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Show J. Clin. Neuro-ophthalmol. 4: 75-78, 1984. Optic Neuropathy Associated with Penicillamine Therapy in a Patient with Rheumatoid Arthritis TERENCE G. KLINGELE, M.D. RONALD M. BURDE, M.D. Abstract Optic neuropathy developed in a patient with rheumatoid arthritis who had been receiving Dpenicillamine for about 1 year. An associated finding included a 2+ positive antinuclear antibody test with a titer of 1:320. Optic disc swelling was resolved on high doses of intravenous steroids. The case resembles two previously reported cases of optic neuropathy which occurred in patients with Wilson's disease who were receiving penicillamine. Introduction A relationship between acute optic neuropathy and penicillamine treatment has been reported twice before.J.2 Both cases were patients with Wilson's disease undergoing treatment with DLpenicillamine who developed bilateral optic neuropathy. The authors proposed a metabolic antagonism of pyridoxine by penicillamine or a toxic role of L-penicillamine as possible causes of the optic neuropathy. A patient was recently seen who was receiving D-penicillamine for rheumatoid arthritis and developed visual loss and disc swelling. Clinical and laboratory findings suggested that the patient's visual loss was secondary to an autoimmune process. Case Report A 63-year-old white male was seen in consultation because of blurred vision. Five years before, a rheumatologist had made the diagnosis of rheumatoid arthritis based on joint changes and a rheumatoid factor positive at a dilution of 1:1200. An antinuclear antibody test (ANA) was negative at the time. He had been relatively From the Departments of Ophthalmology (TGK. RMB), Neurology, and Neurological Surgery (RMB), Washington University School of Medicine, St. Louis, Missouri. June 1984 asymptomatic for the past year. He had been taking prednisone 5 mg a day, sulindac 200 mg twice a day, and penicillamine (DEPEN) 250 mg three times a day until 3 months before admission when the prednisone was discontinued and the penicillamine was reduced to 250 mg p.o. twice a day. He then had begun to experience aching pain in his thumbs, hands, and knees, worsening in the morning. These symptoms were similar to, but of greater severity than symptoms he had experienced before the change in medications. About 2 months before this admission, the patient noted blurred vision in his only eye, his right eye. His left eye had been enucleated following childhood trauma and he wore a prosthesis. He had kidney surgery 20 years ago for nephrolithiasis and recently had a recurrent stone which passed spontaneously. He had submucosal nasal septal surgery and a left knee cartilage operation approximately 5 years before this episode. He had recurrent ear infections and had inner ear surgery on both ears in the distant past. About 1 month before admission he had dental work and was treated with oxacillin, prophylactically without adverse effect. There had been no symptoms of fever, rash, pleurisy, or nasal ulcers. He was a postal worker who smoked four to six pipes full of tobacco a day and consumed moderate amounts of alcohol. Examination of the eyes revealed an anophthalmic left eye with a prosthesis covering wellheaded ball implant. The right eye revealed bestcorrected acuity of 20/30 + 2/6. Color vision was 8 out of 14 pseudoisochromatic plates correctly identified. External examination showed no abnormality. Pressure was 14 mm hg in the right eye. Slit lamp examination was unremarkable. Visual field examination showed an arcuate defect extending superiorly with a nasal step. Fundoscopic examination revealed blurred elevated disc margins with dilated small vessels (Fig. 1). General physical examination revealed blood pressure of 120/70, pulse 80, respiration 20. The ENT examination was unremarkable. The tem- 75 Penicillamine Optic Neuropathy Figure 1. Initial, late phase, fluorescein angiogram of left optic disc showing marked leakage of fluorescein dye from disc capillaries. poral arteries were nontender. The cardio pulmonary examination was normal. Examination of the abdomen was unremarkable. Examination of the extremities revealed mild synovitis in the hands especially in the metacarpal phalangeal and proximal interphalangeal joints. There was no significant deformity. There was a scar on the right knee. There were a few patches of psoriasis over the sacrum. Initially, penicillamine and sulindac were discontinued. Pyridoxine '00 mg a day and decadron 10 mg a day were initiated. After several days of this treatment there was no improvement and the patient was admitted for l:ovaluation. Studies demonstrated that CBC, SMA-6, SMA12, chest film, EKG, and urinalysis were within normal limits. Sedimentation rate was 12 mmj hour. ANA was 2+ homogenous, nucleolar, with dilutions positive to 1:320. Anti-DNA was 1.2% binding (normal 0-3.1 %). C3, C, and total hemolytic complement were within normal limits. Raji-cells were 81 p.g eqjml (normal 0-50 p.g eqj ml). VORL was negative. Treatment was then initiated with 1,000 mg of methylprednisolone LV. given every 12 hours. This was given over a period of 5 days. At the end of this period visual parameters were un-changed. However, the disc edema was remarkably reduced (Fig. 2). The patient was then discharged on prednisone 100 mg p.o. once a day to be followed as an outpatient. His steroids were tapered over a period of 6 months with vision stabilized at 20 j30 with an arcuate defect. Disc swelling disappeared and definite optic pallor ensued. Comments In the two previous reportsU of optic neuropathy associated with penicillamine therapy in Wilson's disease patients, both of which experienced visual disturbance and fundus changes similar to our case, no immunologic studies were reported. Various mechanisms for the optic neuropathy have been suggested. The patient of Tu et aLl improved when the penicillamine was reduced from 2 to 1 gjday and pyridoxine 100 mg a day was given. They attributed the optic neuropathy to penicillamine induced pyridoxine deficiency. However, in the case of Goldstein et al.,z optic neuropathy developed in spite of prophylactic pyridoxine administration on penicillamine 500 mg three times a day. Improvement occurred after reduction of penicillamine to 250 mg three Journal of Clinical Neuro-ophthalmology Klingele, Burde Figure 2. Late phase fluorescein angiogram of left optic disc following 5 days of treatment with methylprednisolone, LOOO mg, I.V./day. Angiogram shows minimal leakage from disc capillaries. times a day. They attributed the optic neuropathy to a toxic effect of L-penicillamine. Others have suggested that the optic neuropathy in these patients may represent a manifestation of Wilson's disease and be unrelated to penicillamine.3 Most. if not all, of the adverse reactions to penicillamine appear to be mediated by immunological mechanisms. By far the largest therapeutic application of penicillamine is in rheumatoid arthritis, a disease generally accepted to be associated with an altered immunologic state. The question has been raised4 as to whether the adverse effects of penicillamine in rheumatoid arthritis, particularly the induction of autoimmune syndromes, are a direct consequence of the drug itself or a result of the abnormal immunologic substrate characteristic of the rheumatoid arthritis patient. Nature has provided a unique opportunity to answer this question in the form of another disorder, Wilson's disease, that is also treated chronically with penicillamine in doses comparable to those employed in rheumatoid arthritis. Wilson's disease is a genetically transmitted disorder of copper metabolism completely unrelated to rheumatoid arthritis and without an immunologic basis in pathogenesis. In general, all of the adverse effects accepted to be due to pen- June 1984 icillamine in rheumatoid arthritis patients including hematologic disturbances, cutaneous reactions, and the induction of autoimmune syndromes, have been reported during penicillamine treatment of Wilson's disease patients as well. 5 Although, penicillamine is known to cause various immunologic disturbances and to be associated with the appearance of positive antinuclear antibody," the clinical significance of the phenomenon has been debated.7.~However, since autoimmune optic neuropathy, which clinically resembles the disorder seen in this patient, is known to be associated with the presence of antinuclear antibody in high titers, this has been the working diagnosis in this case.Q Although autoimmune optic neuropathy could have occurred in this patient unrelated to penicillamine therapy, this seems unlikely since rheumatoid arthritis is not known to be associated with optic neuropathy. However, optic neuropathy does occur in systemic lupus erythematosis,IO but the possibility that this patient had systemic lupus erythematosis instead of rheumatoid arthritis as an initial diagnosis is unlikely in the face of a rheumatoid factor of 1:2000 and a negative ANA.II.I~ Temporal arteritis (giant cell arteritis) may cause ischemic optic neuropathy with disc edema, but is almost 77 Penicillamine Optic Neuropathy always associated with an elevated sedimentation rate. This patient's sedimentation rate was 12 mm/hour. Furthermore, temporal arteritis is not associated with a markedly positive ANA. We believe that this patient had autoimmune optic neuropathy which resulted from penicillamine therapy. References 1. Tu, J., Blackwell, R.Q., and Lee, P.F.: DL-penicillamine as a cause of optic axial neuritis. I.AM.A 2: 119-122,1963. 2. Goldstein, N.P., Hollenhorst, RW., Randall, RV., and Gross, J.B.: Possible relationship of optic neuritis, Wilson's disease and DL-penicillamine. J.AM.A 8: 146-147,1966. 3. Miller, N.R: Anterior toxic optic neuropathies. In Walsh and Hoyt's Clinical Neuro-Ophthalmology, Vol. 4, 1981, p. 258. 4. Jaffe, I.A: Influence of underlying disease on Dpenicillamine induced side effects. In Immunogenetics in Rheumatology, RL. Dawkins, F.T. Christiansen, and P.J. Zilko, Eds. Excerpta Medica, Amsterdam, Oxford, Princeton, 1982, p. 301. 5. Jaffe, I.A: Springer semin. Immunopathol. 4: 193, 1981. 6. Carrono, J,A, Zilko, P.J., and Dawkins, RL.: Autoantibodies induced by D-penicillamine. In Immu-nogenetics in Rheumatology, RL. Dawkins, ~.T. Christiansen, and P.J. Zilko, Eds. Excerpta Medica, Amsterdam, Oxford, Princeton, 1982, pp. 362367. 7. Chalmers, A, Thompson, D., Patterson, AC., Stein, H.B., and Reid, G.D.: Penicillamine (dP induced systemic lupus erythematosis (S.L.E.). Arthritis Rheum. 4: S79, 1982. 8. Weinstein, A, Rothfield, N., and The Cooperating Clinics for the Study of Rheumatic Disease: Lack of antinuclear antibody induction by D-penicillamine in rheumatoid arthritis. Arthritis Rheum. 4: S49,1982. 9. Dutton, J.J., Burde, RM., and Klingele, T.G.: Autoimmune retrobulbar optic neuritis. Am. J. Ophthalmol. 94: 11-17, 1982. 10. Smith, C.A, and Pinals, RS.: Optic neuritis in systemic lupus erythematosus. J. Rheumatol. 9: 6, 1982. 11. Baer, AN., and Pincus, T.: Occult systemic lupus erythematosus in elderly men. I.AM.A 24: 33503352, 1982. 12. Jaffe, I.A: Influence of underlying disease on Dpenicillamine induced side effects. In Immunogenetics in Rheumatology, RL. Dawkins, F.T. Christiansen, and P.J. Zilko, Eds. Excerpta Medica, Amsterdam, Oxford, Princeton, 1982, p. 303. Write for reprints to: Terence G. Klingele, M.D., 16420 East Pavilion, Barnes Hospital, St. Louis, Missouri 63110. Journal of Clinical Neuro-ophthalmology |
