Demyelinating Optic Neuritis

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Demyelinating Optic Neuritis
Classification and external resources
ICD-10 H46
ICD-9 377.3


Demyelinating optic neuritis in an adult is one of the most common reasons why a patient may seek consultation with a neuro-ophthalmologist. This brief guide will help the general ophthalmologist to understand:

  1. Optic neuritis is a clinical diagnosis, thus MRI of the orbit with gadolinium looking for optic nerve enhancement, blood testing for inflammatory or infectious etiologies, and lumbar puncture are not needed for the diagnosis,
  2. Typical (unilateral vision decrease, pain with eye movement) optic neuritis will recover with good visual prognosis by 6-12 months,
  3. The final amount of vision recovery is independent of treatment with or without IV steroids, (IV STEROIDS DO NOT IMPROVE VISUAL OUTCOME, THE NATURAL HISTORY AND PROGNOSIS OF TYPICAL OPTIC NEURITIS IS VERY FAVORABLE WITH OR WITHOUT IV STEROID TREATMENT),
  4. Oral prednisone alone is CONTRAINDICATED because it has been shown to cause more recurrences to the affected eye or new episodes in the contralateral eye compared to placebo or IV steroids followed by oral prednisone,
  5. MRI of the brain is a must after an initial episode of optic neuritis because the number of lesions will stratify patients’ risk for developing clinically definite multiple sclerosis (CDMS) after a clinically isolated syndrome (CIS), and
  6. The ophthalmologist can play a vital role to decrease morbidity from multiple sclerosis (MS) by understanding the role of early treatment with disease modifying drugs (DMD). This article will focus on adults, 18 years and older who present with optic neuritis.


Disease Entity

  • Optic neuritis ICD 377.3
  • Retrobulbar neuritis (acute) ICD 377.32
  • Optic neuritis unspecified, ICD 377.30

Disease

Optic nerve inflammation that is accompanied with decreased vision, optic nerve dysfunction (decreased peripheral vision, decreased color vision, decreased contrast/brightness sense, relative afferent papillary defect (RAPD) and tends to be associated with periorbital pain. The periocular pain (62 to 92%) may precede the visual loss by days and is characteristically precipitated or aggravated by eye movement (87%). When the clinical history and examination suggest optic neuritis and the optic disc appears normal, the term retrobulbar optic neuritis is used. It may be the forme fruste of multiple sclerosis with obvious implications for diagnosis, prognosis and treatment. Prevalence roughly estimated to be 1-5/100,000 depending upon geography and ethnicity.

Etiology

Unknown cause, felt to be an autoimmune process

Risk Factors

  • 3:2-female:male ratio
  • Young age (20-45 years old)
  • A prodromal flu like illness commonly accompanies the event but does not always occur
  • Multiple Sclerosis-up to 75% of patients with CDMS will have at least one episode of optic neuritis in their lifetime. Autopsies of patients with CDMS show up to 90% optic nerve involvement.

General Pathology

Immune-mediated inflammatory demyelination of the optic nerve. The myelin undergoes destruction causing axons to poorly conduct impulses and also the axons themselves become damaged, their frequency related to the degree of inflammation within the lesion. Thus, retinal ganglion cell axons often become damaged in optic neuritis.

Pathophysiology

After myelin destruction occurs, the retinal ganglion cell axons starts to degenerate. Monocytes localize along blood vessels, and macrophagaes follow to remove myelin. Astroctyes then proliferate with deposition of glial tissue where axons may have been present before. These gliotic (sclerotic) areas can be multiple in number througout the brain and spinal cord, hence the term mutliple sclerosis.

Diagnosis

Optic Neuritis is a clinical diagnosis that is made when a patient presents with

  • Unilateral decreased visual acuity
  • Pain with eye movement and/or periorbital discomfort
  • RAPD
  • Visual field defect
  • Optic nerve swelling (35% anterior disc edema, 65% retrobulbar) 


Patients recruited in the Optic Neuritis Treatment Trial (ONTT) were selected based on decreased unilateral vision loss for 8 days or less, but the presence of a RAPD or a visual field defect were not required.

The main ingication of magnetic resonance imaging (MRI) is derived from its prognostic value for the development of MS. It is also far superior to computed tomography (CT) in the diagnosis of optic neuritis. In a retrospective observational series of patients with acute optic neuritis who had gadolinium-enhanced fat-suppressed cranial MRI scans within 20 days of the visual loss, enhancement of the orbital optic nerve occurred in (94%) of patients. This pattern of enhancement is compatible with disruption of the blood–brain barrier. This abnormality is not specific for optic neuritis since various other diseases such as sarcoidosis and radiation optic neuropathy can produce a similar appearance on MRI. An enhancing optic nerve seen on MRI post-gadolinium is helpful but not required to make the diagnosis.

Less commonly, patients may present with absence of eye pain, absence of orbital discomfort, bilateral vision loss, no light perception vision, severe disc swelling with hemorrhages of the optic disc or retinal exudates. These are considered more atypical signs and symptoms of optic neuritis and often turn out to be other entities like neuroretinitis. Three percent of patients in the ONTT presented with no light perception vision.

History

A prodromal viral illness may occur. Patients often experience orbital pain and pain with eye movement prior to visual changes. The pain can be excruciating or very mild like a foreign body sensation. The visual change is often acute and typically worsens over a few days and nadirs around 2 weeks prior to improvement.

Physical examination

  • Snellen visual acuity with best correction for distance and/or near vision
  • Color vision and/or Contrast measurement (Pelli-Robson or VisTech)
  • Swinging flashlight test for RAPD
  • Evaluation of extraocular movement
  • Confrontation and automated visual fields (Although automated perimetry has proven extremely useful in establishing the progression and recovery of visual field loss in optic neuritis, the patterns of visual field defects are not particularly helpful in distinguishing optic neuritis from any other form of optic nerve disease (eg, ischemic, compressive).
  • Amsler grid with best correction central visual field defects (be aware that this test may also be abnormal in macular disease)
  • Biomicroscopy/direct ophthalmoscopy of the optic nerve and retina

Signs

  • Decreased visual acuity
  • Decreased color vision (red desaturation) and/or decreased contrast/brightness sense
  • RAPD unless both eyes are affected or RAPD was present prior in contralateral eye
  • Ocular dysmetria of internuclear ophthalmoplegia
  • Any scotoma on Amsler grid and/or confrontation visual fields or formal visual field testing
  • Disc edema (only 35% noted in ONTT, thus lack of disc edema does not rule out acute optic neuritis)
  • Retinal vascular sheathing, pars planitis (periphlebitis occurs in 5-10% of multiple sclerosis patients)


Symptoms

  • Acute vision loss that tends to worsen over days
  • Eye discomfort or pain particularly with eye movement (mild to severe)
  • Phosphenes (flashes of lights)
  • Vision becomes blurry when body temperature rises during exercise or bathing in warm to hot water (Uhthoff's phenomenon)
  • "Washed out" color vision
  • Dimmed vision (contrast on t.v. is turned down)
  • Dark vision
  • Loss of central vision or part of the peripheral/side vision
  • Altered perception of motion (Pulfrich phenomenon)

Clinical diagnosis

Optic neuritis is diagnosed clinically by symptoms of acute unilateral decrease in vision, eye pain-especially with movement and signs of a RAPD, decreased color vision/contrast/brightness sense and documentation of a visual field defect. A MRI depicting enhancement of the optic nerve after administration of gadolinium is helpful but not required to make the clinical diagnosis and neither is disc swelling required to be present. In a retrospective observational series of patients with acute optic neuritis who had gadolinium-enhanced fat-suppressed cranial MRI scans within 20 days of the visual loss, enhancement of the orbital optic nerve occurred in (94%) of patients. Relative recovery of vision at 6 months from onset tends to be the natural progression of the disease. However, 12% of patients may not recover 20/40 or better vision, and the ones that do recover, have residual vision changes such as decreased contrast.


Diagnostic procedures

MRI is a must to help risk stratify patients for the development of MS after the acute initial onset of optic neuritis. Multiple sclerosis plaques are seen as white matter lesions on MRI scans. MRI of the brain with FLAIR sequences of axial, coronal and sagittal planes can help identify lesions >3mm in size, or large (>6mm) ovoid lesions abutting the lateral ventricles. "Dawson's Fingers" (periventricular white matter lesions on mid-sagittal FLAIR sequences that involve the corpus collosum) are highly suggestive of MS. Not all high-signal abnormalities in white matter are diagnostic of MS, thus one must use caution when considering these findings in the assessment for MS. The lesions can be present in healthy patients over age 50 who have hypertension, atherosclerosis, as well as other diseases such as vasculitis.

MRI Axial FLAIR image demonstrates multiple plaques in a patient with optic neuritis who was diagnosed with multiple sclerosis.MRI Sagittal FLAIR image demonstrates multiple plaques in a patient who presented with optic neuritis and diagnosed with multiple sclerosis.


Optical coherence tomography (OCT) of the nerve fiber layer (NFL) is helpful as an adjunctive measurement of nerve function in patients with optic neuritis. OCT is a diagnostic technique introduced into clinical practice in 1997 and widely utilized by retina specialists. It's use in glaucoma and neuro-ophthalmology is currently evolving and still at its formative stages. OCT uses the principal of reflection of low coherence radiation from tissue to measure layers of the retina and nerve fiber layer at a resolution of <10 microns with spectral-domain OCT. OCT can quantify the onset of optic atrophy and pallor that ensues 6-8 weeks post onset of optic neuritis. Optic atrophy can be subtle on biomicroscopy, thus OCT is useful for detection and quantification of the optic atrophy. OCT of the NFL also serves in patient education and documentation.

OCT NFL of the optic nerves 2.5 months post optic neuritis OD and 3.5 months post optic neuritis OS.  31yo women presented with OD count fingers vision and OS hand motion vision and at the time of this OCT, her vision had returned to 20/20 OU with color plates full OU.  The left optic nerve is thinner than the right optic nerve.  Sectoral atrophy OS is noted from 1 o'c clockwise to 5 o'c.  Although the right optic nerve is close to normal value, there is thinning along the temporal fibers.


A lumbar puncture is not required for the diagnosis of optic neuritis. However, presence of CSF levels of oligoclonal bands and elevated IgG synthesis are data that is considered in the McDonald diagnostic criteria for MS. A spinal tap can also help to rule out elevated intracranial pressure in cases of atypical bilateral optic neuritis with bilateral anterior disc edema. The CSF can also be examined for infectious and inflammatory conditions as well in atypical cases of optic neuritis.

Laboratory test

Typical optic neuritis (unilateral, pain with eye movment, no uveitis) does not require any blood testing.

Bilateral optic neuritis with poor visual recovery is atypical and a blood test for neuromyelitis optica (Devic's disease) should be entertained. The test is the neuromyelitis optica (NMO) antibody which is available commercially.

If vision loss has occurred in a young male with a significant family history of maternally-related males with bilateral vision loss, genetic consulting and testing should be entertained for Leber's hereditary optic neuropathy. Leber’s hereditary optic neuropathy patients are much less likely to recover vision and the contralateral eye is often affected within weeks to months of the first eye.

Differential diagnosis

Differential Diagnosis for Retrobulbar Optic Neuritis (normal appearance of optic nerve and vision loss)

  • Of note, the conditions noted below tend to be painless in nature, whereas 92% of patients with demyelinating optic neuritis present with some form of eye pain and/or eye pain with movement.

With a relative Afferent Pupillary Defect

  • Compressive lesions like meningioma or sphenoid sinus mucocele
  • Central serous chorioretinopathy (OCT of the macula can help to rule out macular etiology)
  • Central retinal artery occlusion
  • Posterior ischemic optic neuropathy
  • Infiltrative lesion
  • Toxic/metabolic (early without optic atrophy, tends to be more symmetric)

No relative Afferent Pupillary Defect

  • Visual field defects from brain infarct, tumor, lesion
  • Retinal degeneration such as retinitis pigmentosa
  • Macular disease (OCT of the macula helpful)
    • Age-related macular degeneration
    • Macular edema (post-cataract surgery, diabetic)
    • Central serous chorioretinopathy
    • Macular hole (traumatic, idiopathic)
    • Epiretinal membrane/surface wrinkling maculopathy
    • Documented apriori contralateral eye RAPD
    • Acute macular neuroretinopathy (AMNR)

Differential Diagnosis of Optic Neuritis (unilateral optic nerve edema, vision loss)

  • Neuromyelitis optica (Devic's disease)
  • Anterior ischemic optic neuropathy (tends to be painless in nature)
  • Neuroretinitis (early before the macular star formation)
  • Chronic relapsing inflammatory optic neuropathy (CRION) (painful)
  • Pending central retinal vein occlusion (painless)
  • Optic papillitis in patient with uveitis (Vogt-Koyanagi-Harada (VKH) syndrome, sarcoidosis)
  • Diabetic papillopathy (painless)
  • Compressive lesion along the anterior pathway of the optic nerve (up to and including optic chiasm)
  • Disc drusen (pseudodisc edema, visual field defects common due to crowding of the disc, painless)
  • Infectious optic neuritis (syphilis, lyme, herpes viradae (HSV, VZV); Bartonella-often with macular star in neuroretinitis)
  • Vasculitis (SLE, granulomatous)
  • Malignant hypertension (tends to be bilateral)
  • Infiltrative-CNS leukemia, CNS lymphoma, metastatic lesion
  • Posterior scleritis (pain with eye movement, decreased vision, B-scan with thickened choroid and fluid-"T-sign")
  • Leber's hereditary optic neuropathy (painless, telangiectatic disc vessels)
  • Vascular lesion-(juxtapapillary hemangioblastoma, combined hamartoma of the retina and RPE)
  • Radiation induced optic neuropathy
  • Mutiple evanescent white dot syndrome (MEWDS)-(painless, "wreath sign" on fluorescein angiography)

Management

Optic Neuritis Treatment Trial (ONTT) Multi-centered, randomized, prospective, controlled clinical trial that was designed to evaluate the efficacy and safety of oral prednisone vs. intravenous methylprednisolone followed by oral prednisone as compared with oral placebo for the treatment of acute optic neuritis. Patients were recruited from July, 1988 to June, 1991. 457 patients (85% Caucasian, range of 18-60 years old) at 15 different medical centers with presentation of symptoms of decreased vision at 8 days or less without any prior episodes of optic neuritis, not currently on any prednisone, and without any significant systemic diseases were randomized to either: 1) oral placebo, 2) 250mg IV solumedrol q6hrs for 3 days then 1mg/kg of prednisone for 11 days, or 3) 1mg/kg of PO prednisone alone for 14 days. Primary outcome measures were contrast sensitivity and visual field and secondary measures were vision and color. The patients were followed for a minimum of 6 months.

ONTT Outcomes

  1. IV steroid treated patients recovered faster within the first 4-6 weeks post onset. However at 6 months to 10 years out, there was no statistical difference in final visual outcome between IV-steroid treated patients and placebo.
  2. ORAL STEROIDS ALONE ARE CONTRAINDICATED FOR ACUTE OPTIC NEURITIS BECAUSE OF HIGHER RATE OF RECURRENCES OF OPTIC NEURITIS.


Practically speaking, physicians may vary in the implementation of the ONTT. Some physicians give 1gm IV bolus daily for 3 to 5 days as outpatient infusion. Furthermore, some physicians may or may not give the 11 day oral prednisone taper that follows.

There still may exist among physicians the misconception that IV steroids improve visual outcome by 6 months out. This is not the case. It is given to hasten recovery the first 4-6 weeks after onset. Ultimate visual outcome is the same with or without the administration of IV steroids in typical optic neuritis.


Medical therapy

  • Side effects of IV steroids should be fully discussed, especially in diabetics.
  • Low dose (60 mg) oral steroids are contraindicated in patients who have acute optic neuritis especially in patients that carry a diagnosis of MS
  • Some MS specialists and neuro-ophthalmologists are using a methylprednisolone (Solumedrol) smoothie. Instead of administering the 1 gram of Solumedrol IV, they dilute the powder in a smoothie drink and the patient drinks one dose daily for 3 days. The the smoothie drink camouflages the bitter taste. It is generally not available at local pharmacies in this form. Also, (repository corticotropin intramuscular/subcutaneous injection) Acthar Gel at 80 units/1 ml IM has been used in the clinic to treat acute optic neuritis.

Medical follow up

Visual acuity, (color vision and/or contrast can elucidate subtle changes not seen on Snellen acuity testing).

If unsure of the the patient had optic neuritis of neuroretinitis, a dilated exam 4 weeks later should show the macular star in neuroretinitis.

A fluorescein angiogram may be performed to rule out true optic nerve edema if Leber Hereditary Optic Neuropathy (LHON) is suspected.

Visual field testing upon onset if possible (Humphrey visual field or Goldmann visual field) and repeat at follow up visual fields at 3, 6 and 12 months.

OCT of the NFL at onset, at 6-8 week visit, and at 6 month follow up for quantitation of optic atrophy.

All patients with suspected optic neuritis should have a fat-suppressed contrast enhanced MRI at the time of presentation for diagnostic and prognostic purposes.


Complications

Visual prognosis is excellent with normal to near normal recovery. Patients may still complain of decreased brightness sense, contrast deficit, and loss of steropsis. It is important to forewarn them at the beginning that eventhough visual recovery is the norm, they still have the possibility of:

  • Permanent visual loss either mild (20/30) to severe (20/200 or worse)
  • Permanent scotomas that may limit driving
  • Recurrences


IV steroids at high dosages for the treatment of optic neuritis according to the ONTT can cause insomnia, mood changes, dyspepsia, weight gain, flushing, nausea, vomiting, and elevated blood pressure. Patients should be advised to take a proton pump inhibitor such as omeprazole and may need to seek medical attention for anxiety and insomnia. Diabetics may be at risk for episodes of hyperglycemia and also for diabetic ketoacidosis. Co-management with the patient's primary physician, internist or endocrinologist is a must. Patient's tend to have more side effects from the oral prednisone taper. Some clinicians abbreviate the taper or prescribe no taper at all, some prescribe a prolonged taper over one month. Also it is advisable to prescribe calcium and vitamin D while taking the corticosteroids.

Prognosis

94% recover 20/40 or better at 5 years out in the ONTT. 20/200 or worse visual outcome occurred in 3% of patients at 5 years out in the ONTT.

Visual recovery tends to occur by 1 month after onset and the majority recover by 1-3 months time. At 6 months, patients tend to have similar visual outcomes no matter if they were treated with IV steroids or placebo. Vision improvement can take up to one year. Prolonged pain with eye movement, lack of recovery, recurrence within 2 months would alert the physician to re-evaluate for atypical causes of optic neuritis such as sarcoidosis, syphilis or an idiopathic autoimmune optic neuritis that is steroid-responsive.

28% of patients developed recurrent optic neuritis which was associated with oral prednisone. As a result, oral steroids is contraindicated in the management of acute optic neuritis.

Since optic neuritis is common among patients who have MS, (up to 75% have at least one episode of optic neuritis in their life time), these patients are at risk for developing CDMS. The ONTT showed that even without any lesions present on MRI, there still was a 16% chance of developing MS in 5 years, 22% in 10 years and 25% in 15 years.

At 10 years, the overall risk of MS was 38% after an initial episode of optic neuritis. That risk is 56% if the MRI had 1 or more lesions. The risk is lower if the patient is male, disc swelling is present, pain is absent, vision is no light perception, severe optic disc swelling with hemorrhages are seen, or macular exudates such as a retinal star pattern occur. In patients with CDMS, the median time to diagnosis was 3 years and 34% of the diagnoses were made in the first 2 years whereas 72% were made within 5 years.

At 15 years, the overall risk of MS was 50% after an initial episode of optic neuritis and strongly related to presence of lesions on a baseline non-contrast-enhanced MRI of the brain. Twenty-five percent of patients with no lesions on baseline brain MRI developed MS during follow-up compared with 72% of patients with 1 or more lesions. Baseline factors associated with a lower risk for MS included male sex, optic disc swelling, and atypical features of optic neuritis.

Patients with signs and symptoms of a clinically isolated syndromes (CIS) such as optic neuritis require prompt MRI brain imaging for lesions to determine if patients are at high risk for the development of CDMS. The role of the initiation of disease modifying MS drugs (DMD) for MS at the time of an the first optic neuritis episode remains controversial.

Additional Resources


References

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