Understanding Further the Phenotypic Spectrum of Central Nervous System Inflammatory Demyelinating Disorders Using Unsupervised Clustering

Gulec B., Everest E., Tutuncu M., Bilge U., Saip S., UYGUNOĞLU U., ...More

ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY, 2026 (SCI-Expanded, Scopus) identifier identifier identifier

  • Publication Type: Article / Article
  • Publication Date: 2026
  • Doi Number: 10.1002/acn3.70389
  • Journal Name: ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, EMBASE, MEDLINE, Directory of Open Access Journals
  • Keywords: atypical demyelinating disorders, double-seronegative disorders, principal component analyses, unsupervised clustering
  • Istanbul University-Cerrahpasa Affiliated: Yes

Abstract

Background Central nervous system (CNS) inflammatory demyelinating syndromes, including multiple sclerosis (MS), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), occasionally overlap. Some patients remain double-seronegative, showing atypical features that challenge current classifications.Objective To better characterize the phenotypic spectrum of antibody-negative atypical inflammatory demyelinating disorders (AIDD) using unsupervised clustering.Methods We retrospectively analyzed 316 patients (MS = 164, AQP4 + NMOSD = 36, double-seronegative NMOSD = 21, MOGAD = 15, AIDD = 80) followed between 2010 and 2023. Principal component analysis and k-means clustering were applied to AIDD cases using clinical, demographic, and radiological data.Results AIDD patients had lower disability and fewer corpus callosum and posterior fossa lesions than MS and NMOSD. Three clusters emerged: (1) myelitis-predominant with unmatched CSF oligoclonal bands and longitudinally extensive spinal lesions, (2) brainstem-dominant with recurrent brainstem attacks, and (3) optic neuritis-dominant with recurrent LEON meeting MS dissemination criteria. Treatment patterns differed; rituximab was most frequent.Conclusion Double-seronegative AIDD represents a heterogeneous clinical spectrum. Unsupervised clustering provides a data-driven framework for refining phenotypic classification and may support biomarker and therapeutic development in antibody-negative CNS demyelination.