From the Penn State Hershey Eye Center, Milton S. Hershey Medical Center (WW, LA, WAC), and Penn State College of Medicine (EZ), Hershey, Pennsylvania.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to William A. Cantore, MD, Penn State Hershey Eye Center, Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033.
Systemic lupus erythematosus (SLE) is a chronic multisystem disease that can present with complications in nearly every organ system. Although central nervous system involvement is a common manifestation of both adult and pediatric patients who have SLE, with a reported incidence of 25% to 75%,1–3 optic nerve involvement remains a rare complication with an incidence of approximately 1%.4 It has been shown that central nervous system disease in SLE is significantly associated with the presence of antiphospholipid (aPL) regardless of whether the mechanism is thrombotic.3,5 There have also been numerous reports of neuromyelitis optica in patients with SLE, with neuromyelitis optica-IgG being a sensitive and specific marker.6,7 We report the occurrence of bilateral acute optic neuritis in a 16-year-old girl with SLE and seropositivity for aPL and neuromyelitis optica antibodies who progressed to bilateral visual acuity of no light perception and only recovered visual acuity of light perception in one eye and 20/400 in the other eye with aggressive therapeutic intervention.
A 16-year-old girl presented to the emergency department with nausea and vomiting, severe headache, and unilateral vision loss of acute onset. The patient denied any other neurological symptoms or a history of similar visual changes. Three days prior, she began to experience symptoms of a lupus flare, including fatigue, muscle cramps, and arthralgias. At the time of presentation, she was receiving a prednisone taper from a previous lupus flare. Current medications included mycophenolate mofetil and hydroxychloroquine. Her medical history was significant for migraines, juvenile idiopathic arthritis, and SLE of 2 years’ duration complicated by nephritis.
Her physical examination was unremarkable for systemic signs of SLE. Visual acuity at initial evaluation was no light perception in the right eye and 20/20 in the left eye. She was found to have enlarged pupils with a 4+ afferent pupillary defect in the right eye. Her left pupil was briskly reactive to light. Results of funduscopic examination were benign with normal-appearing optic nerves bilaterally. The patient’s ocular movements were full and non-painful. Results of the slit-lamp examination and tonometry were normal. The remainder of her neurologic examination at bedside was unremarkable.
Laboratory data revealed neutropenia with a white blood cell count of 2.5 K/uL (reference range: 4.8 to 12.0 K/uL) with an otherwise normal complete blood count. C-reactive protein and erythrocyte sedimentation rate were mildly elevated at 1.48 mg/dL (reference range: < 1.00 mg/dL) and 21 mm/hr (reference range: 0 to 20 mm/hr), respectively. Anti-native DNA was elevated to 1,514 IU/mL (reference range: < 100 IU/mL). Anticardiolipin IgG and lupus anticoagulant were both elevated at 21 GPL U/mL (reference range: < 10 GPL U/mL) and 14 seconds (reference range: 0 to 7 seconds), respectively. Both C3 and C4 were low at 44 mg/dL (reference range: 88 to 165 mg/dL) and 13 mg/dL (reference range: 14 to 44 mg/dL), respectively. Subsequently, she was found to be positive for neuromyelitis optica-IgG (Mayo Medical Laboratories, Rochester, MN).
Magnetic resonance imaging (MRI) of her brain showed multiple white matter lesions along with thickening and enhancement of the bilateral optic nerves and chiasm. Interestingly, her left optic nerve was enhancing significantly more than her right optic nerve on MRI, which was paradoxical to her clinical examination at that time (Fig. 1). Less than 1 day after admission, the patient developed an acute decrease in vision in her left eye and quickly progressed to no light perception with nonreactive pupils bilaterally. A diagnosis of acute bilateral retro-bulbar optic neuritis was made and the patient was treated with high-dose intravenous methylprednisolone at 1 g daily for 4 days followed by an oral prednisone taper. She also received two 50-g doses of intravenous immunoglobulin during her admission. Cyclophosphamide pulse therapy of 750 mg every 2 weeks was initiated on discharge. She was switched to rituximab 5 weeks later with the assistance of the rheumatology division of the pediatrics department, given her lack of significant clinical improvement.
Figure 1. T1-Weighted Coronal Magnetic Resonance Imaging Showing Thickening and Enhancement of the Optic Nerves, Which Is Greater on the Left than on the Right.
Optic neuritis is a rare complication of SLE reported in approximately 1% of patients4,8 and studies on its course and treatment are therefore limited. Furthermore, of the previously reported cases of optic neuritis in SLE, only three patients were of the pediatric population.1,9,10
The pathogenesis of optic neuritis in SLE involves vaso-occlusion of small vessels that leads to subsequent demyelination.11 Both unilateral and bilateral cases of optic neuropathy in SLE have been reported,5 with bilateral being more common. It has been suggested that unilateral disease is due to a focal thrombotic event of the ciliary vasculature that should be treated with anticoagulation, whereas bilateral disease is due to a generalized systemic vasculitic process in which treatment should include immunosuppression.5
In the past, the standard of care for these patients was high-dose steroids (1 mg/kg/d), boluses of methylprednisolone (1 mg/kg/3 days), or both with up to one-third of cases being refractory to treatment. For the patients with SLE and optic neuritis refractory to standard treatment, intravenous cyclophosphamide was shown to be an effective treatment.12 Subsequently, intravenous monthly cyclophosphamide was shown to be more effective than intravenous bimonthly methylprednisolone in patients with severe neurological manifestations of SLE, including optic neuritis, in a controlled clinical trial.13 This study suggested that to achieve an optimal long-term response with no flares, cyclophosphamide therapy should be continued for 2 years.
Central nervous system disease in SLE appears to be significantly associated with the presence of aPL antibodies such as anticardiolipin antibodies and the lupus anticoagulant.5 This association holds true regardless of whether the mechanism involves thrombosis.3 Positive aPL serology along with at least one clinical sign of the aPL syndrome may be predictive of future neurological complications in patients with SLE.3 Although our patient was seropositive for aPL, she did not manifest any of the signs of antiphospholipid syndrome such as arterial or venous thrombosis, thrombocytopenia, cardiac valve involvement, or Coombs-positive hemolytic anemia. However, because of her young age, aPL syndrome cannot be ruled out as a complicating factor of her SLE.
Neuromyelitis optica, also known as Devic disease, is a relapsing demyelinating disease involving the spinal cord and optic nerves and has been reported in numerous cases of SLE with and without aPL syndrome.6,7,14–16 A specific diagnostic marker (neuromyelitis optica-IgG) was recently identified, although its prognostic implications are unclear.6 Criteria for the diagnosis of neuromyelitis optica must include optic neuritis, myelitis, and at least two of the following supportive criteria: MRI evidence of a spinal cord lesion in three or more segments, seropositivity for neuromyelitis optica-IgG, and an MRI of the brain that does not meet imaging criteria for multiple sclerosis.17 Neuromyelitis optica has also been described as a spectrum disorder in which patients are seropositive for neuromyelitis optica-IgG and present with either isolated or recurrent optic neuritis or myelitis.18 Our patient falls along this spectrum of neuromyelitis optica disorders.
Cases have been reported of neuromyelitis optica-IgG positive patients with isolated myelitis,6,16 but we report the first case of a patient with seropositivity for neuromyelitis optica-IgG and aPL antibodies with isolated optic neuritis. The therapeutic and prognostic significance of the detection of the neuromyelitis optica-IgG is not yet understood, but the indication for more aggressive immunosuppression has been suggested.6,16 Recent literature has suggested that rituximab may be a viable option in patients with neuromyelitis optica that is severe or refractory to other immunosuppressive therapy.19,20
Our patient’s final therapeutic regimen consisted of rituximab, oral prednisone, and hydroxychloroquine. After 12 weeks of immunosuppressive therapy, her visual acuity was light perception in the right eye and 20/400 in the left eye, with a minimally reactive pupil in the right eye, a briskly reactive left pupil, and a 3+ right afferent pupillary defect. Dilated fundus examination revealed moderate bilateral optic nerve pallor, which was not appreciated on her initial evaluation (Fig. 2). At her 6-month follow-up appointment, her visual acuity improved to 2/200 in the right eye and was stable at 20/400 in the left eye. Dilated fundus examination showed no change in the appearance of the optic nerves. Based on her slow recovery of usable vision, the patient was referred to the low vision service of the ophthalmology department for additional evaluation and therapy.
Figure 2. Color Optic Nerve Photographs Taken After 12 Weeks of Immunosuppressive Therapy. Visual Acuity at This Visit Was (A) No Light Perception in the Right Eye and (B) 20/400 in the Left Eye.
- Ahmadieh H, Roodpeyma S, Azarmina M, et al. Bilateral simultaneous optic neuritis in childhood systemic lupus erythematosus. J Neuroophthalmol. 1994;14:84–86.
- Steinlin MI, Blaser SI, Gilday DL, et al. Neurologic manifestations of pediatric systemic lupus erythematosus. Pediatr Neurol. 1995;13:191–197. doi:10.1016/0887-8994(95)00110-2 [CrossRef]
- Golstein M, Meyer O, Bourgeois P, et al. Neurological manifestations of systemic lupus erythematosus: role of antiphospholipid antibodies. Clin Exp Rheumatol. 1993;11:373–379.
- Sivaraj RR, Durrani OM, Denniston AK, et al. Ocular manifestations of systemic lupus erythematosus. Rheumatology. 2007;46:1757–1762. doi:10.1093/rheumatology/kem173 [CrossRef]
- Giorgi D, Gabrieli B. Optic neuropathy in systemic lupus erythematosus and antiphospholipid syndrome (APS): clinical features, pathogenesis, review of the literature and proposed ophthalmological criteria for APS diagnosis. Clin Rheumatol. 1999;18:124–131. doi:10.1007/s100670050069 [CrossRef]
- Mehta LR, Samuelsson MK, Kleiner AK, et al. Neuromyelitis optica spectrum disorder in a patient with systemic lupus erythematosus and anti-phospholipid antibody syndrome. Mult Scler. 2008;14:425–427. doi:10.1177/1352458507084107 [CrossRef]
- April RS, Vansonnenberg E. A case of neuromyelitis optica (Devic’s syndrome) in systemic lupus erythematosus: clinicopathologic report and review of the literature. Neurology. 1976;26:1066–1070.
- Drosos AA, Petris CA, Petroutsos GM, et al. Unusual eye manifestations in systemic lupus erythematosus patients. Clin Rheumatol. 1989;8:49–53. doi:10.1007/BF02031068 [CrossRef]
- Vitale C, Kahn MF, deSeze M, et al. Nevrite optique, myelite et maladie lupique: à propos de deux observations. Ann Med Interne. 1973;124:211–216.
- Hackett ER, Martinez RD, Larson PF, et al. Optic neuritis in systemic lupus erythematosus. Arch Neurol. 1974;31:9–11.
- Jabs DA, Miller NR, Newman SA, et al. Optic neuropathy in systemic lupus erythematosus. Arch Ophthalmol. 1986;104:564–568.
- Galindo-Rodríguez G, Aviña-Zubieta JA, Pizarro S, et al. Cyclophosphamide pulse therapy in optic neuritis due to systemic lupus erythematosus: an open trial. Am J Med. 1999;106:65–69. doi:10.1016/S0002-9343(98)00372-6 [CrossRef]
- Barile-Fabris L, Ariza-Andraca R, Olguín-Ortega L, et al. Controlled clinical trial of IV cyclophosphamide versus IV methylprednisolone in severe neurological manifestations in systemic lupus erythematosus. Ann Rheum Dis. 2005;64:620–625. doi:10.1136/ard.2004.025528 [CrossRef]
- Kinney EL, Berdoff RL, Rao NS, et al. Devic’s syndrome and systemic lupus erythematosus: a case report with necropsy. Arch Neurol. 1979;36:643–644.
- Gibbs AN, Moroney J, Foley-Nolan D, et al. Neuromyelitis optica (Devic’s syndrome) in systemic lupus erythematosus: a case report. Rheumatology. 2002;41:470–471. doi:10.1093/rheumatology/41.4.470 [CrossRef]
- Birnbaum J, Kerr D. Devic’s syndrome in a woman with systemic lupus erythematosus: diagnostic and therapeutic implications of testing for the neuromyelitis optica IgG autoantibody. Arthritis Rheum. 2007;57:347–351. doi:10.1002/art.22540 [CrossRef]
- Wingerchuk DM, Lennon VA, Pittock SJ, et al. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66:1485–1489. doi:10.1212/01.wnl.0000216139.44259.74 [CrossRef]
- Weinshenker BG. Neuromyelitis optica is distinct from multiple sclerosis. Arch Neurol. 2007;64:899–901. doi:10.1001/archneur.64.6.899 [CrossRef]
- Wingerchuk DM, Weinshenker BG. Neuromyelitis optica. Curr Treat Options Neurol. 2008;10:55–66. doi:10.1007/s11940-008-0007-z [CrossRef]
- Cree BA, Lamb S, Morgan K, et al. An open label study of the effects of rituximab in neuromyelitis optica. Neurology. 2005;64:1270–1272.