Multiple sclerosis (MS), an inflammatory and neurodegenerative disorder of the central nervous system (CNS), causes progressive neurologic disability over time. Patients with MS frequently have visual symptoms, and the ophthalmologist is often the first physician consulted. Familiarity with both the ocular and neurologic consequences of MS is important for guiding the ophthalmologist to the appropriate diagnosis.
Epidemiology and genetics of multiple sclerosis
The prevalence of MS varies widely. It is more common in whites and in individuals living in latitudes greater than 40 degrees from the equator and is 2–3 times more likely to affect women than men. MS is relatively uncommon in children younger than 10 years; the incidence is highest among young adults (25–40 years). However, onset even after the age of 50 years is not rare.
The cause of MS remains unknown. Vitamin D deficiency is a risk factor for MS. The risk of MS is also significantly increased in first-degree relatives of patients with the disease. Although there is a strong association with the HLA-DRB1 antigen, the genetic associations are multifactorial.
Course and prognosis of multiple sclerosis
Most patients with MS (85%) initially experience a relapsing-remitting clinical course with episodes of neurologic dysfunction that are separated by intervals of months or years. However, MRI studies have revealed that pathologic disease burden in the CNS accumulates even in the absence of clinical activity. Within 10 years, approximately 50% of patients with relapsing-remitting disease exhibit a slow, apparently continuous deterioration in neurologic status (secondary progressive form). In approximately 15% of patients, the disease progresses inexorably from onset with no recognizable attacks (primary progressive form). Near total disability and, in rare instances, death within 1–2 years of onset may result after a fulminant course. In contrast, about 5%–10% of patients experience a relatively benign course without serious disability or life span reduction.
Pathology in multiple sclerosis
Although MS is classically considered a demyelinating disease, axonal damage does occur early and is an integral part of the disease process. This axonal loss manifests as “black holes” on T1-weighted MRI sequences (Fig 14-1). Myelin destruction is associated with local perivascular mononuclear cell infiltration, myelin removal by macrophages, and astrocytic proliferation with production of glial fibrils. The term multiple sclerosis stems from the presence of these numerous gliotic (sclerotic) plaque lesions. Plaques are often situated in the white matter at the ventricular margins, the optic nerves and chiasm, the corpus callosum, and the spinal cord and throughout the brainstem and cerebellar peduncles.
Figure 14-1 Axial magnetic resonance imaging (MRI) scans of a patient with multiple sclerosis (MS) show demyelinating plaques. A, T1-weighted, postgadolinium MRI scan demonstrates enhancing white matter lesions bilaterally, as well as “black holes” (arrows).B, T2-weighted MRI scan shows periventricular, multifocal, hyperintense white matter lesions consistent with demyelination. C, A fluid-attenuated inversion recovery (FLAIR) scan confirms periventricular white matter lesions.
(Reprinted with permission from Slack: Lee AG, Brazis PW, Kline LB. Curbside Consultation in Neuro-Ophthalmology: 49 Clinical Questions. Thorofare, NJ: Slack, 2009.)
Criste G, Trapp B, Dutta R. Axonal loss in multiple sclerosis: causes and mechanisms. Handb Clin Neurol. 2014;122:101–113.
Clinical presentation of multiple sclerosis
The diagnosis of MS is made by identifying neurologic symptoms and signs that occur over time and that affect different areas of the CNS. Ocular symptomatology is commonly part of the clinical picture of MS, and various ocular complications are discussed in the following sections. Nonocular signs and symptoms attributable to MS may precede, follow, or coincide with the ocular signs. Initially, many symptoms of MS are so transient or benign that the patient may fail to remember previous episodes. Typically, significant episodes last for weeks or months. The physician should ask specifically about transient diplopia, ataxia, vertigo, patchy paresthesias, bladder or bowel dysfunction, and extremity weakness. Fatigue and depression are common and may precede the onset of focal neurologic deficits. Symptoms of early MS are often so evanescent and unaccompanied by objective neurologic findings that they may be ignored.
The cerebellum, brainstem, and spinal cord may be involved individually or simultaneously, thus producing single or multiple symptoms. Some of the more common non-ocular symptoms include:
cerebellar dysfunction: ataxia, dysarthria, intention tremor, truncal or head titubation, or dysmetria (sometimes described by the patient as poor depth perception)
mental changes: emotional instability, depression, irritability, or fatigue; later in the course, cognitive dysfunction
motor symptoms: extremity weakness, facial weakness, hemiparesis, or paraplegia
sensory symptoms: paresthesias of face or body (especially in a bandlike distribution around the trunk), Lhermitte sign (an electric shock–like sensation in the limbs and trunk that is produced by neck flexion), or pain (occasionally, trigeminal neuralgia)
sphincter disturbances: frequency, urgency, hesitancy, or incontinence; urinary retention that leads to urinary tract infection
Optic neuritis in multiple sclerosis
The clinical signs and symptoms of optic neuritis are discussed in Chapter 4. Even after recovering from vision loss brought on by demyelinating optic neuritis, patients may experience transient deterioration of vision during exercise or with small elevations in body temperature (Uhthoff phenomenon). Some patients with optic neuritis report phosphenes (bright flashes of light) with movement of the affected eye or photisms (light induced by noise, smell, taste, or touch). Importantly, 25% of patients have optic neuritis as a presenting symptom of MS, and their first evaluation will be performed by an ophthalmologist. Symptoms of optic neuritis occur at some point in 75% of patients, and evidence of optic nerve involvement as demonstrated by an abnormal visual evoked response appears in 90% of patients with MS. Furthermore, autopsy studies show anterior visual pathway demyelination in virtually all patients with clinically definite MS. There is increasing interest in the use of optical coherence tomography (OCT) to measure the retinal nerve fiber layer and retinal ganglion cell layer in MS as a marker for neuronal damage.
After an episode of optic neuritis, many patients want to know their risk of MS. The 15-year follow-up of the Optic Neuritis Treatment Trial (ONTT) showed that the strongest predictive factor in determining the likelihood that MS would develop was the presence or absence of abnormalities on MRI scan of the brain obtained at study entry during an episode of optic neuritis. Overall, clinically definite MS developed in 50% of ONTT patients in 15 years. However, the probability of developing clinically definite MS based on MRI scan appearance ranged from 25% for patients with no lesions on the brain MRI to 72% for patients with 1 or more lesions. Cerebrospinal fluid (CSF) analysis in a subgroup of ONTT patients showed that oligoclonal banding had predictive value for the development of MS, but only in patients with a normal MRI scan at study entry. Patients with a history of prior optic neuritis and nonspecific neurologic symptoms were at higher risk of MS.
Costello FE, Klistorner A, Kardon R. Optical coherence tomography in the diagnosis and management of optic neuritis and multiple sclerosis. Ophthalmic Surg Lasers Imaging. 2011;42(Suppl):S28–S40.
Optic Neuritis Study Group. Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow-up. Arch Neurol. 2008;65(6):727–732.
Funduscopic abnormalities in multiple sclerosis
Retinal nerve fiber layer defects are discussed in Chapter 3. Uveitis is 10 times more common in MS patients than in the general population. Depending on the study, uveitis frequency in patients with MS varies widely, occurring in 0.4%–28.5% of patients. Ocular inflammation may develop concurrent with, prior to, or after the development of neurologic signs and symptoms. MS-related uveitis generally presents as intermediate uveitis (including pars planitis), and common findings include mild vitritis with periphlebitis. See BCSC Section 9, Uveitis and Ocular Inflammation for a more extensive review of MS-related uveitis.
Messenger W, Hildebrandt, L, Mackensen F, Suhler E, Becker M, Rosenbaum JT. Characterization of uveitis in association with multiple sclerosis. Br J Ophthalmol. 2015;99(2):205–209.
Chiasmal and retrochiasmal abnormalities in multiple sclerosis
The white matter within the optic chiasm, optic tracts, and visual radiations is frequently involved pathologically in MS lesions. Lesions in these areas follow a recovery pattern similar to that of optic neuritis. Chiasmal or retrochiasmal visual field defects were observed in 13.2% of patients in the ONTT after 1 year of follow-up (see Chapter 4, Fig 4-29). Progressive multifocal leukoencephalopathy (PML) should be considered when a patient with MS using natalizumab presents with homonymous visual field defects (see Table 14-1 and the section Progressive Multifocal Leukoencephalopathy later in this chapter).
Ocular motility disturbances in multiple sclerosis
Diplopia is a frequent MS symptom. Motility abnormalities resulting from MS are typically localized to the supranuclear, nuclear, and fascicular portions of the ocular motor system. Internuclear ophthalmoplegia, especially when bilateral, may present with exotropia in primary position and bilaterally impaired adduction (ie, wall-eyed, bilateral internuclear ophthalmoplegia, or WEBINO; see Chapter 7, Fig 7-5); it is highly suggestive of MS in someone under age 50 years. Other signs include complete or partial paralysis of horizontal or vertical gaze or a skew deviation (vertical misalignment not attributable to single CN or muscle dysfunction). Although uncommon, MS should be considered in a young adult with an isolated ocular motor CN palsy and no history of trauma. Because ocular motor palsies most likely reflect fascicular involvement, they are frequently accompanied by other brainstem findings. CN VI involvement is most commonly reported, but CN III or CN IV paresis has also been described.
Nystagmus is frequently present in MS. It may be horizontal, rotary, or vertical, and both pendular and jerk types may occur. Concomitant vertical and horizontal nystagmus occurring out of phase produces circular or elliptical eye movements that are highly suggestive of MS. Common cerebellar eye findings include rebound nystagmus, fixation instability (macrosaccadic oscillations), saccadic dysmetria, and abnormal pursuit movements. Occasionally, MS lesions produce dorsal midbrain (Parinaud) syndrome. Patients with eye movement abnormalities typically report symptoms, including diplopia, blurred vision, or oscillopsia. See Chapters 7, 8, and 9 for further discussion on ocular motility disorders.
Diagnosis of multiple sclerosis
MS is diagnosed using the modified McDonald criteria, which are based on the combination of clinical history and presentation, along with neuroradiologic imaging, with or without CSF abnormality or an abnormal visual evoked response. Even an insidious neurologic progression suggestive of MS can lead to a definite diagnosis if appropriate paraclinical abnormalities are present. However, in the absence of other clinical or laboratory manifestations, recurrent optic neuritis is not sufficient for diagnosing MS.
Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald Criteria. Ann Neurol. 2011;69(2):292–302.
Laboratory evaluation of multiple sclerosis
No test unequivocally establishes the presence of MS, which remains a clinical diagnosis. The CSF in patients with definite MS is abnormal in more than 90% of cases. The most common abnormalities are elevation of immunoglobulin G (IgG) level, elevation of the IgG/albumin index, and the presence of oligoclonal IgG bands (in CSF but not in serum). None of these findings, however, is specific for MS.
Neuroimaging in multiple sclerosis
The neuroimaging study of choice for the diagnosis and management of MS is an MRI scan with fluid-attenuated inversion recovery (FLAIR) sequencing and gadolinium-DTPA (diethylenetriaminepentaacetic acid) infusion. The MRI scan is particularly sensitive for the identification of white matter plaques in the CNS, and it is far superior to CT scan for showing the posterior fossa and spinal cord (see Fig 14-1; see also Chapter 2, Fig 2-9, and Chapter 4, Fig 4-8). The MRI scan shows multiple lesions in 85%–95% of patients with clinically definite MS and in 66%–76% of patients with suspected MS. Although the abnormalities apparent on MRI scan are not specific for MS, multifocal lesions that are periventricular and ovoid are most consistent with the condition. The lesions observed with MRI fluctuate over time. Active lesions will enhance with gadolinium-DTPA administration. Hypointense regions on postcontrast T1-weighted scans (black holes) are also a marker of progressive disease. Lesions in the optic nerves of patients with symptomatic optic neuritis are best visualized on MRI scan with fat-suppression techniques and gadolinium-DTPA infusion (see Fig 4-8C).
Treatment of multiple sclerosis
There is no cure for MS; however, several therapies slow the disease and help alleviate specific symptoms. As in the management of optic neuritis, intravenous high-dose corticosteroids are often used to treat acute exacerbations of MS. Although vitamin D deficiency is routinely corrected in newly diagnosed MS patients or in patients at risk of MS, the benefit of such therapy remains unproven.
Disease-modifying therapy (DMT) is typically recommended for long-term treatment of MS. Several studies, including CHAMPS (Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study), ETOMS (Early Treatment of Multiple Sclerosis), BENEFIT (Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment), and PreCISe (Early Glatiramer Acetate Treatment in Delaying Conversion to Clinically Definite Multiple Sclerosis in Subjects Presenting with a Clinically Isolated Syndrome), have demonstrated the benefits of early DMT initiation in subjects with clinically isolated syndrome (CIS) at risk of developing MS. There are several United States Food and Drug Administration (FDA)–approved disease-modifying drugs currently available for relapsing forms of MS (Table 14-1). These drugs, which should be used with caution, are often prescribed by physicians experienced in MS therapy. Novel drugs and combinations of immunomodulating therapies are being investigated.
Macular edema has been reported in 0.5% of patients treated with fingolimod, a once-daily oral medication approved for the treatment of relapsing MS. This ophthalmic complication, also known as FAME (fingolimod-associated macular edema), is more common in patients with diabetes and uveitis and is more likely to develop within 4 months of treatment initiation. The macular edema typically resolves upon cessation of fingolimod therapy. Figure 14-2 lists the screening protocol for FAME.
Eckstein C, Bhatti MT. Currently approved and emerging oral therapies in multiple sclerosis: an update for the ophthalmologist. Surv Ophthalmol. 2016;61(3):318–332.
Jain N, Bhatti MT. Fingolimod-associated macular edema: incidence, detection, and management. Neurology. 2012;78(9):672–680.
Excerpted from BCSC 2020-2021 series: Section 5 - Neuro-Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.