Multiple Sclerosis-Associated Uveitis

Multiple sclerosis (MS) is a neuroinflammatory condition characterized by repeated, focal demyelination in the central nervous system (CNS).¹ The disease is defined clinically as either relapsing-remitting (RRMS) or primary progressive (PPMS). Relapsing-remitting is by far the most common form of the disease, affecting 85%–90% of patients – most of whom are women² in their third through fifth decades of life. The condition is characterized by transient episodes of neurologic dysfunction followed by periods of relative to complete remission. Primary progressive, in contrast, affects men and women equally, tends to occur at a somewhat older age, and shows slower, insidious worsening of neurologic disability over time. Patients with RRMS may convert to a more progressive course known as secondary progressive MS (SPMS). Common systemic complaints in those with MS include fatigue, pain, paresthesias, problems with mobility, speech or swallowing, and bowel, bladder or sexual dysfunction. Frequent ocular manifestations include optic neuritis³ – which affects half or more of those with MS at some point in their illness; oculomotor abnormalities^4,5 – reported in approximately 30%–50% of those affected; and uveitis^2,6 – seen in about 1% of patients. While roughly 1%–2% of patients who present to uveitis referral centers carry the diagnosis MS, the life-time prevalence pf MS may be 10-fold greater for those with intermediate uveitis.² Following exclusion of alternate causes of neuroinflammation, the diagnosis of MS requires the identification of symptoms, signs, and magnetic resonance imaging (MRI) findings consistent with at least two CNS demyelinating events separated in time and space.¹ Patients with uveitis suspected of having MS based on history or clinical findings should be re referred to a neurologist for evaluation and management,⁷ since treatment of neurologic complications is both rapidly evolving⁸ and is often independent of therapies used for ocular inflammation. The pathogenesis of MS remains unclear, although both environmental and genetic factors appear to contribute and multiple lines of evidence suggest that the immunological processes involved in both neurologic and ocular inflammation are similar.⁹ Three original articles^10-12 in this issue of Ocular Immunology & Inflammation (OII) address important aspects of MS-associated uveitis.

Jouve et al.¹⁰ described the clinical characteristics and response to treatment in 36 patients with MS-associated uveitis seen between 2011 and 2013 at two referral centers in Paris, France. The inflammation was bilateral in 32 subjects (88.9%; 68 affected eyes). A total of 25 patients were female (69.4%) and the mean age was 45 years (range 18 to 57 years). Most subjects (69.4%) were Caucasian. Uveitis preceded the diagnosis of MS in 28 patients (77.8%) at a mean of 4.9 years (range 1–17 years). Overall, the inflammation tended more often to be recurring (69.4%; vs chronic = 27.8%) and intermediate (86.1%). Common findings included large/granulomatous keratic precipitates (61.1%), snowball vitreous opacities (61.1%), and periphlebitis (58.3%). Complications included cataract (50.0%), cystoid macular edema (CME; 50.0%), posterior synechiae formation (44.4%), ocular hypertension (27.8%), and glaucoma requiring filtering surgery (2.8%). The cohort was divided into two groups based on systemic treatment status. Specifically, 17 subjects (47.2%) were not receiving systemic treatment for RRMS, whereas 19 (52.8%) were – the vast majority of whom were on an immunomodulatory agent (interferon beta-1a [7, 36.8%], interferon beta-1b [6, 31.6%], or glatiramer acetate [4, 21.5%]), with one patient each having been treated with azathioprine and natalizumab. While the sample sizes were small and the retrospective and non-randomized nature of the study could have introduced very real referral, selection, and/or treatment bias effects¹³ – not the least of which may have been the fact that those with RRMS requiring systemic treatment were prone to worse ocular inflammation – the authors concluded that the uveitis in subjects with RRMS requiring systemic treatment tended more often to be both chronic (42.1% vs 11.8%) and to require long-term oral cortico steroids (73.7% vs 47.1%), although neither of these differences achieved statistical significance (p = 0.06). Otherwise, treatments required to control the uveitis were similar between the two groups, with most patients (91.7%) requiring topical corticosteroids, and only five patients (13.9%) requiring systemic non-corticosteroid immunosuppressive drugs. The authors concluded that patients generally did well, with a mean post-treatment best-corrected vision of 20/25. While the authors suggested from their findings that traditional immunosuppressive drugs, such as azathioprine, should be selected over immunomodulators, such as interferon, for the treatment of uveitis and its complications, it should be noted that others have reported superior results with interferon.^14,15 The authors reminded us that fingolimod, which is used to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability in patients with RRMS, has been associated with the development of CME and so should be used with caution in patients with MS-associated uveitis.¹⁶

Hedayatfar et al.¹¹ described the use of mycophenolate mofetil, 500–1000 mg twice daily, to treat MS-associated uveitis in 15 patients seen in a referral center in Tehran, Iran, from 2010 to 2015. Ages ranged from 17 to 48 years, with mean and median ages of 34.5 and 35 years, respectively. Fourteen patients (93.3%) were female, 11 had intermediate uveitis (93.3%), and one had anterior uveitis (6.7%). The inflammation was both bilateral and chronic in all patients. Twelve patients had MS prior to developing uveitis and were receiving treatment with interferon-beta. The course of MS was relapsing remitting in 11 patients (73.3%) and secondary progressive in four (26.7%). Common findings at presentation in the 30 affected eyes included large keratic precipitates (86.7%), peripheral vascular sheathing (75.9%), snowball vitreous opacities (65.5%), posterior synechiae formation (63.3%), epiretinal membrane formation (31.6%), and CME (26.3%). All patients were treated initially with oral prednisonlone, 1 mg/kg/day, which was tapered slowly following control of the inflammation. Mycophenolate mofetil was added both to prevent relapses and to facilitate prednisone taper. Follow-up ranged from 18 to 51 months, with a mean and median follow-up of 30.7 and 32 months, respectively. At the 1-year follow-up, inflammation was controlled and the oral prednisolone dose was at or below 7.5 mg/day in all patients. Best-corrected vision was either stable or improved in 25 eyes (80.3%), and of the five eyes with decreased vision, three had cataract, one developed ERM, and one experienced optic neuritis. The mycophenolate mofetil was generally well-tolerated with two patients reporting gastrointestinal upset and one describing muscle ache. None of the 15 patients discontinued treatment. The authors concluded that mycophenolate mofetil can be an effective corticosteroid-sparing agent in patients with MS-associated uveitis.

Khalil et al.¹² studied 68 MS patients and 23 age and gender-matched healthy control subjects seen over approximately 8 months in a neurology clinic in Cairo, Egypt, in 2013 and 2014 to determine whether visual field perimetry and/or spectral domain-optical coherence tomography (SD-OCT)-measured thickness of the retinal nerve fiber layer (RNFL), which is comprised of non-myelinated retinal ganglion cell (RGC) axons, or of the ganglion cell complex (GCC), defined as the RNFL together with both the RGC layer and the inner plexiform layer, could be used to document axonal loss in patients with demyelinating disease. One eye was randomly selected from each study participant. The authors found that RNFL and GCC thickness were decreased in MS patients compared to controls by about 20 μm (89.3 ± 15.7 vs 117.8 +/26.2; nominal p < 0.001) and 10 μm (85.6 +/–12.9 vs 96.2 +/–21.0; nominal p = 0.048), respectively, and that both were negatively correlated with disease duration (RNFL, r = –0.530, nominal p < 0.001; GCC, r = −0.639, nominal p = 0.008), but that such decreases did not differ by MS subtype (relapsing remitting vs primary progressive vs secondary progressive). RNFL thickness was also negatively correlated with the MS-expanded disability status scale (EDSS; r = −0.269, nominal p = 0.042); whereas no such correlation was observed for thickness of the GCC. Thickness differences were slightly greater among the 30 eyes with a distant (> 6 months) history of MS-related optic neuritis (RNFL = 84.1 +/–13.5, nominal p = 0.021; GCC = 84.3 +/–11.9, nominal p = 0.023). Thickness measurements showed no correlation with either best-corrected visual acuity or mean deviation on a standardized 24–2 Humphrey visual field. While loss of both RGCs and their axons in patients with MS-related optic neuritis was not surprising, a cause for both RNFL and GCC thinning in the absence of clinically overt optic neuritis is perhaps less obvious. The authors speculated that trans-synaptic RGC degeneration may have occurred following injury to the central visual pathways. They also suggested that high resolution OCT may be used to monitor for both subclinical and ON-related RGC loss over time.

Together, these studies highlight important issues related to the clinical presentation, diagnosis, and management of MS-associated uveitis, including how much remains to be understood regarding this complex and often chronic condition. Demyelinating disease occurs most often in patients with intermediate uveitis - typically in setting of retinal phlebitis, but may also occur in those with anterior or panuveitis, many of whom have granulomatous features. While most patients with MS-associated uveitis do well with a standard approach to therapy, tumor necrosis factor inhibitors should be avoided given reports of demyelinating disease associated with the use of such agents.¹⁷

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper

Funding

This work was supported in part by The Pacific Vision Foundation (ETC) and The San Francisco Retina Foundation (ETC).

Additional information

Funding

This work was supported in part by The Pacific Vision Foundation (ETC) and The San Francisco Retina Foundation (ETC).