Adult Optic Neuritis 

Updated: Jan 22, 2021
Author: Andrew A Dahl, MD, FACS; Chief Editor: Edsel B Ing, MD, MPH, FRCSC, PhD, MA 

Overview

Practice Essentials

Practice Essentials

Optic neuritis (ON) is a demyelinating inflammation of the optic nerve that often occurs in association with multiple sclerosis (MS) and, much less commonly, neuromyelitis optica (NMO). A gradual recovery of all or part of the visual acuity with time is characteristic of ON,[1]  although permanent residual deficits in color vision and contrast and brightness sensitivity are common.[2]  

A case of acute optic neuritis. A. 1.5 Tesla, cont A case of acute optic neuritis. A. 1.5 Tesla, contrast-enhanced spin echo T1-weighted, fat-suppressed coronal MRI through the orbits shows enlargement and contrast enhancement of the left optic nerve in the retrobulbar portion (arrow). B. Coronal spin echo T1-weighted, fat-suppressed MRI of the same patient shows enlargement and contrast enhancement of the nerve in a parasagittal oblique section (arrow).

Signs and symptoms

History

Classically, patients with ON are young, are often female, and have subacute vision loss associated with pain on eye movement.

The patient’s history may reveal the following signs and symptoms of optic neuritis:

  • Preceding viral illness
  • Rapidly developing impairment of vision in 1 eye or, much less commonly, both eyes [3]
  • Dyschromatopsia (change in color perception) in the affected eye, which may occasionally be more prominent than decreased vision [4]  
  • Retro-orbital or ocular pain that occurs in association with the vision changes, which is usually exacerbated by eye movement and may precede vision loss
  • Uhthoff phenomenon, in which visual symptoms are exacerbated by heat or exercise
  • Pulfrich effect, in which objects moving in a straight line appear to have a curved trajectory when viewed with both eyes, presumably caused by asymmetric conduction between the optic nerves

Patients with MS may have recurrent attacks of ON,[5]  which means that a history of episodes of decreased vision in the same or the fellow eye may be elicited.

Neuromyelitis optica is characterized by often severe, bilateral ON and myelitis in a close temporal relationship[6, 7, 8, 9] ; however, ON can occasionally precede the myelopathy.

Physical examination

Signs of ON may include the following:

  • Decreased pupillary light reaction in the affected eye: A relative afferent pupillary defect (RAPD) or Marcus Gunn pupil is commonly observed. When both eyes are affected, an RAPD may not be apparent.
  • Varying degrees of vision reduction: Vision reduction ranges from mildly decreased visual acuity to complete vision loss; it is usually monocular but may be binocular.
  • Abnormal contrast sensitivity and color vision are present in almost all adults with ON even in the absence of a measurable decrease in visual acuity.
  • Field defects: These may include altitudinal, arcuate, nasal step, central scotoma, and centrocecal scotoma.
  • Initially, the optic nerve head may appear normal, with disc pallor months later. Papillitis (swollen disc) may be seen in one third of patients with ON.

Diagnosis

The following blood tests can be performed when optic neuropathies other than demyelinating ON are suspected:

  • Erythrocyte sedimentation rate
  • Thyroid function tests
  • Antinuclear antibody test
  • Measurement of angiotensin-converting enzyme level
  • Rapid plasma reagin test
  • Mitochondrial DNA mutation studies

Magnetic resonance imaging (MRI) is highly sensitive for and specific in the assessment of inflammatory changes in the optic nerves; it is also specific for white matter lesions in the central nervous system. Magnetic resonance imaging also helps to rule out structural lesions.[10, 11]

Visual evoked potentials (VEPs) can be considered in patients in whom a diagnosis of ON is suspected. Visual evoked potentials may be abnormal even when visual acuity is normal and when MRI of the optic nerve reveals no abnormalities. Visual evoked potentials often show a loss of P100 response in the acute phase. With time, P100 recovers but usually continues to show a markedly prolonged latency that persists indefinitely, even after clinical recovery.

Management

For most patients with ON, treatment and recovery proceed as follows:

  • Visual function begins to improve 1 to several weeks after onset, even without any treatment.
  • Permanent residual deficits in color vision and contrast and brightness sensitivity are common. [2]
  • Pharmacologic therapy for patients with ON is directed toward ameliorating the acute symptoms of pain and decreased vision caused by demyelinating inflammation of the nerve; varying regimens of corticosteroids have been used for this purpose.
  • Intravenous (IV) steroids do little to affect ultimate visual acuity in patients with ON, but they do speed the rate of recovery; some clinicians advocate administration of IV steroids for patients with either severe or bilateral vision loss. [12, 13, 14]

Eculizumab, a monoclonal antibody that targets C5, is the first drug specifically approved by the US Food and Drug Administration (FDA) for adults with neuromyelitis optica spectrum disorder (NMOSD) who are seropositive for anti-aquaporin-4 (AQP4) antibody.[15]  The FDA has also approved inebilizumab, a monoclonal antibody that binds to CD19,[16]  and satralizumab [Enspryng] for the treatment of NMOSD in adults who are seropositive for anti-aquaporin-4 or AQP4 antibody.

For patients with ON whose brain lesions on MRI indicate a high risk of developing clinically definite MS, treatment with immunomodulators (eg, interferonbeta-1a, interferon beta-1b, glatiramer acetate) may be considered.[17]

Background

Optic neuritis (ON) is a demyelinating inflammation of the optic nerve that typically first occurs in young adulthood. Many cases of ON are associated with multiple sclerosis (MS) or neuromyelitis optica (NMO), but ON can occur in isolation.[18]  In cases associated with MS, ON is commonly the first manifestation of the chronic demyelinating process.[19]  Long-term follow-up studies have indicated that up to 75% of female patients initially presenting with ON ultimately develop MS.

Occasionally, ON can result from an infectious process involving the orbits or paranasal sinuses or occur in the course of a systemic viral infection.[20, 21, 22, 23, 24, 25, 26, 27, 28]  Certain optic neuropathies, such as anterior ischemic optic neuropathy (AION) or compressive and hereditary optic neuropathies, can resemble ON.[29]

This article reviews ON as a primary demyelinating inflammation of the nerve occurring either in isolation or in association with MS or NMO. (Neuromyelitis optica is a severe form of a demyelinating disease thought to be of autoimmune origin; it affects the optic nerves and the spinal cord, causing recurrent attacks of blindness and paralysis.)[30, 31]  Much information has been gleaned from the Optic Neuritis Treatment Trial (ONTT), and the reader is encouraged to review the follow-up data from this study.[32, 33]  

 

 

 

Etiology

Most cases of optic neuritis (ON) are associated with multiple sclerosis (MS), even though ON can occur in isolation. In MS-associated and isolated monosymptomatic ON, the cause is presumed to be an autoimmune reaction that results in a demyelinating inflammation of the nerve. Pathologic studies in patients with ON associated with MS have shown that the demyelinated lesions in the optic nerve are similar to the MS plaques seen in the brain, with an inflammatory response marked by perivascular cuffing, T cells, and plasma cells. However, little is known about the pathology of isolated ON.

In a single case of chronic, isolated ON, a biopsy specimen showed the presence of perivascular lymphocytic infiltration, multifocal demyelination, and reactive astrocytosis in the retrobulbar portion of the optic nerve. Abnormal intrathecal IgG synthesis, reflected as the presence of oligoclonal bands in the cerebrospinal fluid (CSF), is found in 60-70% of patients with isolated ON, suggesting an immunologic etiology similar to that of MS.[63]

Neuromyelitis optica (NMO) has been recognized as a distinct inflammatory demyelinating disease consisting of ON in combination with longitudinally extensive transverse myelitis. Neuromyelitis optica is associated with the presence of a specific serum, NMO IgG autoantibody, which targets the water channel aquaporin-4.[34, 35, 36]

Approximately two thirds or more of patients with neuromyelitis optica spectrum disorder (NMOSD) have IgG antibodies to aquaporin-4 (AQP4-IgG), a water channel protein that is abundant on astrocytic membranes and proximate to the blood-brain barrier. Patients who are seronegative cannot be distinguished clinically from those who are seropositive. In AQP4-IgG–seropositive disease, binding of AQP4-IgG to AQP4 on astrocytic end-feet initiates the activation of the complement cascade, the infiltration of granulocytes into the central nervous system, and antibody-dependent cell-mediated cytotoxicity.

Levels of interleukin-6 (IL-6) are elevated in the CSF of patients with NMOSD, as compared with patients who have MS or noninflammatory neurologic disorders, and IL-6 levels in serum and CSF are elevated during NMOSD relapses.[14, 15, 16]  Interleukin-6 promotes the differentiation of naive T cells into proinflammatory type 17 helper T cells, which, along with IL-6, promote the differentiation of B cells into AQP4-IgG–producing plasmablasts.

As previously stated, ON can occasionally result from an infectious process involving the orbits or paranasal sinuses or occur in the course of a systemic viral infection.[20, 21, 22, 23, 24, 25, 26, 27, 28]

Epidemiology

Investigators in Sweden and Denmark have reported an annual incidence of 4 to 5 cases of new-onset optic neuritis (ON) per 100,000 persons.[37]  Patients living in temperate climates seem to be predisposed to ON.

Race-, sex-, and age-related demographics

Optic neuritis (ON) appears to affect White individuals more commonly than members of other races. Women are affected twice as often as men.[32]

Typically, patients with first-time, acute ON are young adults 20 to 45 years. Atypical cases of ON may be seen in elderly patients. Bilateral ON in childhood is not uncommon, and it is believed that the risk for progression to MS is lower in childhood.

 

Prognosis

In contrast to ischemic optic neuropathies and compressive optic neuropathies, optic neuritis (ON) is associated with a gradual recovery of visual acuity with time.[1]  For most patients with ON, visual function begins to improve 1 week to several weeks after onset, even without any treatment. However, permanent residual deficits in color vision and contrast and brightness sensitivity are common.[2]

Decreased visual acuity secondary to ON may be permanent. Final visual outcome may be better in patients with an isolated episode of ON, compared with patients who eventually develop multiple sclerosis (MS). Up to 75% of female patients and 35% of male patients initially presenting with ON ultimately develop MS.[38, 39, 40]

Patients with silent demyelinated lesions elsewhere in the brain, observed on magnetic resonance imaging (MRI) performed at the initial presentation, are more likely to develop definite symptomatic MS in the long term than are patients with isolated ON. In addition, patients who have recurrent episodes of ON may be more likely to develop MS.

The 10-year risk of developing clinically definite MS after a single episode of ON was 38% in the entire Optic Neuritis Treatment Trial (ONTT) study group; the 12-year risk was 40%. Most of those who developed MS did so within the first 5 years after the initial episode of ON.

The strongest predictor of MS in the study group was the presence of brain lesions on MRI at the time of the ON episode. Within the study group, patients with at least 1 brain lesion on MRI at the time of the ON episode had a 56% risk of developing symptomatic MS within 10 years. Patients with "normal" MRI findings had a 16% risk for progression to clinically definite MS at 5-year follow-up; this increased to a 22% risk for MS within 10 years.

Most patients with relapsing NMO have an aggressive form of the disease that is associated with frequent and severe exacerbations and poor prognosis.

 

Presentation

History

A history of preceding viral illness and pain on eye movement may be present. Typically, patients with first-time acute optic neuritis (ON) are otherwise healthy young adults. Patients with ON experience rapidly developing impairment of vision in 1 eye or, far less commonly, both eyes during an acute attack.[3]

Symptoms of dyschromatopsia (change in color perception) in the affected eye may occasionally be more prominent than the decreased vision.[4]  In nearly all patients with ON, the visual changes are associated with retro-orbital or ocular pain, usually exacerbated by eye movement. The pain may precede the visual loss.

Patients may report vision loss exacerbated by heat or exercise (Uhthoff phenomenon). Objects moving in a straight line may appear to have a curved trajectory (Pulfrich effect) when viewed bilaterally, presumably as a result of asymmetric conduction between the optic nerves.

Patients with MS may have recurrent attacks of ON[5] ; therefore, a history of episodes of decreased vision in the same or the fellow eye may be elicited. A history of neurologic problems, such as transient episodes of extremity or facial numbness, weakness, or balance difficulties, suggests a diagnosis of MS; a family history of MS may exist.

Neuromyelitis optica is characterized by ON and myelitis in a close temporal relationship[6, 7, 8, 9] ; however, ON can occasionally precede the myelopathy. Some patients with neuromyelitis optica (NMO) have relapses limited to the optic nerves and spinal cord.

In male patients with bilateral, sequential optic neuropathy with little recovery of vision, Leber hereditary optic neuropathy, rather than demyelinating optic neuritis, should be considered as the diagnosis. Patients with Leber hereditary optic neuropathy may have a history of vision loss in maternal uncles.

Chronic relapsing inflammatory optic neuropathy (CRION) is a form of inflammatory optic neuropathy that is frequently bilateral and often painful. It is characterized by relapses and remissions. Magnetic resonance imaging (MRI) findings in the brains of patients with CRION are normal, and MRI of the optic nerves often, but not always, shows high-signal abnormalities that enhance. Corticosteroid treatment is effective in reducing symptoms of CRION, although long‐term immunosuppression is often necessary. The syndrome behaves in a way that is typical of granulomatous optic neuropathy, but during long-term follow-up, no systemic sarcoidosis has been implicated.[41]  

 

Physical Examination

In a patient with a typical initial acute case of optic neuritis (ON), findings on a general physical examination are normal. Pupillary light reaction is decreased in the affected eye, and a relative afferent pupillary defect (RAPD) or Marcus Gunn pupil is commonly found. In bilateral cases, the RAPD may not be apparent.

Measurement of visual acuity reveals variation in reduction from no reduction to complete visual loss. Patients with ON will all have at least mild subjective decreases in color vision and perception of brightness in the affected eye. All patients with decreased visual acuity also have abnormal contrast sensitivity and color vision, as revealed by examination using a Pelli-Robson chart and Ishihara color plates, respectively.

A central scotoma is most commonly seen in patients with ON; however, results of the Optic Neuritis Treatment Trial (ONTT) suggest that altitudinal field defects, arcuate defects, and nasal steps are more common than central scotomas and centrocecal scotomas. Visual field examination may show a central scotoma, often with peripheral extension in any direction. Generalized depression of the entire visual field in the affected eye may be encountered.

In two thirds of cases of acute optic neuritis, the optic nerve appears normal because of only retrobulbar involvement of the nerve. One third of patients with ON have a swollen disc (papillitis). With time, the optic nerve may become pale.

The disc edema of ON, when present, is often diffuse. The presence of segmental changes, altitudinal swelling, pallor, arterial attenuation, and splinter hemorrhages suggest other diagnoses (eg, anterior ischemic optic neuropathy).[42]

Findings on retinal examination are usually normal. If a dilated fundus examination is not performed, other conditions such as central serous retinopathy and retinal detachment may be mistaken for ON.[43]

Patients with NMO often develop a severe, bilateral form of ON and myelitis. Bitemporal or junctional visual field defects, indicating chiasm involvement, may be present. Myelitis may be associated with localized back or radicular pain and the Lhermitte sign (spine or limb paresthesias elicited by neck flexion) early in the course of the disease. Severe neurologic deficits, including paraplegia, are typical. Symptoms such as respiratory failure or hiccups may occur when the cervical spinal cord lesions extend into the medulla.

 

DDx

Diagnostic Considerations

Conditions to consider in the differential diagnosis of optic neuritis (ON) include the following:

  • Neuromyelitis optica
  • Ischemic optic neuropathy (anterior or posterior)
  • Hereditary optic neuropathies
  • Nutritional optic neuropathies
  • Infectious ON from Lyme disease, syphilis, tuberculosis, or brucellosis
  • Optic nerve compression caused by a tumor or trauma
  • Granulomatosis with polyangiitis (Wegener granulomatosis)
  • Necrotizing herpetic retinopathy in persons who are immunocompromised
  • Central serous retinopathy
  • Central retinal artery occlusion or branch retinal artery occlusion
  • Herpes simplex
  • Functional vision loss

Differential Diagnoses

 

Workup

Approach Considerations

Blood tests that can be considered to rule out causes of optic neuropathy other than demyelinating optic neuritis (ON) include the following:

  • Erythrocyte sedimentation rate
  • Thyroid function tests
  • Antinuclear antibody test
  • Measurement of angiotensin-converting enzyme level
  • Rapid plasma reagin test
  • Mitochondrial DNA mutation studies

In a typical patient with ON without any clinical signs or symptoms of systemic disease, however, the yield from these tests is extremely low.

Cerebrospinal fluid (CSF) analysis is often noncontributory to diagnosis; however, the presence of myelin basic protein, oligoclonal bands, and an elevated IgG index and synthesis rate in the CSF support the diagnosis of multiple sclerosis (MS). Even in the absence of other signs or symptoms of MS during the initial presentation, patients with positive findings of demyelination in the CSF are more likely to develop MS in the long term.[44]  Neuromyelitis optica (NMO) IgG is a specific autoantibody marker for NMO.[30, 31]

Formal perimetry should be performed. Optical coherence tomography with nerve fiber layer quantification may be used to document neuroaxonal loss.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is highly sensitive and specific in assessing inflammatory changes in the optic nerves and helps to rule out structural lesions. In addition, MRI may have a value in predicting future development of multiple sclerosis (MS) in patients presenting with first-time, acute ON.[10, 11, 45, 46, 47, 48, 49]

A case of acute optic neuritis. A. 1.5 Tesla, cont A case of acute optic neuritis. A. 1.5 Tesla, contrast-enhanced spin echo T1-weighted, fat-suppressed coronal MRI through the orbits shows enlargement and contrast enhancement of the left optic nerve in the retrobulbar portion (arrow). B. Coronal spin echo T1-weighted, fat-suppressed MRI of the same patient shows enlargement and contrast enhancement of the nerve in a parasagittal oblique section (arrow).

Magnetic resonance imaging performed at the initial presentation reveals that 10-20% of these patients may have clinically silent demyelinated lesions elsewhere in the brain. Magnetic resonance imaging at 3.0T is more sensitive to hyperintense lesions than MRI at 1.5T.[50]  These patients are far more likely to develop definite MS in the long term than are patients with isolated ON. In the Optic Neuritis Treatment Trial (ONTT), researchers reported the 10-year risk for MS to be 56% with at least 1 MR T2 lesion.[32]

Use of fat saturation techniques helps to visualize gadolinium enhancement of the optic nerve and is the best imaging technique with which to visualize inflammation of the optic nerve.

In addition to MRI of the optic nerves and brain/brainstem, MRI of the spinal cord is indicated in patients with suspected neuromyelitis optica. An MRI of the spinal cord characteristically shows cord swelling, signal changes, and enhancement extending over several levels, which is consistent with longitudinally extensive myelitis.[51]

Visual Evoked Potentials

Visual evoked potentials (VEPs) are an important means of evaluating patients with suspected optic neuritis (ON). They may be abnormal even when MRI of the optic nerve reveals no abnormalities.

Visual evoked potentials often show a loss of P100 response in the acute phase; P100 recovers with time, but it usually shows a markedly prolonged latency that persists indefinitely even after clinical recovery.

Visual evoked potentials may be abnormal in patients with suspected MS without a history of ON, thereby providing evidence of subclinical involvement of the optic nerve. For this reason, VEP testing is often performed in patients with a suspected diagnosis of MS.

 

Treatment

Approach Considerations

Finding professional help early in the course of optic neuritis (ON) is important. The Optic Neuritis Treatment Trial (ONTT) was a carefully performed, randomized, clinical trial that yielded useful information. Despite the ONTT, the treatment of ON remains somewhat controversial.[12, 13]  From a vision standpoint, observation without steroid treatment versus intravenous steroid treatment showed no difference in ultimate visual outcome at the 5-year mark.[14]

Eculizumab, a monoclonal antibody that targets C5, is the first drug approved by the FDA for adults with neuromyelitis optica spectrum disorder (NMOSD) who are anti–aquaporin-4 antibody–positive. Approval was based on the PREVENT clinical trial. Results showed that eculizumab reduced the risk for NMOSD relapse by 94.2% compared with placebo (P < .0001). Nearly 98% of eculizumab-treated patients were relapse free at 48 weeks compared with 63.2% of patients in the placebo group. Additionally, compared with placebo, eculizumab reduced the adjudicated on-trial annualized relapse rate by 95.5% (P < .0001).[15]

Inebilizumab is a monoclonal antibody that targets CD19, a protein expressed on a broad range of B cells, including antibody-secreting plasmablasts and plasma cells. After binding to CD19, these cells are rapidly depleted from the circulation. Aquaporin-4 –IgG (AQP4-IgG ) autoantibodies are produced by plasmablasts and plasma cells and bind primarily to astrocytes in the central nervous system (CNS). Binding of AQP4-IgG antibodies to CNS cells is believed to trigger attacks that can damage the optic nerve, spinal cord, and brain. Approval was based on the N-Momentum trial (n = 230). Participants were randomly assigned to treatment and control groups, with 174 participants receiving inebilizumab and 56 receiving placebo. At the recommendation of the independent data-monitoring committee, the randomized controlled period was stopped before complete enrollment because of clearly demonstrated efficacy. Twenty-one of 174 (12%) participants receiving inebilizumab had an attack compared with 22 (39%) of 56 participants receiving placebo (P < .0001).[16]

Satralizumab is the third drug approved by the US Food and Drug Administration (FDA) for adults with neuromyelitis optica spectrum disorder (NMOSD) who are anti-AQP4 antibody–positive. Satralizumab is a recombinant humanized IgG2 antibody targeting the interleukin-6 receptor. The efficacy of satralizumab for the treatment of NMOSD in adult patients was established in 2 studies. SAkuraStar[52]  was a randomized placebo-controlled trial in 64 patients without concurrent immunosuppressive therapy. SAkuraSky[53]  was a randomized placebo-controlled trial in 52 adult patients with concurrent immunosuppressive therapy. In the SAkuraStar monotherapy study, 76.5% of satralizumab-treated patients were relapse free at 96 weeks, compared with 41.1% who received placebo. In the SAkuraSky study, which evaluated satralizumab when used concurrently with baseline IST, 91.1% of satralizumab-treated AQP4 antibody–positive patients were relapse free at 96 weeks, compared with 56.8% who received placebo.[52, 53]

Early reports with a small number of patients demonstrated some benefit with plasma exchange for patients with acute, severe ON. Further controlled studies are recommended. In 2016, a randomized controlled trial of erythropoietin in the treatment of ON was initiated.[54]

Rituximab therapy, used off-label, is considered to be among the most efficient treatments for neuromyelitis optica spectrum disorders (NMOSDs), "even in the absence of class I studies."[55]  In a case series of 20 patients with highly relapsing NMO, Kim and colleagues[56]  reported significantly reduced relapse rates and clinical stabilization or improvement with mitoxantrone treatment. Further studies conducted in a prospective and controlled fashion are required to determine whether mitoxantrone is a viable treatment option.

Intravenous immunoglobulin (IVIg) and plasma exchange (PLEX) are alternative immunomodulatory therapies that may offer additional benefit for treatment of acute ON. It remains to be determined whether IVIg may benefit patients with NMOSD and ON when delivered in conjunction with or after a round of high-dose corticosteroids.

Plasma exchange has been used successfully in the treatment of steroid-refractory ON and NMOSD-ON. Depending on the study, improvement in visual function has been noted in 45% to 55% of treated patients. Unfortunately, because of their retrospective design, these investigations failed to define criteria for the optimal use or timing of PLEX. In many instances, the short interval between completion of IVMP and institution of PLEX makes it unclear how much clinical benefit is related to delayed effects of IVMP. Male sex, lower baseline disability, rapid initiation of treatment, and shorter relapse duration have been associated with greater response to PLEX. Although early initiation of PLEX correlates with treatment response, delayed PLEX therapy may still be a reasonable treatment option for patients with acute ON who may not have immediate access to facilities with the necessary equipment.

Deschamps et al found that half of patients with poor visual recovery (visual acuity worse than or equal to 20/200) after high-dose INSM experienced improvement to visual acuity of 20/30 or better after PLEX (mean time to PLEX, 30 days).[64] Because PLEX incurs significant cost and may result in serious adverse effects such as hypotension, infection, hypocalcemia, and coagulopathy, a randomized, prospective study of PLEX versus IVMP for the treatment of acute NMOSD-ON is warranted.

Immunoadsorption is an alternative form of therapeutic apheresis that allows for selective removal of antibodies from plasma using modified membranes. Therapeutic apheresis offers the potential advantage of removing pathogenic autoantibodies while sparing other plasma proteins, eliminating the need for protein replacement and potentially minimizing complications. Immunoadsorption has been reported to benefit patients with steroid-refractory ON and NMOSD-ON. The relative efficacy and safety of PLEX and immunoadsorption have not been directly evaluated. Immunoadsorption is not approved in the United States.

For individuals who are unresponsive to IVMP and PLEX, immunosuppression with intravenous (IV) cyclophosphamide may represent an avenue of final resort. Although no clinical studies have been published on the response of severe ON to IV cyclophosphamide, a subset of patients with acute transverse myelitis have benefited from this approach. Given the risks of high-dose IV cyclophosphamide, however, careful patient selection and employment of an experienced hospital team are advised.

Other Agents

Early reports with a small number of patients found some benefit with plasma exchange in acute, severe optic neuritis. Further controlled studies are recommended. In 2016, a randomized controlled trial of erythropoietin in the treatment of optic neuritis was initiated.[52]

Rituximab therapy, utilized off-label, is considered to be among the most efficient treatments of neuromyelitis optica spectrum disorders (NMOSDs), even in the absence of class I studies.[53] In a case series of 20 patients with highly relapsing NMO, Kim et al reported significantly reduced relapse rates and clinical stabilization or improvement with mitoxantrone treatment.[54] Further studies conducted in a prospective and controlled fashion are required to determine whether mitoxantrone is a viable treatment option.

Intravenous immunoglobulin (IVIg) and plasma exchange (PLEX) are alternative immunomodulatory therapies that may offer additional benefit for acute ON treatment. It remains to be determined whether IVIg may benefit patients with NMOSD-ON when delivered in conjunction with or after a round of high-dose corticosteroids.

Plasma exchange (PLEX) has been used successfully in the treatment of steroid refractory ON and NMOSD-ON. Depending on the study, improvement in visual function has been noted in 45%–55% of treated patients. Unfortunately, because of their retrospective design, these investigations failed to define criteria for the optimal use or timing of PLEX. In many instances, the short interval between completion of IVMP and institution of PLEX makes it unclear how much clinical benefit is a result of delayed effects of IVMP. Male sex, lower baseline disability, rapid initiation of treatment, and shorter relapse duration have been associated with greater response to PLEX. Although early initiation of PLEX correlates with treatment response, delayed PLEX therapy may still be a reasonable treatment option for patients with acute ON who may not have immediate access to facilities with the necessary equipment. Deschamps and colleagues found that half of the patients with poor visual recovery (visual acuity worse than or equal to 20/200) after high-dose IVSM improved to visual acuity of 20/30 or better after PLEX (mean time to PLEX, 30 days). Because PLEX incurs significant cost and may result in serious side effects such as hypotension, infection, hypocalcemia, and coagulopathy, a randomized, prospective study of PLEX versus IVMP for the treatment of acute NMOSD-ON is warranted.

Immunoadsorption (IA) is an alternative form of therapeutic apheresis that allows for selective removal of antibodies from plasma using modified membranes. Therapeutic apheresis offers the potential advantage of removing pathogenic autoantibodies while sparing other plasma proteins, therefore eliminating the need for protein replacement, and potentially minimizing complications. Immunoadsorption has been reported to benefit steroid refractory ON and NMOSD-ON. The relative efficacy and safety of PLEX and IA are yet to be directly evaluated. Immunoadsorption is not approved in the United States.

For individuals who are unresponsive to IVMP and PLEX, immunosuppression with intravenous cyclophosphamide may represent an avenue of final resort. Although no clinical studies have been published on the response of severe ON to intravenous cyclophosphamide, a subset of patients with acute transverse myelitis have benefited from this approach. Given the risks of high-dose IV cyclophosphamide, however, careful patient selection and an experienced hospital team are advised.

Inpatient care

Patients with neuromyelitis optica often require supportive care because they are prone to many complications, such as deep venous thrombosis, pulmonary embolism, urinary tract infection, decubiti, and contractures related to the myelopathy. Mechanical ventilation may be needed as well because of respiratory compromise.

Consultations

Consultations with ophthalmology and neurology are recommended for complete evaluation and treatment of patients with suspected optic neuritis.

Steroid Therapy

The ONTT protocol used intravenous steroids (methylprednisolone 250 mg qid for 3 days) with oral steroid taper and showed a decreased short-term risk for development of MS in patients with central nervous system (CNS) white matter plaques, but they had no long-term protective benefit from MS.

Intravenous steroids do little to affect the ultimate visual acuity in patients with optic neuritis, but they do speed the rate of recovery. Some clinicians advocate IV steroids in patients with severe visual loss or bilateral visual loss.

Intravenous steroids are sometimes administered in an outpatient setting or at home. Admission to the hospital is recommended for the duration of high-dose intravenous steroid treatment because of the potential risk for serious adverse effects from this treatment.

The ONTT showed strong evidence against the use of conventional-dose oral steroid monotherapy in the treatment of optic neuritis, since oral steroids alone increased the rate of optic neuritis recurrence.[57, 58]

Medical Care

For patients with optic neuritis (ON) whose brain lesions on magnetic resonance imaging (MRI) indicate a high risk for development of clinically definite multiple sclerosis (MS), treatment with immunomodulators (eg, interferon beta-1a, interferon beta-1b, glatiramer) may be considered.[17] 17 Intravenous immunoglobulin  treatment of acute ON has been shown to have no beneficial effect.

Dress polycarbonate safety glasses are an option for patients whose vision does not completely recover.

 

Medication

Medication Summary

Eculizumab, a monoclonal antibody that targets C5, is the first drug specifically approved by the US Food and Drug Administration (FDA) for adults with neuromyelitis optica spectrum disorder (NMOSD) who are seropositive for anti-aquaporin-4 (AQP4) antibody.[15]  Inebilizumab, a monoclonal antibody that binds to CD19, and satralizumab, a monoclonal antibody that targets the interleukin-6 (IL-6) receptor, are also approved for treating NMOSD.[16, 52, 53]

Other pharmacologic therapy for optic neuritis (ON) is directed at ameliorating the acute symptoms of pain and decreased vision caused by demyelinating inflammation of the nerve. Varying regimens of corticosteroids have been used for this purpose. A 3-day course of high-dose intravenous (IV) methylprednisolone followed by a rapid oral taper of prednisone has been shown to provide a rapid relief of symptoms in the acute phase. This treatment may also delay the short-term development of multiple sclerosis (MS) after ON; however, IV steroids do little to affect the ultimate visual acuity in patients with ON.

For patients with ON whose brain lesions on magnetic resonance imaging (MRI) indicate a high risk of developing clinically definite MS, treatment with immunomodulators (eg, interferon beta-1a, interferon beta-1b, glatiramer acetate) may be considered.[17]  Intravenous immunoglobulin treatment of acute ON has been shown to have no beneficial effect.

Monoclonal Antibodies

Class Summary

Monoclonal antibodies (eg, eculizumab, inebilizumab, satralizumab) that target aquaporin-4-antibody production or binding have been approved by the FDA for adults with neuromyelitis optica spectrum disorder (NMOSD).

Eculizumab (Soliris)

Monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. The precise mechanism by which eculizumab exerts its therapeutic effect in NMOSD is unknown, but is presumed to involve inhibition of aquaporin-4-antibody–induced terminal complement C5b-9 deposition. It is indicated for adults with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody–positive.

Inebilizumab (Uplizna)

Monoclonal antibody that binds with high affinity to CD19, a protein expressed on a broad range of B cells, including antibody-secreting plasmablasts and plasma cells. After binding to CD19, these cells are rapidly depleted from the circulation. Approximately 80% of patients with NMOSD have autoantibodies to a water channel protein called aquaporin-4 (AQP4). These AQP4-IgG autoantibodies are produced by plasmablasts and plasma cells and bind primarily to astrocytes in the central nervous system. Binding of AQP4-IgG antibodies to CNS cells is believed to trigger attacks, which can damage the optic nerve, spinal cord, and brain.

Satralizumab (Enspryng)

Monoclonal antibody that targets the interleukin 6 (IL-6) receptor. Cytokine IL-6 is thought to be a key cause of NMOSD, triggering the inflammation cascade and leading to damage and disability. It is indicated for NMOSD in adults who are antiaquaporin-4 (AQP4) antibody positive. 

Corticosteroids

Class Summary

These have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Methylprednisolone (Solu-Medrol, Depo-Medrol, Medrol)

Methylprednisolone is a synthetic corticosteroid used intravenously as an anti-inflammatory and immunosuppressant agent. It has been shown to facilitate the recovery of vision in the acute phase of optic neuritis even though it may not change the long-term visual outcome. In addition, treatment with methylprednisolone may delay the development of MS.

Prednisone

Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. It is a commonly used oral agent. Prednisone is used for an oral taper of steroids, which may reduce the emotional effects of steroid withdrawal and the risk of the development of adrenocortical insufficiency. However, these risks are not very high after only 3 days of treatment with high-dose steroids, and most neurologists do not use a prednisone taper.

Prednisolone (Pediapred, Prelone, Orapred)

Prednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. It is a commonly used oral agent. Prednisolone is used for an oral taper of steroids, which may reduce the emotional effects of steroid withdrawal and the risk of the development of adrenocortical insufficiency. However, these risks are not very high after only 3 days of treatment with high-dose steroids, and most neurologists do not use a prednisone taper.

 

Questions & Answers

Overview

What is optic neuritis (ON)?

What are the signs and symptoms of optic neuritis (ON)?

How is optic neuritis (ON) characterized?

What are the physical signs of optic neuritis (ON)?

Which blood tests are indicated when optic neuropathies other than optic neuritis (ON) are suspected?

Which imaging studies and procedures are indicated in the workup of optic neuritis (ON)?

How is optic neuritis (ON) treated?

How is adult optic neuritis (ON) characterized?

What educational information is available for adults with optic neuritis (ON) and multiple sclerosis (MS)?

What causes optic neuritis (ON)?

How common is optic neuritis (ON)?

What are the demographics of optic neuritis (ON)?

What is the prognosis of optic neuritis (ON)?

Presentation

What is the clinical history of optic neuritis (ON)?

What are the physical findings in optic neuritis (ON)?

DDX

Which conditions should be considered in the diagnosis of optic neuritis (ON)?

What are the differential diagnoses for Adult Optic Neuritis?

Workup

What are the approach considerations in the workup of optic neuritis (ON)?

When is MRI indicated in the workup of optic neuritis (ON)?

How is the visual evoked potentials (VEPs) test used in the workup of optic neuritis (ON)?

Treatment

What are the approach considerations for the treatment of optic neuritis (ON)?

When is inpatient care indicated in the treatment of optic neuritis (ON)?

Which specialist consultations are indicated in the treatment of optic neuritis (ON)?

What is the role of steroid therapy in the treatment of optic neuritis (ON)?

What is the medical care for optic neuritis (ON)?

Medications

Which medications are used in the treatment of optic neuritis (ON)?

Which medications in the drug class Monoclonal Antibodies are used in the treatment of Adult Optic Neuritis?

Which medications in the drug class Corticosteroids are used in the treatment of Adult Optic Neuritis?