Neuro-Ophthalmologic Manifestations of Multiple Sclerosis (MS)

Updated: Feb 21, 2019
  • Author: Fiona Costello, MD, FRCP; Chief Editor: Hampton Roy, Sr, MD  more...
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Neuro-ophthalmic manifestations are frequently encountered in persons with multiple sclerosis (MS). Affected individuals may experience problems with how they see the world (afferent visual pathway symptoms) and/or how their eyes move together (efferent visual pathway disorders).

Optic neuritis is an inflammatory injury of the optic nerve that causes vision loss, which is common in MS. Some individuals with MS also experience homonymous visual field defects caused by lesions in retrochiasmal or retrogeniculate regions of the afferent visual pathway. Efferent visual pathway lesions in the central nervous system (CNS) may create a perception of oscillopsia, a visual disturbance in which objects appear to jiggle or move owing to nystagmus (involuntary eye movements). Seeing two objects instead of one (diplopia) with a binocular view can arise from ocular misalignment caused by lesions of the brainstem and cerebellum.

Because patients with MS who have visual symptoms tend to seek ophthalmic attention, eye care experts play a vital role in the localization of visual disturbances that may either represent the first clinical manifestation of MS or affect individuals with established diagnoses. 

Special considerations

Patients with visual disturbances in the setting of a suspected or established MS diagnosis should be cautioned to avoid activities that present a safety risk to themselves or others. In some instances, this may require a patient to cease driving, at least temporarily.

Patient education

Various resources are available to patients who present with visual manifestations linked to MS, as follows:

MS research resources are as follows:

MS professional organizations are as follows:

MS information can be obtained at JAMA Patient Page: Multiple Sclerosis


Multiple Sclerosis

MS is a CNS disorder that is characterized by both inflammatory and neurodegenerative mechanisms of brain and spinal cord injury. [1, 2] Consequently, most patients with MS tend to experience both episodic relapses and progressive neurological impairment throughout the disease course. Affecting more than 2 million people worldwide, MS is the leading cause of nontraumatic neurological disability in young adults. [2] The diagnosis of MS can be established based on clinical and radiological criteria in patients who experience two or more neurological events consistent with multifocal CNS inflammation that are disseminated in space (DIS) and disseminated in time (DIT). Since the publication of the original McDonald criteria [3] and subsequent iterations, [4, 5] radiological endpoints have played a critical role in the diagnosis of MS.

Most (85%) patients with MS begin their clinical disease course with episodes of neurological dysfunction (relapses), which are followed by complete or incomplete recovery. [1, 2] Over time, most patients with relapsing-remitting MS (RRMS) transition to secondary progressive multiple sclerosis (SPMS). Patients with SPMS present with features of worsening neurological disability with or without clinically overt relapses. [1, 2] Approximately 15% of patients with MS experience a primary progressive course from onset, either without preceding relapses (known as primary progressive multiple sclerosis [PPMS]) or with superimposed neurological events, known as progressive relapsing MS. [1, 2]

Diagnostic criteria for multiple sclerosis

Current diagnostic criteria for MS include clinical and paraclinical measures. To render the diagnosis of MS, due diligence is necessary to exclude alternative diagnoses. The revised McDonald criteria [5] rely on the principle that an attack is a neurological disturbance consistent with the diagnosis of MS persisting for 24 hours or more in the absence of fever or infection. [5] In order to meet the criterion of dissemination in time, 30 days or more is required between events of neurological disturbance. Dissemination in space requires that the second event occurs in a different anatomic location than the first. [5]

Using the 2010 McDonald criteria revision [5] (see Table 1), the diagnosis of MS can be confirmed at the time of initial presentation, since the baseline MRI scan may be used to demonstrate both dissemination in space and time with respect to lesions of the brain and spinal cord.

Table 1. Summary of the Revised McDonald Criteria Used for the Diagnosis of Multiple Sclerosis (Open Table in a new window)

Number of Clinical Attacks


Additional Criteria Required


Objective clinical evidence of ≥2 lesions OR a single lesion with historical evidence of prior lesion



Objective clinical evidence of 1 lesion

DIS: ≥1 T2 MRI lesion in ≥2 typical* CNS regions OR the occurrence of another clinical attack


Objective clinical evidence of ≥2 lesions

DIT: Simultaneous asymptomatic gadolinium-enhancing and non-enhancing lesions OR a new T2 and/or gadolinium-enhancing lesion on follow-up MRI OR the occurrence of a second clinical attack


Objective clinical evidence of a single lesion

DIS: ≥1 MRI T2 lesion in ≥2 typical* CNS regions OR await further clinical attack(s)


DIT: Defined as simultaneous asymptomatic gadolinium-enhancing and non-enhancing lesions OR a new T2 and/or gadolinium-enhancing lesion on follow up MRI OR the occurrence of a second clinical attack

*Two of the following four T2 lesions: periventricular, juxtacortical, infratentorial, and spinal cord.

Current disease-modifying therapies for multiple sclerosis

Disease-modifying therapies (DMT) decrease clinical and subclinical CNS inflammation with the intention of reducing the accumulation of disability and disease progression. These medications are used in the management of patients with RRMS, patients with clinically isolated syndrome (CIS) who are at risk of developing MS, and patients with SPMS. Because of the chronic nature of MS and the potential adverse effects of therapy, treatment needs to be tailored to the needs of the patient, ideally by a clinician with expertise in managing the disease.

Table 2. Disease-Modifying Therapies Used in the Treatment of Multiple Sclerosis [6, 7, 8, 9]   (Open Table in a new window)



MS Subtype

Dosing Frequency

Adverse Effects

Interferon β-1a (Avonex)


Relapsing forms of MS, CIS

Once weekly

Flulike symptoms, liver enzyme changes, bone marrow suppression, thyroid dysfunction

Interferon β-1a (Rebif)


Relapsing forms of MS, CIS

22 mcg or 44mcg three times weekly

Flulike symptoms, liver enzyme changes, bone marrow suppression, thyroid dysfunction

Interferon β-1b (Betaseron)



Relapsing forms of MS, CIS

Three times weekly

Flulike symptoms, liver enzyme changes, bone marrow suppression, thyroid dysfunction

Glatiramer acetate (Copaxone)


Relapsing forms of MS, CIS


Skin irritation, skin lipoatrophy, panic attack–like events

Natalizumab (Tysabri)


Relapsing forms of MS

Once monthly

Nausea, infection, liver dysfunction, progressive multifocal leukoencephalopathy (PML)*

Fingolimod (Gilenya)


Relapsing forms of MS


Macular edema, bradyarrhythmia, QT interval prolongation, hypertension, severe varicella-associated complications in nonimmune patients, increased risk of herpes zoster in all patients, mild infections, PML (rare)

Dimethyl fumarate (Tecfidera)


Relapsing forms of MS

Twice daily

Flushing, gastrointestinal distress, rare lymphopenia, PML (rare)

Teriflunomide (Aubagio)


Relapsing forms of MS

Once daily

Nausea, headaches, alopecia, liver dysfunction, presumed teratogenicity

Alemtuzumab (Lemtrada)


Relapsing forms of MS

Minimum of two cycles (baseline and year one)

Infusion reactions, mild-moderate infections, thyroid dysfunction, idiopathic thrombocytopenic purpura, anti-glomerular basement membrane disease [6]

Daclizumab (withdrawn from the market)


Relapsing forms of MS**


Mild-moderate infections, allergic reactions, dermatitis/rash, lymphadenopathy, oropharyngeal pain, liver irritation, depression [7]

*Progressive multifocal leukoencephalopathy (PML) risk increases with a history of immunosuppression, JC virus positivity, and use of the drug >2 years. Risk for the entire cohort is roughly 3-4/10,000. [8]

** The US Food and Drug Administration has recommended this drug be used only if the patient manifests an inadequate therapeutic response to 2 or more other DMTs.


Afferent Visual Pathway Manifestations of Multiple Sclerosis

Optic neuritis

Optic neuritis is an inflammatory injury of the optic nerve that represents the best characterized CIS associated with MS. [10] In fact, approximately 20% of patients with MS present with optic neuritis as the first clinical disease manifestation. [10] The annual incidence of optic neuritis is 1-5 per 100,000 per year. [11]

Clinical features at presentation

Many of the cardinal clinical features of optic neuritis have been identified based on the Optic Neuritis Treatment Trial (ONTT). [12, 13] The ONTT revealed that most patients with typical optic neuritis are white (85%) and female (77%) with a mean age of approximately 32 years. [12, 13]

Among adults, sporadic optic neuritis cases are typically unilateral; however, bilateral simultaneous vision loss may be observed. Nonetheless, in this setting, other demyelinating optic neuropathies and potential optic neuritis mimics need to be considered, including neuromyelitis optica (NMO) and Leber hereditary optic neuropathy (LHON) (see Table 3).

From a clinical perspective, a comprehensive history is imperative for differentiating optic neuritis from its potential mimics. Patients with optic neuritis often report subacute-onset vision loss that worsens over hours to days. This mode of onset helps distinguish optic neuritis from anterior ischemic optic neuropathy (AION). [14] In contrast, AION is generally unaccompanied by pain, and symptoms are frequently noted upon morning awakening. Patients with compressive optic neuropathies may report sudden-onset awareness of vision loss. However, a detailed discussion often reveals that these individuals have experienced sudden-onset awareness of a longer-standing problem, rather than sudden-onset vision loss itself. [14]

Ninety-two percent of individuals with typical optic neuritis experience pain that is frequently provoked by eye movements, within the first two weeks of symptom onset. [10, 11, 12, 13, 14] Patients may also report intermittent flashes of light in the affected eye, known as photopsias or phosphenes. [15] Patients with optic neuritis may also describe worsening vision with increased body temperature, referred to as Uhthoff phenomenon. [11, 16]

Common examination findings in patients with optic neuritis

In patients with suspected optic neuritis, several features on initial examination can help localize the diagnosis. Initially, the severity of vision loss in the affected eye may range from mild (Snellen visual acuity equivalent of 20/20) to, in rare cases, no light perception with high-contrast letter acuity testing. [14] In patients with unilateral optic neuritis or bilateral optic neuritis with asymmetric involvement, a relative afferent pupillary defect (RAPD) is apparent in the affected or, in cases of bilateral involvement, more severely affected eye. [14] Visual field loss in optic neuritis tends to follow the topography of the retinal nerve fiber layer (RNFL), with cecocentral, altitudinal, and arcuate deficits frequently observed.

Keltner and colleagues [17] classified visual field abnormalities observed during longitudinal follow-up of patients with ONTT and reported that both the affected and fellow eyes in patients with optic neuritis showed visual field losses. [17] These findings illustrated the role of perimetry in detecting both clinically overt and clinically occult optic nerve involvement in patients with MS.

Dyschromatopsia, or decreased color vision, is typical in eyes with optic neuritis. [14] This finding can be particularly helpful in localizing the diagnosis in patients with mild central vision loss who have disproportionate deficits in color vision function. [14] Often, patients continue to note subjective color desaturation in their affected eyes after high-contrast visual acuity function has returned to a Snellen equivalent of 20/20.

Traditionally, in cases of retrobulbar optic neuritis, the optic nerve has been described as normal in appearance, whereas patients with anterior optic neuritis, or papillitis, present with mild to moderate optic disc swelling at presentation (see image below). [14] As was exemplified in the ONTT, severe optic disc edema, [18] vitreous cells, and/or hemorrhage are uncommon in the setting of typical optic neuritis. [14] Therefore, the observation of these fundus features should prompt investigation for other potential etiologies of vision loss.

Pediatric optic neuritis

Several features of the clinical presentation and course differentiate pediatric optic neuritis from the adult-onset syndrome. While both children and adults present with vision loss, pain upon eye movements, dyschromatopsia, and visual field defects, children are more likely to present with more severe vision loss. [19] Children with optic neuritis more frequently demonstrate papillitis or anterior optic neuritis than their adult counterparts. [19] Moreover, younger pediatric patients are more likely than adolescents or adults to experience bilateral simultaneous optic nerve involvement.ref48} Although the presence of unilateral or bilateral optic nerve involvement does not predict the risk of MS in children, MS risk increases with age. [19]

Normal-appearing right optic nerve and mild left o Normal-appearing right optic nerve and mild left optic disc edema.

Optic neuritis: Making the diagnosis

In cases characterized by a typical history and expected examination findings, optic neuritis can be reliably diagnosed based on clinical grounds. However, certain red flags should raise concern for a potential mimic and therefore prompt additional investigations (see Table 3). [14]

For example, young men who present with painless bilateral sequential or simultaneous optic nerve dysfunction should undergo testing for LHON. Middle-aged women who develop unilateral or bilateral optic neuritis should be evaluated for NMO because the management of optic neuritis in patients with NMO differs from that of patients with MS. Additional features that should increase the clinical suspicion for NMO include poor clinical recovery, lack of typical MRI findings for MS, cerebrospinal fluid (CSF) pleocytosis, and manifestations of transverse myelitis. Previously, NMO was diagnosed based on clinical parameters and spinal MRI, which tend to show extensive longitudinal lesions of three or more vertebral body segments. In recent years, the aquaporin 4 immunoglobulin G (IgG) antibody has been relied on to expand the clinical and neuroimaging spectrum of NMO. [20] The criteria for NMO spectrum disorders (NMOSD) devised by Wingerchuk and colleagues facilitate the diagnosis in patients who have not experienced clinical involvement of optic nerves or spinal cord. [20]

Some pediatric patients with recurrent optic neuritis harbor antibodies against myelin oligodendrocyte glycoprotein (anti-MOG antibodies). Anti-MOG antibodies can be found in patients with NMOSD features who are aquaporin 4–seronegative. These patients tend to be younger, present with positive oligoclonal bands in CSF, and develop brain MRI abnormalities during their disease course. A 2011 study reported that the mean time to the second attack was longer in the anti-MOG antibody–positive group. [21] Therefore, anti-MOG antibodies can serve as a diagnostic and potentially prognostic tool, and testing should be considered in aquaporin 4–seronegative patients with the NMO phenotype. [21] The distinction between optic neuritis associated with NMOSD versus MS is important because patients with the former often require long-term treatment with immunosuppressive drugs to obtain disease control.

Table 3. Differential Diagnoses of Optic Neuritis (Open Table in a new window)


Clinical Features

Investigations to Consider


Painless, altitudinal visual field defect is common, vision loss noted upon awakening, vascular risk factors, phosphodiesterase type 5 inhibitor use, nocturnal antihypertensive use, sleep apnea, physiological disc at risk, patients with NAION have optic disc edema acutely

Sleep study, 24-hour blood pressure monitoring, investigations for hypertension and diabetes

Compressive optic neuropathy (pituitary lesions, meningiomas, aneurysm)

Painless, progressive vision loss, color loss disproportionate to visual acuity deficit, nonglaucomatous optic disc cupping, temporal visual field cut, bilateral visual field involvement

Cranial and orbital MRI/MRA or CT/CTA

Infectious optic neuropathies (eg, tuberculosis, syphilis, Lyme disease, among others)

Associated uveitis, papillitis or retrobulbar optic neuropathy, macular star, infectious symptomatology

Serum/CSF culture/sensitivity; specific serological testing for syphilis, Lyme, Bartonella henselae, HIV, toxoplasmosis, viral hepatitis B and C; Epstein-Barr virus; histoplasmosis; tuberculin testing; chest imaging; serum sedimentation rate, C-reactive protein

Inflammatory/demyelinating optic neuropathies not associated with MS or an underlying systemic disorder: NMO, CRION, ADEM, anti-MOG–associated optic neuritis

Poor recovery, unilateral or bilateral optic neuritis, associated transverse myelitis, recurrent symptoms

Brain MRI, cervical spine MRI, anti-NMO antibody testing

Genetic optic neuropathies (LHON, autosomal-dominant optic neuropathy)

Bilateral vision loss, painless, poor recovery, family history

Genetics referral with specific mutation testing

Toxic/nutritional (tobacco-alcohol amblyopia and Cuban and Tanzanian epidemic optic neuropathies)

Bilateral optic nerve involvement, history of drug use (ethambutol, selenium, amiodarone), restricted nutritional intake, glue sniffing, methanol ingestion

Vitamin B-12 levels, toxic screen

Sarcoid optic neuropathy

Steroid responsive, poor recovery, systemic symptoms and signs

Chest imaging, serum ACE, Gallium scan, tissue diagnosis, bronchoalveolar lavage, soluble IL-2 receptor

Connective tissue/vasculitic optic neuropathy (lupus, Wegener granulomatosis, Sjögren syndrome, Behçet disease)

Steroid responsive, associated systemic symptoms and signs

Serum ESR, Sjögren specific antibodies, CRP, ANCA, ENA panel, ANA

Orbital inflammation/optic perineuritis

Orbital signs (proptosis)

MRI or CT orbital imaging, blood work including TSH ANCA, CRP, ESR, ACE

Uveitis/posterior scleritis

Severe pain, floaters, vitreous reaction

Fluorescein angiography, B-scan ultrasonography of orbits

Autoimmune optic neuropathy (Similar to CRION)

Steroid responsive

Skin biopsy for immunoglobulin deposition

Big blind spot syndromes

Blind spot on visual field testing, painless, photopsias, bilateral ocular involvement

Full-field/multifocal ERG, fluorescein angiography

Abbreviations: ACE = angiotensin converting enzyme; ADEM = acute disseminated encephalomyelitis; anti-DS DNA = anti-double-stranded DNA; anti-MOG = anti-myelin oligodendrocyte glycoprotein; ANA = anti-nuclear antigen; AON = autoimmune optic neuropathy; CRION = chronic relapsing inflammatory optic neuropathy; CSF = cerebrospinal fluid; ESR = erythrocyte sedimentation rate; FTA-ABS = fluorescent treponemal antibody absorption; HIV = human immunodeficiency virus; MRI = magnetic resonance imaging; NAION = nonarteritic anterior ischemic optic neuropathy; NMO-IgG = neuromyelitis optica immunoglobulin G; PCR = polymerase chain reaction; VDRL = Venereal Disease Research Laboratory

Table 3. Differential Diagnoses of Optic Neuritis (Modified From Table 2-1 in Costello F. Inflammatory optic neuropathies. Continuum (Minneap Minn). Aug 2014; 20 (4 Neuro-ophthalmology): 816-37.] [14]

Optic neuritis: Ancillary studies

In the setting of typical optic neuritis, laboratory studies are not generally useful in facilitating diagnosis. [18] However, additional investigations can be helpful in detecting potential mimics, such as NMO-associated optic neuritis, lupus-related optic neuropathy, and syphilitic optic nerve injury.

Specific clinical features should prompt consideration of these alternate diagnoses. Therefore, ancillary investigations should be selected based on the history and physical examination findings and may include any of the following:

  • Complete blood count (CBC) to evaluate for features of anemia, leukemia, or leukocytosis
  • Serum vitamin B-12 and folate levels (eg, bilateral central scotoma)
  • Lyme titers (eg, endemic area, tick exposure, rash of erythema chronica migrans)
  • Tuberculin skin testing, chest radiography, or QuantiFERON-TB testing (eg, tuberculosis [TB] exposure, endemic area)
  • Fluorescent treponemal antibody (FTA) testing (eg, syphilis serology) or nontreponemal testing (eg, Venereal Disease Research Laboratories [VDRL] testing or rapid plasma reagin [RPR] testing)
  • Antinuclear antibody (eg, systemic lupus erythematosus)
  • HIV testing (eg, high-risk patients)
  • Angiotensin-converting enzyme (ACE) level, lysozyme (eg, sarcoidosis)
  • Erythrocyte sedimentation rate (eg, inflammatory disorders)
  • Serum NMO antibody IgG (anti–aquaporin-4 [AQP4] antibody) testing
  • Serum anti-MOG antibody testing [21]
  • Mononuclear spot test (monospot test) (infectious mononucleosis due to Epstein-Barr virus)

Cerebrospinal fluid analysis

Cerebrospinal fluid analysis is not generally required to diagnose typical cases of optic neuritis. As MRI has assumed a greater role in determining the immediate and future risk of MS in patients with optic neuritis, lumbar puncture has fallen somewhat out of favor. That said, CSF analysis still plays an important diagnostic role in atypical cases of optic neuritis, such as suspected infectious optic neuropathies secondary to syphilis, tuberculosis, or Lyme disease. Moreover, CSF markers have predictive value in determining the future risk of MS in some patients. In a 2015 study of 357 children with isolated optic neuritis, positive oligoclonal bands in the CSF and abnormal cranial MRI findings conferred a 27-fold higher hazard ratio for developing MS compared to double-negative findings. [22]

Visual evoked potentials

In clinical practice, visual evoked potentials (VEP) testing is typically unnecessary to confirm the diagnosis of optic neuritis. When mild optic neuritis or subclinical optic nerve damage is suspected, VEP testing can be useful in capturing the effects of prior demyelinating injury. Abnormal VEP findings in this context include increased latencies and reduced amplitudes of waveform. However, VEP abnormalities are not restricted to optic neuritis and may also occur with other conditions, such as optic-nerve compression, infiltration, and nondemyelinating inflammation. [23] Multifocal VEP can be a more sensitive and specific tool for detecting optic neuritis in suspected clinically overt or clinically occult cases of optic neuritis, although the technique is not widely available for routine clinical use. [23]

Optical coherence tomography

Optical coherence tomography (OCT) is a noninvasive ocular imaging technique that provides high-resolution images of retinal architecture in vivo.

Changes in peripapillary retinal nerve fiber layer (RNFL) thickness represent axonal damage, whereas loss of macular volume and ganglion layer thickness provide indirect measures of neuronal injury in the afferent visual pathway. [24] In the context of acute optic neuritis, OCT-measured peripapillary RNFL thickness tends to be elevated in the optic neuritis eye initially presumably owing to axoplasmic flow stasis. [24] In contrast, macular volume and ganglion layer measures, as determined with OCT, are comparable between affected and unaffected eyes of patients at symptom onset but later decline for up to 12 months. [24]

Postacute visual outcomes including high- and low-contrast letter acuity, color vision, and visual field sensitivity correlate with the amount of OCT-measured RNFL, ganglion layer, and macular volume loss detected 6-12 months after optic neuritis. [24]

Recurrent optic neuritis has been associated with worse OCT measures. In a study of pediatric patients with CNS demyelinating syndromes, there was a 9-μm (9%) decrement in RNFL thickness for each additional optic neuritis episode. [25]

One disadvantage of OCT is that a so-called floor effect can complicate detection of new changes in RNFL thickness in the setting of pre-existing optic atrophy, since mean RNFL values do not decrease below a measure of approximately 30 μm, regardless of the extent of optic nerve injury. [24]

Optic neuritis: Acute management

The ONTT showed that high-dose intravenous corticosteroids (250 mg administered every 6 hours for 3 days followed by oral prednisone [1 mg/kg/day] for 11 days) accelerated visual recovery relative to oral prednisone (1 mg/kg/day) and oral placebo. [13] However, intravenous corticosteroid treatment ultimately provided no measurable long-term benefits to vision. Subsequent studies have shown that the bioavailability of 1250 mg of oral prednisone (or 500 mg po bid) is comparable with 1 g of intravenous methylprednisolone (IVMP). [14, 26, 27]

Martinelli et al compared the efficacy and safety of 1000 mg IVMP versus 1000 mg oral methylprednisolone in patients experiencing MS relapse. [27] Both treatment groups demonstrated reduced gadolinium-enhancing MRI lesions over time with a noninferiority effect evident between the two routes of administration. [27] Patients in both treatment groups also showed significant improvement in Expanded Disability Status Scale (EDSS) scores in this study. [27] Burton et al compared the efficacy of oral versus intravenous steroids for MS relapses and reported no significant differences in clinical, radiological, or pharmacological outcomes between the groups. [28] Therefore, in clinical practice, high-dose oral steroids are often substituted for intravenous treatment, because it is a more convenient option for patients and their caregivers.

The decision to use or defer steroids in a patient with optic neuritis should weigh patient-related factors in the balance. In 2000, the Quality Standards Subcommittee of the American Academy of Neurology (AAN) reviewed the role of high-dose corticosteroids in the treatment of acute optic neuritis. The recommendation from the AAN was that treatment should be given with the intention to hasten recovery but not to improve ultimate visual outcome. Moreover, treatment decisions should take other non–evidence-based factors into account, such as quality of life, risk to the patient, and visual function in the fellow eye. [29]

Prognosis for visual recovery

Visual recovery after acute optic neuritis tends to be favorable and frequently occurs within 3-6 weeks of symptom onset. During this time, patients develop optic atrophy, with temporal optic disc pallor (see image below). In the ONTT, mean visual acuity one year after entry improved to 20/20 (Snellen equivalent), with less than 10% having a visual acuity worse than 20/40. [30] Early features that may predict less-favorable recovery following optic neuritis include visual acuity of 20/50 or worse, contrast sensitivity less than 1.0 log units, and visual field mean deviation of -15 decibels or less 1 month after initial presentation. [31] Motion perception deficits have shown to persist a year after optic neuritis, despite recovery of high- and low-contrast visual acuity, color vision, and visual field performance. [32] Persistent deficits in motion perception may partly explain why many patients with optic neuritis describe problems with visual tracking in the postacute phase.

The evolution of temporal optic disc pallor (arrow The evolution of temporal optic disc pallor (arrow) after left optic neuritis.

The risk of developing multiple sclerosis

Studies have shown that the risk of developing MS increases over time in patients who present with optic neuritis as a CIS. In a study conducted by Rodriguez et al, the 10-year risk of clinically definite MS was 39%, the 20-year risk was 49%, and the 40-year risk was 60%. [33] In the longitudinal follow-up from the ONTT, the 15-year risk of developing clinically definite MS was 25% in patients with no brain lesions on baseline MRI, compared with 72% in patients with one or more lesions (see image below). [34]

Cranial MRI study showing typical white matter les Cranial MRI study showing typical white matter lesions (arrows).

The risk of MS was 3 times higher in women in the ONTT. [34] Moreover, MS was more than twice as likely to develop in cases of retrobulbar optic neuritis than in cases of papillitis. [34] However, in the ONTT era, MS was diagnosed based on clinical criteria, whereas MS can currently be diagnosed at the time of the first clinical event based on MRI evidence of dissemination lesions in space and time. [5]


Patients with MS are known to experience various forms of ocular inflammation, including uveitis, retinal perivascular sheathing (periphlebitis), and retinitis. [35, 36] Uveitis refers to inflammation of the uveal tract and is 10 times more common in patients with MS (incidence of 1%-2%) than in the general population. [35, 36] Intermediate uveitis or pars planitis is the most frequent form of uveitis seen in MS. Among patients with pars planitis, 8%-12% will be diagnosed with MS. [36]

Patients with uveitis report blurred vision, floaters, photophobia, pain, and eye redness. Ocular complications include retinal neovascularization, cystoid macular edema, cataracts, retinal detachment, and epiretinal membrane formation. While uveitis and complications thereof can occur as part of MS itself, they may also arise as a consequence of MS therapy. Specifically, patients with MS who use fingolimod, a sphingosine-1-phosphate receptor modulator, may develop fingolimod-associated macular edema (FAME).

The clinical features of FAME typically manifest within months of therapy initiation, although patients may or may not have symptomatic vision loss. [37] Patients with MS who have coexisting diabetes or a history of uveitis may be at an increased risk of developing FAME. [37] Dilated fundus examination, OCT, and fluorescein angiography (see image below) are the primary diagnostic tests in the evaluation of FAME. Affected individuals may be treated with cessation of fingolimod therapy, observation, nonsteroidal anti-inflammatory agents, and/or corticosteroids. [37]

Posterior visual pathway lesions

MS lesions in the retrochiasmal and retrogeniculate visual pathways also affect patients with MS, albeit not with the same reported frequency of optic neuritis events. These lesions can be more difficult to diagnose, because affected patients do not experience pain and may not be aware of their deficits. If central vision is affected, patients with retrochiasmal or retrogeniculate lesions may describe missing parts of words of sentences with a binocular view, which is a hint that the visual deficit affects both eyes.

Vision loss is characterized by homonymous visual field deficits, which may or may not completely resolve over time. Homonymous defects can impair an MS patient’s ability to drive safely, particularly when he or she is unaware of the deficit. Furthermore, homonymous field deficits represent a potential red flag among patients with MS who use natalizumab since they are at risk of developing progressive multifocal leukoencephalopathy (PML), a CNS infection caused by John Cunningham (JC) virus. This condition occurs more frequently in patients with MS who have previously used immunosuppressant drugs, who have serum positivity for JC virus, and who have a longer duration of drug use. [38] Natalizumab-associated PML is typically heralded by cognitive, motor, and language deficits, but vision loss and homonymous visual field deficits have been reported as presenting features in 8 of 28 (29%) and 5 of 28 (18%) patients, respectively. [38]

More recently, PML has also been reported in the context of dimethyl fumarate use. [39] Therefore, newly onset homonymous visual field loss in patients with MS who have a history of natalizumab use (or immunosuppression due to combination therapies or newer DMT agents) should prompt consideration of PML, in part because of the high rate of morbidity and mortality associated with this diagnosis. Treatment starts with cessation of fingolimod treatment, which is often enough to alleviate manifestations of FAME. Upon suspicion that a patient has developed FAME, referral to a general ophthalmologist, neuro-ophthalmologist, or retina specialist is appropriate.

Optical coherence tomography (OCT) and fluorescein Optical coherence tomography (OCT) and fluorescein angiography (FA) showing cystoid macular edema in fingolimod-associated macular edema (FAME).

Efferent Visual Manifestations of Multiple Sclerosis

Patients with MS frequently present with ocular motility abnormalities on examination, although they may not report related symptoms. Demyelinating lesions in the brainstem and/or cerebellum can lead to ocular misalignment caused by gaze palsies or damage to the ocular motor cranial nerves. The resulting ocular misalignment can cause horizontal, vertical, and/or oblique diplopia.

Involvement of the brainstem and/or cerebellum can also cause damage to neural integrators in the CNS (medial vestibular nuclei, nucleus prepositus hypoglossus, interstitial nuclei of Cajal, and superior vestibular nuclei), [40] which help stabilize images on the retina during eye and head movements. This can lead to nystagmus, which is defined as repetitive to-and-fro involuntary eye movements initiated by slow drifts of the eye. [41] Patients with nystagmus may note a perception that their world is moving, termed oscillopsia, and report blurred vision, imbalance, dizziness, and spatial disorientation. [41]

Patterns of nystagmus can be localizing from an anatomical perspective and therefore help facilitate the diagnosis of MS. Nystagmus should not be confused with saccadic abnormalities that impair steady fixation in patients with MS. [40, 41] Furthermore, patients with MS may report focusing difficulties when watching objects in motion or when they themselves are in motion. These particular symptoms may arise from smooth pursuit abnormalities and impaired suppression of the vestibule-ocular reflex. [40]

Efferent visual pathway lesions may be challenging to identify in patients with MS and even more difficult to treat. To alleviate symptoms of diplopia, Fresnel prisms can be used temporarily to allow correction of ocular misalignment in primary position during the time required for recovery. In patients with persistent large-angle ocular deviations, ground-in prisms or, in rare cases, strabismus surgery may be feasible treatment options.


Ocular motor nerve and nuclear palsies

MS lesions in the brainstem may cause acquired ocular misalignment due to damage of the nuclei or fascicles of one of the three ocular motor nerves. Therefore, MS should be considered in any young individual presenting with painless acute- to subacute-onset diplopia.

Sixth cranial nerve: Nuclear and fascicular lesions

The paired abducens nuclei reside in the dorsal pons, separated from the floor of the fourth ventricle by the genu of the facial nerve (facial colliculus). [42] The abducens nucleus contains the neurons needed for horizontal gaze; interneurons travelling via the medial longitudinal fasciculus (MLF) connect the abducens nucleus with the contralateral oculomotor nucleus, coordinating abduction in one eye (governed by the lateral rectus) with adduction in the contralateral eye (medial rectus).

An abducens nuclear lesion causes horizontal gaze palsy ipsilateral to the side of the lesion, whereas a fascicular lesion causes ipsilateral abduction weakness with preserved adduction in the contralateral eye. Because of the proximity of the abducens nucleus to the facial nerve, patients may have a gaze palsy associated with a lower motor seventh nerve palsy, termed facial colliculus syndrome. [43] In one-and-a-half syndrome, an MS lesion involving the abducens nucleus and the ipsilateral MLF causes an ipsilateral gaze palsy and ipsilateral internuclear ophthalmoplegia (INO). [40] This causes either partial or complete loss of loss of horizontal gaze function, except for the abduction in the eye opposite from the INO, which may manifest features of abducting nystagmus. [40]

Third cranial nerve: Nuclear and fascicular lesions

The oculomotor (third) nerve nuclear complex is located in the midbrain at the level of the superior colliculus. [42] Of the four paired subnuclei within this complex, the most medial innervates the superior rectus muscle. This is the only portion of the oculomotor nucleus that sends its axons to the opposite eye. [42] A nuclear third nerve lesion causes bilateral superior rectus weakness, bilateral ptosis, and, often, ipsilateral deficits reflective of third nerve fascicle dysfunction. [40] In the case of a third nerve palsy, a fascicular lesion may cause partial or complete deficits in the following functions: ipsilateral elevation (superior rectus and inferior oblique muscles), depression (inferior rectus), and adduction of the eye (medial rectus); upper eyelid elevation; and pupillary constriction. [42] In rare cases, these lesions may be highly selective and may cause weakness of a single muscle, which can lead to diagnostic confusion.

The oculomotor nerve runs in close proximity to numerous midbrain structures; therefore, features of a third nerve palsy can be associated with other neurological deficits, including contralateral hemiparesis (Weber syndrome), contralateral tremors (or chorea, athetosis) (Benedict syndrome), and contralateral cerebellar ataxia (Nothnagel syndrome). [44] Lesions of the dorsal midbrain in individuals with third nerve palsies may also manifest as paralysis of upgaze, light-near dissociation of the pupils, skew deviation, lid retraction, and convergence-retraction nystagmus. [44]

Fourth cranial nerve

The trochlear or fourth nucleus lies below the oculomotor nucleus, dorsal to the MLF, at the level of the inferior colliculus. [42] A lesion of the fourth nerve nucleus or proximal fascicle causes hyperdeviation (elevation) of the contralateral eye. [40] The hyperdeviation of a fourth nerve palsy is greatest in contralateral gaze and is exacerbated by ipsilateral head tilt. A head tilt opposite the side of the higher or hyperdeviated eye tends to alleviate some symptoms. In patients with MS, a demyelinating lesion may cause combined INO and contralateral fourth nerve palsy because of the anatomic proximity of the MLF and the fourth nerve nucleus and fascicle. [40] A trochlear nerve palsy may be difficult to distinguish from a skew deviation when the magnitude of hypertropia increases with ipsilateral head tilt.

In 2010, Wong [45] proposed the “upright-supine test” to differentiate skew deviation from trochlear nerve palsy. During this clinical test, a near target is held one third of a meter in front of the patient, in both the upright and supine positions. The examiner looks for a vertical deviation that decreases by 50% or more from the upright to supine position, suggesting skew deviation. [45] Alternatively, if the upright-supine test finding is negative and the vertical deviation decreases by less than 50% from the upright to supine position, the vertical strabismus is likely caused by a fourth nerve palsy. [45]

Internuclear ophthalmoplegia

INO is a disconnection syndrome characterized by impaired horizontal gaze. Affected individuals have slowed or limited adduction in the eye ipsilateral to the lesion, with associated abducting nystagmus in the contralateral eye. [40] Unilateral or bilateral INO(s) are caused by damage to the MLFs. [40] The MLFs support the rapid neural transmission necessary for abduction of one eye and adduction of the fellow eye to be synchronous in horizontal gaze. Unlike other myelinated tracts in which slight impairment may produce no clinical deficits, the system for coordinated horizontal saccades is extremely sensitive to transmission speeds, making INO a common manifestation observed and reported in MS. [40, 46]

Patients with INO may deny symptoms, particularly with chronicity. Symptomatic patients may describe experiencing blurred vision, oscillopsia, and diplopia. Patients with INO may note worsening symptoms with fatigue or increased body temperature (Uhthoff phenomenon). [40] The reported variability and fatigability may be mistaken for the “pseudo-INO” of myasthenia gravis.

On clinical examination, the adduction deficit in INO may manifest as slowing during the horizontal duction (adduction lag with a full excursion of the eye) or as incomplete adduction producing an incomitant exotropia The adduction lag in INO may be easily overlooked during smooth pursuit testing, and the clinician may need to provoke a quick horizontal saccade to unveil the disruption. Despite deficient adduction during horizontal saccades, medial rectus function is often intact in INO; this feature can be demonstrated with testing convergence, which is mediated by separate inputs to the medial rectus subnucleus that are distinct from the inputs arriving via the MLF. [40] Intact convergence has been interpreted to mean that MLF damage is relatively caudal in the brainstem whereas with more rostral involvement of the supranuclear input to the medial rectus or subnuclei may cause impaired convergence. [40] Because the MLF also contains fibers that mediate vertical eye movements (pursuit, vestibular, and otolithic pathways), vertical gaze deficits may be observed. Patients with bilateral INO may have impaired vertical gaze holding, resulting in primary-position or gaze-evoked vertical nystagmus. [40, 46]

Examining for internuclear ophthalmoplegia (INO) ( Examining for internuclear ophthalmoplegia (INO) (1 of 5).
Examining for internuclear ophthalmoplegia (INO) ( Examining for internuclear ophthalmoplegia (INO) (2 of 5).
Examining for internuclear ophthalmoplegia (INO) ( Examining for internuclear ophthalmoplegia (INO) (3 of 5).
Examining for internuclear ophthalmoplegia (INO) ( Examining for internuclear ophthalmoplegia (INO) (4 of 5).
Examining for internuclear ophthalmoplegia (INO) ( Examining for internuclear ophthalmoplegia (INO) (5 of 5).

Variants of internuclear ophthalmoplegia

Wall-eyed internuclear ophthalmoplegia

Patients with unilateral INO do not typically have significant exotropia (outwardly deviating eye) in primary gaze because convergence tone is intact. [40] In contrast, bilateral MLF lesions can cause exotropia in wall-eyed bilateral INO (WEBINO) syndrome. WEBINO syndrome differs from paralytic pontine exotropia of one-and-a-half syndrome, which is characterized by a unilateral horizontal gaze palsy and INO due to a pontine lesion involving the paramedian pontine reticular formation and MLF. [47]

One-and-a-half syndrome

One-and-a-half syndrome is a clinical disorder characterized by a conjugate horizontal gaze palsy in one direction with an associated INO. The syndrome usually results from a single unilateral lesion of the paramedian pontine reticular formation or the abducens nucleus on one side (causing the conjugate gaze palsy), with interruption of internuclear fibers of the ipsilateral MLF (causing failure of adduction of the ipsilateral eye). Consequently, the single preserved horizontal eye movement is the abducting eye contralateral to the MLF lesion. [40, 48]

Skew deviation

Skew deviation refers to a vertical ocular misalignment caused by supranuclear lesions disrupting inputs to the ocular motor nuclei. [48] Skew deviation may cause vertical diplopia or misalignment in patients with INO because the MLF contains utricular pathways that maintain vertical eye position in addition to interneurons from the abducens nucleus to the medial rectus subnucleus. [40]

In skew deviation caused by a pontine lesion, the ipsilateral eye is lower, whereas, with a midbrain lesion, the ipsilateral eye is higher. [40]

Ocular tilt reaction

Ocular tilt reaction consists of skew deviation, ocular torsion, head tilt, and deviation of the subjective visual vertical, which are all tilted toward the lower or hypotropic eye. [49] The side of the tilt is named for the lower eye. [49] Static ocular tilt reactions from hypofunction are ipsiversive (lower eye on the side of the lesion) with peripheral vestibular and pontomedullary lesions and contraversive with pontomesencephalic lesions. [49] Paroxysmal ocular tilt reaction is rare but has been described in MS. [49]


Nystagmus is common in MS, affecting up to 30% of patients. [49] Common mechanisms that contribute toward the development of nystagmus include impaired fixation, vestibular imbalance, and abnormal gaze-holding. [49] Recognizing patterns of nystagmus can be useful in localizing lesions in patients with MS. Unfortunately, although much is known about the anatomy, physiology, and pharmacology of the ocular motor system, therapeutic options for nystagmus remain somewhat limited. Most reports of putative therapies have been based on a small number of subjects, and not all patients always respond positively to the treatment. [41]

Table 4. Patterns of Nystagmus in Multiple Sclerosis (Open Table in a new window)

Type of Nystagmus

Clinical Features

Anatomical Site


Gazeevoked nystagmus

Slow drift of eyes away from target followed by a corrective saccade (jerk) in the direction of eccentric gaze [49]

Lesions in the brainstem or cerebellum that impair neural integrator function [49]


Pendular nystagmus

Horizontal, vertical, or mixed components in one or both eyes with a back-and-forth slow phase without a corrective saccade (jerk)

Brainstem or cerebellar lesions which damage neural integrator function [49]

Gabapentin (100 – 400 po tid); memantine (15-60mg per day); clonazepam (0.5-1mg tid) [40, 49]

Downbeat nystagmus

Tonic upward deviation of the eyes followed by a fast downward saccade; may increase with downgaze and lateral gaze [40, 41]

Lesion of the cervicomedullary junction or cerebellum that disrupt input from the posterior semicircular canals [40]

Clonazepam 0.5 mg tid; baclofen 10 mg tid; gabapentin; 3,4-diaminopyridine 20 mg tid; 4-aminopyridine 10 mg tid; base down prisms [41]

Upbeat nystagmus

A downward drift of the eyes is followed by an upward saccade; usually increases on up gaze. Vertical smooth pursuit is usually disrupted by the nystagmus. [40, 41]

Pontomedullary or pontomesencephalic lesions of the ventral tegmental tract that disrupt projections from the anterior semicircular canals [41]

Baclofen 5-10 mg tid 4-aminopyridine 10 mg tid [41]

Periodic alternating nystagmus

A spontaneous horizontal beating nystagmus, the direction of which changes periodically. Periods of oscillation range from 1 second to 4 minutes (typically 1-2 minutes). [41]

Vestibulocerebellar damage; lesions of the inferior cerebellar vermis that affect velocity storage mechanisms and the stability of the vestibulo-ocular reflex [41]

Baclofen 5-10 mg tid, phenothiazine, barbiturates, and memantine [41]

Seesaw nystagmus

A pendular or jerk oscillation characterized by an intorsion and elevation of one eye and a corresponding extorsion and depression of the other; during the next half-cycle, the torsional and vertical movements reverse [41]

Unilateral mesodiencephalic lesions that affect the interstitial nucleus of Cajal and vestibular afferents from the vertical semicircular canals (jerk hemi-seesaw); the pendular form of seesaw nystagmus is associated with lesions affecting the optic chiasm [41]

Clonazepam and gabapentin [41]

Saccadic abnormalities

Patients with multiple sclerosis may demonstrate abnormal saccadic intrusions, causing vision loss and oscillopsia. [40, 49] Stable visual fixation is maintained by pause-cell neurons in the brainstem; these are located in the pontine raphe between the two abducens nuclei. [41] Pause cells prevent unwanted saccadic pulses by inhibiting saccadic premotor burst neurons located in the paramedian pontine reticular formation (PPRF) and the midbrain. [41, 49]

One example of a saccadic intrusion that may affect patients with MS is the square wave jerk, which is a quick movement of the eye away from and back to primary position, which occurs with an intersaccadic latency of 150-200 milliseconds. [41, 49] Larger saccadic interruptions with a shorter intersaccadic latency (up to 80 milliseconds) are termed macro square wave jerks. [41] Opsoclonus consists of repetitive bursts of conjugate saccadic oscillations, with horizontal, vertical, and torsional elements. [41] , During each burst of these high-frequency oscillations, the movement is continuous, without an intersaccadic interval. [41]

In ocular flutter, there is no intersaccadic latency, although the pattern is of saccadic eye movement restricted to the horizontal plane. [41] Both opsoclonus and ocular flutter have been described in patients with MS. [49] Variable treatment benefits have been reported with corticosteroids, thiamine, propranolol (40-80 mg orally 3 times daily), nitrazepam (15-30 mg orally daily), and clonazepam (0.5-2 mg orally three times daily). [41]

Patients with MS may also present with features of underactive or overactive saccadic eye function due to altered inputs from the posterior fastigial nuclei and cerebellum (dorsal vermis), which calibrate the size of saccadic pulses. [40] Hypermetric saccades result from damage to the deep nuclei, whereas hypometric saccades arise from damage to the vermis alone. [40] Saccadic dysmetria, particularly of the hypermetric variety, has been reported to affect approximately 40% of patients with MS [49] and frequently contributes to the efferent visual pathway symptoms in this patient population.

Vestibular ocular reflex abnormalities

Some patients with MS report difficulties tracking objects while they are in motion or when they are observing a moving target. Normally, during visual tracking, head movements accompany eye movements, with smooth pursuit allowing suppression of the normal vestibular ocular reflex. With MS lesions of the cerebellar floccus, vestibular ocular reflex cancellation is ineffective, which causes loss of fixation during head and eye movements. [40] Consequently, affected individuals experience retinal slippage [40] off the target of interest, and compensatory catch-up saccades are produced.

The integrity of the vestibular ocular reflex can be tested by asking the patient to perform rapid head thrusts while attempting to fixate on a stationary target. [49] If vestibular ocular reflex function is impaired, fixation will not be maintained and a compensatory saccadic eye movement opposite the direction of the head movement will be detectable. [49] In this context, patients may describe oscillopsia but lack clinically apparent nystagmus. [49]

Patients with multiple sclerosis are also predisposed to impaired suppression of the normal vestibular ocular reflex. [49] Normal suppression of the vestibular ocular reflex is needed to combine smooth head and eye movements during visual tracking. [49] To determine whether this problem exists clinically, a patient can be asked to focus on the thumb of his or her outstretched hand while rotating in a swivelling chair. If vestibular ocular reflex cancellation is impaired, a series of catch–up saccades is observed while the head is in motion. [49] The eyes will be observed to drift off the target (thumb) opposite the direction of the patient’s head movement. [40] Abnormal suppression of the vestibular ocular reflex often indicates cerebellar dysfunction and occurs in concert with smooth pursuit abnormalities. [49] Vestibular rehabilitation therapy may prove beneficial for some patients with MS. [50]



Neuro-ophthalmic manifestations are common in MS, and it is therefore important to recognize the clinical manifestations of afferent and efferent visual pathway dysfunction in these patients.

Eye care specialists can play an important role on the multidisciplinary team approach required to oversee the care of affected individuals. Moreover, nonophthalmic specialists should be familiar with the clinical features and potential implications of visual symptoms in patients with MS; knowledge thereof can help guide selection of appropriate therapies and optimize surveillance efforts aimed at detecting disease activity and progression.


Questions & Answers


What are the neuro-ophthalmic manifestations of multiple sclerosis (MS)?

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