Siatkowski, R. Michael MD; Scott, Ingrid U. MD; Verm, Alan M. MD; Warn, Ann A. MD; Farris, Bradley K. MD; Strominger, Mitchell B. MD; Sklar, Evelyn M.L. MD
Ophthalmologic and central nervous system (CNS) manifestations occur in 20 to 40% of patients with SLE (1–3). Involvement of the optic nerve or chiasm occurs in only 1% of patients with systemic lupus erythematosus (SLE), typically after the diagnosis has been established and multiple other manifestations are present (1,2,4). Optic neuropathy or chiasmopathy is rarely a presenting sign of SLE or the event that leads to this diagnosis (4,5). Two reports of magnetic resonance imaging (MRI) in SLE-related optic neuropathy do not identify any anterior visual pathway abnormalities (6,7), although another found enhancing optic nerve lesions in three of six patients with known SLE (8). We report six patients with rapid visual loss owing to anterior visual pathway disease who were ultimately diagnosed with SLE.
After appropriate Institutional Review Board approval, patient charts were retrospectively reviewed and historical and clinical data extracted. Six patients from either the Dean A. McGee Eye Institute or the Bascom Palmer Eye Institute were identified.
Pertinent details are summarized in Table 1. Following are more detailed case reports to demonstrate the events that led to the diagnosis of SLE in these patients.
A 55-year-old man developed progressive loss of vision OS over 9 days. It was accompanied by periocular pain exacerbated by eye movements. Two years earlier, he had experienced an acute loss of vision OD to the no light perception (NLP) level. Workup at that time consisted of a normal complete blood count (CBC) and MRI of the brain, which revealed numerous periventricular white matter lesions. He was diagnosed with multiple sclerosis (MS), and observation was recommended. Visual (VA) acuity OD remained NLP.
On examination, VA was NLP OD and counting fingers (CF) OS, with only a small nasal field remaining. The right optic disk was diffusely pale. The left disk was normal. MRI of the brain and orbits revealed enlargement and gadolinium enhancement of the left intracranial optic nerve, chiasm, and tract (Fig. 1). CBC was notable for lymphopenia [536 cells/mm3 (normal, >1,500/mm3)]. Antinuclear antibody (ANA) titer was positive at a dilution of 1:80, and anti–double-stranded DNA (dsDNA) antibody titer was 19.3 U/mL (normal, <1.0 U/mL). Anticardiolipin antibody titer was normal, and the venereal disease research laboratory test was nonreactive. Further history revealed the onset of multiple arthralgias several months after the first episode of visual loss.
A diagnosis of SLE was made, and 250 mg intravenous methylprednisolone every 6 hours was administered for 5 days followed by an oral prednisone taper. VA OS returned to 20/25 over 8 weeks, at which time the patient was on 20 mg prednisone daily. Prednisone was tapered over the following 10 weeks. Twelve days after completing the taper, VA OS deteriorated to 20/200 but returned to 20/30 1 week after reinstitution of 80 mg prednisone daily. Prednisone was tapered over 6 weeks, but 3 weeks later VA OS again deteriorated to 20/70. Despite reinstitution of 80 mg prednisone daily, VA OS declined to CF. Repeat anti-dsDNA antibody titer was still elevated, but had fallen to 7.0 U/mL. After another course of intravenous methylprednisolone, VA OS improved to and stabilized at 20/100. VA OD remained NLP. The patient was discharged on oral prednisone but was noncompliant and temporarily lost to follow-up. He returned 1 year later, with examination unchanged.
A 51-year-old woman presented with a 3-day history of progressive visual loss OS, with periocular pain not exacerbated by eye movement. History was pertinent for a stroke at age 44 resulting in right hemiplegia. Workup at that time consisted of MRI revealing a left parietal infarct, and normal echocardiogram, CBC, carotid Doppler study, and sedimentation rate.
VA was 20/20 OD and CF OS, with only a temporal island of vision remaining. The right optic disk appeared normal, and the left was swollen inferiorly. Gadolinium-enhanced MRI of the brain revealed the old parietal infarct and numerous scattered subcortical white matter lesions. No abnormalities of the pregeniculate optic pathways were identified. CBC was notable for leukopenia [3,400/mm3 (normal, >4,000/mm3)] and lymphopenia (748/mm3). ANA titer was positive at a dilution of 1:1,280, and anti-dsDNA antibody titer was 34.1 U/mL. Anticardiolipin antibody titer was normal. Review of systems was notable for arthralgias in both knees and wrists.
A diagnosis of SLE was established. Intravenous methylprednisolone 250 mg every 6 hours was administered for 5 days followed by an oral prednisone taper over 6 weeks. Examination after the patient completed the prednisone taper demonstrated a VA of 20/20 OD and 20/25 OS.
Eight weeks later, VA deteriorated acutely to NLP OD and 20/200 OS. Both optic disks demonstrated mild pallor. Intravenous methylprednisolone was reinstituted, with improvement in VA to 20/70 OD; VA OS remained at 20/200. Three months later, on a dose of 10 mg prednisone daily, the patient developed deterioration of VA to CF OD and OS, along with a transverse myelitis at the fourth thoracic level. After 5 days of intravenous methylprednisolone, VA returned to 20/400 OD and 20/200 OS. Six months later, VA was unchanged and the patient remained on prednisone 10 mg daily.
A 32-year-old woman developed progressive visual loss OD over 7 days, associated with periocular pain made worse by eye movement. Medical history was remarkable for 3 months of arthralgias involving wrists, knees, and ankles at age 19. Ocular examination revealed VA of LP OD and 20/15 OS. The right disk was slightly swollen and the left disk appeared normal. VA OD improved to hand motions over 1 week after injection of 40 mg triamcinolone acetonide into the sub-Tenon's space. Over the next several weeks, VA OD improved to CF.
Two months later, the patient developed bilateral eye pain. VA remained CF OD but had decreased to LP OS. After receiving 250 mg intravenous methylprednisolone every 6 hours for 3 days, VA improved to 2/400 OD and 20/40 OS. During oral prednisone taper at a dose of 30 mg/d, VA OS deteriorated to 20/80. With reinstitution of another 3-day course of intravenous steroids, VA OS improved to 20/30 and remained 2/400 OD. Chronic steroid or immunosuppressive treatment was recommended, but the patient refused because of a desire to become pregnant.
Four months later, VA deteriorated to CF OU. Both optic disks were pale. MRI revealed enlargement and gadolinium enhancement of both optic nerves and chiasm (Fig. 2). ANA titer was positive at a dilution of 1:640 and anti-dsDNA antibody titer was 2.1 U/mL. Anticardiolipin antibodies were 24 MPL/mL (normal, <10 MPL/mL) and rapid plasma reagin (RPR) was positive at 1:16 dilution.
Diagnosis of SLE was made. The patient was treated again with intravenous methylprednisolone, followed by monthly cyclophosphamide. VA at last follow-up 7 months later was 5/200 OD and 20/200 OS. The patient later discontinued the cyclophosphamide and became pregnant. She developed facial changes that were originally interpreted by her obstetrician as chloasma but that were thought by the rheumatologist to be typical of a malar rash.
A 42-year-old woman developed sudden visual loss OD 2 days before presentation. It was accompanied by a diffuse periocular pain not worsened by ocular movement. VA was 2/200 OD and 20/25 OS, and both optic disks appeared normal. MRI with gadolinium revealed enhancement of both optic nerves with multiple foci of increased signal in the cerebral white matter. The patient was presumed to have idiopathic optic neuritis and observation was recommended. Six days after presentation, VA declined to 1/200 OD and 20/40 OS. CBC was notable for leukopenia (2,300/mm3) and lymphopenia (805/mm3). ANA titer was positive to 1:620 and anti-dsDNA antibody titer was 5.7 U/mL.
Diagnosis of SLE was made, and the patient was treated with 250 mg intravenous methylprednisolone every 6 hours for 5 days followed by oral prednisone with a slow taper over 3 months, followed by therapy with azathioprine. VA improved to 20/25 OU. The patient also developed recurrent bouts of psychosis and depression.
One month after the steroids were tapered, the patient developed recurrent vision loss to 8/200 OD and 20/30 OS. She was again treated with 3 days of intravenous methylprednisolone followed by oral prednisone taper. A regimen of monthly intravenous cyclophosphamide was instituted. VA improved to 20/40 OD and 20/25 OS. Four months later, VA OD decreased to 20/100, and the patient received another 3-day course of intravenous methylprednisolone. On monthly cyclophosphamide and 20 mg prednisone daily, vision stabilized at 20/40 OD and 20/25 OS and remained so 1 year later.
A 38-year-old woman experienced painless progressive loss of vision OD over 2 days to the NLP level. She was diagnosed with idiopathic optic neuritis and observation was recommended. Six weeks later, she noted visual loss OS. On examination at the neurologist's office, VA was NLP OD and 20/80 OS. Computed tomography of the brain and orbits was normal. She was treated with 250 mg intravenous methylprednisolone every 6 hours for 5 days with no improvement in vision. MRI revealed gadolinium enhancement of both optics nerves and the chiasm (Fig. 3). ANA titer was positive at 1:160, and anti-dsDNA titer was elevated at 9.0 U/mL. Urinalysis showed 2+ proteinuria. Lumbar puncture showed a normal opening pressure with no cells, and normal protein and glucose. Further review of systems yielded the presence of upper extremity arthralgias for several months, establishing the diagnosis of SLE. During oral prednisone taper, VA OS deteriorated to CF OS. At last examination, on chronic low dose daily prednisone, VA OS was 5/225; VA OD remained NLP.
A 66-year-old woman had painless, progressive visual loss bilaterally for 1 week. There was also a 2-year history of fatigue and arthralgias, and an episode of transient paresthesias of the left leg 1 year earlier. In addition, she complained of two episodes of slowly healing “cold sores” in her mouth during the past year. Family history was positive for SLE in her mother, who was said to have died of complications of the disease.
Examination revealed VA of 20/200 OU with bitemporal field loss. MRI of the brain showed multiple white matter lesions and enhancement of the optic chiasm (Fig. 4). ANA titer was positive to a dilution of 1:360 and anti-dsDNA antibody titer was 12.1 U/mL. A diagnosis of SLE was made. She was treated with 5 days of intravenous methylprednisolone followed by oral prednisone taper over several weeks. VA improved to 20/40 OD and 20/30 OS and remained stable 3 months later. The bitemporal defect partially cleared. One year later, the patient developed transverse myelitis, which improved with intravenous corticosteroid treatment. She was placed on monthly cyclophosphamide at that time.
We report the clinical course and MRI findings of six patients with visual loss secondary to optic neuropathy or chiasmopathy, the sign that eventually led to the diagnosis of SLE. In two of these patients, visual loss was the first sign of the disease, whereas in the other four, past events had occurred that were consistent with SLE but which were not prominent enough to prompt the diagnosis. The clinical features of these patients are summarized in Table 1.
Although optic neuropathy occurs in only 1% of patients with SLE during the course of their disease, it has been documented as a presenting sign in patients who later meet diagnostic criteria for SLE (1,2,4,5). Involvement of the optic nerve in SLE can occur as acute retrobulbar neuritis, papillitis, anterior ischemic optic neuropathy, posterior ischemic optic neuropathy, or slowly progressive visual loss (9). Although none of the patients in our series had previously been diagnosed with SLE, several had notable histories. Patient 3 had 3 months of diffuse joint tenderness 13 years before her optic neuropathy, and patient 2 had a stroke 7 years earlier. Patient 6 had a history of paresthesias and fatigue, as well as a positive family history of SLE. Patient 1 had a previous episode of visual loss in the fellow eye, and patient 5 developed proteinuria. In addition, patients 2 and 6 developed transverse myelitis, and patient 4 experienced psychosis and depression after the diagnosis of SLE was established.
According to the American Rheumatism Association, diagnosis of SLE is established if any four or more of 11 criteria are present serially or simultaneously, during any interval of observation (Table 2) (14). All the patients in our series meet these criteria.
Before optic atrophy has developed, anterior visual pathway disease in SLE may respond dramatically to treatment with corticosteroids. Treatment with intravenous methylprednisolone in five of our six patients resulted in initial improvement of vision. However, recrudescence during steroid taper was common (five of six cases), requiring retreatment with intravenous methylprednisolone and either chronic oral steroids or immunosuppressive agents.
MRI characteristics were consistent with those reported by Sklar et al. (8) In their series, six of nine patients with vasculitis-related optic neuropathy and three of six with known SLE demonstrated enlargement and enhancement of segments of the optic nerves and/or chiasm with gadolinium. All but one patient in our series had enhancing lesions of the anterior visual pathways. In the one patient without radiologic evidence of optic pathway abnormalities (case 2), numerous deep and subcortical white matter lesions were present, consistent with previously reported findings in SLE patients with nonfocal symptoms (10).
CNS involvement in SLE may be caused by either small-vessel vaso-occlusive disease and/or hypercoagulability secondary to lupus anticoagulant (3,10). True vasculitis is rare, although histopathologic studies of optic neuropathy in SLE demonstrated focal fibrinoid necrosis of arterioles with perivascular lymphocytic and plasma cell infiltration. Areas of demyelination and gliosis can also be seen, either as primary lesions or a secondary response to focal necrosis (11–13). The MRI appearance of cerebral vaso-occlusive disease is characterized by subcortical white matter changes (10), as seen in several of our patients.
The clinical overlap between neurologic manifestations of SLE and MS is well-known, and many authors believe that there may be a common pathogenesis for both (13,14,15,16). It has been suggested that MS is frequently misdiagnosed as SLE-related CNS vasculopathy and vice versa (17). Further confusing the issue is that fact that as many as 81% of MS patients have a positive ANA titer (18), although usually not to the level found in our patients. This clinical conundrum again surfaces in our patients, who experienced sudden or subacute visual loss with pain, a feature well-known to be common in patients with MS-related optic neuritis and not typically seen in optic neuropathy of vasculopathic origin.
However, there are some factors that may be helpful in distinguishing these two entities. First, although the exact incidence of positive anti-dsDNA titers in MS in unknown, it is surely much less common than in SLE. Even in those MS patients who may have measurable anti-DNA serum antibodies, extremely high levels would not be expected; such a finding would lend much more credence to a diagnosis of SLE. Also, the temporal profile of visual recovery may help to distinguish between these two diseases. In cases of “typical” optic neuritis, the Optic Neuritis Treatment Trial showed a visual recovery to 20/40 or better in 95% of cases, with or without treatment. Such a course was not typical of our patients, and, in fact, many of them required chronic immunomodulation to maintain vision. Even so, VA of 20/40 or better at last follow-up was achieved in only one of three of our patients, and there was a tendency for a slow “step-wise” visual loss. Finally, 50% of our patients were older than 50 years, another factor that is atypical for optic neuritis owing to MS or other demyelinating disease.
Another entity that may present similarly to SLE-associated optic neuropathy is the so-called “autoimmune optic neuropathy” originally described by Dutton et al. (17). They described several patients with visual loss associated with arthralgias, positive rheumatoid factor, or suspicion for other collagen-vascular disease. Similar to our cases, the visual loss in these patients responded dramatically to systemic steroid treatment. However, all their patients were under 50 years of age, their ANA titer was low, and none had detectable anti-DNA antibodies. Autoimmune optic neuropathy may thus be somewhat of a “middle ground” between optic neuritis and SLE-associated optic neuropathy.
Alternatively, the patients described by Dutton et al. may have progressed in the future to develop true SLE or other rheumatologic/collagen-vascular diseases. Patients who may have 10% dysfunction of a joint or a kidney may be asymptomatic and not seek medical attention. However, patients with 10% optic nerve dysfunction typically are acutely aware of visual loss, prompting early presentation to a physician and further investigation. Thus, it is not surprising that patients with optic neuropathy that is ultimately determined to be secondary to SLE (or other vasculitides) may present with visual loss early in their overall disease course, before the formal diagnostic criteria are satisfied.
We believe that all patients with optic neuropathy or chiasmopathy associated with systemic findings not characteristic of demyelinating disease (e.g., arthralgias, leukopenia, skin rash) should be evaluated with gadolinium-enhanced MRI and serologic testing for collagen vascular diseases. In addition, patients with similar presentation but who are atypical for MS (e.g., age >40, poor visual recovery, multiple relapses) should undergo similar testing. Elevated ANA and anti-dsDNA antibody titers strongly suggest a diagnosis of SLE. In such patients, MRI will frequently demonstrate enhancing optic nerve and/or chiasmal lesions. Treatment with high-dose intravenous methylprednisolone should be instituted with close vigilance for relapses during oral steroid taper. Such occurrences may necessitate the use of either chronic steroids or cytotoxic immunosuppressive medications to stabilize or improve vision or to prevent other complications of the vasculitis process. Finally, perhaps consideration should be given to the recognition of optic neuropathy or chiasmopathy, in addition to seizures and psychosis, as a CNS manifestation in the diagnostic criteria for SLE.
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