Can brain damage in neuromyelitis optica spectrum disorder keep progressing silently?

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease in which the immune system attacks the central nervous system, especially the optic nerves and spinal cord. These attacks, also known as flare-ups or relapses, can lead to blindness, paralysis, chronic pain, and lasting neurological disability. In recent years, biologic drugs designed to target the immune system have greatly reduced relapse rates in patients with NMOSD, marking a major advance in the treatment of this disease.

Despite this progress, an important question has remained unanswered: What happens to the brain between relapses? Researchers have traditionally viewed NMOSD as a disease in which most damage occurs during inflammatory flare-ups. However, recent studies have hinted that this perspective may not tell the full story. In other neurological diseases, such as multiple sclerosis, gradual neurodegeneration can continue even when patients appear clinically stable. Early findings in NMOSD raised the possibility that a similar gradual process might also occur in this disease.

To tackle this knowledge gap, a research team led by Assistant Professor Hiroki Masuda from the Graduate School of Medicine, Chiba University, Japan, conducted an MRI study tracking changes in brain volume over time in patients with NMOSD and healthy volunteers. Their work, which was published online in the Journal of Neurology, Neurosurgery & Psychiatry on April 15, 2026, was co-authored by Dr. Masahiro Mori and Professor Satoshi Kuwabara from Chiba University, as well as Dr. Lina Anderhalten and Professor Friedemann Paul from the Neuroscience Clinical Research Center (NCRC), Charité – Universitätsmedizin Berlin, Germany.

The study enrolled 72 patients with a specific subtype of NMOSD defined by the presence of aquaporin-4 antibodies (proteins produced by the immune system that drive the disease), recruited from sites in Japan and Germany. These patients were matched by age and sex with 52 healthy volunteers. Importantly, only patients who remained relapse-free between their two MRI scans were included, ensuring that any brain changes observed could not simply be attributed to acute attacks. The researchers compared brain volumes measured at the two time points using a statistical technique to account for differences between the MRI scanning equipment used at different sites.

The results showed that patients with NMOSD exhibited significantly faster rates of whole-brain atrophy compared with healthy participants, even during periods without relapses. Here, brain atrophy refers to the gradual shrinking of brain tissue—an important marker of neurodegeneration. The researchers also found that patients with lower volumes of subcortical gray matter, which consists of deep brain regions involved in functions such as memory, emotion, and information processing, tended to have greater neurological disability. “These findings suggest that neurodegeneration in NMOSD may occur through mechanisms independent of clinical relapses,” remarks Dr. Masuda. “However, the association between subcortical gray matter volume and neurological disability should be interpreted carefully, because subcortical gray matter volume was also associated with disease duration and relapse number, which may partly reflect cumulative disease burden over time.”

The team also investigated whether biologic therapies influenced long-term volumetric brain changes. Patients who began biologic treatment earlier, as well as those who spent a larger proportion of their disease duration receiving biologic therapy, tended to show lower rates of subcortical gray matter atrophy over time.

According to the researchers, these findings could have important implications for how NMOSD is monitored and treated in the future. Current treatment strategies largely focus on preventing relapses, based on the assumption that neurological damage mainly occurs during attacks. However, these new results suggest that more subtle forms of brain injury may continue even when patients appear clinically stable. “Our work highlights the need for further studies on cognitive function and for treatment strategies that address not only relapse prevention but also long-term neurodegeneration,” explains Dr. Masuda. “Monitoring brain atrophy and cognitive function may become important even in clinically stable patients with NMOSD, as subtle cognitive decline may occur even in the absence of relapses. However, these changes are likely to be much milder and more slowly progressive than those typically observed in multiple sclerosis.”

Further research efforts will hopefully lead to new monitoring approaches and treatment strategies for NMOSD, which in turn will help preserve patients’ cognitive functions and minimize neurological decline.

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Reference:

Title of original paper: Biologic therapy and brain atrophy in neuromyelitis optica: a Japanese–German longitudinal MRI study

Authors: Hiroki Masuda¹, Lina Anderhalten^2,3, Masahiro Mori¹, Tadashi Shiohama^4,5, Norihide Maikusa^6,7, Shigeki Hirano¹, Akiyuki Uzawa¹, Mayumi Muto^1,8, Ryohei Ohtani^1,9, Tomohiko Uchida⁹, Reiji Aoki¹, Hitomi Kitagawa¹⁰, Yoshiyuki Hirano¹¹, Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI), Friedemann Paul^2,3, and Satoshi Kuwabara¹

Affiliations:
(1) Department of Neurology, Graduate School of Medicine, Chiba University, Japan

(2) Experimental and Clinical Research Center (ECRC), A Cooperation Between Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité-Universitätsmedizin Berlin, Germany

(3) Neuroscience Clinical Research Center (NCRC), Charité-Universitätsmedizin Berlin, Germany

(4) Department of Pediatrics, Chiba University, Japan

(5) Department of Pediatrics, International University of Health and Welfare Narita Hospital, Japan

(6) Center for Evolutionary Cognitive Sciences, The University of Tokyo, Japan

(7) Department of Radiology, National Center of Neurology and Psychiatry, Japan

(8) Department of Neurology, Chiba Rosai Hospital, Japan

(9) Department of Neurology, Eastern Chiba Medical Center, Japan

(10) Research Center for Child Mental Development, Chiba University, Japan

(11) Chiba University Research Center for Child Mental Development, Japan

Journal: Journal of Neurology, Neurosurgery, and Psychiatry

DOI: https://doi.org/10.1136/jnnp-2025-338166

About Assistant Professor Hiroki Masuda from Chiba University, Japan
Dr. Hiroki Masuda is an Assistant Professor, a researcher, and a clinician in the Department of Neurology at Chiba University Graduate School of Medicine, Japan. He specializes in neuroimmunology, neurodegenerative diseases, and neuroprotection, with a strong focus on understanding the underlying mechanisms and treatments for autoimmune neuroinflammatory disorders. He has authored over 40 scientific publications.

Funding:
Collection of MRI data from Chiba-HCs was supported by the AMED Brain/MINDS Beyond Program (Grant Number: JP18dm0307002), JSPS KAKENHI (Grant Numbers: 19K03309, 21K03084, 23K22361, 24K21493, 25K00879, 25K06842, and 25H01085).