Multiple Sclerosis

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upon flexion of the neck), Uhthoff's phenomenon. (worsening of symptoms with increasing tempera- ture or physical stress), diplopia, and internuclear.
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Multiple Sclerosis Friederike Mackensen and Matthias D. Becker

Contents 74.1

Introduction . . . . . . . . . . . . . . . . . . . . . . .

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74.2

Clinical Manifestations . . . . . . . . . . . . . .

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74.3

Etiology and Pathogenesis . . . . . . . . . . . .

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74.4

Diagnostics . . . . . . . . . . . . . . . . . . . . . . . .

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74.5

Differential Diagnosis . . . . . . . . . . . . . . .

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74.6

Treatment . . . . . . . . . . . . . . . . . . . . . . . . .

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74.7

Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Core Messages

• The most common ocular manifestation of MS is optic neuritis. • Approximately 1 % of MS patients develop uveitis and 1–14 % of uveitis patients have MS. • Uveitis in patients with MS is generally a bilateral disease and most often manifests as intermediate uveitis. • Uveitis can predate the onset of neurological symptoms for many years; in intermediate uveitis of the “MS-like” type, cMRI may lead to an early diagnosis.

74.1

F. Mackensen, MD, FEBO (*) Interdisciplinary Uveitis Center, Department of Ophthalmology, University of Heidelberg, Im Neuenheimer Feld 400, Heidelberg 69120, Germany e-mail: [email protected] M.D. Becker, MD, PhD, FEBO, MSc Department of Ophthalmology, Triemli Hospital Zürich, Birmensdorfer Str. 497, Zürich CH-8063, Switzerland e-mail: [email protected]

Introduction

Multiple sclerosis (MS) or encephalomyelitis disseminata is the most common autoimmune inflammatory demyelinating disease of the central nervous system. The disease was described by Charcot in the nineteenth century, who noticed a combination of symptoms, nystagmus, tremor, and staccato speech, in patients who later on autopsy were shown to have multiple gliotic plaques in their brains. Today we know the autoimmune origin of the disease, especially the involvement of autoaggressive T cells directed against myelin, but the details of the multifactorial pathogenesis are still in the dark. Eye involvement, as in the “Charcot triad,” is frequent.

M. Zierhut et al. (eds.), Intraocular Inflammation, DOI 10.1007/978-3-540-75387-2_74, © Springer-Verlag Berlin Heidelberg 2016

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Essentially every part of the visual sensory system can be involved [13]. The most frequent associated ocular disorder is optic neuritis [7, 24], followed by ocular motor defects. Uveitis associated with MS is generally of the intermediate uveitis type, with mild periphlebitis and snowbank or less frequently granulomatous anterior uveitis. Even though a T-cell-mediated process seems to be the key element in MS-related uveitis, the pathomechanism of uveitis is even less clear than that of the neurologic disease, which is due to the fact that no myelin is present in the uveal tissue. MS as a potential association with uveitis should not be forgotten, especially in the age of TNF alpha inhibitors, since these agents seem to worsen and are even suspected to trigger off demyelinating disease [38]. The pattern and course of MS is categorized as follows [35]: • Relapsing-remitting MS (RRMS) is characterized by clearly defined relapses with full recovery or with sequelae and residual deficit upon recovery. There is no disease progression during the periods between disease relapses. • Primary-progressive MS (PPMS) is characterized by disease progression from onset with occasional plateaus and temporary minor improvements allowed. • Secondary-progressive MS (SPMS) is characterized by an initial RR disease course followed by progression with or without occasional relapses, minor remissions, and plateaus. • Progressive-relapsing MS (PRMS) is characterized by progressive disease from onset, with clear acute relapses, with or without full recovery. Progression continues during the periods between disease relapses. The International Panel on MS Diagnosis made several changes to the older diagnostic (Poser) criteria in 2001 while at the same time reaffirming the need to demonstrate dissemination of clinical events and MRI lesions [42]. These so-called “McDonald” diagnostic criteria were revised in 2005 [51]. Thus, diagnostic confidence is assigned as follows: a diagnosis of “MS” is given if diagnostic criteria are fulfilled, it is “possible MS” if the criteria are not completely

met, and the diagnosis of “not MS” is given if the criteria are fully explored and not met. The core requirement of the diagnosis is the concept of dissemination in space and time, either in two clinical attacks or MRI findings. It is not clear if the McDonald criteria are sufficiently accurate in patients with a clinically isolated syndrome (which may be uveitis as well) to make decisions regarding disease-modifying therapy. The incidence and prevalence of MS varies geographically [19]. High-frequency areas of the world include all of Europe (including Russia), southern Canada, northern United States, New Zealand, and southeast Australia. In many of these areas, the prevalence is more than 100 per 100,000; the highest reported rate of 300 per 100,000 is in the Orkney Islands. This geographic variance may be explained in part by racial differences; white populations, especially those from Northern Europe, appear to be most susceptible; people of Asian, African, or American Indian origin have the lowest risk. There also appears to be an association between latitude and the risk of MS, with the risk increasing from south to north [3]. Persons migrating from a high- to low-risk area after puberty carry their former high risk with them, while those that migrate during childhood seem to have the risk associated with the new area to which they migrated. Women are affected twice as often as men. The mean age of MS onset is 30 years of age; women generally fall ill earlier than men. This is similar to the peak age of onset of uveitis patients [29]. Frequencies of uveitis vary from 0.4 to 26.9 % in patients with MS [6, 10, 12, 52], and MS is found in 0.8–14 % of patients with uveitis [29, 30, 39, 55]. These differences are attributable to variations in patient populations, criteria for diagnosis of both diseases, and examination techniques, most of all retrospective case reports versus prospective ocular exams of consecutive MS patients (see Tables 74.1 and 74.2). Still, this makes uveitis in MS patients ten times more common than in the normal population, where prevalences of 0.1 % are estimated for uveitis [23].

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Table 74.1 Case series on frequency of MS in patients with uveitis Authors Maca et al. [36]

Year 2006

Smith and Rosenbaum [74] Biousse et al. [10] Raja et al. [53] Malinowski et al. [39] Jakob et al. [29]

2004 1999 1999 1993 2009

Number of patients/ diagnosis 1,973/uveitis 296/intermediate uveitis 1,450/uveitis

MS at uveitis diagnosis [% of patients] 0.8 10.0 1.0

MS during follow-up [% of patients] NA NA NA

1,530/uveitis 53/intermediate uveitis 54/intermediate uveitis 1,916/uveitis 438/intermediate uveitis

1.0 5.7 NA 3.1 10.5

NA 16.2 14.8 NA NA

MS multiple sclerosis, NA not applicable Table 74.2 Case series on frequency of uveitis in patients with MS Authors Breger and Leopold [12] Porter [52] Bamford et al. [6]

Year 1966

N 52

Type of study Prospective ocular review

1972 1978

60 128

Arnold et al. [4] Biousse et al. [10]

1984 1999

47 1,098

Prospective ocular review Prospective ocular review, FLA Autopsy/histology Retrospective chart review

% with uveitis 26.9

% with other intraocular findings NK

10 2.4

5 periphlebitis 11 perivenous sheathing 8.5 periphlebitis NK

2.1 1.1

MS multiple sclerosis, NA not applicable, NK not known, FLA fluorescein angiography

Activity of retinal sheathing in MS does not seem to correlate with optic neuritis, systemic exacerbations, or severity of neurologic disease. Schmidt et al. showed in a small series that MS patients with concomitant intraocular inflammation are not distinct from “classic” MS with regard to the clinical course of disease, disability, and neuroimaging features [60]. Bamford and coworkers [6] in contrast found perivenous sheathing to be associated with slightly more frequent MS relapses.

partial resolution (relapses and remission). Neurological symptoms as paresthesias in the extremities, Lhermitte’s sign (electric shock-like sensations that run down the back and/or limbs upon flexion of the neck), Uhthoff’s phenomenon (worsening of symptoms with increasing temperature or physical stress), diplopia, and internuclear ophthalmoplegia or a history suggestive of optic neuritis should prompt further investigations.

74.2.2 Ocular Disease

74.2

Clinical Manifestations

74.2.1 General Disease Multiple sclerosis (MS) is a clinical diagnosis. There are no clinical findings that are unique to this disorder, but some are highly characteristic. The typical patient presents as a young adult (age between 15 and 50) with two or more clinically distinct episodes of CNS dysfunction with at least

After ter Braak and van Herwaarden [62] described the first six patients with probable MS and iridocyclitis, choroiditis, and/or venous sheathing [62], Rucker was the first to describe isolated periphlebitis in MS patients [56]. Intermediate uveitis is the most frequent form [73] of MS-associated uveitis and can be accompanied by retinal vasculitis. In MS patients, the vasculitis seems to affect exclusively the veins (“periphlebitis”) and can be seen with and

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a

b

c

Fig. 74.1 (a) Fundus photographs of a patient with intermediate uveitis and extensive periphlebitis with hemorrhages, area of ischemia, and neovascularizations. (b) Fluorescein angiography composite picture of the early phase of the same patient before treatment. (c) Fluorescein

angiography composite picture after treatment with periocular corticosteroid injections, systemic interferon, and laser photocoagulation of the ischemic areas with improvement but still ongoing mild activity in one area and a neovascularization at 12 h

without uveitis. It encompasses both active vasculitis and chronic venous sclerosis [4]. The chronic form of sheathing appears typically as dense, white linear stripes following the course of several generations of the venous tree, corresponding to extravasated leukocytes (Fig. 74.1a) [26]. There may be associated constriction and dilation of the veins, with occasional retinal hemorrhage. However, there are also focal lesions in MS-associated uveitis, especially in the acute phase. Venous sclerosis seems to be the result of persistent inflammation. Retinal arteriolar involvement in MS-associated uveitis has not been described to our knowledge. Another sign of intermediate uveitis are snowbanks and snowballs (Fig. 74.2). Especially in the intermediate uveitis accompanying MS, snowbanks in combination with retinal vasculitis seem

to be typical [10, 12]. In patients with this type of uveitis, secondary changes like the formation of CME are frequently seen, or more rarely occlusive vasculitis with vasoproliferation can develop [31], which then may be complicated by vitreous hemorrhage [65]. Especially macular edema with subsequent epiretinal membrane formation is a challenge and a threat to visual prognosis. Further complications include cataract and glaucoma. In the database of the Interdisciplinary Uveitis Center Heidelberg (tertiary referral center), 59 out of 1,916 total uveitis patients (3.1 %) had an association with MS [29]. It was the fourth most frequent disease association found in our clinic, after sarcoidosis, ankylosing spondylitis, and juvenile idiopathic arthritis. Seventyfour percent of these patients were female. Seventy-eight percent had intermediate uveitis

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There was a delay between the onset of neurologic and ocular symptoms of a mean of 9 years. As in 40 % of the patients in this series, the onset of uveitis predated neurological symptoms; the diagnosis of MS should be reconsidered over time in patients with intermediate uveitis. A problem may be the fact that some patients do not fulfill the diagnostic criteria for “definite” MS, suggesting that uveitis with incomplete McDonald criteria may need an additional diagnostic term as, for example, “MS-like uveitis.” Fig. 74.2 Fundus photographs of a patient with intermediate uveitis, focused on the snowballs in the vitreous. In the background, out of focus, the optic disc can be perceived

Fig. 74.3 Anterior uveitis with granulomatous keratic precipitates in a patient with MS and cataract

and 10 % anterior uveitis. In another evaluation we found 80% with intermediate and 15% with anterior uveitis [73]. Conversely, the prevalence of MS in patients with intermediate uveitis at the Interdisciplinary Uveitis Center in Heidelberg was 10.5 %. This concurs with the literature: intermediate uveitis is most frequently associated with MS [10, 12, 36]. Anterior uveitis is rare in patients with MS, but if it occurs, it is of the granulomatous subtype [34, 43] (Fig. 74.3). To give one example, in a publication from 1999 [10], the authors reviewed records from consecutive patients in an MS clinic (n = 1,098) and in a uveitis clinic (n = 1,530) in France to select patients with “definite MS” and uveitis. A total of 12 patients from the MS clinic (1.1 %) and 16 from the uveitis clinic (1 %) were identified.

74.3

Etiology and Pathogenesis

Optic neuritis and MS are pathogenetically similar and clearly linked. Even though uveitis is ten times as frequent in MS patients as in the normal population, the association is less frequent than that of MS and other autoimmune diseases [20]. Therefore, a causal association is still debated. On this background, the higher frequency of intermediate uveitis in patients with MS is thought to be based on a common autoimmune/ immunogenetic predisposition: intermediate uveitis and MS have been shown to be associated with the HLA-DR15 haplotype [40, 53]. On the other hand, the embryologic development of ocular tissue shows that the uvea has its origins in the neural rim, which may indicate expression of neuroectodermal antigens similar to nerve tissue. This hypothesis is strengthened by the observation that antibodies directed against retinal antigens can be found in sera of MS patients [22, 67]. Increasing attention has centered on the Epstein-Barr virus (EBV), which causes infectious mononucleosis, as a possible cause or trigger of MS [5]. In a meta-analysis of 14 case-control and cohort studies, the risk of MS was increased after infectious mononucleosis (relative risk 2.3, 95 % CI 1.7–3.0) [63]. EBV DNA or local antibody production has been occasionally found in intraocular fluids of patients with uveitis, but so far there is not enough evidence to link the pathogen to the disease [59, 68]. Substantial evidence exists that there is no association between vaccines and MS [58].

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856 Table 74.3 Differential diagnosis (DD) of MS-associated uveitis Diagnosis Sarcoidosis Behçet’s disease Oculocerebral lymphoma Neurosyphilis Neuroborreliosis Vogt-Koyanagi-Harada syndrome SLE retinopathy Herpetic infections

Clinical signs leading the DD Multifocal periphlebitis, granulomatous uveitis Occlusive retinal vasculitis, oral and genital ulcers Age of patient Systemic illness (rash, etc.) Erythema migrans Panuveitis with exudative detachments, hearing loss, skin depigmentation Cotton-wool spots, Roth spots Retinal arteriolitis, retinal necrosis

Experimental autoimmune encephalomyelitis (EAE) is a well-established rodent model of CNS-specific inflammatory disease and is known to be the best animal model for studying the etiology and pathogenesis of MS. It is mediated by T cells and results in progressive demyelination and paralysis. As in MS, EAE is characterized by a breakdown of the blood-brain barrier. The inflammatory response is characterized by mononuclear infiltrates located around vessels of the CNS white matter, by activation of local microglia and astrocytes, and in the most severe cases, it may be eventually followed by demyelination. Anterior uveitis (AU) has been found to coincide with EAE in rabbits, in monkeys, in the Lewis rat [1, 66], and in mice [16, 61]. The encephalitogenic T cells are specific for the antigen myelin basic protein (MBP), which is a component of the myelinated sheath surrounding nerve bundles. These myelinated nerve bundles are abundant in the spinal cord and in the iris; thus, this “autoantigen” is located at sites of inflammation. In the rodent models of EAE, AU generally persists after the paralysis has subsided. EAE and AU can be induced actively by immunizing with MBP in the presence of adjuvant or passively by using adoptive transfer of MBP-specific T cells that have been generated against the whole antigen or encephalogenic peptides. Treatment with IFN-γ reduced ocular inflammation in this model [50]. More recently, it was shown that treatment with recombinant T-cell receptor ligands can prevent the disease and reduce disease activity [2]. Despite these findings, most EAE studies have focused on the

Diagnostic tests ACE level, chest X-ray or CT MRI imaging, HLA-B51, pathergy MRI imaging, CSF exam, diagnostic vitrectomy Syphilis serology, CSF exam Lyme serology, CSF exam Ocular ultrasound, MRI imaging, CSF exam, audiometry ANA Diagnostic vitrectomy

problems of spinal cord and brain disease, and there is little information on ocular pathologic events in the course of this experimental illness.

74.4

Diagnostics

Besides the fact the MS is a clinical diagnosis, diagnostic workup may be helpful in excluding other conditions, especially considering that other diseases may mimic its manifestations (see Table 74.3). Magnetic resonance imaging (MRI) is the test of choice to support the clinical diagnosis of MS. The characteristic lesion demonstrated on MRI is the cerebral or spinal plaque. Pathologically, plaques consist of a discrete region of demyelination, typically in the periventricular region. Patients with clinically definite MS have typical white matter lesions on MRI in over 90 % of cases. However, CNS lesions due to other disorders (e.g., ischemia, systemic lupus erythematosus, Behçet’s disease, other vasculitides, HTLV-I, sarcoidosis) may appear similar to MS lesions on MRI. This is particularly true for ischemic lesions, which make MRI criteria much less reliable for the diagnosis of MS in patients over the age of 50 [48]. MRI is a better predictor of progression to clinically definite MS than CSF analysis [45]. Spinal cord MRI lesions are nearly as common as brain MRI lesions in MS patients [11]. Gadolinium-DTPA is used to assess plaque activity [64]. CSF analysis: Qualitative assessment of CSF for oligoclonal bands using isoelectric focusing is

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relapsing-remitting course. Table 74.3 illustrates the differential diagnostics from the ophthalmologist’s point of view, which is the differential diagnosis of intermediate uveitis and/or retinal vascular changes. Most important are sarcoidosis and Behçet’s disease.

74.6

Fig. 74.4 Fluoresceineangiography of a patient with intermediate uveitis showing leakage from affected vessels which indicates breakdown of the blood-retinal barrier

the most important diagnostic CSF study when determining a diagnosis of MS. A common finding in MS is an elevation of the CSF immunoglobulin level relative to other protein components, suggesting intrathecal synthesis. Oligoclonal bands (OCBs) are found in 85–95 % of patients with clinically definite MS [57]. Up to 8 % of CSF samples from non-MS patients also contain OCBs; most are the result of chronic CNS infections, viral syndromes, and neuropathies. Fluorescein angiography of active retinal vasculitis demonstrates delayed uptake, persistence of dye, staining, and leakage from affected vessels, which indicates breakdown of the bloodretinal barrier (Fig. 74.4) [69]. Some vessels show staining of leakage in areas without clinically detectable vessel changes. Venous sclerosis may show either late staining or normal appearance on angiography (Fig. 74.1b, c). HLA typing and positivity for HLA-DR15 might be taken as another indication to ask for MRI and CSF investigation.

74.5

Differential Diagnosis

The differential diagnosis of MS includes all CNS inflammatory or infectious diseases such as systemic lupus erythematosus (SLE), Sjögren’s disease, polyarteritis nodosa, Behçet’s disease, syphilis, and retroviral diseases, which all may produce multifocal lesions with or without a

Treatment

A close collaboration between neurologists and ophthalmologists is helpful to optimize the treatment of these patients. It is debatable whether uveitis should be considered as manifestation of MS, in which case it would count as a new event, or an association based on an individual predisposition towards autoimmune disease. Thus, it is sometimes difficult to decide if immunomodulatory treatment to prevent progression of MS is indicated. In general, treatment of MS should be early and aggressive. Evidence supporting this strategy can be found in clinical trials showing that early treatment with interferon reduces the attack rate, whether measured clinically or by MRI, in patients with clinically isolated syndromes suggestive of multiple sclerosis [14]. A number of agents can be used to decrease the frequency of relapses and reduce disability in patients with relapsing-remitting MS. These include three different interferon beta drugs (Avonex®, Rebif®, Betaseron®), glatiramer acetate (Copaxone®), natalizumab (Tysabri®), mitoxantrone, and newer oral agents as fingolimod (Gilenya®) [46]. In cases of stable or subclinical neurologic disease that requires no treatment, the usual stepwise approach for the treatment of uveitis can be applied [27]. We generally consider visual impairment and/or presence of macular edema as an indicator for treating intermediate uveitis, not just the presence of inflammatory cells or mild sheathing of the retinal vessels alone. In the case of anterior chamber cell involvement, topical steroids are useful. Especially in unilateral/asymmetric disease and/or complicating macular edema, depot injections are used. Alternatively systemic corticosteroids, for example, prednisone in a dose of 1 mg/kg bodyweight, can be given. When corticosteroids cannot be

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reduced below the Cushing level, corticosteroidsparing agents should be introduced. As there is little data on the effectivity of these medications in patients with both uveitis and MS, we will postulate from the MS experience. There is little data on the effectivity of MTX or AZA (commonly used in uveitis) in multiple sclerosis, but both drugs seem to have a mild positive influence on MS [21]. Data on CSA and MMF are even scarcer. There may be a role for MMF as an adjunctive therapy for MS [44]; trials investigating the effect of interferon in combination with MMF are currently ongoing. There is increasing evidence that interferon is very effective in the treatment of uveitis associated with MS, especially the accompanying macular edema [9, 17]. Final results of a randomized, controlled, clinical trial indicate superiority of interferon over MTX in patients with intermediate uveitis with or without MS [37]. Daclizumab is a humanized monoclonal antibody that has specific binding activity for the alpha chain component of the high-affinity interleukin 2 receptor, which mediates the expansion of T cells after binding by interleukin 2. Therefore, daclizumab specifically targets activated lymphocytes thought to be directly involved in the inflammatory component of MS lesions. Clinical data from small open-label studies and phase 2 clinical trials in patients with RRMS and secondary-progressive MS suggest that daclizumab is well tolerated and is associated with reductions in MRI evidence of disease activity [46]. There are few case series published which indicate effectivity of daclizumab in noninfectious uveitis, including patients with intermediate uveitis or retinal vasculitis [47]. Glatiramer acetate (Copolymer 1, Copaxone®) has been shown to reduce relapses in MS as effectively as interferon beta [46]. As glatiramer acetate mimics myelin basic protein, which is an important component of the myelin sheath of nerves and thus is able to divert T-cell reaction to this component, a mode of action in uveitis seems less likely. It has only been investigated in the mouse model [71]. In our experience, a clinical effect on uveitis activity is not apparent. Natalizumab is a recombinant monoclonal antibody directed against alpha 4 integrins, which

is thought to diminish migratory capacity of immune cells, a very effective treatment for RRMS [46]. Natalizumab treatment is associated with a risk of developing progressive multifocal leukoencephalopathy (PML), a rare potentially fatal neurologic disease caused by reactivation of the polyomavirus JC (JCV). Effectivity for uveitis is unclear so far; the mode of action would indicate a potential role in uveitis as well. Mitoxantrone, a synthetic anthracenedione derivative, is an established cytotoxic, antineoplastic agent. Its presumed mechanism of action in MS is immunosuppression. In antineoplastic studies, the drug showed several immunomodulatory effects, inducing macrophage-mediated suppression of B-cell, T-helper, and T-cytotoxic lymphocyte function [46]. No data exists to our knowledge regarding its use in uveitis. Fingolimod is a sphingosine analogue that acts as an agonist of the sphingosine-1-phosphate receptor and thereby alters lymphocyte migration, resulting in sequestration of lymphocytes in lymph nodes. Clinical trial for MS led to approval of this first oral immunomodulatory treatment for MS [15, 32]. Two publications report the use of fingolimod in experimental autoimmune uveoretinitis [33, 54]. The mode of action makes it attractive for the use in uveitis patients as well. Macular edema as a potential side effect of this drug has been observed in 0.4 % of patients with the approved dose of 0.5 mg/day and in 1.2 % of patients treated with the higher dose [28, 70]. Fingolimodassociated macular edema typically resolves after cessation of therapy. Therefore, ophthalmic monitoring is recommended during this therapy. Further novel oral therapies for MS are teriflunomide, dimethyl fumarate, laquinimod, and cladribine [49]. There is a pilot study with four patients offering a promising perspective on fumaric acid esters in noninfectious uveitis [25]. The other agents have to our knowledge not been investigated in uveitis so far. Laser photocoagulation may be useful in case of severe ischemia and/or neovascularization, leading to non-perfusion areas. In cases of neovascularization, intravitreal application of VEGF inhibitors might be an option [41]. Vitrectomy may be indicated in successfully medically stabilized patients with secondary

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complications as vitreous opacities or epiretinal membranes [8].

74.7

Prognosis

The prognosis of uveitis associated to MS seems to be good: Malinowski and coworkers did not find a statistically significant change of visual acuity (VA) in intermediate uveitis patients over time [39] compared to baseline. But there was a high variation of visual acuity in their patients, and the mean VA was only 20/44. Donaldson and coworkers found a mean visual acuity after 10 years of follow-up of 20/30, with a third of the patients not requiring treatment and maintaining normal visual acuity [18]. Complicating factors are macular edema, neovascularization, and cataract formation. Visual outcome in MS patients is heavily influenced by the occurrence of optic neuritis, which may lead to irreversible visual loss. As immunomodulatory treatment with interferon has been shown to reduce progression of MS and optic neuritis flares, the diagnosis of MS should be kept in mind in patients with intermediate uveitis and investigations reconsidered over the years. This patient cohort has a substantially higher risk to develop MS over time (16.2 % over 5 years) [39]. On the other hand MS patients with uveitis seem to have a more lenient disease than patients with MS but no uveitis [72]

Take-Home Pearls

• MS must be considered in the differential diagnosis of young patients with bilateral intermediate uveitis, venous retinal vasculitis, and macular edema. • MRI and CSF investigations should be initiated in patients with intermediate uveitis and neurological symptoms. • MS should be ruled out before TNF alpha inhibitors are considered for the management of patients with intermediate uveitis. • Interferons are an emerging treatment for intermediate uveitis and macular edema.

• New oral agents for MS are promising improving patient quality of life, but fingolimod-associated macular edema as an infrequently occurring adverse event requires ophthalmic monitoring.

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15. 16.

17.

18. 19. 20.

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23.

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