Commentary on “Demyelinating Plaque-associated Uveitis”

Alireza Hedayatfar

Eye Research Center, The Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran

Introduction and Purpose

Uveitis, the inflammation of the uveal tract, is known to be associated with multiple sclerosis (MS), with both conditions sharing immunopathogenic mechanisms rooted in autoimmunity against neuroectoderm-derived tissues¹. In both disorders, a common genetic predisposition is observed through the shared expression of the HLA-DRB1*15:01 haplotype, implicated in immune regulation², as well as polymorphisms in cytokine-related genes, such as the interleukin-2 receptor alpha gene, which influence T and B cell proliferation³. Histopathological parallels also support this association, notably the resemblance between perivenular inflammatory cuffs in MS plaques and snowbank formations in intermediate uveitis (IU)^4,5. In MS, autoreactive lymphocytes infiltrate the central nervous system (CNS), leading to perivenular demyelination⁶, while in IU, retinal perivascular inflammation driven by T-cell-mediated immune responses produces analogous changes⁷.

The purpose of this commentary is to summarize the findings of the recent study on demyelinating plaque-associated uveitis (DPU)⁸, to highlight its clinical significance, and to explore its potential implications for diagnostic frameworks, therapeutic decision-making, and interdisciplinary collaboration. Additionally, we discuss how DPU could inform future revisions to MS diagnostic criteria.

Summary of the Study Findings

The recent study conducted by Hedayatfar et al. systematically described DPU as a subset of uveitis patients with demyelinating plaques on CNS magnetic resonance images (MRI) who do not meet the McDonald diagnostic criteria for MS⁹. The study cohort consisted of 32 Persian patients (mean age, 36.3 ± 9.9 years; range, 20–56 years), with 93.8% being female. Bilateral ocular involvement was seen in 75% of patients, while 25% had unilateral disease. Most cases presented with an insidious onset and a chronic course of inflammation. Uveitis was primarily classified as IU (90.6%) and, to a lesser extent, as isolated anterior uveitis (9.4%).

Systemic neurological symptoms were reported by only 28.1% of patients. A family history of MS was present in a minority (6.3%), reinforcing that DPU patients are often neurologically asymptomatic at presentation. Nevertheless, during follow-up, 20% of initially DPU-labeled patients developed definite MS.

Clinical Features and Diagnostic Implications

DPU shares clinical features with MS-associated uveitis (MSU) and idiopathic IU. Notably, DPU commonly presents as granulomatous uveitis, characterized by granulomatous keratic precipitates and iris nodules. Cystoid macular edema (CME), found in over one-third of eyes, was the leading cause of visual impairment.

Fluorescein angiography (FA) findings are crucial for precise diagnosis. Peripheral retinal perivascular leakage was common in DPU, MSU, and idiopathic IU. However, a prominent leakage extended to the mid or posterior retina, is more suggestive of DPU or MSU and is less characteristic of purely idiopathic IU. (Table 1)

Table 1: Comparison of DPU, MSU, and Idiopathic IU

Treatment Challenges and Recommendations

One of the most critical therapeutic implications of identifying DPU lies in the contraindication of tumor necrosis factor-alpha (TNF-α) inhibitor therapy. TNF-α blockers, while effective for idiopathic uveitis, have been associated with new or exacerbated demyelinating events^10,11. Misdiagnosis can lead to inappropriate treatment, as highlighted by the finding that several DPU patients initially received TNF inhibitors before correct diagnosis.

DPU management relies on treatment by classical immunomodulatory agents such as methotrexate, mycophenolate mofetil, azathioprine, cyclosporine A, and, occasionally, anti-CD20 therapy (e.g., rituximab). Systemic corticosteroids are used for rapid inflammatory control, while periocular corticosteroids are preferred in cases of unilateral CME or when systemic steroid exposure needs to be minimized.

In this study, visual outcomes were favorable, with over 80% of eyes achieving a visual acuity of 20/40 or better at two-year follow-up.

Real-World Challenges in Diverse Clinical Settings 

Access to healthcare varies significantly across regions, and although this study was conducted in Tehran, a major referral center, many patients must travel from underserved areas to receive specialized care. In such settings, the diagnosis of DPU can be particularly challenging. Additionally, ophthalmologists in different geographical areas around the world may face multiple barriers to obtaining neuroimaging. These include insurance limitations, lack of familiarity with appropriate imaging protocols, and insufficient collaboration with radiologists or neurologists. Such challenges can delay diagnosis and appropriate management.

To improve outcomes, it is essential to raise clinical awareness of DPU, strengthen interdisciplinary communication, and promote equitable access to neuroimaging for at-risk patients, regardless of practice location or available resources.

Future Directions and Theoretical Considerations

Given the association between DPU and the subsequent development of MS in a significant subset of patients, DPU may be conceptualized as an ophthalmologic analog of a "radiologically isolated syndrome" (RIS) — a concept in MS research that describes asymptomatic patients with demyelinating plaques. Future studies should prospectively track neurological outcomes in DPU patients to determine whether DPU could eventually be incorporated into MS diagnostic frameworks.

Currently, there is no consensus on the indications of neuroimaging among patients with uveitis. Neuroimaging is primarily requested for uveitis patients who are candidates for anti-TNF therapy, those exhibiting neurologic symptoms or signs related to MS, and individuals with a positive family history of MS¹². We believe that in a population where demyelinating diseases are prevalent, we should maintain a low threshold for performing neuroimaging to avoid missing DPU. That means, in addition to the widely accepted indications mentioned above, neuroimaging should be considered in any young or middle-aged patient, even those who are neurologically asymptomatic, who presents with chronic granulomatous intermediate and/or anterior uveitis, particularly if the patient is female and prominent and extensive perivascular leakage is observed on FA.

One limitation of the original paper is that it does not specify the imaging characteristics used to define “demyelinating plaques.” Since the ophthalmology records did not systematically collect detailed neuroimaging findings, we primarily relied on the neurologist's report to evaluate the significance of the lesions. Future studies should include lesion location and characteristics to further strengthen the diagnostic framework. Additionally, because the updated version of the McDonald criteria was not available at the time of the study, it should be considered in future research.

Conclusion

The recognition of DPU as a distinct clinical entity offers significant implications for diagnosis, treatment, and long-term patient monitoring. By lowering the threshold for neuroimaging in patients with compatible clinical and angiographic features, ophthalmologists can play a crucial role in the early detection of CNS demyelination and prevention of inappropriate therapies such as anti-TNF. Collaborative interdisciplinary care and future research into the natural history of DPU will further define its place within the spectrum of demyelinating diseases.

References

1. Casselman P, Cassiman C, Casteels I, et al. Insights into multiple sclerosis-associated uveitis: a scoping review. Acta Ophthalmol. 2021; 99(6): 592-603. doi: 10.1111/aos.14697. PMID: 33326162.
2. Olsson T, Barcellos LF, Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol. 2017; 13(1): 25-36. doi: 10.1038/nrneurol.2016.187. PMID: 27934854.
3. Lindner E, Weger M, Steinwender G, et al. IL2RA gene polymorphism rs2104286 A>G seen in multiple sclerosis is associated with intermediate uveitis: possible parallel pathways? Invest Ophthalmol Vis Sci. 2011; 52: 8295-8299.
4. Kerrison JB, Flynn T, Green WR. Retinal pathologic changes in multiple sclerosis. 1994; 14(5): 445-51. doi: 10.1097/00006982-199414050-00010. PMID: 7899721.
5. Abu El-Asrar AM, Herbort CP, Tabbara KF. Retinal vasculitis. Ocul Immunol Inflamm. 2005; 13(6): 415-33. doi: 10.1080/09273940591003828. PMID: 16321886.
6. Ciccarelli O, Barkhof F, Bodini B, et al. Pathogenesis of multiple sclerosis: insights from molecular and metabolic imaging. Lancet Neurol. 2014; 13(8): 807-22. doi: 10.1016/S1474-4422(14)70101-2. PMID: 25008549.
7. Przeździecka-Dołyk J, Węgrzyn A, Turno-Kręcicka A, et al. Immunopathogenic Background of Pars Planitis. Arch Immunol Ther Exp (Warsz). 2016; 64(2): 127-37. doi: 10.1007/s00005-015-0361-y. PMID: 26438050; PMCID: PMC4805694.
8. Hedayatfar A, Anvari P, Herbort CP, et al. Demyelinating plaque-associated uveitis. Graefes Arch Clin Exp Ophthalmol. 2024; 262: 575-582.
9. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018; 17(2): 162-173. doi: 10.1016/S1474-4422(17)30470-2. PMID: 29275977.
10. Bosch X, Saiz A, Ramos-Casals M; BIOGEAS Study Group. Monoclonal antibody therapy-associated neurological disorders. Nat Rev Neurol. 2011; 7(3): 165-72. doi: 10.1038/nrneurol.2011.1. PMID: 21263460.
11. Kemanetzoglou E, Andreadou E. CNS demyelination with TNF-α blockers. Current neurology and neuroscience reports. 2017; 17: 1-5.
12. Petrushkin H, Kidd D, Pavesio C. Intermediate uveitis and multiple sclerosis: to scan or not to scan. Br J Ophthalmol. 2015; 99(12): 1591-3. doi: 10.1136/bjophthalmol-2015-307269. PMID: 26338960.