What are the typical clinical features of optic neuritis?

Optic neuritis (ON) is a common manifestation of multiple sclerosis (MS), and refers to inflammation of the optic nerve. It can be the initial demyelinating event in up to 20% of patients, and occurs in almost half of patients with MS.1 ON associated with demyelinating disease is generally characterized by acute to subacute, painful, and monocular vision loss. Vision typically worsens over hours to days (not months), and recovery is expected to begin within 1 month of symptom onset. The pain that occurs with optic neuritis is usually ocular, retroocular, periorbital, or a frontal headache. This pain is generally exacerbated with extraocular movements, and occurs in the vast majority of patients with typical ON.2 Patients with features atypical of ON, such as those that suggest other etiologies (i.e. abrupt onset of vision loss suggestive of a vascular etiology), warrant ophthalmology evaluation.

How to approach the patient with suspected optic neuritis?

The diagnosis of ON involves primarily clinical, electrophysiologic, and imaging evaluations. Clinically, patients typically describe central (less commonly arcuate, cecocentral, or hemianopic) vision loss that progresses over hours to days. Examination is commonly notable for impaired visual acuity, red desaturation, and an afferent pupillary defect. Funduscopic examination can appear normal acutely, but disc edema can be present in approximately one-third of patients (particularly those with anterior optic neuritis).1, 2 Optic disc pallor is generally seen weeks to months following onset of typical optic neuritis. The presence of hemorrhages or exudates on funduscopic examination is more suggestive of other, non-demyelinating etiologies of optic neuropathy and warrants ophthalmology evaluation.

Imaging modalities used in the diagnosis of optic neuritis include orbital MRI and optical coherence tomography (OCT). These tools can be particularly helpful if the clinical history or physical examination findings are atypical for ON. Orbital MRI with and without contrast, performed with fat saturation sequences, generally reveals enlargement and enhancement of the affected optic nerve in the acute setting. The enhancement and edema seen on MRI generally improves over time with classic demyelinating ON.

OCT evaluates the optic nerve axonal integrity by measurement of the retinal nerve fiber layer (RNFL), and is generally used to evaluate for evidence of prior ON. The pattern of RNFL thinning most specific to MS is temporal.3 RNFL can appear normal in the acute setting but starts to decline within 4 weeks of ON. OCT at onset of ON is also potentially confounded by edema of the optic disc, which may lead to overestimates of baseline RNFL.4 Ganglion cell layer (GCL) thickness, another OCT measure, is not confounded by disc edema but declines in a similar time frame to RNFL and therefore may be more useful as a baseline measurement. The decrease in RNFL is thought to continue for 6 months following ON onset.5

Visual evoked potentials (VEPs) can also provide valuable information regarding optic nerve impairment in ON. VEPs evaluate optic nerve function by calculating P100 latency and amplitude, which are generally abnormal in the setting of acute and remote optic neuritis. Prolonged P100 latency is a characteristic of remote optic neuritis.1

In terms of other clinical testing, low contrast letter acuity has also emerged as a highly sensitive means by which to detect and quantify visual dysfunction following ON. Such modalities were not available for use in the ONTT, and therefore we are now able to evaluate visual impairment with greater sensitivity following ON.6

What is the neurologic differential diagnosis of optic neuritis?

Once primarily ophthalmological causes of monocular vision loss (i.e. CRAO, CRVO, uveitis, glaucoma, retinal pathology, trauma, or corneal pathology) have been ruled out, the differential diagnosis of optic neuropathy, of which optic neuritis is a cause, can be broad. Vascular, inflammatory/autoimmune, infectious, neoplastic, and metabolic causes are considerations.1, 4, 7, 8 A clinician should further narrow the diagnosis based on the timing of symptoms and associated features (Below).

Vascular

  • Anterior ischemic optic neuropathy (AION), arteritic or nonarteritic.
    • Older patients, sudden onset, lack of pain, severe vision loss with prolonged/limited recovery, hemorrhages present, altitudinal defect; see vasculitides below if arteritic.
  • Vasculitides (polyarteritis nodosa, granulomatosis with polyangiitis, temporal arteritis).
    • Check ANCA, ESR, CRP; generally vascular presentation (acute onset).
    • Temporal arteritis generally associated with Arteritic ION.
  • Systemic lupus erhythematosus, antiphospholipid syndrome.
    • Check ANA, cardiolipin antibodies, lupus anticoagulant, beta-2 glycoprotein antibodies.

Inflammatory/autoimmune

  • Multiple sclerosis.
    • Painful, acute to subacute vision loss associated with red desaturation.
  • Isolated/idiopathic.
    • Painful, acute to subacute vision loss associated with red desaturation.
  • Neuromyelitis optic spectrum disorders (NMOSD).
    • Can be bilateral, recurrent ON.
  • Anti-MOG syndrome.
    • Can be bilateral, recurrent ON.
  • Sjogren’s syndrome.
  • Systemic lupus erythematosus.
    • Can be bilateral, recurrent ON.
  • Vasculitides.
    • Can be bilateral, recurrent ON.
  • Sarcoidosis.
    • Can be associated with other signs of intraocular/intraorbital inflammation (anterior uveitis, dry eye, other cranial neuropathies, glaucoma, optic nerve sheath enhancement).
  • Paraneoplastic.
    • Painless vision loss, optic disc edema, Anti-CRMP5 (CV-2) antibodies.
  • CRION (chronic relapsing inflammatory optic neuropathy).
    • Granulomatous inflammation, generally responsive to steroids, can be bilateral, painful.

Infectious

  • Syphilis.
    • Usually secondary or tertiary syphilis stages.
  • Meningitis/encephalitis.
  • HIV.
  • Acute viral infections (EBV, HSV, VZV, West Nile Virus, CMV).
    • Neuroretinitis, macular edema (“star”).
  • Toxoplasmosis.
    • Neuroretinitis, macular edema (“star”).
  • Bartonella henselae.
    • Neuroretinitis, macular edema (“star”).
  • Tuberculosis.
    • Neuroretinitis, macular edema (“star”).
  • Chikungunya.
    • Travel history, preceding infectious symptoms9.
  • Mucormycosis (cavernous sinus).
    • Associated with diabetes.
  • Lyme disease.

Neoplastic (compressive and/or infiltrative)

  • Lymphoma.
    • Compressive involving the orbit.
  • Meningioma.
    • Optic nerve sheath meningioma, but can have paraclinoid or sphenoid wing meningiomas causing compression.
  • Optic nerve glioma.
    • Associated with neurofibromatosis type 1.
  • Metastatic disease.
    • Including carcinomatous meningitis.

Compressive

  • Abscess.
  • Carotid-ophthalmic artery aneurysm.
  • Thyroid orbitopathy.
  • Orbital pseudotumor.
  • Pseudotumor cerebri.
    • Papilledema, increased opening pressure on LP.

Metabolic

  • Vitamin B12 deficiency.
    • Generally bilateral, early dyschromatopsia.
  • Folate deficiency.
    • Generally bilateral.
  • Vitamin B1 deficiency.
    • Generally bilateral.

Genetic

  • Leber’s hereditary optic neuropathy.
    • Progressive vision loss over >10-14 days, young men.
  • Kjer type autosomal dominant optic atrophy.
    • Usually presents in childhood, bilateral and symmetric optic atrophy.

Toxic/Drug-induced

  • TNF-inhibitors (infliximab).
  • Lead.
  • Methanol.
    • Associated nausea, abdominal pain, metabolic acidosis, usually bilateral.
  • Tobacco-alcohol amblyopia.
    • Longstanding tobacco and alcohol dependence, generally bilateral, may be related to nutritional deficiencies.
  • Ethambutol.
    • Dyschromatopsia may be earliest symptom.
  • Amiodarone.
    • Insidious, slowly progressive visual loss, with prolonged disc swelling.
  • Radiation.
    • Slowly progressive vision loss, 6-24 months after radiation therapy.

Trauma

  • Traumatic optic neuropathy.

What is an appropriate diagnostic evaluation for secondary causes of unilateral optic neuritis?

When a patient presents with unilateral acute optic neuritis, one should obtain a brain MRI with and without gadolinium contrast in order to evaluate for other signs of central nervous system demyelinating disease, specifically multiple sclerosis. Spinal cord MRI can also be considered to evaluate for subclinical spinal cord lesions, or to investigate further if a history suggestive of myelitis is reported.

Laboratory evaluation could include testing for the previously mentioned differential diagnosis of ON: HIV, RPR, ACE, ESR, CRP, aquaporin-4 antibody, Bartonella testing, ANA, ENA, and Lyme testing.4 Testing should be expanded depending on relevant history and findings, as outlined in the table of differential diagnostic considerations above. In the appropriate clinical setting (i.e. when MS, NMOSD, neurosarcoidosis, or CNS infections are suspected), evaluation could include lumbar puncture for assessment of CNS oligoclonal bands, pleocytosis, elevated protein, and/or specific infectious studies.

At the Mellen Center, we typically do not perform an extensive evaluation for typical demyelinating optic neuritis, unless a patient’s history or examination is suggestive of other potential etiologies. Atypical features, including lack of eye pain, systemic symptoms, atypical fundus findings, and bilateral disease, generally prompt a more extensive evaluation.

How should this evaluation change if the optic neuritis is bilateral?

More extensive evaluation is warranted if ON is bilateral, and this should include toxic/metabolic causes as outlined in the Table above. Bilateral optic neuritis can be a presenting symptom of neuromyelitis optica spectrum disorders (NMOSD), anti-myelin oligodendrocyte glycoprotein (MOG) syndrome, sarcoidosis, paraneoplastic optic neuropathy (CRMP-5), infections, and chronic relapsing inflammatory optic neuropathy (CRION). If a patient has bilateral optic neuritis and aquaporin-4 antibody testing is negative, anti-MOG antibody testing should be completed at the Mayo Clinic Laboratory. However, seronegative NMOSD is a possibility and should be considered in the appropriate clinical context, particularly in the setting of severe vision loss with poor recovery.10 If symptoms worsen following a steroid taper, sarcoidosis should be more strongly considered, and chest CT should be completed to evaluate for hilarlymphadenopathy. If paraneoplastic or metastatic disease is suspected, CT of the chest, abdomen, and pelvis should be completed, and a serum paraneoplastic antibody evaluation should be performed via the Mayo Clinic Laboratory to test for the presence of CRMP-5 antibodies.

How should this evaluation change if the optic neuritis is recurrent?

Optic neuritis can be recurrent, and potential causes include NMOSD, anti-MOG syndrome, CRION, and sarcoidosis. Therefore, the evaluation for recurrent ON is similar to that of bilateral ON. In any patient with unilateral ON, we generally test for aquaporin-4 antibodies. If this is negative and recurrent ON occurs, aquaporin-4 antibody testing can be repeated in 6 months, as this positive result would change management. Another consideration is anti-MOG syndrome, an increasingly recognized cause of optic neuritis.11

What strategies are used in the management of acute optic neuritis?

When a patient presents with acute inflammatory ON, treatment includes possible methylprednisolone, 1000mg IV daily for 3-5 days, followed by prednisone taper (60mg for 4 days, 40mg daily for 4 days, then 20mg daily for 4 days). However, a clinician may opt to defer steroids based upon the patient’s clinical characteristics. In the Optic Neuritis Treatment Trial (ONTT), visual recovery was faster in patients receiving IV methylprednisolone compared to those receiving placebo or oral prednisone.12

However, long-term visual outcomes were not significantly different between these groups.

If a patient has visual acuity worse than 20/40, use of IV methylprednisolone followed by a prednisone taper is recommended. If visual acuity is better than 20/40, treatment with IV methylprednisolone should be considered if a patient has baseline visual impairment in the fellow eye, severe pain, scotoma, or an occupation that demands visual precision.13 If a patient’s brain MRI demonstrates gadolinium enhancing lesions, the impetus to treat with IV methylprednisolone is higher.

What is the prognosis for recovery of vision after optic neuritis?

Following an episode of typical ON, patients can be followed using several clinical and imaging modalities to monitor recovery. Visual acuity tends to recover over a period of weeks, and begins 2-4 weeks after onset.1 Monitoring of RNFL and GCL thinning following an episode of ON generally reveals RNFL thinning as early as 4 weeks, but up to 6 months after the clinical episode.5

The prognosis for subjective visual recovery after acute demyelinating optic neuritis due to MS is generally good, and recovery begins within 2 to 4 weeks.1, 14 However, objective evidence including low contrast letter acuity and OCT measures demonstrate longstanding evidence of damage following each ON episode.6 Optic neuritis due to other etiologies (infectious and inflammatory (including NMOSD)) is variable.

If a patient does not meet criteria for MS or NMOSD at the time of optic neuritis and no other causes are found, what is the appropriate monitoring and treatment strategy?

Following an episode of typical optic neuritis, as reported in the ONTT, 35% of patients developed recurrent ON at ten-year follow-up. This recurrence was more common in patients with abnormal brain MRI. The risk of MS was higher for patients who had brain MRI lesions typical for MS at baseline, and generally lower for males, normal brain MRI at ON presentation, optic disc swelling, and atypical clinical features of ON.1, 15, 16

Given this risk of developing MS or other neuro-inflammatory disorders following ON, brain MRI should be repeated in 6 months, then after 1 year, to evaluate for the development of lesions that could indicate the development of MS via dissemination in time following a clinically isolated syndrome (CIS). Patients should be followed clinically for development of new neurological symptoms that could be consistent with a demyelinating event.

If a patient is diagnosed with CIS at the time of optic neuritis typical for MS, with risk of MS development, a decision should be made whether initiation of disease modifying therapy is warranted. It is established that MS disease modifying therapies reduce the risk of MS development following a clinically isolated syndrome.17 Such a decision is based upon characteristics of an individual patient, including presence of brain MRI lesions.

If a patient has recurrent optic neuritis not meeting MS or NMOSD criteria, what is the appropriate management strategy?

If a patient has recurrent optic neuritis, an underlying cause cannot be identified, and steroid responsiveness is apparent, the diagnosis of CRION should be considered. CRION refers to a relapsing form of optic neuritis characterized by inflammation. Patients with CRION tend to have recurrent ON upon steroid withdrawal, so chronic immunosuppression is generally advised with medications including azathioprine, methotrexate, or IVIG.18 Another consideration in recurrent ON is anti-MOG syndrome, an increasingly recognized etiology of central nervous system demyelinating disease, including optic neuritis.11 Commercial testing for anti-MOG antibodies is available, and could be conducted if aquaporin-4 antibody testing is negative. The management of anti-MOG syndrome is thought to be similar to that of NMOSD.

If a patient with known multiple sclerosis presents with monocular vision loss, what etiologies should be considered?

Although optic neuritis is more common earlier in the course of MS, patients with MS can have optic neuritis at any point in their disease. The diagnosis of ON should therefore be considered in an MS patient who reports monocular vision loss, but other etiologies should be considered as well. Such diagnoses include temporal arteritis and ischemic optic neuropathy, which can be seen in older patients; these possible etiologies warrant emergent ophthalmological evaluation in a patient with sudden onset vision loss, scalp tenderness, jaw claudication, or new onset headaches. If the patient reports halos, ophthalmology evaluation is warranted to rule out uveitis, which can be associated with MS.

Patients with MS who are on disease modifying therapies may also experience vision issues related to these medications. Specifically, patients on fingolimod are at risk for macular edema and can present with blurry or wavy central vision. Patients on natalizumab who are JC virus antibody-positive and therefore at risk for progressive multifocal leukoencephalopathy (PML) can present with hemianopsia that they may perceive as monocular vision loss. Migraines are also common in patients with MS, and visual aura can often be misinterpreted as optic neuritis by patients.

If a patient had previous optic neuritis and reports recurrence of symptoms that are not as severe as their initial episode, a pseudoexacerbation should be considered and the patient should be evaluated for infection. Additionally, patients with prior ON can experience Uhthoff’s phenomenon, with worsening of visual function associated with heat.

References:

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