Optic Nerve Disorders

Optic Nerve Disorders

Optic neuropathies are generally classified as anterior, those in which the optic nerve head is swollen, and posterior, those in which there is decreased optic nerve function but a normal appearing optic nerve head.


Optic neuritis refers to inflammation of the optic nerve. The term optic neuritis most often refers to the optic neuropathy associated with demyelinating disease. This is the most common acute optic neuropathy in individuals under the age of 45. It is also a frequent presenting sign of multiple sclerosis (MS). Demyelinating optic neuritis can be considered in three categories: acute, chronic, or asymptomatic (subclinical). Acute optic neuritis is the most common form of optic neuritis.

Epidemiology and Etiology

  • MS: Optic neuritis may be the initial presentation of this disorder

  • Age of onset: 20 to 50 years, mean age of 30 to 35 years

  • Gender: More common in women (Female : male ratio is 3:1)

    Incidence: Between 1 and 5 per 100,000

  • Prevalence: Approximately 115 per 100,000

Clinical Characteristics

Diagnostic Evaluation

  • Neuroimaging: MRI is the modality of choice for investigating optic neuritis. If the patient has a typical presentation of optic neuritis, an MRI need not be performed to exclude a compressive lesion or to confirm the diagnosis (which is made on clinical grounds). An MRI can be performed to detect subclinical demyelinating plaques (Fig. 5-3) to

    • assist in determining the prognosis for developing MS,

    • evaluate patient’s potential benefit from intravenous methylprednisolone and disease-modifying therapy.

  • Cerebrospinal fluid (CSF) examination may be performed; however, this testing is not necessary and is being performed less frequently. The following abnormalities have been identified in patients with optic neuritis, although none is diagnostic of MS:

    • Pleocytosis and elevated protein

    • Oligoclonal bands

    • Myelin basic protein

    • Increased IgG index.

  • Visual-evoked responses (VER) are almost always abnormal, showing a prolonged latency on the side of the affected optic nerve.

  • No serologic tests or CSF studies need to be performed unless the patient’s course does not follow that of typical optic neuritis or the patient’s history or examination suggests an underlying systemic illness (Table 5-1).

TABLE 5-1. Results of Investigations of Patients in Optic Neuritis Treatment Trial

Etiologic studies

ANA positive in titer <1:320 in 13%; one patient developed a connective tissue disorder within 2 years

Chest radiograph: No case of sarcoidosis or TB was identified

CSF analysis: No lumbar puncture offered any unsuspected information

FTA-ABS: No case of active syphilis was identified

Natural History

  • Initially, the visual loss may worsen over several days to 2 weeks.

  • Improvement initially is rapid and starts approximately 3 weeks after onset.

  • Recovery of vision is nearly complete by 5 weeks after onset.

  • Improvement may continue up to 1 year.

The present recommendations for the investigation and treatment of patients with optic neuritis are based on the results of two multicentered studies: the ONTT and Controlled High-Risk Subjects AVONEX Multiple Sclerosis Prevention Study (CHAMPS). Both studies investigated the risk of developing clinically definite multiple sclerosis (CDMS) in patients with optic neuritis alone (ONTT) or with their first demyelinating episode that could be optic neuritis (CHAMPS). The details of the ONTT are listed in Table 5-2.

TABLE 5-2. Optic Neuritis Treatment Trial

Multicentered control clinical trial

389 patients with isolated acute unilateral optic neuritis between 18 and 46 years

Inclusion criteria:

Clinical syndrome consistent with unilateral optic neuritis (including RAPD, visual field defect in affected eye)

Visual symptoms of 8 days or less

No previous episode of optic neuritis in the affected eye

No previous corticosteroid treatment for optic neuritis or multiple sclerosis

No evidence of systemic disease other than MS as a cause for optic neuritis

Randomized to three treatment groups

Oral prednisone 1 mg/kg per day for 14 days, plus 3 day oral taper

Intravenous methylprednisolone 250 mg QID for 3 days followed by 1 mg/kg per day for 11 days orally, plus a short taper

Oral placebo for 14 days

TABLE 5-3. ONTT Baseline Data

Gender: 77% female

Race: 85% Caucasian

Age: Mean 32 ± 7 years


Photopsias, 30%

Orbital pain, 92%

Pain worsened with eye movement, 87%


Baseline visual acuity

20/20, 11%

20/50-20/40, 25%

20/50-20/190, 29%

20/200-20/800, 20%

Finger counting, 4%

Hand motion, 6%

Light perception, 3%

No light perception, 3%

Color vision

Ishihara color plates abnormal, 88%

Farnsworth Munsell 100 Hue abnormal, 94%

Visual field

Focal defects (altitudinal, arcuate, nasal step, central, or paracentral defects), 52%

Diffuse defects, 48%

Contrast sensitivity: Abnormal, 98%

Ophthalmoscopic appearance

Optic disc swelling, 35%

Optic disc or peripapillary hemorrhages, 6%

Abnormal fellow eye

Visual activity, 13.8%

Contrast sensitivity, 15.4%

Color vision, 21.7%

Visual field, 48%

TABLE 5-4. Visual Recovery

No significant difference between three arms of treatment groups at 1 year in mean VA, color vision, contrast sensitivity, or visual field

Patients treated with IV methylprednisolone recovered VA significantly faster than other two treatment arms; this effect was greatest in the first 15 days

Most of visual recovery occurs within first 6 weeks although continues up to 1 year

Patients treated with oral prednisolone had an increased rate of recurrent attacks of optic neuritis in the previously affected eye and in the fellow eye

Median VA in all three treatment groups was 20/16

Less than 10% have VA 20/50 or worse

Of patients with baseline VA of worse than 20/200, 6% had this level of vision at 6 months Of patient with initial VA of light perception or no light perception, 64% had a final VA of 20/40 or better

After 15 years, 72% have visual acuity of 20/20 in affected eye

At 15 years, visual function is more likely to be abnormal if patient has MS.

The visual defects and their response to the treatment protocols are in Tables 5-3 and 5-4, respectively. The ONTT also calculated the risk of developing CDMS in patients with optic neuritis. The risk and the effect of treatment on these risks are shown in Table 5-5 and Figure 5-4. Table 5-6 shows the risk at the yearly follow-up periods.

The only accurate predictor of increased risk to develop CDMS was the presence of lesions on the initial MRI scan (Fig. 5-5). The CHAMPS (Table 5-7) extended the ONTT by including other neurologic events (50% of the patients had optic neuritis) and
investigated the efficacy of interferon beta-1a versus placebo both on the development of CDMS and on the development or evolution of MRI lesions (Fig. 5-6). The results and conclusions of CHAMPS are shown in Table 5-7 also. Subsequent studies have shown that other disease modifying agents may be used in place of interferon beta-1a.

TABLE 5-5. Cumulative Risk of Development of Multiple Sclerosis

Based on initial MRI results (at 15 years)

The overall risk of MS at 15 years is approximately 50%

If the MRI is normal with no T2 white matter lesions, the risk of MS after 15 years is 25%

If the MRI shows one (or more) T2-weighted white matter lesions larger than 3 mm in diameter, the risk is 56% at 5 years and 72% at 15 years

Patients in the group treated with IV methylprednisolone had a reduced rate of development of MS during the first 2 years only in patients who had abnormal brain imaging at time of diagnosis

Progression to MS

The cumulative probability of developing MS by 13 years after optic neuritis was 50% and strongly related to the presence of lesions on a baseline brain MRI. If a patient has a normal MRI at presentation, the risk of developing MS was 25% compared to 72% of patients with 1 or more lesions (Fig. 5-5B).

TABLE 5-6. Cumulative Probability of Clinically Definite Multiple Sclerosis by Treatment Group

Treatment Group

Time Period

Intravenous N = 133 (%)

Placebo N = 126 (%)

Oral Prednisone N = 129 (%)

6 mo




1 yr




2 yr




3 yr




4 yr




5 yr




After 10 years, the risk of developing MS was very low for patients without baseline lesions but remained substantial for those with lesions. Among patients without lesions on MRI, baseline factors associated with a substantially lower risk for MS included male sex, optic disc swelling, and certain atypical features of optic neuritis.

TABLE 5-7. The Controlled High-Risk Subjects AVONEX Multiple Sclerosis Prevention Study (CHAMPS)


Multicentered randomized double-blind control clinical trial

Eligibility criteria

18 to 50 years

First isolated, well-defined neurologic event consistent with demyelination involving either the optic nerve (optic neuritis), spinal cord (incomplete transverse myelitis), or brainstem or cerebellum MRI abnormality: Two or more silent lesions of the brain at least 3 mm in diameter characteristic of MS Onset of symptoms 14 days or less before intravenous corticosteroid therapy and no more than 27 days before randomization

Treatment groups

Interferon-beta-1a 30 µg weekly by intramuscular injection following intravenous methylprednisolone 1 g per day for 3 days with an 11-day subsequent oral prednisone 1 mg/kg

Placebo intramuscular injection weekly following intravenous methylprednisolone 1 g per day for 3 days with an 11-day subsequent oral prednisone 1 mg/kg


Cumulative probability of development of CDMS during the 3-year follow-up period was significantly lower in the interferon-beta-1a group (adjusted rate ratio, 0.49; 95% CI, 0.33-0.73)

MRI changes at 18 months: The median increase in lesion volume was 1% in the interferon beta-1a group compared to 16% in the placebo group

Side effects of treatment

Influenza-like syndrome: 54% of interferon beta-1a group vs. 26% of placebo group

Depression: 20% of interferon beta-1a group vs. 13% of placebo group


Weekly intramuscular interferon beta-1a initiated at the time of a first clinical demyelinating event may be beneficial in patients who have MRI evidence of prior subclinical demyelination, reducing the risk of CDMS by approximately half

Interferon beta-1a is well tolerated, with no serious treatment-related adverse effects

FIGURE 5-1. Composite of visual field abnormalities found in the ONTTT. (Keltner JL, Johnson CA, Spurr JO, et al. Baseline visual field profile of optic neuritis: the experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol. 1993;111:233, with permission).

FIGURE 5-2. The optic disc is elevated and hyperemic with opacification of the retinal nerve fiber layer. The fellow optic disc was normal.

FIGURE 5-3. Axial MRI shows enhancing periventricular plaques characteristic of MS.

FIGURE 5-4. Incidence of development of CDMS per treatment group in the initial phase of the ONTT. (Beck RW, et al., for the Optic Neuritis Study Group. A randomized controlled trial of corticosteroids in the treatment of acute optic neuritis. New Engl J Med. 1992;326:581-588, with permission).

FIGURE 5-5. A. Percentage of patients developing CDMS is directly related to the number of lesions on MRI. (Optic Neuritis Study Group. The 5-year risk of MS after optic neuritis: experience of the Optic Neuritis Treatment Trial. Optic Neuritis Study Group. Neurology. 1997;49:1404-1413, with permission). B. At 13 years.

FIGURE 5-6. Percentage of patients developing CDMS over 37 months was less in the treated group. (Jacobs LD, et al. CHAMPS [Controlled High-Risk Subjects AVONEX Multiple Sclerosis Prevention Study]. New Engl J Med. 2000;343:898-904, with permission).


Some patients who present with acute optic neuritis may have neuromyelitis optica (NMO) or Devic disease. This is a rare, idiopathic, autoimmune, severe inflammatory disorder that results in astrocyte loss and demyelination in the optic nerves and spinal cord. NMO may assume a relapsing course, which may lead to a mistaken diagnosis of MS.

Epidemiology and Etiology

  • It is thought that specific autoantibodies (NMO-IgGs) target aquaporin-4, a water channel on astrocytes within the central nervous system (CNS).

  • Although the exact series of pathological events is not known, the autoantibody undermines the integrity of the myelin surrounding the optic nerves and the spinal cord leading in most cases to significant visual impairment and neurological compromise.

  • NMO has a predilection for women and Asian individuals.

Clinical Characteristics

  • The clinical course of NMO is variable.

  • Clinical features of NMO include unilateral or bilateral optic neuritis, transverse myelitis, or both. The myelopathy may precede the neuropathy or follow the visual loss.

  • The visual impairment from optic neuritis in NMO is more often bilateral, although at times sequential, than MS on presentation,

  • Neuro-ophthalmic features include

    • pain on eye movement

    • central loss of vision

    • profound visual field defects

    • dyschromatopsia

    • retinal nerve fiber layer thinning on optical coherence tomography

  • Other neurological features include

    • decreased coordination

    • paraplegia or quadriplegia

    • sensory impairment

    • bladder and bowel impairment

    • fatal respiratory failure

Natural History

  • The prognosis of NMO is generally poor. The cycle of remission and relapse in NMO tends generally to be more frequent and severe. Visual loss is profound and often permanent with associated paraplegia.

  • Treatment consists of high-dose intravenous steroids with a slow taper. Recent evidence suggests long-term immunosuppressive therapy is beneficial. Plasmapheresis may be used acutely in severe cases or with paraplegia.

Diagnostic Evaluation

  • If acute optic neuritis is bilateral, painless, unremitting or if the patient has a history of systemic autoimmune disease or is of Asian descent, the patient should be tested for NMO-IgG antibody titer (Table 5-8).

  • Neuroimaging: The diagnosis of NMO is usually made with an abnormal cervical spine
    MRI (long T2-weighted hypersignal over more than three segments) and a brain MRI which is typically normal. The brain MRI may show T2-weighted hypersignals that are atypical for MS, for example, not involving the periventricular white matter (Fig. 5-7).

  • Serological tests: Patients usually have a positive NMO immunoglobulin (aquaporin 4 antibody) on serological testing.

  • CSF: CSF usually demonstrates a neutrophilpredominant white blood cell (WBC) count that exceeds 50 cells/mo and elevated protein. Furthermore, the CSF is free of oligoclonal bands in approximately 75% of the patients.

  • Serological tests: Seropositivity for NMOimmunoglobulin G (IgG) autoantibodies is highly specific for NMO.

TABLE 5-8. Diagnostic Criteria for Neuromyelitis Optica




Acute optic neuritis and myelitis


Normal appearing brain MRI Spinal MRI demonstrates cord enlargement and cavitation involving at least three contiguous vertebral segments


Decreased serum/CSF albumin ratio with normal IgG synthesis rate and general absence of oligoclonal bands


Seropositivity for NMO-IgG autoantibodies


Leber stellate neuroretinitis is characterized by loss of vision associated with concomitant swelling of the optic nerve and hard exudates arranged in a star configuration at the macula (Fig. 5-8). Although this is primarily a retinal disorder, it is included in this section because it is frequently confused with optic neuritis.

Epidemiology and Etiology

  • Neuroretinitis is considered to be an infectious or immune-mediated process. Up to 50% of patients have an antecedent viral illness, usually affecting the respiratory tract, a few weeks before the onset of visual symptoms.

  • Neuroretinitis usually affects children and young adults although it may occur in persons of all ages.

  • The vast majority of patients with neuroretinitis have no cause identified or it is associated with cat-scratch disease (Bartonella henselae). Other various infections have been implicated and include syphilis, Lyme disease, and toxoplasmosis.

  • Many causes of optic disc swelling, e.g., papilledema and hypertensive optic neuropathy, may have retinal exudates in a stellate formation; however, the star formation is usually incomplete (Fig. 5-9; see Fig. 5-23). Therefore, the presence of disc edema and a macula star is not pathognomonic for neuroretinitis.

Clinical Characteristics

Natural History

  • Neuroretinitis is usually a self-limiting condition, with the optic disc swelling resolving in 6 to 8 weeks. The macular star can take several months and even up to 1 year to resolve. The majority of patients regain good vision.

  • If visual symptoms persist, the patient usually complains of metamorphopsia or blurred central vision.

Diagnostic Evaluation

  • History of being scratched by a kitten, which maximally exposes the patient to cat-scratch fever. In this circumstance, titers for Bartonella henselae should be drawn.

  • A swollen optic nerve and exudates, and a star or hemistar figure in the macula may be seen in other conditions, for example, hypertensive optic neuropathy or papilledema (see p. 62; Fig. 5-9). In these conditions the macula star often is located only nasal to the macula suggesting it is ‘spillover’ from optic nerve head swelling. Therefore, the patient’s blood pressure should be obtained.

  • It should be noted that this fundus picture is not recognized as the equivalent of optic neuritis. It does not increase the risk of developing MS.


Sarcoidosis is a multisystem granulomatous inflammation with ocular, neurologic, and neuro-ophthalmic manifestations. Optic neuropathy may develop at any time during the course of systemic sarcoidosis or it can be the initial manifestation of the disease.


  • Sarcoidosis is a granulomatous inflammatory process that is identified pathologically by a noncaseating granuloma. Epithelioid and giant cells are characteristic findings on histopathologic studies.

  • The optic neuropathy of sarcoidosis is produced by one of the three possible mechanisms.

    • Compression produced by a granuloma or by pachymeningitis (Fig. 5-10)

    • Infiltration by inflammatory cells. Sarcoid granulomas may be seen in the optic disc (Fig. 5-11).

    • Ischemia due to obliterative arteritis

Clinical Characteristics

Diagnostic Evaluation

  • MRI will show enhancement of the optic nerve or the portion of the anterior visual pathway that is involved (Fig. 5-14). The meninges may be thickened and show abnormal enhancement.

  • Serum ACE levels may be abnormally high.

  • Chest X-ray or imaging will often show hilar adenopathy or pulmonary nodules or infiltrates.

  • Pulmonary function studies often are abnormal.

  • Gallium scan documents involvement of the lung and lacrimal glands in many patients.

  • Definitive diagnosis is established by biopsy. Tissue is usually obtained from the enlarged hilar lymph nodes via bronchoscopy or from the lacrimal glands if they appear involved by the process (Fig. 5-15). Blind conjunctival biopsy has a very low yield, while biopsy of a conjunctival lesion (granuloma) visible on the slit lamp examination has a much higher yield.

TABLE 5-9. Other Neuro-ophthalmic Manifestations of Sarcoidosis

Afferent visual pathway

Chiasmal involvement

Bitemporal hemianopia, junctional scotoma, and bilateral optic nerve involvement

Postchiasmal visual pathway: The pattern of the visual field defects depends on the area of the visual pathway that is involved; mechanism of damage can include compression, infiltration, or vascular occlusion related to angiitis.

Efferent visual pathway

Abducens nerve palsy most common; may be unilateral or bilateral

Supranuclear gaze palsy and ocular flutter have been described

Pupils (uncommon)

Tonic pupil

Orbital involvement

Orbital mass (granuloma)

Infiltration of extraocular muscles

Diffuse infiltration of orbit


Abnormalities of the optic nerve may be encountered in both secondary and tertiary syphilis. Optic neuropathy involvement in syphilis may either be optic neuritis, neuroretinitis, or perineuritis. Syphilitic optic neuropathy may occur in isolation or associated with other features of intraocular inflammation.


  • Optic neuritis occurs during the secondary and tertiary stage of infection. We consider that syphilitic optic neuropathy implies neurosyphilis.

Clinical Characteristics

  • The general ocular signs of syphilis are listed in Table 5-11.

Diagnostic Evaluation

  • The best method to prove a syphilitic infection is to demonstrate the spirochete in a
    tissue biopsy or CSF. This is not usually feasible, so indirect methods of testing for syphilis are routinely employed. Syphilitic optic neuropathy implies neurosyphilis and suspected cases should undergo CSF analysis.

  • The serologic tests for syphilis are listed in Table 5-12. Specific testing recommendations appear in Table 5-13.

TABLE 5-12. Tests for Syphilis

Treponemal tests


High specificity and sensitivity in all stages of syphilis

Once reactive, these tests do not revert to normal

Used for confirming diagnosis of syphilis

Used routinely for suspected late syphilis

False positive can occur with other treponemal infections

False negative can occur with HIV infection


Immunofluorescence: FTA-ABS, fluorescent treponemal antibody


MHA-TP: Microhemagglutination treponemal test for syphilis

HATTS: Hemagglutination treponemal test

TPHA: Widely used in Canada and Europe but not available in the United States

Nontreponemal (reagin) tests


Initial screening or to quantitate the serum reagin antibody titer, but there are significant false negatives in primary, latent, or late syphilis

Reflects activity of disease: For example, a rise in titers seen between primary and secondary syphilis; persistent fall in titers following treatment provides evidence of an adequate response to therapy

Non-treponemal tests usually become nonreactive after treatment. However, a significant number may continue to have low titers for long periods of time


VDRL: Venereal Disease Research Laboratories test

Advantages: Standard test used for CSF; less expensive

Disadvantage: Uses heated serum; reagent must be prepared fresh daily

False positive with non-treponemal tests can occur with: autoimmune diseases, pregnancy, vaccination, IV drug abuse, tuberculosis and non-syphilitic treponemal infections

False negative can occur with HIV infection

RPR: Rapid plasma reagin

Advantages: Easy to perform; uses unheated serum; test of choice for rapid serologic diagnosis

Disadvantage: More expensive than VDRL

TABLE 5-13. CSF Testing in Syphilitic Optic Neuropathy

Indications for lumbar puncture

Seropositive patient with neurologic or neuro-ophthalmic signs and symptoms

All patients with untreated syphilis of unknown duration

HIV-positive patients who are also seropositive

Test to perform


Very specific if fluid is not contaminated with blood

Low sensitivity: May be nonreactive in progressive symptomatic syphilis

CSF protein, cell count


Nonarteritic anterior ischemic optic neuropathy (NAION) is a frequently encountered disorder characterized by painless loss of vision associated with optic disc swelling. Its name indicates that it is not caused by giant cell arteritis (GCA).

Pathogenesis and Etiology

  • NAION is thought to be the result of vascular insufficiency in the posterior ciliary circulation affecting the distal optic nerve, although this has not been proven.

  • The incidence of NAION is between 2 to 10 per 100,000 persons over the age of 50. The average age of onset is between 55 and 65 (range 40 to 70) years, although it is becoming more frequently diagnosed in younger patients with known risk factors.

  • Risk factors that are thought to be important include the following:

Jul 14, 2016 | Posted by in OPHTHALMOLOGY | Comments Off on Optic Nerve Disorders

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