BARCELONA, Spain — For the first time in a decade, diagnostic criteria for neuromyelitis optica spectrum disorder (NMOSD) are being overhauled, with changes that redefine the condition and its boundaries.

One of the most significant changes is in the name itself: the “D” in NMOSD will now stand for disease rather than disorder. The update reflects a broader effort to distinguish seropositive NMOSD — driven by aquaporin-4 immunoglobulin G (AQP4-IgG) antibodies — from other disorders with overlapping symptoms, said Dean M. Wingerchuk, MD, director of the Division of Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Phoenix.

Wingerchuk presented the revised criteria on revisions on September 24 at Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2025, characterizing them as substantial and clinically significant.

A Decade of Scientific Advances

The serum AQP4-IgG antibody is the only required biomarker, Wingerchuk noted, emphasizing its role as both causative and essential. That centrality qualifies NMOSD as a disease entity rather than a disorder or syndrome based on a collection of clinical symptoms.

Currently patients without APQ4-IgG are diagnosed with seronegative NMSOD or, in the absence of myelin oligodendrocyte glycoprotein-associated antibodies (MOGAs), double-negative NMSOD. By requiring APQ4-IgG, these terms will be retired when the new criteria are published.

The International Panel for Neuromyelitis Spectrum Disorder is drafting new diagnostic criteria. Its 26-member steering committee first met in 2023 to begin the process, with input from 130 clinicians and researchers across 35 countries.

Last updated in 2015, the new diagnostic criteria will incorporate a decade of scientific advances that have clarified distinctions among NMOSD, which accounts for two third of cases; MOGA disease (MOGAD), which accounts for about another third; and a range of rare syndromes or disorders with overlapping symptoms, said Wingerchuk.

The new criteria are not yet finalized but are in the final stages of preparation for publication, said Wingerchuk.

Key components for an NMOSD diagnosis include using the best available assay to evaluate serum rather than cerebrospinal fluid, which is not considered optimal. The reference standard is a live cell-based assay (LCBA), although Wingerchuk noted that confirmation with an LCBA is not required if seropositivity is demonstrated using a fixed cell-based assay. Enzyme-linked immunosorbent assays (ELISAs) are not recommended.

“If a positive result from an ELISA is obtained, the result should be confirmed, ideally by LBCA,” Wingerchuk said.

With the new criteria, patients with a suspected NMOS disorder now have only three possible outcomes from appropriate testing: NMOSD, indicated by the presence of AQP4-IgG; MOGAD, indicated by the presence of MOG antibodies; or seronegative status.

Although seronegativity may reflect a false negative result, phenotypes become the primary method of classification once true negative seropositivity has been established.

Better Diagnostic Accuracy

With the new criteria, greater attention to the features of seronegative patients with NMOS may allow for more accurate characterization of phenotypes, such as those with brainstem involvement or isolated regions of disease activity, said Sara Mariotto, MD, PhD, a clinician and researcher in the Department of Neuroscience, Biomedicine, and Movement Disorders at the University of Verona, Verona, Italy.

“These are rare disorders, but the categorization of seronegative neuromyelitis syndromes separate from NMSOD and MOGAD offers a potential to look more closely at features and treatments targeted at these syndromes,” said Mariotto, a researcher focused on the molecular features of NMOS now classified as double-negative NMOSD.

Both Mariotto and Alvaro Cobo Calvo, MD, PhD, of the Multiple Sclerosis Center of Catalonia in Barcelona, Spain, also discussed the implications of the new diagnostic criteria for double-negative NMOSD.

Speaking in the same session where the criteria were presented, they noted that the extent of overlap between double-negative NMOSD and NMOSD remains largely unknown.

Showing multiple differences in the molecular features of double-negative NMOSD relative to APQ4-IgG-positive NMSOD, Calvo concluded that at least some of these phenotypes “might represent a different pathological entity entirely.”

During the discussion that followed, there were concerns expressed about the reliance on LBCA, which remains a specialized test that is not available worldwide. Wingerchuk provided some background about the decision to call ELISA “not recommended.”

“The decision was not that ELISA is a terrible test. It is not, but it is not as reliable as LBCA,” he said. He said the new criteria aim to encourage health systems worldwide to invest in LBCA, given its greater accuracy for categorizing NMO, but acknowledged that “in the meantime, we can only do the best we can.”

Asked how revolutionary the new criteria are, Brenda Banwell, MD, co-director of Johns Hopkins Children’s Center in Baltimore, cautioned against drawing too many conclusions until they are published and widely available, but she speculated that they would help clarify a complex set of diseases.

“By improving diagnostic accuracy, the criteria are likely to have an immediate impact on organizing how we think about these diseases and disorders,” she said. “With more biological specificity, there might also be more or better opportunities to develop and test targeted therapeutics.”

Wingerchuk reported financial relationships with Alexion, AstraZeneca, Bristol-Myers Squibb, Genentech, Horizon, Incyte, Merck, Novartis, and Reistone. Mariotto reported financial relationships with Alexion, Biogen, Horizon, Novartis, Roche, Sanofi, and UCB. Calvo and Banwell reported no relevant financial relationships.