Optic neuritis: Pathophysiology, clinical features, and diagnosis

INTRODUCTION — Optic neuritis is an inflammatory, demyelinating condition that causes acute, usually monocular, visual loss. It is highly associated with multiple sclerosis (MS). Optic neuritis is the presenting feature of MS in 15 to 20 percent of patients and occurs in 50 percent at some time during the course of their illness [1-4].

The term "optic neuritis" is sometimes applied to other inflammatory and infectious conditions affecting the optic nerve. These and other causes of optic neuropathy are discussed separately. (See "Optic neuropathies".)

The epidemiology, pathophysiology, clinical features, and diagnosis of demyelinating optic neuritis will be covered here. Prognosis and treatment of optic neuritis and other clinical manifestations of MS are discussed separately. (See "Optic neuritis: Prognosis and treatment" and "Manifestations of multiple sclerosis in adults" and "Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis".)

EPIDEMIOLOGY — Most cases of acute demyelinating optic neuritis occur in females (two-thirds) and typically develop in patients between the ages of 20 and 40 years [5-7].

The incidence of optic neuritis is highest in populations located at higher latitudes, in the northern United States and western Europe, and is lowest in regions closer to the equator. In the United States, studies have estimated the annual incidence of optic neuritis to be as high as 6.4 per 100,000 [8,9]. In the United States, optic neuritis occurs more frequently in White compared with Black Americans [10]. In Asia, optic neuritis is proportionately more common relative to the incidence of multiple sclerosis (MS) than in the United States or Western Europe [11].

PATHOPHYSIOLOGY — The most common pathologic basis for optic neuritis is inflammatory demyelination of the optic nerve. The pathology is similar to that of acute multiple sclerosis (MS) plaques in the brain, with perivascular cuffing, edema in the myelinated nerve sheaths, and myelin breakdown. Inflammation of the retinal vascular endothelium can precede demyelination and is sometimes visibly manifest as retinal vein sheathing [12]. Myelin loss exceeds axonal loss.

It is believed that the demyelination in optic neuritis is immune mediated, but the specific mechanism and target antigen(s) are unknown. Systemic T cell activation is identified at symptom onset and precedes changes in the cerebrospinal fluid (CSF) [13]. Systemic changes also normalize earlier (within two to four weeks) than central changes. T cell activation leads to the release of cytokines and other inflammatory agents. B cell activation against myelin basic protein is not seen in peripheral blood but can be demonstrated in the CSF of patients with optic neuritis [14].

As with MS, a genetic susceptibility for optic neuritis is suspected. This is supported by an over-representation of certain human leukocyte antigen (HLA) types among patients with optic neuritis [15,16].

CLINICAL FEATURES

Acute features — Optic neuritis is usually monocular in its clinical presentation. In approximately 10 percent of cases, symptoms occur in both eyes, either simultaneously or in rapid succession [17]. Bilateral optic neuritis is more common in children younger than 12 to 15 years old; higher incidences have been reported in Black South African patients as well as in patients from Korea and Singapore [17-22]. Because bilateral symptoms are relatively uncommon, they should suggest an alternative cause of optic neuropathy. However, subclinical visual deficits in acuity, contrast sensitivity, color vision, and visual field in the contralateral eye can often be elicited by detailed visual testing in patients with clinically monocular disease [9,23]. Because these deficits usually resolve along with the clinical deficits in the symptomatic eye, it is unlikely that these findings represent prior episodes of optic neuritis.

Other clinical features of optic neuritis were systematically characterized in the Optic Neuritis Treatment Trial (ONTT), which enrolled 457 patients, aged 18 to 46 years, with acute unilateral optic neuritis [7,24]. The two most common symptoms of optic neuritis are vision loss and eye pain:

●Vision loss typically develops over a period of hours to days, peaking within one to two weeks. Continued deterioration after that time suggests an alternative diagnosis [1,2]. Greater than 90 percent of patients in the ONTT had a significant decrease in central visual acuity. In most, the visual acuities ranged from 20/25 to 20/190 (median visual acuity 20/60). However, some patients had 20/20 acuity (11 percent), and, at the other extreme, a few had no light perception (3 percent).

●Eye pain occurred in 92 percent of patients in the ONTT and often worsened with eye movement [7]. The onset of pain generally coincided with the visual acuity loss and improved along with it.

Other common visual symptoms and signs include:

●An afferent pupillary defect always occurs in optic neuritis if the other eye is uninvolved and otherwise healthy. This is demonstrated by shining a light alternately in one eye and then the other and finding that the direct response to light is more sluggish in the affected eye. The room should be dark, and the patient should fixate on a distant target to prevent miosis due to accommodation. (See "The detailed neurologic examination in adults", section on 'Afferent pupillary defect'.)

●The visual field defect in optic neuritis is typically characterized as a central scotoma [1,25]. However, in the ONTT, almost all types of visual field defects were seen, including diffuse vision loss and altitudinal, arcuate, hemianopic, and cecocentral defects. Nonetheless, a defect that extends to the periphery should suggest a compressive lesion, while an altitudinal defect, particularly an inferior altitudinal defect, is more common in anterior ischemic optic neuropathy [1,25]. Visual field defects usually resolve; in the ONTT, 56 percent had normalized at one year and 73 percent had normalized at 10 years [26,27].

●Papillitis with hyperemia and swelling of the disk, blurring of disk margins, and distended veins is seen in one-third of patients with optic neuritis (picture 1) [7]. Two-thirds of these patients have retrobulbar neuritis with a normal funduscopic examination (picture 2). Papillitis is more common in children less than 14 years old and in certain ethnic populations, including Black South Africans and patients from Korea and Singapore [11,18-20]. Peripapillary hemorrhages are rare in optic neuritis but are a common accompaniment to papillitis due to anterior ischemic optic neuropathy [1].

Patients with optic neuritis due to myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) frequently have bilateral papillitis, which may be mistaken for papilledema (figure 1).

●Photopsias (flickering or flashes of light) are often precipitated with eye movement and were reported by 30 percent of patients in the ONTT [7].

●Loss of color of vision out of proportion to the loss of visual acuity is specific to optic nerve pathology. Abnormal color vision by Ishihara plates was found in 88 percent of involved eyes in the ONTT; this increased to 94 percent with the more sensitive Farnsworth-Munsell 100 hue test [7].

●Other signs of ocular inflammation may be observed by the ophthalmologist on funduscopic or slit lamp examination. Perivenous sheathing or periphlebitis retinae can be seen in approximately 12 percent of patients with optic neuritis and implies a high risk for multiple sclerosis (MS) [9,12]. Uveitis, cells in the anterior chamber, and/or pars planitis are uncommonly seen in optic neuritis and are more typical of infections and other autoimmune diseases. (See "Optic neuropathies".)

Chronic features — Even after clinical recovery, signs of optic neuritis can persist. These signs in a patient without a history of optic neuritis may suggest a previous, subclinical attack. When a patient presents with a possible first attack of MS elsewhere in the central nervous system, these signs are often sought because evidence of other demyelinating episodes separated in "time and space" can affect prognosis and treatment decisions. (See "Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis".)

Chronic signs of optic neuritis can include:

●Persistent visual loss. Most patients with optic neuritis recover functional vision within one year. However, on testing, deficits in color vision, contrast sensitivity, stereo acuity, and light brightness are detectable in most patients at up to two years [28]. (See "Optic neuritis: Prognosis and treatment", section on 'Recovery of vision'.)

●A relative afferent pupillary defect remains in approximately one-fourth of patients two years after presentation [28].

●Color desaturation refers to a qualitative intereye difference in color perception that can be tested by comparing vision of a red object with each eye. A patient with monocular "red desaturation" may report that the red color appears "washed out," pink, or orange when viewed with the affected eye.

●Temporary exacerbations of visual problems in patients can occur with increased body temperature (Uhthoff phenomenon). Hot showers and exercise are classic precipitants.

●Optic atrophy to at least some degree almost always follows an attack of optic neuritis, despite the return of visual acuity [29]. Normal, 20/20 visual acuity requires less than one-half of normal foveal axons [30]. The disc appears shrunken and pale, particularly in its temporal half (temporal pallor). The disk pallor extends beyond the margins of the disk into the peripapillary retinal nerve fiber layer.

●The pattern-shift visual evoked response (VER) remains delayed in most patients, even with visual recovery. Although latencies continue to shorten (improve) up to two years after presentation, abnormalities are seen in most (80 percent) at two years [28,31,32]. (See 'Visual evoked response' below.)

DIFFERENTIAL DIAGNOSIS — In a young child, infectious and postinfectious causes of optic nerve impairment should be considered as alternatives to optic neuritis, while in an older patient (>50 years), ischemic optic neuropathy (due, for example, to diabetes mellitus or giant cell arteritis) is a more likely diagnosis than optic neuritis.

Alternative diagnoses should also be considered in patients with a bilateral presentation or those with other neurologic or systemic symptoms.

In cases of recurrent optic neuritis that are not due to neuromyelitis optica (NMO), myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), or multiple sclerosis (MS), other causes of recurrent optic neuritis should be thoroughly investigated (such as sarcoidosis, lupus, chronic relapsing inflammatory optic neuropathy [CRION], or paraneoplastic optic neuropathy [serum CRMP5/CV2 antibody]).

The differential diagnosis of optic nerve diseases is summarized in the tables and is discussed separately (table 1 and table 2). (See "Optic neuropathies".)

EVALUATION AND DIAGNOSIS

Diagnosis — In general, optic neuritis is a clinical diagnosis based upon the history and examination findings. Because important findings on funduscopic examination help differentiate typical from atypical cases of optic neuritis, an ophthalmologic examination should be considered an essential feature of the clinical evaluation.

Magnetic resonance imaging (MRI) study of the brain and orbits with gadolinium contrast provides confirmation of the diagnosis in most cases and also provides an assessment of the risk of subsequent multiple sclerosis (MS).

Patients with recurrent or bilateral optic neuritis and those who present with additional neurologic signs or symptoms should undergo further evaluation to determine if the optic neuritis is due to a broader neurologic disease such as neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). (See 'Antibody testing' below.)

Further diagnostic testing is directed toward excluding other causes of visual loss in atypical cases. (See 'Differential diagnosis' above.)

Magnetic resonance imaging — An MRI study of the brain and orbits with gadolinium contrast provides confirmation of the diagnosis of acute demyelinating optic neuritis and important prognostic information regarding the risk of developing MS.

Innovations in MRI technology (eg, short tau inversion recovery [STIR], fast spin echo [FSE], and fluid-attenuated inversion recovery with fat suppression techniques [FLAIR], diffusion tensor imaging [DTI]) have improved imaging of the optic nerve [33-35]. Optic nerve inflammation can be demonstrated in approximately 95 percent of patients with optic neuritis with gadolinium contrast-enhanced MRI of the brain and orbits (image 1) [6,36-38]. The longitudinal extent of nerve involvement as seen on MRI correlates with visual impairment at presentation and with visual prognosis [31,36,38]. Gadolinium enhancement persists for a mean of 30 days since onset [31]. The signal abnormality in the nerve can still be seen after recovery of vision, and is also present in as many as 60 percent of patients with MS who do not have a clinical history of optic neuritis [31,39-41].

The brain MRI often shows white matter abnormalities characteristic of MS (image 2). Typical lesions are ovoid, periventricular, and larger than 3 mm (see "Evaluation and diagnosis of multiple sclerosis in adults", section on 'Lesion characteristics'). The reported prevalence of white matter abnormalities varies substantially among patients with optic neuritis (23 to 75 percent) [42]. In the ONTT, almost 40 percent of patients had MRI lesions, but this trial represents a selected patient group [7]. Small case series of unselected patients have noted a higher coincidence of MRI brain lesions [31,43,44]. Individuals with white matter abnormalities are at a higher risk of developing MS. (See "Optic neuritis: Prognosis and treatment".)

The yield of spinal cord imaging is low in unselected patients. Among 115 patients presenting with optic neuritis, MRI abnormalities in the spinal cord were seen in only four patients with a normal brain MRI [42].

Lumbar puncture — Lumbar puncture is not an essential diagnostic test in optic neuritis but should be considered in atypical cases (eg, those with bilateral presentation, <15 years in age, or symptoms suggesting infection) [45,46]. (See "Optic neuropathies", section on 'Infections'.)

Approximately 60 to 80 percent of patients with acute optic neuritis have nonspecific abnormalities in the cerebrospinal fluid (CSF), including lymphocytes (10 to 100) and elevated protein [43].

Other CSF findings in optic neuritis can include [47]:

●Myelin basic protein in approximately 20 percent

●Immunoglobulin G (IgG) synthesis in 20 to 36 percent

●Oligoclonal bands (OCB) in 56 to 69 percent

The presence of OCB implies a higher risk of developing MS. However, since OCB are also associated with white matter lesions on brain MRI, their presence is not clearly of independent prognostic importance [47]. (See "Optic neuritis: Prognosis and treatment".)

Other testing — When there are relevant clues to an alternative diagnosis (table 2), measurement of the erythrocyte sedimentation rate, antinuclear antibodies, and angiotensin converting enzyme levels and serologic and CSF tests for Lyme disease and syphilis should be obtained [45,46]. (See "Optic neuropathies".)

Fluorescein angiography — Fluorescein angiography is not routinely performed in the evaluation of optic neuritis and is often normal. Up to 25 percent demonstrate either dye leakage or perivenous sheathing [12]. These findings may identify patients at somewhat higher risk for developing MS.

Visual evoked response — A delay in the P100 of the visual evoked response (VER) is the electrophysiologic manifestation of slowed conduction in the optic nerve as a result of axonal demyelination [48]. This test is not usually helpful in the diagnosis of acute optic neuritis, unless there is a suspicion that the visual loss is functional.

Abnormalities in the VER can persist after recovery of full vision. At one year, 80 to 90 percent will be abnormal; 35 percent will return to normal at two years [28,31,32]. The VER is often employed to find evidence of previous, asymptomatic episodes of optic neuritis, but the sensitivity and specificity are imperfect [1].

The multifocal VER is a technical advance that appears to be more sensitive and specific for identifying optic neuritis, but this technology is not generally available [1,49].

Optical coherence tomography — Optical coherence tomography (OCT) measures the thickness in the retinal nerve fiber layer and detects thinning in most (85 percent) of patients with optic neuritis [48,50-53]. These abnormalities are also common in patients with MS who do not have a clinical history of optic neuritis [54]. While lower values correlate with impaired visual outcome, the utility of OCT as a prognostic tool is limited in that abnormal values do not show up until early swelling disappears. In one study, OCT was less sensitive than VER in detecting subclinical optic neuritis [55].

A number of studies have found that a greater severity of optic nerve injury seen on OCT suggests neuromyelitis optica (NMO) rather than optic neuritis associated with MS [56-58].

Antibody testing — Serum NMO antibody testing (both aquaporin-4 autoantibody and MOG antibody) is suggested for individuals with recurrent optic neuritis, particularly if the MRI brain is negative for any abnormal T2/FLAIR lesions outside of the affected optic nerve(s) [59].

Patients with recurrent optic neuritis appear to be particularly at risk for NMOSD or MOGAD. This is particularly true for patients with a normal brain MRI and those with optic neuritis events in rapid succession or with a presentation of severe vision loss [60]. In one series of 51 patients with either severe or recurrent optic neuritis, six patients were seropositive for the aquaporin-4-specific serum autoantibody, a sensitive biomarker for NMO, while 10 patients were seropositive for antibodies to MOG, which has also been associated with NMO [61-64]. In other studies, seropositivity for the aquaporin-4-specific serum autoantibody was predictive of subsequent NMO among patients with recurrent optic neuritis [65,66]. MOG antibody testing is recommended for patients with recurrent optic neuritis who test negative for aquaporin-4-specific serum autoantibody.

Other features of optic neuritis that suggest MOGAD are papillitis and bilateral, longitudinally extensive enhancement of the optic nerves (especially the anterior segments) and optic nerve sheaths on contrast-enhanced MRI.

Rare patients should be tested for glial fibrillary acidic protein (GFAP) by measuring GFAP antibodies in the serum and CSF. GFAP astrocytopathy may cause optic neuritis (frequently papillitis) [67]. In addition, patients may present with encephalopathy, headache, or transverse myelitis. The MRI brain with contrast sometimes shows a unique pattern of linear radial enhancement along the perivascular vessels, perpendicular to the lateral ventricles.

The clinical features and diagnosis of NMOSDs and MOGAD are discussed in detail separately. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis" and "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple sclerosis and related disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Optic neuritis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical features – Optic neuritis is an acute inflammatory demyelinating injury to the optic nerve.

In typical cases, painful, monocular visual loss evolves over several hours to a few days. One-third of patients have visible optic nerve inflammation on funduscopic examination (papillitis); in the remainder, the inflammation is retrobulbar. (See 'Acute features' above.)

Chronic signs of optic neuritis include a relative afferent pupillary defect, color desaturation, and optic atrophy. These often persist despite recovery of normal vision. (See 'Chronic features' above.)

●Evaluation and diagnosis – The diagnosis of optic neuritis is made in the setting of unilateral painful loss of vision in an adult younger than 50 years old. An ophthalmologic examination is an essential feature of the clinical evaluation. (See 'Diagnosis' above.)

Magnetic resonance imaging (MRI) study of the brain and orbits with gadolinium contrast provides confirmation of the diagnosis in most cases and also provides an assessment of the risk of subsequent multiple sclerosis (MS). (See 'Magnetic resonance imaging' above.)

Other tests, including lumbar puncture, fluorescein angiography, and visual evoked potentials, are used in atypical cases. Antibody testing is recommended for patients with recurrent optic neuritis and those with neurologic or MRI features suggesting a neuromyelitis optica spectrum disorder (NMOSD) or other antibody-associated disease. (See 'Evaluation and diagnosis' above.)

●Differential diagnosis – Common entities in the differential diagnosis of optic neuritis are presented in the tables (table 1 and table 2). (See "Optic neuropathies".)