Disability Dynamics Independent of Attacks in AQP4-IgG+ NMOSD and MOGAD: Insights from a Multicenter Cohort Study

Highlight

• Confirmed disability improvement (CDI) and confirmed disability worsening (CDW) independent of attacks occur in both AQP4-IgG+ NMOSD and MOGAD patients, albeit infrequently.
• Lower prior attack number correlates with higher CDI rates in AQP4-IgG+ NMOSD, underscoring the importance of early attack prevention.
• Younger patient age is associated with increased chances of disability improvement in both diseases.
• Annualized CDI and CDW rates are comparable between AQP4-IgG+ NMOSD and MOGAD.

Study Background

Neuromyelitis optica spectrum disorder (NMOSD) characterized by aquaporin-4 immunoglobulin G antibodies (AQP4-IgG+) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are autoimmune demyelinating diseases of the central nervous system, primarily affecting the optic nerves and spinal cord. Both conditions manifest with relapses or attacks leading to neurological disability. Traditionally, the disability trajectory in these diseases has been attributed mainly to attack-induced damage. However, emerging evidence suggests that disability can also evolve independently of acute attacks, either improving or worsening over time. Such progression without overt inflammatory attacks has been well-documented in multiple sclerosis but less understood in AQP4-IgG+ NMOSD and MOGAD, particularly regarding confirmed disability improvement (CDI). Understanding factors influencing attack-independent disability changes is critical for optimizing management and improving patient outcomes.

Study Design

This retrospective multicenter cohort study utilized data from the German Neuromyelitis Optica Study Group (NEMOS) registry, including adult patients diagnosed with AQP4-IgG+ NMOSD or MOGAD who had serial Expanded Disability Status Scale (EDSS) measurements. EDSS episodes were defined as intervals consisting of at least three EDSS assessments without clinical attacks, each episode starting at least 90 days following an attack to minimize confounding from acute relapse effects.

Confirmed disability improvement (CDI) and confirmed disability worsening (CDW) were defined per established thresholds, adjusting for baseline EDSS scores: an EDSS decrease or increase sustained over at least 6 months, with magnitude thresholds scaled by baseline disability levels to ensure clinically meaningful change. Primary outcomes evaluated were the annualized rates of CDI and CDW independent of attacks. Multivariable Anderson-Gill regression models were employed to identify clinical factors associated with these outcomes, adjusting for confounders.

Key Findings

The study analyzed 338 EDSS episodes from 307 patients (202 with AQP4-IgG+ NMOSD and 105 with MOGAD) with median ages of 56 and 41 years, respectively. Female predominance was notable, especially higher in AQP4-IgG+ NMOSD (88%) compared to MOGAD (49%).

The adjusted annualized rates of CDI and CDW showed no statistically significant difference between the two diseases: AQP4-IgG+ NMOSD had an annualized CDI rate of 0.083 (95% CI 0.029–0.233) and CDW rate of 0.025 (95% CI 0.007–0.092), while MOGAD patients had CDI and CDW rates of 0.057 (95% CI 0.012–0.277) and 0.036 (95% CI 0.002–0.513), respectively. This suggests that attack-independent fluctuations in disability are comparably rare but existent in both conditions.

Regarding factors influencing disability trajectories, in AQP4-IgG+ NMOSD, a lower number of prior attacks was significantly associated with higher CDI rates (hazard ratio [HR] 0.89, 95% CI 0.82–0.97), implying that early-stage patients or those with fewer attacks tend to experience greater disability improvement independent of relapse activity. Additionally, younger age was linked to increased CDI rates in both disease groups, with HR of 0.96 (95% CI 0.94–0.99) per year younger, indicating enhanced potential for neurological recovery or plasticity in younger patients.

No clear clinical predictors for attack-independent CDW emerged, likely due to the limited number of events and the heterogeneous pathophysiology underlying gradual disability progression.

Expert Commentary

This study introduces important new insights into the natural history of AQP4-IgG+ NMOSD and MOGAD. The identification of attack-independent disability improvement is novel, emphasizing that these diseases may harbor intrinsic biological processes enabling functional recovery beyond acute relapse resolution. It also highlights that preventing attacks early in disease may maximize patients’ chances of recovery.

The rarity of confirmed attack-independent worsening confirms that, unlike multiple sclerosis, chronic progression without relapse is uncommon but still clinically relevant. The retrospective design and relatively small numbers of CDI and CDW episodes limit the study’s power to detect additional predictors or mechanistic pathways. Prospective studies incorporating imaging and biomarkers of neurodegeneration versus repair are needed to elucidate underlying processes.

From a clinical standpoint, these findings reinforce the need for robust relapse prevention strategies early in disease course and suggest that age and previous attack burden should inform prognostic discussions. They also challenge the view of fixed disability status outside of attacks and support continued assessment of functional changes independent of relapses.

Conclusion

Confirmed disability improvement and worsening independent of attacks occur infrequently but meaningfully in AQP4-IgG+ NMOSD and MOGAD. Early attack prevention and younger patient age are favorable factors for disability improvement, underscoring the importance of timely diagnosis and therapy initiation. These findings extend understanding of disability trajectories beyond relapse-induced damage and call for further prospective studies to clarify mechanisms and therapeutic targets promoting recovery and preventing progression.

Funding and Clinical Trials

The study was supported by data from the German Neuromyelitis Optica Study Group (NEMOS). No direct clinical trial registration was cited. Funding sources for registry maintenance and ancillary analyses were not explicitly declared.

References

Engels D, Schindler P, Havla J, et al; Neuromyelitis Optica Study Group (NEMOS). Factors Associated With Disability Improvement and Worsening Independent of Attacks in Patients With AQP4-IgG+ NMOSD and MOGAD: A Multicenter Cohort Study. Neurology. 2026 Jul 2;107(2):e218199. doi:10.1212/WNL.0000000000002181. PMID: 42391599.

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