A Clinical Review of the 2025 Neuromyelitis Optica Spectrum Disorder Guidelines

Neuromyelitis optica spectrum disorder (NMOSD) is a rare but severe autoimmune inflammatory disorder of the central nervous system that can lead to irreversible disability if not recognized and treated early. Advances in antibody testing and disease classification over the past decade have significantly reshaped the understanding of NMOSD. Recently published, the updated NMOSD diagnostic guidelines aim to clarify disease classification, improve diagnostic accuracy, and support timely clinical decision-making across diverse practice settings.

An international consensus group of NMOSD experts collaborated to develop updated diagnostic criteria to ensure the guidelines reflect both scientific progress and real-world clinical challenges. These recommendations incorporate emerging knowledge surrounding aquaporin-4 (AQP4) antibody–positive disease, recognition of antibody-negative presentations, and differentiation from disease mimics such as MOG-associated disorder. These updates build upon pervious NMOSD guidelines, addressing gaps created by the evolution of the disease and expanding therapeutic options.

The new guidelines span the full diagnostic spectrum of NMOSD, from appropriate use and timing of antibody testing to clinical scenarios in which retesting or alternative diagnostic pathways should be considered. They also highlight the implications of diagnostic classification on treatment access, particularly in the context of FDA-approved therapies indicated for AQP4 antibody–positive patients. In addition to guiding clinical care, the updated criteria are intended to support more precise patient selection for clinical trials and future research.

As part of ongoing coverage, NeurologyLive® spoke with Benjamin Greenberg, MD, MHS, an internationally recognized expert in NMOSD, for an in-depth discussion of the updated guidelines. In this interview, Dr. Greenberg shared key takeaways from the recommendations, discussed their implications for everyday clinical practice, and highlighted remaining challenges in diagnosing antibody-negative disease. He also offered insight into how the revised criteria may shape future research efforts and therapeutic development in NMOSD.

Top Takeaways from the Guidelines

Dr. Greenberg emphasized that the updated NMOSD guidelines reflect a more refined understanding of the disease and its mimics. One of the most significant changes is the explicit recognition of conditions that can resemble NMOSD, particularly MOG-associated disorder, which was not well understood when earlier guidelines were created. The new criteria encourage clinicians to actively consider and test for these mimics when appropriate.

He also highlighted the importance of simplifying and clarifying disease nomenclature. Over time, overlapping terminology created confusion in clinical practice. The new guidelines clearly group patients with aquaporin-4 (AQP4) antibodies under NMOSD, while separating out those who test negative. This distinction represents a deliberate move away from blended clinical and testing criteria toward a more biologically grounded framework.

Major Takeaways

• Increased focus on identifying NMOSD mimics, especially MOG-associated disorder
• Clear separation of AQP4 antibody–positive NMOSD from antibody-negative cases
• Simplified and clarified nomenclature to reduce diagnostic confusion
• Shift away from mixed clinical and testing criteria used in prior guidelines

Clinical Implications on Patient Care

From a clinical standpoint, Dr. Greenberg noted that one of the primary motivations behind the updated guidelines was to protect patient access to treatment. FDA-approved therapies for NMOSD are specifically indicated for patients who are AQP4 antibody–positive, and the consensus group was careful to ensure that changes in classification would not inadvertently exclude eligible patients from these medications.

He also underscored the importance of acknowledging that antibody-negative patients may still have NMOSD. The guidelines are designed to prevent patients—many of whom have carried this diagnosis for years—from being abruptly excluded from diagnostic consideration. Additionally, the criteria account for global disparities in access to advanced diagnostic testing, offering pathways for clinicians practicing in settings where such resources may be limited.

Major Takeaways

• Diagnostic reclassification was designed to preserve access to FDA-approved NMOSD therapies
• Antibody-negative patients are still clinically relevant and should not be dismissed
• Criteria provide guidance for diverse clinical scenarios, not just ideal testing conditions
• Global variability in access to antibody testing was a key consideration in guideline development

Unanswered Questions

Dr. Greenberg explained that the guidelines intentionally acknowledge uncertainty around antibody testing, particularly in patients who test negative for AQP4 antibodies. A key challenge is determining when retesting is appropriate and when clinicians should revisit the diagnosis altogether. The guidelines encourage thoughtful clinical judgment rather than rigid interpretation of a single test result.

He gave the example of patients who receive acute treatments such as high-dose steroids or plasmapheresis before antibody testing is performed. In these cases, antibody levels may be suppressed, resulting in false-negative results. The criteria address these situations by recommending retesting, delayed testing, or storing blood samples when immediate testing is not possible but clinical suspicion remains high.

Major Takeaways

• Negative AQP4 antibody results do not definitively rule out NMOSD
• Acute treatments can lead to false-negative antibody testing
• Retesting should be considered when clinical suspicion remains high
• The guidelines support delayed or stored testing when immediate access is unavailable

Looking Ahead: What the Guidelines Mean for the Future of the Field

Dr. Greenberg noted that NMOSD diagnostic guidelines serve two critical purposes: guiding clinical care and shaping research. In clinical practice, accurate and early diagnosis is essential, as current NMOSD therapies are highly effective and outcomes improve significantly when treatment is initiated early. The updated criteria aim to support faster, more confident diagnosis in real-world settings.

From a research perspective, the guidelines help define more homogeneous patient populations for clinical trials. Separating antibody-positive and antibody-negative patients allows for more precise study designs and opens the door to deeper investigation into the underlying biology of antibody-negative disease. This clarity is expected to accelerate discovery and, ultimately, the development of new targeted therapies.

Major Takeaways

• Early and accurate diagnosis enables timely use of highly effective therapies
• Clear diagnostic categories improve consistency in clinical trials
• Separation of antibody-positive and antibody-negative patients supports future research
• Guidelines create a foundation for new discoveries and treatment development

Transcript edited for clarity