Importantly, disease control extended beyond NMOSD. The patient has remained free of clinical or laboratory evidence of SLE activity and is currently maintained on hydroxychloroquine monotherapy, representing a substantial reduction in her prior immunosuppressive burden. Likewise, her APS has remained stable with no thrombotic events observed during follow-up. These findings are noteworthy given the reported efficacy of aHSCT in selected patients with severe refractory SLE, where sustained remission and significant reductions in immunosuppressive requirements have been described. Although the contribution of aHSCT to the long-term control of her coexisting autoimmune diseases cannot be definitively established, the absence of lupus or APS reactivation following transplantation further supports the potential of immune reconstitution strategies to induce durable disease control across multiple autoimmune conditions [15].

AHSCT has emerged as a promising and increasingly recognized therapeutic option for patients with severe, refractory NMOSD [16]. Although the existing evidence is largely derived from case reports [17–19] and a limited number of prospective cohort studies [20, 21], the cumulative results are consistently encouraging and support further investigation of this approach, as shown in Table 1.

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Table 1. Summary of Reported Cases of aHSCT in NMOSD

Several cohorts have demonstrated that long-term disease control is achievable in a subset of patients, with 5-year relapse-free survival rates ranging from 66% to 80% [21]. Similarly, a meta-analysis of nine studies including 39 NMOSD patients treated with aHSCT reported a progression-free survival rate of 69%, further supporting its role as a clinically meaningful therapeutic intervention in refractory disease [22]. Collectively, these findings suggest that aHSCT can effectively suppress disease activity for prolonged periods in selected patients.

However, the durability of remission appears to be strongly influenced by persistent AQP4-IgG seropositivity. Across multiple studies, continued seropositivity following aHSCT was associated with an increased risk of relapse, further supporting the pathogenic role of AQP4-IgG in NMOSD [23, 24]. These findings underscore the importance of long-term clinical and serological monitoring after aHSCT and suggest that reinitiation of immunosuppressive therapy may be warranted in selected patients with persistent seropositivity or evidence of disease reactivation.

These observations support the concept that aHSCT may reset immune function without completely eradicating the autoreactive B-cell and plasma-cell populations responsible for AQP4-IgG production. Very long-term follow-up data indicate that disease recurrence may occur even after prolonged periods of remission, and that immune reconstitution following transplantation may not provide permanent protection against disease reactivation, emphasizing the need for continued long-term monitoring [24].

Importantly, the heterogeneity of study designs, different conditioning regimens, and patient populations limits direct comparability across studies. Questions persist regarding the long-term durability of remission following transplantation, and the procedure’s efficacy relative to emerging alternative therapies has yet to be adequately established. Larger prospective studies with extended follow-up are therefore needed to define the true long-term efficacy and safety profile of aHSCT in this population.

Although clinical evidence remains limited, available data provide consistently encouraging signals regarding the efficacy and safety of aHSCT, supporting its role as a potentially valuable immunotherapeutic strategy in the management of NMOSD, particularly in patients refractory to conventional immunosuppressive therapies. Based on current evidence, aHSCT should be considered a viable therapeutic option in this setting. However, persistent AQP4-IgG seropositivity following transplantation may indicate an ongoing risk of disease reactivation, warranting careful long-term monitoring and consideration when assessing treatment outcomes. Larger multicenter studies with standardized protocols and long-term follow-up are needed to better define the role of aHSCT within the evolving therapeutic landscape of NMOSD.

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