Chapter 190 – Inflammatory Optic Neuropathies and Neuroretinitis

Chapter 190 – Inflammatory Optic Neuropathies and Neuroretinitis

 

LAURA J. BALCER

ROY W. BECK

 

 

 

 

 

DEFINITION

• Optic neuritis refers to inflammation of the optic nerve. Such inflammation may spare the optic disc (retrobulbar optic neuritis) or may cause optic disc swelling (papillitis).

 

KEY FEATURES

• Abrupt vision loss.

• Dyschromatopsia.

• Afferent pupillary defect.

 

ASSOCIATED FEATURES

• Pain, particularly on eye movement.

• Inflammation of the optic disc with adjacent retinal inflammation (referred to as neuroretinitis).

 

 

 

INTRODUCTION

Optic neuritis, or primary inflammation of the optic nerve, is referred to as papillitis when the optic disc is swollen and retrobulbar neuritis when the disc appears normal. The most common form of optic neuritis is acute demyelinating optic neuritis. Much of our current knowledge about acute demyelinating optic neuritis has been derived from the Optic Neuritis Treatment Trial (ONTT). This was a multicenter trial supported by the National Eye Institute that assessed the benefit of corticosteroid treatment of optic neuritis, and investigated the relation between optic neuritis and multiple sclerosis (MS). [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Although numerous autoimmune conditions, such as sarcoidosis, may be associated with acute or chronic optic nerve inflammation, this chapter will focus on acute demyelinating optic neuritis.

EPIDEMIOLOGY AND PATHOGENESIS

The annual incidence of optic neuritis, as estimated in population-based studies, is approximately 5 per 100,000 per year, while the prevalence is 115 per 100,000.[15] The majority of patients who develop optic neuritis are between the ages of 20 and 50 years. Women are affected more commonly than men. In the ONTT, 77% of the patients were women, 85% were white, and the mean age was 32 ± 7 years. In most cases, the pathogenesis of optic neuritis is inflammatory demyelination, whether or not MS is diagnosed clinically.[16] [17] It is likely that many cases of monosymptomatic optic neuritis occur as the initial manifestation of MS.[18]

OCULAR MANIFESTATIONS

Loss of vision in patients who have acute demyelinating optic neuritis is usually abrupt and occurs over several hours to days. Progression for a longer period is possible but suggests an alternative underlying cause. Visual loss is usually monocular, although occasionally both eyes are affected, particularly in children.

Mild pain in or around the eye is present in more than 90% of patients. Such pain may precede or occur concomitantly with visual loss, is usually exacerbated by eye movement, and generally lasts no more than a few days. The presence of pain, particularly on eye movement, is a helpful (although not definitive) clinical feature that differentiates acute demyelinating optic neuritis from nonarteritic anterior ischemic optic neuropathy (AION).[19]

On examination of the patient, optic nerve dysfunction is evident. The severity of visual loss varies from a mild visual field defect to severe loss of central acuity (3% of ONTT participants had no light perception).[3] Color vision and contrast sensitivity are impaired in almost all cases, often out of proportion to visual acuity. Among primary visual outcome measures in the ONTT, contrast sensitivity demonstrated the highest percentage of eyes with abnormalities (even after 5 years of follow-up).[8] Visual field loss, which may be diffuse (48% of 415 ONTT patients tested) or focal (52% are nerve fiber bundle defects, central or cecocentral scotomas, hemianopic defects), is also common in acute optic neuritis.[4]

An afferent pupillary defect (APD) is detected in almost all unilateral cases of optic neuritis. If an APD is not present, a pre-existing optic neuropathy in the fellow eye must be suspected. In fact, asymptomatic visual dysfunction is fairly common among fellow eyes of patients who have apparent unilateral optic neuritis. [7]

The optic disc appears normal in approximately two thirds of patients who have acute demyelinating optic neuritis (retrobulbar optic neuritis), while disc swelling is present in about one third of cases (papillitis) ( Fig. 190-1 ). Although the clinical features are similar in both forms, optic disc hemorrhages were uncommon in the ONTT (6%), and their presence should suggest an alternative diagnosis.

DIAGNOSIS AND ANCILLARY TESTING

The diagnosis of acute demyelinating optic neuritis is based on an appropriate history (typical versus atypical course) and clinical signs and symptoms as described above. Diagnostic tests, including magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, and serological studies, usually are performed for the following reasons[10] [11] : (1) to determine if the cause of the acute optic neuropathy is noninflammatory (such as a compressive lesion), or a nonidiopathic inflammatory or infectious process in cases that are not typical for acute demyelinating optic neuritis, and (2) to determine the prognosis or risk for subsequent development of clinically definite MS (CDMS) in monosymptomatic cases for which the history and clinical signs are typical.

In patients who have suspected optic neuritis, MRI of the brain and orbits with fat suppression and gadolinium should be performed, even in typical cases, to confirm the diagnosis and to assess for the presence of other white matter lesions.[10] [11] Follow-up of the ONTT cohort to 5 years and beyond has confirmed that the number of white matter lesions, specifically two or more, is highly predictive of the development of CDMS in monosymptomatic

 

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Figure 190-1 Optic disc swelling (papillitis) associated with acute optic neuritis.

 

 

 

Differential Diagnosis of Acute Unilateral Optic Neuropathy

Anterior ischemic optic neuropathy

 

Tumor

 

Aneurysm

 

Vasculitis

 

Neuroretinitis

 

Metastatic carcinoma

 

Lymphoreticular disorder

 

Sinusitis

 

Granulomatous inflammation

 

Leber’s hereditary optic neuropathy (although always bilateral, this frequently presents initially with visual loss in only one eye)

 

 

 

 

patients (51% for two or more lesions versus 16% for normal MRI findings). [10]

DIFFERENTIAL DIAGNOSIS

The diagnosis of acute visual loss begins with the localization of the involved portion of the visual system. An optic neuropathy is presumed when no ocular cause for visual loss is apparent and an APD is present. The differential diagnosis for acute optic neuropathy is outlined in Box 190-1 . Because most cases of optic neuritis produce unilateral visual loss, discussion here is limited to unilateral optic neuropathies. When there is acute visual loss and unilateral optic disc swelling, both optic neuritis and AION must be considered. Although the clinical profiles of these disorders overlap, AION is typically painless, occurs in patients over 50 years of age, and may be associated with optic disc hemorrhages. When the optic disc is normal in patients who have unilateral optic neuropathy, a compressive lesion must be excluded; this usually is differentiated from acute optic neuritis by a history of progressive visual loss beyond the typical period of 1–2 weeks.

Other inflammatory, infectious, and neoplastic disorders may produce infiltration or demyelination, or both, of the optic nerve. These conditions may appear as either acute or progressive visual loss, and include sarcoidosis, systemic lupus erythematosus, syphilis, postviral syndromes, lymphoma, and leukemia.

Neuroretinitis, characterized by optic disc edema and macular exudates, must be differentiated from acute demyelinating optic neuritis ( Fig. 190-2 ). Macular edema is initially diffuse; hard exudates form within days, frequently in a star-shaped pattern. Deep, whitish lesions are noted at the level of the retinal

 

 

Figure 190-2 Optic disc edema and macular star formation. Color fundus photograph from a 13-year-old girl who came to medical attention with counting fingers acuity secondary to cat-scratch (Bartonella) neuroretinitis.

pigment epithelium, scattered throughout the fundus. Both types of retinal findings are important to recognize, because their presence virtually excludes idiopathic demyelination or MS as the cause. Most cases of neuroretinitis are caused by viral syndromes, although cat-scratch disease and toxoplasmosis also must be considered.

Viral and Postviral Syndromes

Parainfectious optic neuritis typically follows the onset of a viral infection by 1–3 weeks, but it also can occur as a postvaccination phenomenon. It is more common in children than adults and likely occurs by an immunological process that produces optic nerve demyelination. Postviral (or parainfectious) optic neuritis may be unilateral but is frequently bilateral. The optic discs may appear normal or swollen; retinal involvement (neuroretinitis) is common when there is optic disc swelling. Associated meningoencephalitis, with MRI changes and CSF pleocytosis, is not unusual. Visual recovery after parainfectious optic neuritis usually is excellent, even with no treatment. Corticosteroids may or may not hasten recovery, but this treatment is reasonable to consider, particularly in cases of bilateral, severe visual loss.

Sarcoidosis

Granulomatous inflammation of the optic nerve is a frequent ocular manifestation of sarcoidosis and may be an initial sign of this disorder. Clinical findings may be similar to those of acute demyelinating optic neuritis. However, the optic disc may have a characteristic lumpy, white appearance, suggestive of granulomatous infiltration. Recovery of vision is rapid in most cases following corticosteroid treatment. In fact, rapid recovery of vision with corticosteroid treatment and subsequent deterioration following taper is atypical for acute demyelinating optic neuritis and should suggest an infiltrative process such as sarcoidosis.

Syphilis

Syphilitic optic neuritis has become more common since the increase in prevalence of human immunodeficiency virus (HIV) infection (see below). Optic nerve involvement may be unilateral or bilateral. Vitreous cellular reaction is a typical feature that differentiates syphilis infection from acute demyelinating optic neuritis, in which the vitreous humor usually is clear. The diagnosis is established with identification of positive syphilis serological and CSF VDRL (Venereal Disease Research Laboratories) test results. Treatment with penicillin produces visual recovery in most cases; however, recurrences are possible.

 

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Lyme Disease

Although optic neuritis has been reported in patients with positive Lyme serological test results or other neurological findings suggestive of Lyme disease, definitive evidence of a causal relationship with Borrelia burgdorferi infection or rapid improvement of optic neuropathy following antibiotic treatment has not been established in most cases.[20] Acute demyelinating optic neuritis, particularly in patients with a history of or MRI findings consistent with MS (or two or more white matter lesions suggesting high MS risk in monosymptomatic patients), must be strongly considered in such patients, given the recent recommendations for early interferon treatment (see Treatment ). Syphilis infection may produce false-positive Lyme disease serological examination results and, therefore, must also be considered in patients with optic neuropathy or other neurological manifestations.

Optic Neuritis in Human Immunodeficiency Virus Disease

In immunocompromised patients, particularly those with HIV infection, many other infectious diseases may cause optic neuropathy, including tuberculosis, toxoplasmosis, toxocariasis, cytomegalovirus, herpes zoster, Cryptococcus, and other fungi. Primary central nervous system lymphoma infiltrating the optic nerves and chiasm has been reported recently in patients who have HIV.[21]

Systemic Lupus Erythematosus and Other Vasculitides

Optic neuritis may occur in patients who have systemic lupus erythematosus (SLE), polyarteritis nodosa, and other vasculitides. Involvement of the optic nerve occurs in about 1% of patients who have SLE. Rarely, the disease manifests with optic neuropathy. The pathogenesis is related to ischemia, which may produce demyelination alone or in combination with axonal necrosis. Clinical manifestations may include those of acute optic neuritis (both papillitis and retrobulbar neuritis), acute ischemic optic neuropathy, or chronic progressive visual loss. The diagnosis of SLE as a cause of optic neuropathy is established by identification of systemic symptoms and signs of the disease, and by serological testing. Treatment with high-dose corticosteroids is indicated and has been demonstrated to reverse severe visual loss. [22]

The term autoimmune optic neuritis has been suggested for cases of steroid-responsive optic neuritis with serological evidence of vasculitis (such as antinuclear antibodies [ANA]) but no signs of systemic involvement. [23] However, the existence of “autoimmune optic neuritis,” distinct from either SLE or MS, is unproved. Patients with acute demyelinating optic neuritis or MS also may have positive ANA serological test results. Among ONTT participants, the ANA finding was positive at a titer <1:320 in 13% and >1:320 in 3%; only one patient developed a diagnosable connective tissue disease during the first 2 years of follow-up. Visual outcomes for these patients were similar between the placebo and intravenous methylprednisolone groups.

SYSTEMIC ASSOCIATIONS

Although inflammation of the optic nerve occurs in numerous systemic disorders as outlined above, acute demyelinating optic neuritis occurs most often in MS (among 50% of patients with MS) and frequently represents the first well-documented manifestation of MS (in 20% of patients with MS).[9] [10] [18] [24] The most comprehensive information to date regarding the relation of acute demyelinating optic neuritis to MS has been provided by the ONTT. Follow-up of the ONTT cohort to 5 years and beyond has continued to demonstrate that brain MRI is the most powerful predictor of subsequent CDMS risk in monosymptomatic patients.[9] [10] The presence of two or more white matter lesions was associated with a 51% risk of CDMS after 5 years, while the risk was 37% for those with 1 or 2 lesions, and only 16% if the MRI results were normal (excluding optic nerve enhancement). [9] [10] Monosymptomatic patients who have two or more brain white matter lesions seen with MRI therefore, are, considered to be at high risk for the development of CDMS following acute demyelinating optic neuritis. Among patients who have normal brain MRI findings (no white matter lesions) in the ONTT, lack of pain, presence of optic disc swelling, and mild visual acuity loss were features associated with a reduced risk of CDMS.

PATHOLOGY

Although the exact underlying cause is unknown, the pathophysiology of acute optic neuritis and MS is that of primary inflammatory demyelination.[16] [17] Very little is written about the pathology of “isolated” optic neuritis, and no autopsy data has been reported. The inflammatory response in MS plaques is marked by perivascular cuffing, T cells, and plasma cells. Although MS, itself, previously was thought to be exclusively a disease of myelin with sparing of nerve axons, neuronal and axonal loss have been demonstrated to occur pathologically.[16]

TREATMENT

The ONTT has been the most comprehensive investigation to date regarding the treatment of acute demyelinating optic neuritis with corticosteroids, and it has had a significant impact on the practice patterns of both ophthalmologists and neurologists. [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] The ONTT enrolled 457 patients, aged 18 to 46 years, with acute unilateral optic neuritis. Follow-up data from the ONTT cohort (Longitudinal Optic Neuritis Study [LONS]) has been extensive and has provided important information regarding clinical features, long-term visual outcome, vision-specific health-related quality of life, and the role of brain MRI in determining risk for development of CDMS.

Patients in the ONTT were randomized to one of three treatment groups as follows:

• Oral prednisone (1?mg/kg per day) for 14 days with 4-day taper (20?mg on day 1, 10?mg on days 2 and 4)

• Intravenous methylprednisolone (250?mg every 6 hours for 3 days) followed by oral prednisone (1?mg/kg per day) for 11 days with 4-day taper

• Oral placebo for 14 days[1]

Visual acuity and contrast sensitivity were primary visual outcome measures in the ONTT, while development of CDMS was a secondary end point. MRI scanning of the brain and orbits with gadolinium was performed for all patients.

Major findings of the ONTT may be summarized as follows: (1) intravenous methylprednisolone treatment hastened recovery of visual function but did not affect long-term visual outcome after 6 months to 5+ years compared with placebo or oral prednisone—this benefit for intravenous methylprednisolone was greatest within the first 15 days, (2) patients treated with oral prednisone alone (without intravenous methylprednisolone) unexpectedly demonstrated an increased risk of recurrent optic neuritis (30% after 2 years versus 16% for the placebo group and 13% for those receiving intravenous steroids) that has persisted throughout the 5+ year follow-up period,[8] [10] and (3) monosymptomatic patients in the intravenous methylprednisolone group had a reduced rate of development of CDMS during the first 2 years of follow-up, but this benefit did not persist beyond 2 years and was seen only in patients with brain MRI scans that indicated a high risk for subsequent CDMS (MRI scans with two or more white matter lesions).[9] [10]

Among patients at high risk for the development of CDMS as established by MRI criteria from the ONTT (two or more white matter lesions), a recent randomized trial of 383 patients (the Controlled High-Risk Avonex MS Prevention Study [CHAMPS]) demonstrated that treatment with interferon ß-1a (Avonex) following acute monosymptomatic demyelinating optic neuritis or other first demyelinating event (including brainstem syndrome or incomplete transverse myelopathy) significantly reduced the

 

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Figure 190-3 Kaplan-Meier estimates of the cumulative probability of clinically definite multiple sclerosis (MS) according to treatment group in the Controlled High-Risk Avonex MS Prevention Study (CHAMPS).[24] The cumulative probability of the development of clinically definite MS during the 3-year follow-up period was significantly lower in the interferon ß-1a group than in the placebo group (P = 0.002 by the Mantel log-rank test). (From Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon ß-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med. 2000;343:898–904.)

3-year cumulative probability or CDMS versus placebo (rate ratio 0.56, P = 0.002, Kaplan-Meier analysis/Mantel log-rank test) ( Fig. 190-3 ).[24] CHAMPS participants in the interferon ß-1a group also had significantly reduced rates of accumulation of new but clinically silent lesions on brain MRI (P < 0.001 for both T2-enhancing and gadolinium-enhancing lesions after 18 months of follow-up). Results were similar in the subgroup of patients in CHAMPS who experienced optic neuritis as their first demyelinating event (192 patients), supporting the initiation of interferon ß-1a in patients at high risk for CDMS by MRI criteria.[25] All patients in CHAMPS (interferon ß-1a and placebo groups) also received a 3-day course of intravenous methylprednisolone followed by oral prednisone, as per the ONTT protocol (see above). Although the potential for long-term benefit of interferon ß-1a in patients with acute monosymptomatic demyelinating optic neuritis (or other first demyelinating event) and high-risk brain MRI findings is not known, results from CHAMPS provide rationale for early therapy.

Early interferon therapy following a first demyelinating event is likewise supported by results of a randomized trial of interferon ß-1a (Rebif) performed in Europe (Early Treatment of Multiple Sclerosis Study [ETOMS]). [26] Patients in ETOMS (n = 308) were randomized to receive interferon ß-1a (Rebif) 22?µg subcutaneously weekly or placebo; treatments were begun within 3 months following a first demyelinating event. During the 2-year follow-up period, a significantly lower proportion of patients developed CDMS in the interferon ß-1a than in the placebo groups (52/154 [34%] versus 69/154 [45%], P = 0.047, chi-square test). Time to occurrence of a second demyelinating event (CDMS) in 30% of patients was also significantly shorter for the treatment group than the placebo group (569 days versus 252 days, hazard ratio 0.65, P = 0.023, Cox proportional hazards model). With respect to MRI parameters, patients in the interferon ß-1a group had significantly fewer lesions on T2-weighted images (P <0.001, analysis of covariance).

Other Treatments

In experimental models of MS, intravenous immunoglobulin G (IVIG) has been shown to promote remyelination of the central nervous system.[27] A small pilot study in 1992 suggested that IVIG treatment may have some benefit in patients with resolved optic neuritis who have significant visual deficits.[28] However, a recent randomized trial of IVIG versus placebo in 55 patients with MS and persistent visual acuity loss (20/40 or worse) following optic neuritis did not demonstrate a significant benefit for recovery using visual acuity (logMAR units) as the primary outcome measure.[29]

Management Recommendations

In patients with a typical clinical course and examination findings for acute monosymptomatic demyelinating optic neuritis (first demyelinating event), MRI of the brain (T2-enhanced and gadolinium-enhanced images) should be performed to determine whether they are at high risk for the development of CDMS. Patients whose clinical course is atypical for acute demyelinating optic neuritis should also receive MRI of the orbits with gadolinium and fat saturation. The presence of two or more white matter lesions on MRI (3?mm diameter or larger, at least one lesion periventricular or ovoid) should prompt consideration of one of the following treatments based on data from the ONTT, CHAMPS, and ETOMS [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [24] [25] [26] :

• Intravenous methylprednisolone (1?g per day, single or divided doses, for 3 days) followed by oral prednisone (1?mg/kg per day for 11 days, then 4-day taper)

• Interferon ß-1a (Avonex 30?µg intramuscularly once weekly) Rebif (22?µg subcutaneously weekly)

In monosymptomatic patients who have fewer than two MRI white matter lesions, and in those for whom a diagnosis of CDMS has been established, intravenous methylprednisolone treatment (followed by oral prednisone as outlined) may be considered on an individual basis to hasten visual recovery, but this has not been demonstrated to improve long-term visual outcome. Based on findings from the ONTT, oral prednisone alone (without prior treatment with intravenous methylprednisolone) may increase the risk of recurrent optic neuritis and should be avoided.

COURSE AND OUTCOMES

At least some visual improvement is expected in all patients who have acute demyelinating optic neuritis. Visual improvement usually begins rapidly in patients treated with intravenous methylprednisolone. Even with no treatment, however, most patients start to recover vision within 2–3 weeks of symptom onset. Once recovery begins, most patients achieve near maximal improvement within 1–2 months, although recovery up to 1 year is possible. Severity of the initial visual loss appears to be the only predictor of visual outcome.[2]

Despite favorable recovery of vision, frequently to 20/20 or better, many patients with acute demyelinating optic neuritis continue to experience subtle visual abnormalities that affect their daily function and quality of life. [12] [13] Persistent abnormalities of visual acuity (15–30%), contrast sensitivity (63–100%), color vision (33–100%), the visual field (62–100%), stereopsis (89%), light brightness sense (89–100%), afferent pupillary reaction (55–92%), optic disc appearance (60–80%), and the visual-evoked potential (63–100%) have been demonstrated in such patients. Recurrent episodes of optic neuritis in the initially affected or fellow eye may occur also; approximately 30% of ONTT participants had a second episode in either eye within the 5-year follow-up period.[8] [9]

During and even beyond the recovery of vision following acute demyelinating optic neuritis, patients frequently experience transient worsening of symptoms with exposure to heat (Uhthoff’s symptom).[30] Positive visual phenomena and photopsias are also common and were reported by 30% of ONTT participants.[1] [3]

 

 

REFERENCES

 

1. Beck RW, Cleary PA, Anderson MA, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med. 1992; 326:581–8.

 

2. Beck RW, Cleary PA, Backlund JC, et al. The course of visual recovery after optic neuritis: experience of the Optic Neuritis Treatment Trial. Ophthalmology. 1994; 101:1771–8.

 

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3. Optic Neuritis Study Group. The clinical profile of acute optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol. 1991;109:1673–8.

 

4. Arnold AC. Visual field defects in the Optic Neuritis Treatment Trial: central vs. peripheral, focal vs. global. Am J Ophthalmol. 1999;128:632–4.

 

5. Beck RW, Kupersmith MJ, Cleary PA, et al. Fellow eye abnormalities in acute unilateral optic neuritis: experience of the Optic Neuritis Treatment Trial. Ophthalmology. 1993;100:691–8.

 

6. Beck RW, Cleary PA. The Optic Neuritis Study Group: Optic Neuritis Treatment Trial: one-year follow-up results. Arch Ophthalmol. 1993;111:773–5.

 

7. Beck RW. The Optic Neuritis Treatment Trial: three-year follow-up results. Arch Ophthalmol. 1995;113:136–7.

 

8. Optic Neuritis Study Group. Visual function five years after optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol. 1997;115:1545–52.

 

9. Beck RW, Cleary PA, Trobe JD, et al. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med. 1993;329:1764–9.

 

10. Optic Neuritis Study Group. The 5-year risk of multiple sclerosis after optic neuritis: experience of the Optic Neuritis Treatment Trial. Neurology. 1997;49: 1404–13.

 

11. Beck RW, Arrington J, Murtagh FR, et al. Brain MRI in acute optic neuritis: experience of the Optic Neuritis Study Group. Arch Neurol. 1993;8:841–6.

 

12. Cleary PA, Beck RW, Bourque LB, et al. Visual symptoms after optic neuritis: results from the Optic Neuritis Treatment Trial. J Neuroophthalmol. 1997; 17:18–28.

 

13. Cole SR, Beck RW, Moke PS, et al. The National Eye Institute Visual Function Questionnaire: experience of the ONTT. Invest Ophthalmol Vis Sci. 2000; 41:1017–21.

 

14. Trobe JD, Sieving PC, Guire KE, et al. The impact of the Optic Neuritis Treatment Trial on the practices of ophthalmologists and neurologists. Ophthalmology. 1999;106:2047–53.

 

15. Rodriguez M, Siva A, Cross SA, et al. Optic neuritis: a population-based study in Olmsted County, Minnesota. Neurology. 1995;45:244–50.

 

16. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338:278–85.

 

17. Ulrich J, Groebke-Lorenz W. The optic nerve in multiple sclerosis: a morphological study with retrospective clinico-pathological correlations. Neuro-ophthalmol. 1983;3:149–59.

 

18. Kurtzke JF. Optic neuritis or multiple sclerosis. Arch Neurol. 1985;42:704–10.

 

19. Swartz NG, Beck RW, Savino PJ, et al. Pain in anterior ischemic optic neuropathy. J Neuroophthalmol. 1995;15:9–10.

 

20. Balcer LJ, Winterkorn JMS, Galetta SL. Neuro-ophthalmic manifestations of Lyme disease. J Neuroophthalmol. 1997;17:108–21.

 

21. Lee AG, Tang RA, Roberts D, et al. Primary central nervous system lymphoma involving the optic chiasm in AIDS. J Neuroophthalmol. 2001;21:95–8.

 

22. Frohman LP, Frieman BJ, Wolansky L. Reversible blindness resulting from optic chiasmatis secondary to systemic lupus erythematosus. J Neuroophthalmol. 2001;21:18–21.

 

23. Kupersmith MJ, Burde RM, Warren FA, et al. Autoimmune optic neuropathy: evaluation and treatment. J Neurol Neurosurg Psychiatry. 1988;51:1381–6.

 

24. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon ß-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med. 2000;343:898–904.

 

25. CHAMPS Study Group. Interferon ß-1a for optic neuritis patients at high risk for multiple sclerosis. Am J Ophthalmol. 2001;132:463–71.

 

26. Rodriguez M, Lennon VA. Immunoglobulins promote remyelination in the central nervous system. Ann Neurol. 1990;27:12–7.

 

27. Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomized study. Lancet. 2001;357: 1576–82.

 

28. van Engelen BG, Mommes OR, Pinckers A, et al. Improved vision after intravenous immunoglobulin in stable demyelinating optic neuritis [Letter]. Ann Neurol. 1992;32:834–5.

 

29. Noseworthy JH, O’Brien PC, Petterson TM, et al. A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis. Neurology. 2001;56:1514–22.

 

30. Scholl GB, Song HS, Wray SH. Uhthoff’s symptom in optic neuritis: relationship to magnetic resonance imaging and development of multiple sclerosis. Ann Neurol. 1991;30:180–4.