Neurological involvement in IgG4-related disease: focus on neuro-ophthalmologic features

IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder that can affect multiple organs, yet neurological involvement has been considered rare and remains under-characterized.

We retrospectively analyzed 77 adult patients with IgG4-RD registered in our database between 2014 and 2023. Clinical, laboratory, imaging, histopathological, and therapeutic data were reviewed, with particular focus on neurological manifestations.

Neurological involvement was identified in 17 patients (22%), comprising neuro-ophthalmologic disease (n = 10), hypertrophic pachymeningitis (n = 6), and hypophysitis (n = 1). Patients with neurological involvement did not differ in age or sex from overall cohort (mean age 47.5 years; female-to-male ratio 1:1.3). Neuro-ophthalmologic disease was the predominant manifestation, typically presenting with the triad of headache, proptosis, and diplopia. Misdiagnoses such as idiopathic orbital inflammation or Tolosa-Hunt syndrome were frequent. MRI findings included orbital mass effect, optic sheath enhancement, and in some cases intracranial extension. Biopsy confirmed diagnosis in the majority, and histopathological features were indistinguishable from other organ involvements of IgG4-RD. While 60% achieved remission with glucocorticoids alone, the remainder required rituximab due to resistance or relapse. Notably, patients with neurological involvement were diagnosed earlier than those with extra-neurological disease, reflecting the clinical impact of neurological symptoms.

Neurological involvement in IgG4-RD may be more common than previously recognized, with neuro-ophthalmologic disease emerging as the leading phenotype. The symptom triad of headache, proptosis, and diplopia should prompt consideration of IgG4-RD in patients with orbital disease. Early recognition and timely immunosuppressive therapy are crucial to improving outcomes, and prospective studies are warranted to further delineate the neurological spectrum of this condition.