Eye Symptoms, Signs, and Therapy in Multiple Sclerosis
Collin M. McClelland and Steven L. Galetta
KEY POINTS FOR CLINICIANS
• Demyelinating optic neuritis (DON) is a hallmark manifestation of multiple sclerosis (MS) and is marked by acute or subacute onset of vision loss, eye pain, and a relative afferent pupillary defect (RAPD) in unilateral cases.
• Intravenous steroids do not alter the long-term visual outcome of isolated DON but expedite visual recovery and show a protective effect against MS development for 2 years.
• Neuromyelitis optica (NMO)-associated optic neuritis may present similar to DON. Providers should maintain a low threshold for serum NMO antibody testing in cases of DON as NMO requires a different long-term treatment.
• Optical coherence tomography (OCT) is a noninvasive imaging test that can be used clinically to aid in the diagnosis of MS by detecting subtle optic nerve atrophy. It can be used in the management of MS by serially measuring retinal nerve fiber layer thickness as a structural correlate of optic nerve disease in MS patients.
• Maculopathies, including fingolimod-associated macular edema, often have subtle fundus findings and can mimic DON. Unlike DON, they characteristically lack pain and often do not demonstrate an RAPD.
• Demyelination rarely causes isolated ocular motor (cranial nerve [CN] III, IV, and VI) palsies. Alternative etiologies should always be carefully evaluated.
MS frequently affects both the afferent visual system and the efferent ocular motor system. An estimated one third of MS patients develop DON during their disease course, whereas up to three out of four suffer from abnormalities of ocular movement. A basic understanding of neuro-ophthalmology is important for all providers who manage MS patients.
The neuro-ophthalmic effects of MS include highly characteristic features such as DON and internuclear ophthalmoplegia (INO), as well as other manifestations such as nystagmus, cranial nerve (CN) palsies, uveitis, and saccadic abnormalities. Vision loss may also arise from treatment complications including fingolimod-associated macular edema (ME), corticosteroid-induced central serous chorioretinopathy (CSR), and natalizumab-associated progressive multifocal leukoencephalopathy (PML). This chapter reviews high-yield clinical knowledge pertinent to the diagnosis and management of MS-associated visual impairment.
EVALUATION: AFFERENT PATHOLOGY
A hallmark feature of MS, DON occurs in about 50% of MS patients during the course of the disease and may be the presenting feature in about 20%. While the term optic neuritis is often used as a synonym for DON associated with MS, the term optic neuritis also refers to optic nerve inflammation that complicates other inflammatory and infectious conditions. Referring to MS-associated optic neuritis as idiopathic DON lessens the ambiguity.
The optic neuritis treatment trial (ONTT) defined the presenting characteristics (1), optimal treatment (2), visual prognosis (3), and long-term risk of MS in patients with DON (4). MS and DON share similar patient demographics; DON is common in young patients (mean age = 31.8), whites (85%), and females (F:M = 3:1) (1). The diagnosis of DON remains clinical and is characterized by vision loss over hours to days, eye pain, and the presence of a RAPD 209in unilateral cases. Visual impairment can affect central vision, peripheral vision, and color vision; a thorough exam for suspected DON should assess all these aspects of visual function. In most clinical settings, visual acuity is tested on a high-contrast distance Snellen acuity chart or a near card using the patient’s glasses correction for the distance tested. If a patient’s glasses are not available, use of a pinhole occluder is one means to estimate the best corrected visual acuity for both near and distance vision testing. Presenting visual acuity in DON ranges from normal to no light perception, with severe vision loss occurring in a minority of patients (Table 23.1) (1).
DON is characterized by acute vision loss, eye pain, and a relative afferent pupillary defect (in unilateral cases).
Dyschromatopsia, or abnormal color perception, occurs in most DON cases (88%–94%) and can be tested easily in clinic using pseudoisochromatic color plates (e.g., Ishihara color plates) or subjective red desaturation testing using a red bottle top (1). Visual field loss on formal perimetry testing occurs in nearly all patients with symptomatic DON. Although confrontation testing techniques are helpful for large visual field defects, more subtle defects require formal visual field testing. Automated static threshold perimetry (e.g., Humphrey visual field testing) was used in the ONTT, which found that the most common pattern (45%) was a diffuse depression or a large central scotoma (1). The study found that virtually any pattern of visual field loss may occur with DON and there is no specific pattern that strongly suggests DON. Unfortunately, the presenting features of vision loss in DON are nonspecific and occur in many other optic neuropathies and retinopathies. Diagnosis, therefore, often relies on more distinguishing features such as eye pain, fundus appearance, and the presence of visual recovery.
VA: 20/20 or greater
VA: Finger counting or lesser
Note that 20/200 or worse vision in both eyes typically defines the legal VA criteria for blindness. VA worse than 20/200 in an eye is considered a functionally blind eye.
DON, demyelinating optic neuritis; VA, visual acuity.
Source: The clinical profile of optic neuritis. Experience of the optic neuritis treatment trial. Optic neuritis study group. Arch Ophthalmol. 1991;109(12):1673-1678.
Eye pain is described in about 92% of DON cases, may vary from mild to severe, is not typically associated with conjunctival injection, and is often worse with eye movement (1). The pain may precede or follow vision loss and usually subsides in 3 to 5 days. DON without eye pain is atypical and raises concern for alternative diagnoses (Table 23.2). Almost all DON cases will exhibit an RAPD on the swinging flashlight test (Video 23.1). The absence of an RAPD raises concern (Table 23.2) for bilateral DON, retinopathy-mimicking DON, or prior insult to the contralateral optic nerve. About two thirds of DON cases have normal-appearing optic nerves, whereas the other one third typically show only mild optic disc edema (1). Hemorrhages around the optic nerve head (peripapillary) and retinal exudates caused by swelling and lipid deposition associated with severe disc edema occur in about 5% of cases and suggest “atypical optic neuritis” related to infectious or nondemyelinating inflammatory disorders (Table 23.2). While laboratory tests for DON mimics (e.g., sarcoidosis, lupus, antineutrophil cytoplasmic antibodies (ANCA) vasculitides) are rarely helpful in classic presentations of DON, the presence of peripapillary hemorrhages, retinal exudates, or severe disc edema should prompt a targeted evaluation.
The presence of peripapillary hemorrhages, retinal exudates, or severe disc edema in the setting of acute optic nerve dysfunction should prompt a targeted evaluation for causes of atypical optic neuritis.
Optic disc edema accompanied by macular exudates forming a sunburst-like pattern surrounding the fovea (Figure 23.1) is highly suggestive of neuroretinitis, a diagnosis not associated with MS. While most cases of neuroretinitis are idiopathic, specific etiologies (Table 23.2) should be considered and tested for depending on clinical context.
On fundus examination, most cases of demyelinating optic neuritis (DON; two thirds) have normal-appearing optic nerves. The other one third usually shows mild disc edema.
While neuroimaging is not usually necessary to diagnose DON, MRI of the brain is indicated to assess characteristic white matter lesions in patients without known MS (see the section on management). In cases when DON is difficult to distinguish clinically from nonarteritic anterior ischemic optic neuropathy (NAION), dedicated orbital MRI sequences may be beneficial (5). DON demonstrates optic nerve enhancement in nearly all cases (>90%) while it is rarely seen in NAION (about 7%) (5). In cases with acute painful vision loss, RAPD, and orbital signs (e.g., proptosis, conjunctival injection/chemosis, or restricted motility), MRI of the orbits may be helpful to evaluate for orbital pseudotumor or idiopathic orbital inflammatory syndrome. Usually idiopathic and considered within the spectrum of orbital pseudotumor, optic perineuritis is primarily a radiographic diagnosis characterized by peripheral enhancement of the optic nerve (6). Peripheral vision loss tends to predominate in optic perineuritis, although central acuity can be affected and mimic DON. Distinction from DON is important because optic perineuritis is exquisitely sensitive to steroids (intravenous [IV] or oral) and is not associated with MS.
ALTERNATIVE DIAGNOSES TO CONSIDER
Severe disc swelling (including peripapillary hemorrhages or exudates)
“Atypical optic neuritis”: Autoimmune-associated (lupus, Sjogren’s, sarcoid, inflammatory bowel disease), infectious (syphilis, HIV, Lyme disease, tuberculosis), papilledema, hypertensive retinopathy, anterior ischemic optic neuropathy (nonarteritic and giant cell arteritis)
Macular star of exudates
Neuroretinitis (cat-scratch disease, Lyme disease, syphilis, toxoplasmosis, sarcoid, tuberculosis, numerous viral etiologies)
Lack of visual recovery
Neuromyelitis optica-associated optic neuritis, compressive lesions (malignancy or aneurysm), sarcoidosis, ischemic optic neuropathy, maculopathies (CSR, ME, choroidal neovascular membrane, retinal vascular occlusion, etc.), nutritional/toxic (B12 deficiency, vitamin A deficiency, folate deficiency, cigarette smoking), metabolic (Leber hereditary optic neuropathy)
Nondemyelinating optic neuritis associated with uveitis: Sarcoid-, syphilis-, Lyme disease-, Behcet-, tuberculosis-, and inflammatory bowel disease-associated optic neuritis
Optic nerve sheath enhancement on MRI
“Optic perineuritis”: Orbital pseudotumor, sarcoid, inflammatory bowel disease, Lyme disease, syphilis, Wegener’s disease, and optic nerve sheath meningioma
Lack of pain
Ischemic optic neuropathy, neuromyelitis optica-associated optic neuritis, Leber hereditary optic neuropathy, numerous maculopathies (CSR, ME, choroidal neovascular membrane, retinal vascular occlusion, etc.). Consider retrochiasmatic visual loss.
Lack of a relative afferent pupillary defect
Numerous maculopathies (CSR, ME, choroidal neovascular membrane, retinal vascular occlusion, etc.), bilateral optic neuropathy (including bilateral DON), media opacities (e.g., posterior subcapsular cataract, corneal pathology, vitreous hemorrhage)
Numerous maculopathies (CSR, ME, choroidal neovascular membrane, retinal vascular occlusion, etc.)
TNF-I-associated optic neuritis. TNF-Is are known to occasionally incite inflammation throughout the CNS.
CNS, central nervous system; CSR, central serous chorioretinopathy; DON, demyelinating optic neuritis; ME, macular edema; TNF-I, tumor necrosis factor inhibitor.
Some maculopathies may mimic DON. Fingolimod (Gilenya) has been shown to cause ME in 0.5% to 0.6% of patients (7). ME is associated with painless central vision loss in one or both eyes, typically with normal pupillary function (no RAPD). The result of a breakdown of the blood retinal barrier, ME frequently occurs in association with diabetes, uveitis, and retinal vein occlusions. The fundus findings of ME are often subtle, and diagnosis relies heavily on ocular coherence tomography (OCT) (Figure 23.2) and fluorescein angiography (FA). The greatest risk for ME occurs in the first 3 to 4 months of fingolimod treatment. Patients should receive a baseline pretreatment ophthalmic exam followed by a repeat exam 3 to 4 months after starting fingolimod (7). If no ME is present after 4 months on therapy, patients may resume routine once yearly eye care. Patients with risk factors for ME (such as diabetes and uveitis) may require closer follow-up.
SD-OCT, spectral domain ocular coherence tomography.
Fingolimod-associated macular edema typically causes painless central vision loss and when it occurs it typically occurs in the first 4 months of treatment.
CSR is a maculopathy marked by painless detachment of the neurosensory retina (8). CSR causes subacute onset of central vision loss that may mimic DON. CSR is important to MS providers because it can be triggered by glucocorticoid administration and, unlike DON, will worsen with prolonged steroid therapy (9). Patients are classically middle aged (mean = 41 years), predominantly male (M:F = 6:1), and exhibit type A personalities (8). Exam findings are often subtle (Figure 23.3A) and include mild elevation of the detached macula, an absence of the normal foveal light reflex, and abnormal macular coloration. Diagnosis is facilitated by FA (Figure 23.3B) and OCT (Figure 23.3C).
CSR, central serous chorioretinopathy; FA, fluorescein angiography; SD-OCT, spectral domain ocular coherence tomography
In addition to corticosteroids and fingolimod, there are other medications used in the treatment of MS that can have visual and ocular side effects (Table 23.3). Both CSR- and fingolimod-associated ME are maculopathies most easily distinguished from unilateral DON by the lack of pain and absence of an RAPD. Metamorphopsia, or the wavy distortion of straight lines, is a specific symptom of maculopathies not usually described in optic neuropathies.