Copyright 1998 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.1998
Optic neuritis is a syndrome of visual loss due to inflammation of the optic nerve. It is usually either idiopathic or associated with multiple sclerosis. Less commonly, it can accompany other systemic inflammatory disorders such as systemic lupus erythematosus, syphilis, or sarcoidosis. An entity known as autoimmune optic neuropathy, also called autoimmune optic neuritis, appears to be distinct from other forms of optic neuritis because it has a different clinical course with characteristic associated laboratory findings.1,2
We describe 2 patients with autoimmune optic neuropathy and typical abnormalities on skin biopsy specimens. The first patient is the youngest case of this disorder reported to date and histopathologic findings of the optic nerve are available on the second patient.
An otherwise healthy 17-year-old boy noticed loss of vision in his left eye while watching television. After 2 days of worsening vision, he was found to have visual acuity of 20/20 OD and hand motion at 1 ft (30 cm) OS. His left optic disc had moderate edema; the right optic disc was normal. He was treated for 3 days with intravenous methylprednisolone sodium succinate (1 g/d) followed by an 11-day course of oral prednisone (1 mg/kg per day). His vision slowly improved to 20/50 OS. Two weeks after discontinuing the prednisone, the patient experienced a similar episode in his right eye. General medical and neurologic examination results were normal.
The following laboratory studies were normal: brain magnetic resonance imaging, chest x-ray films, cerebrospinal fluid analysis, complete blood cell count, liver function tests, angiotensin-converting enzyme levels, antinuclear antibodies, antineutrophilic cytoplasmic antibodies, erythrocyte sedimentation rate, human immunodeficiency virus serology, VDRL, FTA-ABS, CH50, Lyme titers, blood cultures, and urinalysis. The patient was again treated with the same course of corticosteroids with substantial improvement in his vision; visual acuity improved during treatment to 20/50 OU. Ten days after treatment was stopped, his vision again worsened and he was referred to the Neuro-ophthalmology Unit of the Department of Ophthalmology and Visual Sciences at the University of Iowa, Iowa City.
At that time, his visual acuity was 20/80−1 OD and 20/50−1 OS with a spherical correction of−6.50 OD and−6.00 OS and there was a small relative afferent pupillary defect (0.5 log unit) in the right eye. There was moderate bilateral optic disc pallor, more in the right eye.
A magnetic resonance image of the orbit and brain showed mild enhancement of the retrobulbar right optic nerve. Laboratory measurements of the previously listed tests were again normal, including a repeated cerebrospinal analysis for immunoglobulins, oligoclonal bands, and myelin basic protein. In addition, assays for anticardiolipin antibody, rheumatoid factor, lupus anticoagulant, and mitochondrial DNA screen for most common mutations found in Leber hereditary optic neuropathy were negative. Within 1 week, the patient's visual acuity decreased to less than 20/200 OU and results of a visual field examination found markedly depressed vision bilaterally. The presence of a dense inferior altitudinal defect in the right eye and a loss of the I2e isopter in the left eye were accompanied by a 0.6–log unit relative afferent pupillary defect in the right eye. The optic disc appearance and findings of the remainder of the ophthalmologic examination were unchanged. A 4-mm punch biopsy specimen of non–sun-exposed buttock skin was obtained by the dermatology service.
The hematoxylin-eosin–stained frozen section showed a mild mononuclear perivascular infiltrate within the dermis and no leukocytoclastic response. Direct immunofluorescent staining was positive for IgM and C3 in a granular pattern in the walls of small blood vessels within the superficial papillary dermis. In addition, IgM and C3 were found at the dermoepidermal junction in a granular to fibrillar staining pattern (Figure 1). No specific staining was seen for IgA. These results indicated the presence of immune complex deposition, and the diagnosis of autoimmune optic neuropathy was made.
Case 1. Left, Image from skin biopsy specimen shows dermoepidermal and perivascular IgM deposition; right, dermoepidermal and perivascular C3 deposition (immunofluorescent, original magnification ×100).
The patient again received identical methylprednisolone treatment. His visual acuity began to improve on day 3 of this regimen, as did results of his kinetic perimetry examination. Ten weeks later, his visual acuity had improved to 20/25 OD and 20/30 OS. Both eyes had regained the ability to see the I2e isopter and the inferior altitudinal defect in the right eye had resolved. The patient continued to take 80 mg/d of oral prednisone for 8 additional weeks and his dose was then tapered over a year. His examination findings remained stable for 2 years.
A 25-year-old woman experienced rapidly progressive visual loss in her right eye approximately 5 months prior to referral. The visual loss was accompanied by pain with eye movement but no other symptoms. She was diagnosed as having optic neuritis and was treated with the same regimen as patient 1. She experienced recovery of vision to 20/25 OD over the following 7 weeks. She then experienced the same symptoms in the right eye 1 month later. A magnetic resonance image showed a small scarlike lesion in the thalamus. She underwent a detailed evaluation similar to that of patient 1, with normal results. The patient was again treated with an identical regimen of intravenous and oral corticosteroids and experienced improvement of visual function in her right eye.
She had a mild episode of arthritis as a child and had occasional migraine headaches. She had a brother and paternal aunt with systemic lupus erythematosus.
Following a third episode of visual loss in her right eye, the patient was referred to us. Visual acuity was 6/200 OD and 20/15 OS and there was a 1.8–log unit relative afferent pupillary defect in the right eye. Goldmann perimetry showed a large central scotoma with an enlarged blind spot in the right eye. Results of the visual field examination of the left eye were normal. Her examination was otherwise unremarkable except the right optic disc showed temporal pallor, while the left optic disc was normal. Her general medical and neurologic examination findings were otherwise normal.
A magnetic resonance image at that time showed mild enhancement of the right intraorbital optic nerve and both lacrimal glands appeared mildly enlarged (Figure 2). A laboratory evaluation, again similar to that of patient 1, was repeated and showed no abnormalities. In addition, sarcoidosis was suspected and bilateral conjunctival biopsies were performed, results of which were normal. A lacrimal gland biopsy was performed through an anterior orbitotomy with the specimen showing no signs of inflammation.
Patient 2. T1-weighted magnetic resonance image (with gadolinium and fat suppression) demonstrates optic nerve enhancement of the right eye. The lacrimal glands are also enhanced slightly.
A trial of oral prednisone was then initiated with some subjective improvement after the third day of treatment. However, the patient experienced mania with psychotic features due to the prednisone, which was then discontinued. Nine days later, with her visual acuity at hand motion in the temporal visual field of the right eye, a medial orbitotomy and optic nerve biopsy was performed, which showed chronic perivascular nongranulomatous inflammation and mild gliosis (Figure 3). No immune complex staining was performed on the optic nerve specimen.
Histological section of the optic nerve. Perivascular aggregates of chronic inflammatory cells are present without evidence of necrotizing vasculitis or optic nerve necrosis (hematoxylin-eosin, original magnification×200).
Later, an assay for antiphospholipid antibodies showed elevated IgM (12.6 IgM phospholipid units, normal value, <11 units). An assay for IgG was normal. In addition, a 4-mm punch biopsy specimen of non–sun-exposed (buttock) skin was obtained, which showed direct immunofluorescent microscopy findings suggestive of autoimmune connective tissue disease, specifically IgM and C3 granular staining of the dermal-epidermal junction and focal granular deposits in small vessel walls. Her visual acuity remained at light perception in the right eye and 18 months later she developed progressive visual loss over a 6-day period in her left eye. Visual acuity worsened to 20/40 OS and Goldmann perimetry revealed inferonasal depression and a cecocentral scotoma.
She was pretreated with lithium carbonate to prevent mania and then given the methylprednisolone and prednisone regimen described above. Her visual acuity improved to 20/20 OS over 2 months. Results of Goldmann visual examination returned to normal during this same time. She is currently being treated with a very slow prednisone taper while taking lithium.
Autoimmune retrobulbar optic neuropathy, now more commonly called autoimmune optic neuropathy, was first described by Dutton et al.1 They described a disorder characterized by progressive visual loss and serologic evidence of an autoimmune disorder. Long-term corticosteroid or immunosuppressive therapy seemed to promote visual recovery and prevent further attacks. Affected patients had laboratory evidence of an autoimmune phenomenon but lacked the clinical manifestations of a systemic collagen vascular disease. Several groups have attempted to identify reliable laboratory markers (antinuclear antibodies, anticardiolipin antibodies, skin biopsies with immunofluorescent staining) to allow earlier diagnosis and treatment.2,3 Use of these markers is complicated by negative results when prior pulses of corticosteroids have been given.
Abnormal skin biopsy findings were the most consistent markers of autoimmune optic neuropathy according to Bielory et al.3 Hematoxylin-eosin staining typically showed a perivascular infiltration by lymphocytes and neutrophils, which was found in the biopsy specimens from both of our patients. Direct immunofluorescence microscopy showed IgM, IgG, IgA, or complement in immune complex deposition around dermal blood vessels and at the dermal-epidermal junction. Both patients displayed a similar IgM and C3 staining pattern. For non–sun-exposed skin, the rate of immune complex deposition around blood vessels is between 0% and 1.7%.4
Autoimmune optic neuropathy should be considered whenever a patient with optic neuritis has an atypical recurring course. This usually is seen as recurrent bouts of visual loss as treatment is tapered or stopped. Our first patient was initially seen at age 17 years, and is to our knowledge the youngest reported patient in the literature with this condition. Our second case is important for 2 reasons. First, it shows the importance of long-term, slow tapering of immunotherapy. Second, this case provides the first histopathologic study of optic nerve tissue affected by autoimmune optic neuropathy. It implies autoimmune optic neuropathy is a disorder characterized by chronic perivascular nongranulomatous inflammation. These cases remind us that autoimmune optic neuropathy can be difficult to diagnose unless it is suspected and it is appropriately evaluated.
This study was supported in part by grants from Research to Prevent Blindness Inc, New York, NY, and a Department of Veterans Affairs Merit Review.
Corresponding author: Michael Wall, MD, University of Iowa, College of Medicine, Department of Neurology, 200 Hawkins Dr, 2007 RCP, Iowa City, IA 52242-1053.
Riedel P, Wall M, Grey A, Cannon T, Folberg R, Thompson HS. Autoimmune Optic Neuropathy. Arch Ophthalmol. 1998;116(8):1121-1124. doi: