[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.158.83.210. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Clinicopathologic Reports, Case Reports, and Small Case Series
July 2002

Retrobulbar Optic Neuritis Associated With Infliximab

Arch Ophthalmol. 2002;120(7):985-987. doi:

Tumor necrosis factor (TNF) α is a cytokine derived chiefly from macrophages.1 The liberation of TNF-α is thought to stimulate the inflammatory process by binding to cell surface receptors. Infliximab is a chimeric antibody of the IgG class, which binds TNF-α, inhibiting its activity.2 The Food and Drug Administration has approved infliximab, as an intravenous infusion, for the treatment of rheumatoid arthritis and Crohn disease.3

Cytokine-targeted therapy in patients with rheumatoid arthritis has been increasing and has generally been reported to be safe, although headache and respiratory congestion may occur. Review of the package insert for infliximab lists "neurologic events" as possible adverse affects and adds that "Infliximab and other agents that inhibit TNF have been associated in rare cases with exacerbation of clinical symptoms and/or radiographic evidence of de-myelinating disease."4

Inhibition of TNF-α has also been studied in multiple sclerosis (MS), in which high TNF-α levels have been noted in MS plaques and mononuclear cells of patients with demyelinating disease.5 In animal models of MS, the infusion of TNF-α is associated with worsening symptoms.6 However, a randomized, controlled study of lenercept, another TNF-α inhibitor that also inhibits the cytokine lymphotoxin, found no benefit in patients with MS.7 Furthermore, patients treated with lenercept had a significant increase in the rate of relapses and a trend toward more severe relapses.

One report of an exacerbation of preexisting demyelinating disease in 2 patients with rapidly progressive MS has suggested a possible link between infliximab and demyelination.8 In these 2 patients, TNF-α infusion was associated with increased disease activity on magnetic resonance imaging (MRI). The number of lesions observed with contrast-enhanced MRI remitted and then increased again after rechallenge with the TNF-α inhibitor.

To our knowledge, there have been no reports of optic neuritis associated with infliximab. We describe a 55-year-old woman with rheumatoid arthritis who developed retrobulbar optic neuritis of the left eye after the infusion of infliximab. Although the optic neuritis may have been coincidental to the use of infliximab, we believe that this case report should heighten awareness of a possible link between loss of vision from demyelination and TNF-α inhibition.

Report of a Case

A 55-year-old woman with a 2-year history of rheumatoid arthritis chiefly affecting the hands sought treatment with a 5-day history of decreased vision in the left eye accompanied by pain with eye movement. She had no paresthesia, weakness, or bowel and bladder dysfunction and no history of neurologic disease. She had initially been treated with methotrexate (one 12-mg subcutaneous injection per week) for 1 year; however, because of persistent stiffness of the hands, infliximab was added. Initially, she received 240 mg (3 mg/kg) of infliximab every 2 weeks for 3 doses, followed by an infusion of the same dose every 8 weeks, for a total of 9 infusions. Her loss of vision and pain with eye movement began 3 days after her last infusion of infliximab. She reported improvement in the stiffness in her hands within weeks of beginning the infliximab. She was also taking conjugated estrogens (Premarin; Wyeth Pharmaceuticals, St David's, Pa) and folic acid. There was no family history of demyelinating disease.

Best-corrected visual acuity was 20/25 OD and 20/50 OS. She identified 14 of 14 Ishihara pseudoisochromatic color plates with the right eye and 6 of 14 with the left eye, and she had a left relative afferent pupillary defect. Findings from automated perimetry were normal in the right eye and showed a superior altitudinal visual field defect in the left eye (Figure 1). Her optic discs were healthy. Gadolinium-enhanced MRI of the brain and orbits revealed mild enhancement of the orbital portion of the left optic nerve (Figure 2). There were no other lesions consistent with demyelination within the brain.

Figure 1.
Findings from automated perimetry
(Humphrey 24-2 threshold program [Zeiss Humphrey Systems, Dublin, Calif] shows
gray scale [right] and pattern deviation [left]) of the right eye (A) are
normal. The left eye (B) shows a superior altitudinal defect.

Findings from automated perimetry (Humphrey 24-2 threshold program [Zeiss Humphrey Systems, Dublin, Calif] shows gray scale [right] and pattern deviation [left]) of the right eye (A) are normal. The left eye (B) shows a superior altitudinal defect.

Figure 2.
Axial (A) and coronal (B) T1-weighted
magnetic resonance imaging with contrast shows enhancement of the retrobulbar
portion of the left optic nerve.

Axial (A) and coronal (B) T1-weighted magnetic resonance imaging with contrast shows enhancement of the retrobulbar portion of the left optic nerve.

She was treated with 1 g of intravenous methylprednisolone per day for 3 days, followed by a tapering dose of oral prednisone over the next 10 days. Three weeks after seeking treatment, her vision slowly improved to 20/30 OS, and her visual field deficit resolved.

Comment

The patient's clinical course was consistent with retrobulbar optic neuritis. Although optic neuritis associated with central nervous system demyelination is well known to occur after age 50 years, most cases occur between the ages of 20 and 50 years.8 In a study of the incidence of monosymptomatic optic neuritis in Stockholm, Sweden, only 1 (0.7%) of 147 patients was aged 55 years or older.9 Hence, our patient's age of 55 years is somewhat atypical for an initial episode of demyelinating optic neuritis.

Although the relationship between the onset of visual symptoms and the infusion of infliximab may have been coincidental, this association is similar to that seen in the prior report of the exacerbation of rapidly progressive MS in 2 patients treated with this TNF-α inhibitor.10 In both patients, an increase in the number of gadolinium-enhancing lesions on MRI was noted between 3 and 10 days after the initial infusion. A second infusion, given 2 weeks after the first dose, caused a second, smaller spike of lesions on MRI, which decreased over the ensuing 3 weeks. In addition, the number of lymphocytes and the IgG index in the cerebrospinal fluid, both indicative of MS activity, increased after the initial infusion. The authors speculated that the inability of infliximab to penetrate the blood-brain barrier, as documented by the failure to detect the cytokine in the cerebrospinal fluid, may have rendered the TNF-α inhibitor ineffective.

A randomized, placebo-controlled study of 168 patients with MS (excluding patients with rapidly progressive MS) treated with lenercept, another TNF-α antagonist, found an increase in the frequency of exacerbations and a trend toward more severe exacerbations when compared with the placebo.7 The increased rate of exacerbations was noted both 24 and 48 weeks after the onset of treatment. In addition, there was a statistically significant dose-dependent decrease in the time to first exacerbation in patients treated with lenercept.

Other explanations have been proposed attempting to link TNF-α inhibition and an increased risk of demyelination. Robinson et al1 have suggested that TNF-α antagonists may directly alter the immune response, increasing autoimmune activity and enhancing demyelination. Other investigators have noted a possible link between MS susceptibility and polymorphism of the promoter region of the TNF-α gene sequence,11 and some have suggested a role for an alteration in adhesion molecule expression.12

Although this patient's retrobulbar optic neuritis may have been coincidental to the infusion of infliximab, we believe that this case report underscores both the clinical awareness of the possible association and the need for further study of the possible link between TNF-α antagonism and demyelination, especially in light of the increasing use of this cytokine inhibitor.

The authors have no proprietary interest in any of the products described in this article.

Dr Foroozan has a fellowship from the Heed Ophthalmic Foundation, Cleveland, Ohio.

Corresponding author and reprints: Robert C. Sergott, MD, Neuro-Ophthalmology Service, Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107.

References
1.
Robinson  WHGenovese  MCMoreland  LW Demyelinating and neurologic events reported in association with tumor necrosis factor alpha antagonism. Arthritis Rheum. 2001;441977- 1983Article
2.
Kremer  JM Rational use of new and existing disease-modifying agents in rheumatoid arthritis. Ann Intern Med. 2001;134695- 706Article
3.
Elliot  MJRavinder  NMFeldmann  M  et al.  Randomised double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor alpha (cA2) vs placebo in rheumatoid arthritis. Lancet. 1994;3441105- 1110Article
4.
 Remicade (infliximab) [package insert].  Malvern, Pa Centocor Inc2001;
5.
Killestein  JKalkers  NFMeilof  JFBarkhof  Fvan Lier  RAWPolman  CH TNF alpha production by CD4+ T cells predicts long-term increase in lesion load on MRI in MS. Neurology. 2001;571129- 1131Article
6.
Probert  LAkassoglou  KPasparakis  MKontgeorgos  GKollias  G Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor alpha. Proc Natl Acad Sci U S A. 1995;9211294- 11298Article
7.
The Lenercept Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group, TNF neutralization in MS. Neurology. 1999;53457- 465Article
8.
Rodriguez  MSiva  ACross  SAO'Brien  PCKurland  LT Optic neuritis: a population-based study in Olmsted County, Minnesota. Neurology. 1995;45244- 250Article
9.
Jin  Y-Pde Pedro-Cuesta  JSoderstrom  MStawiarz  LLink  H Incidence of optic neuritis in Stockholm, Sweden, 1990-1995, I: age, sex, birth, and ethnic-group related patterns. J Neurol Sci. 1998;159107- 114Article
10.
van Oosten  BWBarkhof  FTruyen  L  et al.  Increased MRI activity and immune activation in 2 multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology. 1996;471531- 1534Article
11.
Fernandez-Arquero  MArroyo  RRubio  A  et al.  Primary association of a TNF gene polymorphism with susceptibility to multiple sclerosis. Neurology. 1999;531361- 1363Article
12.
Selmaj  KW Tumour necrosis factor and anti-tumour necrosis factor approach to inflammatory demyelinating diseases of the central nervous system. Ann Rheum Dis. 2000;59suppl 1i94- i102Article
×