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Optic Neuropathy in Uremia
Optic Neuropathy in Uremia Latif M. Hamed, M.D., Kirk E. Winward, M.D., Joel S. Glaser, M.D., and Norman J. Schatz, M.D.
We examined three patients who developed optic neuropathies while undergoing chronic hemodialysis. One patient developed severe bilateral deterioration of vision, but recovered totally four weeks after discontinuing deferoxamine chelation therapy. Another patient had bilateral visual loss associated with chronic papilledema of idiopathic increased intracranial pressure. A third showed atypically severe consecutive anterior ischemic optic neuropathy. The latter two patients showed little improvement with high-dose intravenous methylprednisolone therapy combined with more vigorous hemodialysis. These cases, in addition to those previously described, underscore the heterogeneity of optic nerve disease in patients with uremia. NERVOUS SYSTEM DYSFUNCTION occurs commonly in patients with uremia, both before and after institution of an adequate maintenance dialysis regimen. Recent reviews have addressed this topic in detail. 1-3 Ocular morbidity may result from the primary condition causing the renal failure (for example, diabetes, hypertension), the uremic state itself, toxicity of concurrent medications, complications of dialysis, or other intercurrent illnesses. Knox and coworkers! described six patients with uremia and optic neuropathy. Five of these patients showed a favorable visual response upon institution of hemodialysis or corticosteroid therapy, or both. The authors recommended that patients with renal failure and rapid visual loss should be considered for
Accepted for publication March 28, 1989. From the Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida. Dr. Hamed is a 1988-1989 Heed Foundation Fellow. This study was presented in part at the 1988 Neuro-ophthalmology Course, University of Miami School of Medicine, Department of Ophthalmology, Bascom Palmer Eye Institute, Dec. 10, 1988, Key Biscayne, Florida. Reprint requests to Latif M. Hamed, M.D., Bascom Palmer Eye Institute, P.O. Box 016880, Miami, FL 33101. 30
prompt combined hemodialysis and corticosteroid therapy. In contrast, we studied three patients with uremia who developed optic neuropathies while undergoing adequate maintenance hemodialysis. Two were treated according to the recommendations of Knox and associates, but showed little visual improvement. Case Reports Case 1 A 61-year-old man had been undergoing chronic hemodialysis for 11 years for hypertension-induced nephrosclerosis. He experienced abrupt deterioration of vision in both eyes over several days, first noted upon awakening on June 4, 1988. He had had a dull frontal headache during the preceding two weeks. Chronic medical therapy included ranitidine hydrochloride, verapamil, folic acid, allopurinol, and digoxin. Intravenous deferoxamine therapy, 2 g after each hemodialysis, had been started two months earlier to reduce increased serum aluminum levels. When examined on June 16, 1988, visual acuity was R.E.: 20/400 and L.E.: 20/200. No Ishihara pseudoisochromatic color plates were identified with either eye. Visual field testing showed large bilateral central scotomas. The pupils were each 4 mm in diameter and symmetrically sluggish to light. Results of slit-lamp examination were normal. Tensions by applanation tonometry were normal. The fundi showed moderate hypertensive retinal vascular changes bilaterally, but the optic disks appeared normal. Systemic blood pressure was 140/80 mm Hg. Laboratory data included a serum hemoglobin level of 13.6 g/dl, a hematocrit of 41.3%, a white blood cell count of 7,000 cells/mm" (60% polymorphonuclear leukocytes, 29% lymphocytes, 10% monocytes, and 1% eosinophils), a blood urea nitrogen level of 45 mg/dl, and a creatinine level of 12.4 mg/dl. A toxic heavy metal screen was negative. Results of magnetic resonance imaging of the brain were normal as
©AMERICAN JOURNAL OF OPHTHALMOLOGY
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were results of standardized A-scan orbital echography of the optic nerves. Results of follow-up examination one week later were unchanged. In consultation with the patient's nephrologist, deferoxamine was discontinued; the medical and hemodialysis regimen was otherwise unchanged. Ten days later, visual acuity had gradually improved to R.E.: 20/60 and L.E.: 20/50. There were bilateral relative central scotomas to red color testing only. On July 11, 1988, visual acuity was R. E.: 20/40 and L.E.: 20/30. Pupillary light reactions were brisker. The patient believed his vision had returned to baseline. He identified ten of 15 Ishihara pseudoisochromatic color plates with each eye. Visual function has remained stable since. Case 2
A 40-year-old man with a history of glomerulonephritis had been undergoing hemodialysis for eight years. He had poorly controIled systemic hypertension, and had recently experienced frequent blood pressure fluctuations ranging from 120170 to 210/100 mm Hg. The baseline hematocrit level was approximately 22%. During the preceding six months he had had several episodes of hemorrhage from an infected Goretex arteriovenous graft that required transfusion of four units of packed red blood cells. In July 1987, an ophthalmologic examination had shown bilateral optic disk edema, with visual acuity of 20/25 in each eye. On March 22, 1988, another examination showed a visual acuity of 20/25, normal Humphrey automated visual fields, and mild bilateral optic disk edema.
31
In early August 1988, the patient noted an abrupt loss of peripheral visual field with preservation of central vision in the right eye. Over the next several days, the field loss continued, leaving only a "small tunnel of vision" in the right eye. On examination, visual acuity was R.E.: 20/30 and L.E.: 20/20. A marked right afferent pupillary defect was noted. The patient correctly identified six of 15 Ishihara pseudoisochromatic color plates with the right eye and allIS with the left eye. Results of slit-lamp examination were normal. Marked disk edema was present bilaterally, with pallor on the right (Fig. 1). The maculas were clear. Blood pressure was 180/120 mm Hg. Humphrey automated visual fields showed only a small central island of vision in the right eye and an inferior arcuate scotoma in the left eye. Standardized A-scan echography demonstrated enlargement of both optic nerves with positive 30-degree tests, indicative of increased subarachnoid fluid. Results of magnetic resonance imaging of the head were normal. Laboratory data included a hematocrit of 23%, a blood urea nitrogen level of 92 mgldl, a creatinine level of 16 mg/dl, and a nonreactive rapid plasma reagin test. Lumbar puncture demonstrated an opening pressure of 290 mm H 20 , no white blood cells, a protein level of 81 mgldl, a glucose level of 44 mgldl, negative bacterial and fungal stains and cultures, and negative cytologic studies. The patient was treated with 500 mg of intravenous methylprednisolone twice daily for five days, and underwent dialysis three times in the next four days. Two units of packed red blood cells were transfused, raising the hematocrit level to 28%. The systemic hypertension re-
Fig. 1 (Hamed and associates). Case 2. Profound optic disk edema in the right eye (left) and left eye (right) with surrounding retinal folds caused by intracranial hypertension.
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mained unstable, with systolic pressures of 150 to 220 mm Hg and diastolic pressures of 80 to 120 mm Hg, despite aggressive medical therapy. After the first day of corticosteroid therapy the patient noticed a subjective improvement in the visual field of the right eye, and automated perimetry showed a mild improvement. Visual acuity remained stable as did the appearance of the optic disks. The patient was discharged on a slowly tapering regimen of oral prednisone. One month later results of the examination were unchanged, without improvement in the visual field or acuity. On Oct. 4, 1988, visual acuity was R.E.: 20/30 and L.E.: 20/20. Disk edema and confrontation fields were unchanged. The patient was lost to follow-up before institution of other therapy for intracranial hypertension. Case 3 A 41-year-old woman with endstage renal disease secondary to reflux nephropathy had been undergoing hemodialysis for the preceding nine years. She had undergone cadaveric renal transplantation in February 1987, but soon afterwards developed a cytomegalovirus infection and Listeria meningitis, with subsequent graft failure. She recovered and did well with reinstitution of hemodialysis. Upon awakening on May 8, 1988, the patient noted blurred vision in the right eye. She had developed menorrhagia in the preceding weeks, which required transfusion as the base-
July, 1989
line hematocrit level of 20% had dropped to 13%. Additionally, her previously wellcontrolled hypertension had recently become labile, and in the morning of visual loss the recorded blood pressure was 200/130 mm Hg. Visual acuity was R.E.: 20/50 and L.E.: 20/20. There was a right afferent pupillary defect. Results of slit-lamp examination were unremarkable. Ophthalmoscopy showed right optic disk edema without hemorrhages or exudates (Fig. 2, left). Except for attenuated arterioles, the left fundus was normal. Vision in the right eye deteriorated over the next two days to light perception. Results of the neurologic examination were normal. Laboratory data included a hematocrit level of 16%, a blood urea nitrogen level of 81 mg/dl, and a creatinine level of 15.6 mg/dl; white blood cell count, fluorescent treponema 1 antibody-absorption, vitamin B12, antinuclear antibody, and hepatitis B surface antigen were all normal or negative. Results of a chest x-ray, head and orbit computed tomographic scans, and a lumbar puncture were unremarkable. Oral prednisone, 80 mg per day, was initiated and was tapered over six weeks. Visual acuity gradually improved to R.E.: 4/200. Diffuse optic disk pallor ensued. The left eye remained unchanged. On July IS, 1988 (nine weeks after the episode in the right eye), the vision in the left eye became blurred and worsened over the next 24 hours. On examination, visual acuity was hand motions in the left eye with a sluggish pupil,
Fig. 2 (Hamed and associates). Case 3. Pallid optic disk edema with severe loss of vision in the right eye (left) and left eye (right) occurred nine weeks apart.
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normal anterior segment, and modest disk edema that was more pronounced nasally. The right eye was unchanged. Blood pressure was 154/104 mm Hg. Oral prednisone, 100 mg per day, and a subtenon injection of triamcinolone acetonide were given. Upon awakening the following morning, visual acuity was no light perception in the left eye. The left optic disk demonstrated increased swelling (Fig. 2, right), and standardized A-scan echography demonstrated enlargement of the optic nerve sheath with increased subarachnoid fluid. The blood pressure was 170/ 110 mm Hg, blood urea nitrogen level was 115 mg/dl, creatinine level was 15.0 mg/dl, and hematocrit was 20%. Results of magnetic resonance imaging of the brain and orbits as well as a lumbar puncture were unremarkable. Intravenous methylprednisolone, 2 g per day, was administered for five days. The patient underwent hemodialysis three times in the next four days, reducing the blood urea nitrogen level to 67 mg/dl and the creatinine level to 7.8 mg/dl, Three units of packed red blood cells were transfused, increasing the hematocrit to 33%. The hypertension was significantly improved with medical management. During hospitalization, the patient's visual acuity slowly improved from no light perception to counting fingers in the left eye. On discharge, 100 mg of oral prednisone per day was given and tapered slowly. Six months later visual acuity was R.E.: 20/200 and L.E.: 20/800. Discussion
Knox and associates! described six patients with bilateral optic neuropathy associated with uremia, anemia, and moderate to severe systemic hypertension. Typically, the visual loss was bilateral, occurred over several days or weeks, and ranged from 20/60 to no light perception. They speculated that focal edema of the optic disk was the probable mechanism of this disorder. Dialysis alone produced rapid improvement of vision in two patients, and a slower improvement in a third patient. Combined dialysis and systemic corticosteroids in one patient, and corticosteroids alone in another, also produced visual improvement. One patient, whose visual loss was associated with concurrent cryptococcal meningitis, did not improve. The authors advocated prompt combined dialysis and corticosteroid therapy as the
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optimal management of patients with "uremic optic neuropathy." Our patients differ in several important respects. The patients seen by Knox and associates were not already undergoing maintenance hemodialysis, and the symptoms in four patients responded quickly to institution of the therapeutic regimen indicated above. Our patients had been undergoing stable maintenance hemodialysis for 11, eight, and nine years, respectively, at the onset of visual symptoms. Uremic optic neuropathy, as described by Knox and associates, was the initial diagnosis in each of our patients, but intravenous corticosteroid therapy, more vigorous hemodialysis, blood pressure control, and blood transfusions in Patients 2 and 3 produced minimal improvement in vision. Patient 1 showed total recovery of vision four weeks after discontinuing deferoxamine therapy. Deferoxamine is a chelating agent used to treat aluminum or iron overload occurring in hemodialysis and iron storage diseases, respectively. In some cases, it has been associated with visual loss as a result of adverse effects on the crystalline lens," retina, 6-9 and optic nerves.P:" Cataract, night blindness, visual field defects, toxic retinal pigmentary degeneration, and optic neuropathy have been linked circumstantially to deferoxamine therapy. The optic neuropathy may be subclinical, with delayed P-100 latencies on visual-evoked potential testing, or may show rapid bilateral visual loss. Taylor and colleagues's found that 30% of patients receiving long-term deferoxamine therapy with normal results of ophthalmologic examination showed abnormal visual-evoked potentials suggesting optic nerve dysfunction. Generally, the condition is reversible upon cessation of the chelating agent. Lakhanpal, Schocket, and [iji'? described eight patients who had developed ocular toxicity with visual loss within days of initial exposure to deferoxamine; six cases were due to presumed retrobulbar neuropathy, and two to pigmentary retinopathy. All showed improved vision after cessation of the drug. In another study of 89 patients receiving subcutaneous deferoxamine, 13 had acute onset of visual loss or deafness, or both. Four of these showed optic neuropathy, with marked loss of visual acuity, defective color vision, and delayed visual-evoked potentials. These four patients had been taking the drug for an average of nine months (range, four months to one year) before detection of the visual loss. All four patients
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showed improved vision within several weeks after discontinuation of deferoxamine, but all had residual optic atrophy. 11 The mechanism of deferoxamine ocular toxicity is unknown. By measuring serum concentrations of trace metals in 26 dialysis patients before and after intravenous infusion of deferoxamine, Simon and associates" showed that the toxicity is not likely a result of depletion of essential trace metals (Zn, Cu, Mn), They described a patient who had acute visual loss with dyschromatopsia after the first deferoxamine infusion. Visual recovery occurred within 48 hours. They argued that the almost immediate visual loss is incompatible with depletion of trace metals, and more suggestive of direct deferoxamine toxicity. Others have described similar cases. 14 In our Patient 2, the initial diagnosis was uremic optic neuropathy, but the pattern of visual field loss and the failure to respond to the therapeutic regimen advocated by Knox and associates! were more consistent with idiopathic intracranial hypertension. The association of the latter condition with uremia is supported by others. Larsson15 described 11 uremic patients with systemic and intracranial hypertension. The systolic blood pressure ranged from 170 to 270 mm Hg (mean, 220 mm Hg), the diastolic pressure from 80 to 170 mm Hg (mean, 135 mm Hg), and the intracranial pressure from 200 to 600 mm H 20 (mean, 350 mm H 20). Sudden impairment of vision was an initial symptom in most of these patients. Bar and Savir" described four uremic patients with similar clinical findings, but the intracranial pressures were not reported. They attributed these cases to renal retinopathy, that is, severe hypertensive retinopathy in the presence of mild to moderate systemic hypertension, the discrepancy explained by a synergistic effect of the concurrent uremia. One patient described by Hilton and coworkers" required placement of a shunt to treat idiopathic hydrocephalus with papilledema. The pathogenesis of intracranial hypertension in uremia is unknown. It has been speculated that it is related to systemic hypertension." Alteration of the blood-brain barrier has been reported to occur frequently in patients with uremia of diverse origins. IS Meningeal signs, cerebrospinal fluid pleocytosis, and increased cerebrospinal fluid protein and urea levels are frequently associated findings,19,2O and may be confused with chronic meningitis in the immunosuppressed patient. The profound loss of vision in our Patient 3
(visual acuity of R.E.: light perception and L.E.: no light perception), and the subsequent, albeit minimal, improvement is inconsistent with typical bilateral, consecutive nonarteritic ischemic optic neuropathy. However, in the setting of uremia, anemia, systemic hypertension, and other yet unknown factors associated with severe azotemia, it is possible that even a young patient may suffer an atypical and unusually severe episode of nonarteritic ischemic optic neuropathy. Visual loss in patients with uremia may be caused by a variety of associated conditions: uremic encephalopathy with brain edema and cortical blindness (uremic amaurosis)": related hematologic and vasculopathic conditions (anemia, hypertension, disseminated intravascular coagulation) predisposing to ischemic optic neuropathy, maculopathy, or uveal effusions; chronic papilledema; deferoxamine toxicity; and opportunistic infections in immunocompromised patients after renal transplantation. The possible role of uremic toxins including parathyroid hormone, urea, creatinine, myoinositol, transketolase, guanidine derivatives, and middle molecules is not estabIished.l-" Our report as well as those of others underscore the heterogeneity of pathophysiologic processes afflicting the optic nerve in patients with uremia in a manner analogous to the diverse central and peripheral nervous system disorders in this condition. Obviously, not all uremia-associated nervous system disorders, including optic neuropathies, are responsive to dialysis or corticosteroid therapy. The group described by Knox and associates' represents a subset in a larger spectrum of optic neuropathies associated with uremia.
References 1. Fraser, C. L., and Arieff, A. I.: Nervous system complications in uremia. Ann. Intern. Med. 109:143, 1988. 2. Raskin, N. H., and Fishman, R. A.: Neurologic disorders in renal failure (two parts). N. Eng!. J. Med. 294:143, 204, 1976. 3. Tyler, H. R.: Neurologic disorders in renal failure. Am. J. Med. 44:734, 1968. 4. Knox, D. L., Hanneken, A. M., Hollows, F. c.. Miller, N. R., Schick, H. L., Jr., and Gonzales, W. L.: Uremic optic neuropathy. Arch. Ophthalmol. 106:50, 1988. 5. Bloomfield, S. E., Markenson, A. L., Miller,
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D. R., and Peterson, C. M.: Lens opacities in thalassemia. J. Pediatr. Ophthalmol. 15:154, 1978. 6. Arden, G. B., Wonke, B., Kennedy, c., and Huehns, E. R.: Ocular changes in patients undergoing long-term deferoxamine treatment. Br. J. Ophthalmol. 68:873, 1984. 7. Davies, S. G., Marcus, R. E., Hungerford, J. L., Miller, M. H., Arden, G. B., and Huehns, E. R.: Ocular toxicity of high dose intravenous deferoxamine. Lancet 2:181, 1983. 8. Easterbrook, M., and Mortimer, G. B.: Ocular signs in chronic renal failure. Br. J. Ophthalmol.
54:724, 1970.
9. Rubinstein, M., Dupont, P., Doppee, J. P., Dehon, C., Ducobu, J., and Hainaut, J.: Ocular toxicity of deferoxamine. Lancet 1:817, 1985. 10. Lakhanpal, V., Schocket, S. S., and Jiji, R.: Deferoxamine (Desferal)-induced toxic retinal pigmentary degeneration and presumed optic neuropathy. Ophthalmology 91:443,1984. 11. Olivieri, N. F., Buncic, R. J., Chew, E., Gallant, T., Harrison, R. V., Keenan, N., Logan, W., Mitchell, D., Ricci, G., Skarf, B., Taylor, M., and Freedman, M. H.: Visual and auditory neurotoxicity in patients receiving subcutaneous deferoxamine infusions. N. Engl. J. Med. 314:869, 1986. 12. Taylor, M. J., Keenan, N. K., Gallant, T., Skarf, B., Freedman, M. H., and Logan, W. J.: Subclinical VEP abnormalities in patients on chronic deferoxamine therapy. Longitudinal studies. Electroencephalogr. Clin. Neurophysiol. 68:81, 1987. 13. Simon, P., Ang, K. 5., Meyrier, A., Allain, P.,
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and Mauras, Y.: Deferoxamine, ocular toxicity, and trace metals. Lancet 2:512, 1983. 14. Pengloan, J., Dantal, J., Rossazza, c.. Abazza, M., and Nivet, H.: Ocular toxicity after a single intravenous dose of deferoxamine in two hemodialyzed patients. Nephron 46:211, 1987. 15. Larsson, S. W.: Choked disc in nephritis. Acta Ophthalmol. 1:193, 1923. 16. Bar, S., and Savir, H.: Renal retinopathy. The renewed entity. Metab. Pediatr. Syst. Ophthalmol. 6:33, 1982. 17. Hilton, A. F., Harrison, J. D., Lamb, A. M.,
Petrie, J. J. B., and Hardie, I.: Ocular complications in haemodialysis and renal transplant patients. Aust. J. Ophthalmol. 10:247, 1982. 18. Freeman, R. B., Sheff, M. F., Maher, J. F., and Schreiner, G. E.: The blood-cerebrospinal fluid barrier in uremia. Ann. Intern. Med. 56:233, 1962. 19. Madonick, M. J., Berke, K., and Schiffer, 1.: Pleocytosis and meningeal signs in uremia. Report on sixty-two cases. Arch. Neurol. Psychiatry 64:431, 1950. 20. Schreiner, G., and Maher,
J. F.: Uremia. Biochemistry, Pathogenesis and Treatment. Springfield, Illinois, Charles C Thomas, 1961, pp. 256-269. 21. Walsh, F. B., and Brown, A. B.: Bilateral blindness of sudden onset. Trans. Ophthalmol. Soc. Aust, 23:13, 1963. 22. Bab, A. L., Ahmad, S., Bergstrom, J., 'and
Scribner, B. H.: The middle molecule hypothesis in perspective. Am. J. Kidney Dis. 1:46, 1981.
OPHTHALMIC MINIATURE
"You must be nervous about your cataract operation on Tuesday. I would be. It's not so much what they're going to do-that's almost certain to improve things-but the thinking about it beforehand. The eye calls forth imaginings in a way that most other organs don't. I wonder why that is; I wonder if it's because the eye has been used so often as a symbol. The window of the soul ... the 'power behind the eye' Emerson said could charm down insanity or wild beasts ... 'if thine eye offend thee ... ' Maybe that's it: the whole thing'S too graphic for comfort." Gail Godwin, A Southern Family New York, William Morrow and Company, Inc., 1987, p. 466.
We examined three patients who developed optic neuropathies while undergoing chronic hemodialysis. One patient developed severe bilateral deterioration of vision, but recovered totally four weeks after discontinuing deferoxamine chelation therapy. Another patient had bilateral visual loss associated with chronic papilledema of idiopathic increased intracranial pressure. A third showed atypically severe consecutive anterior ischemic optic neuropathy. The latter two patients showed little improvement with high-dose intravenous methylprednisolone therapy combined with more vigorous hemodialysis. These cases, in addition to those previously described, underscore the heterogeneity of optic nerve disease in patients with uremia. NERVOUS SYSTEM DYSFUNCTION occurs commonly in patients with uremia, both before and after institution of an adequate maintenance dialysis regimen. Recent reviews have addressed this topic in detail. 1-3 Ocular morbidity may result from the primary condition causing the renal failure (for example, diabetes, hypertension), the uremic state itself, toxicity of concurrent medications, complications of dialysis, or other intercurrent illnesses. Knox and coworkers! described six patients with uremia and optic neuropathy. Five of these patients showed a favorable visual response upon institution of hemodialysis or corticosteroid therapy, or both. The authors recommended that patients with renal failure and rapid visual loss should be considered for
Accepted for publication March 28, 1989. From the Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida. Dr. Hamed is a 1988-1989 Heed Foundation Fellow. This study was presented in part at the 1988 Neuro-ophthalmology Course, University of Miami School of Medicine, Department of Ophthalmology, Bascom Palmer Eye Institute, Dec. 10, 1988, Key Biscayne, Florida. Reprint requests to Latif M. Hamed, M.D., Bascom Palmer Eye Institute, P.O. Box 016880, Miami, FL 33101. 30
prompt combined hemodialysis and corticosteroid therapy. In contrast, we studied three patients with uremia who developed optic neuropathies while undergoing adequate maintenance hemodialysis. Two were treated according to the recommendations of Knox and associates, but showed little visual improvement. Case Reports Case 1 A 61-year-old man had been undergoing chronic hemodialysis for 11 years for hypertension-induced nephrosclerosis. He experienced abrupt deterioration of vision in both eyes over several days, first noted upon awakening on June 4, 1988. He had had a dull frontal headache during the preceding two weeks. Chronic medical therapy included ranitidine hydrochloride, verapamil, folic acid, allopurinol, and digoxin. Intravenous deferoxamine therapy, 2 g after each hemodialysis, had been started two months earlier to reduce increased serum aluminum levels. When examined on June 16, 1988, visual acuity was R.E.: 20/400 and L.E.: 20/200. No Ishihara pseudoisochromatic color plates were identified with either eye. Visual field testing showed large bilateral central scotomas. The pupils were each 4 mm in diameter and symmetrically sluggish to light. Results of slit-lamp examination were normal. Tensions by applanation tonometry were normal. The fundi showed moderate hypertensive retinal vascular changes bilaterally, but the optic disks appeared normal. Systemic blood pressure was 140/80 mm Hg. Laboratory data included a serum hemoglobin level of 13.6 g/dl, a hematocrit of 41.3%, a white blood cell count of 7,000 cells/mm" (60% polymorphonuclear leukocytes, 29% lymphocytes, 10% monocytes, and 1% eosinophils), a blood urea nitrogen level of 45 mg/dl, and a creatinine level of 12.4 mg/dl. A toxic heavy metal screen was negative. Results of magnetic resonance imaging of the brain were normal as
©AMERICAN JOURNAL OF OPHTHALMOLOGY
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were results of standardized A-scan orbital echography of the optic nerves. Results of follow-up examination one week later were unchanged. In consultation with the patient's nephrologist, deferoxamine was discontinued; the medical and hemodialysis regimen was otherwise unchanged. Ten days later, visual acuity had gradually improved to R.E.: 20/60 and L.E.: 20/50. There were bilateral relative central scotomas to red color testing only. On July 11, 1988, visual acuity was R. E.: 20/40 and L.E.: 20/30. Pupillary light reactions were brisker. The patient believed his vision had returned to baseline. He identified ten of 15 Ishihara pseudoisochromatic color plates with each eye. Visual function has remained stable since. Case 2
A 40-year-old man with a history of glomerulonephritis had been undergoing hemodialysis for eight years. He had poorly controIled systemic hypertension, and had recently experienced frequent blood pressure fluctuations ranging from 120170 to 210/100 mm Hg. The baseline hematocrit level was approximately 22%. During the preceding six months he had had several episodes of hemorrhage from an infected Goretex arteriovenous graft that required transfusion of four units of packed red blood cells. In July 1987, an ophthalmologic examination had shown bilateral optic disk edema, with visual acuity of 20/25 in each eye. On March 22, 1988, another examination showed a visual acuity of 20/25, normal Humphrey automated visual fields, and mild bilateral optic disk edema.
31
In early August 1988, the patient noted an abrupt loss of peripheral visual field with preservation of central vision in the right eye. Over the next several days, the field loss continued, leaving only a "small tunnel of vision" in the right eye. On examination, visual acuity was R.E.: 20/30 and L.E.: 20/20. A marked right afferent pupillary defect was noted. The patient correctly identified six of 15 Ishihara pseudoisochromatic color plates with the right eye and allIS with the left eye. Results of slit-lamp examination were normal. Marked disk edema was present bilaterally, with pallor on the right (Fig. 1). The maculas were clear. Blood pressure was 180/120 mm Hg. Humphrey automated visual fields showed only a small central island of vision in the right eye and an inferior arcuate scotoma in the left eye. Standardized A-scan echography demonstrated enlargement of both optic nerves with positive 30-degree tests, indicative of increased subarachnoid fluid. Results of magnetic resonance imaging of the head were normal. Laboratory data included a hematocrit of 23%, a blood urea nitrogen level of 92 mgldl, a creatinine level of 16 mg/dl, and a nonreactive rapid plasma reagin test. Lumbar puncture demonstrated an opening pressure of 290 mm H 20 , no white blood cells, a protein level of 81 mgldl, a glucose level of 44 mgldl, negative bacterial and fungal stains and cultures, and negative cytologic studies. The patient was treated with 500 mg of intravenous methylprednisolone twice daily for five days, and underwent dialysis three times in the next four days. Two units of packed red blood cells were transfused, raising the hematocrit level to 28%. The systemic hypertension re-
Fig. 1 (Hamed and associates). Case 2. Profound optic disk edema in the right eye (left) and left eye (right) with surrounding retinal folds caused by intracranial hypertension.
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mained unstable, with systolic pressures of 150 to 220 mm Hg and diastolic pressures of 80 to 120 mm Hg, despite aggressive medical therapy. After the first day of corticosteroid therapy the patient noticed a subjective improvement in the visual field of the right eye, and automated perimetry showed a mild improvement. Visual acuity remained stable as did the appearance of the optic disks. The patient was discharged on a slowly tapering regimen of oral prednisone. One month later results of the examination were unchanged, without improvement in the visual field or acuity. On Oct. 4, 1988, visual acuity was R.E.: 20/30 and L.E.: 20/20. Disk edema and confrontation fields were unchanged. The patient was lost to follow-up before institution of other therapy for intracranial hypertension. Case 3 A 41-year-old woman with endstage renal disease secondary to reflux nephropathy had been undergoing hemodialysis for the preceding nine years. She had undergone cadaveric renal transplantation in February 1987, but soon afterwards developed a cytomegalovirus infection and Listeria meningitis, with subsequent graft failure. She recovered and did well with reinstitution of hemodialysis. Upon awakening on May 8, 1988, the patient noted blurred vision in the right eye. She had developed menorrhagia in the preceding weeks, which required transfusion as the base-
July, 1989
line hematocrit level of 20% had dropped to 13%. Additionally, her previously wellcontrolled hypertension had recently become labile, and in the morning of visual loss the recorded blood pressure was 200/130 mm Hg. Visual acuity was R.E.: 20/50 and L.E.: 20/20. There was a right afferent pupillary defect. Results of slit-lamp examination were unremarkable. Ophthalmoscopy showed right optic disk edema without hemorrhages or exudates (Fig. 2, left). Except for attenuated arterioles, the left fundus was normal. Vision in the right eye deteriorated over the next two days to light perception. Results of the neurologic examination were normal. Laboratory data included a hematocrit level of 16%, a blood urea nitrogen level of 81 mg/dl, and a creatinine level of 15.6 mg/dl; white blood cell count, fluorescent treponema 1 antibody-absorption, vitamin B12, antinuclear antibody, and hepatitis B surface antigen were all normal or negative. Results of a chest x-ray, head and orbit computed tomographic scans, and a lumbar puncture were unremarkable. Oral prednisone, 80 mg per day, was initiated and was tapered over six weeks. Visual acuity gradually improved to R.E.: 4/200. Diffuse optic disk pallor ensued. The left eye remained unchanged. On July IS, 1988 (nine weeks after the episode in the right eye), the vision in the left eye became blurred and worsened over the next 24 hours. On examination, visual acuity was hand motions in the left eye with a sluggish pupil,
Fig. 2 (Hamed and associates). Case 3. Pallid optic disk edema with severe loss of vision in the right eye (left) and left eye (right) occurred nine weeks apart.
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normal anterior segment, and modest disk edema that was more pronounced nasally. The right eye was unchanged. Blood pressure was 154/104 mm Hg. Oral prednisone, 100 mg per day, and a subtenon injection of triamcinolone acetonide were given. Upon awakening the following morning, visual acuity was no light perception in the left eye. The left optic disk demonstrated increased swelling (Fig. 2, right), and standardized A-scan echography demonstrated enlargement of the optic nerve sheath with increased subarachnoid fluid. The blood pressure was 170/ 110 mm Hg, blood urea nitrogen level was 115 mg/dl, creatinine level was 15.0 mg/dl, and hematocrit was 20%. Results of magnetic resonance imaging of the brain and orbits as well as a lumbar puncture were unremarkable. Intravenous methylprednisolone, 2 g per day, was administered for five days. The patient underwent hemodialysis three times in the next four days, reducing the blood urea nitrogen level to 67 mg/dl and the creatinine level to 7.8 mg/dl, Three units of packed red blood cells were transfused, increasing the hematocrit to 33%. The hypertension was significantly improved with medical management. During hospitalization, the patient's visual acuity slowly improved from no light perception to counting fingers in the left eye. On discharge, 100 mg of oral prednisone per day was given and tapered slowly. Six months later visual acuity was R.E.: 20/200 and L.E.: 20/800. Discussion
Knox and associates! described six patients with bilateral optic neuropathy associated with uremia, anemia, and moderate to severe systemic hypertension. Typically, the visual loss was bilateral, occurred over several days or weeks, and ranged from 20/60 to no light perception. They speculated that focal edema of the optic disk was the probable mechanism of this disorder. Dialysis alone produced rapid improvement of vision in two patients, and a slower improvement in a third patient. Combined dialysis and systemic corticosteroids in one patient, and corticosteroids alone in another, also produced visual improvement. One patient, whose visual loss was associated with concurrent cryptococcal meningitis, did not improve. The authors advocated prompt combined dialysis and corticosteroid therapy as the
33
optimal management of patients with "uremic optic neuropathy." Our patients differ in several important respects. The patients seen by Knox and associates were not already undergoing maintenance hemodialysis, and the symptoms in four patients responded quickly to institution of the therapeutic regimen indicated above. Our patients had been undergoing stable maintenance hemodialysis for 11, eight, and nine years, respectively, at the onset of visual symptoms. Uremic optic neuropathy, as described by Knox and associates, was the initial diagnosis in each of our patients, but intravenous corticosteroid therapy, more vigorous hemodialysis, blood pressure control, and blood transfusions in Patients 2 and 3 produced minimal improvement in vision. Patient 1 showed total recovery of vision four weeks after discontinuing deferoxamine therapy. Deferoxamine is a chelating agent used to treat aluminum or iron overload occurring in hemodialysis and iron storage diseases, respectively. In some cases, it has been associated with visual loss as a result of adverse effects on the crystalline lens," retina, 6-9 and optic nerves.P:" Cataract, night blindness, visual field defects, toxic retinal pigmentary degeneration, and optic neuropathy have been linked circumstantially to deferoxamine therapy. The optic neuropathy may be subclinical, with delayed P-100 latencies on visual-evoked potential testing, or may show rapid bilateral visual loss. Taylor and colleagues's found that 30% of patients receiving long-term deferoxamine therapy with normal results of ophthalmologic examination showed abnormal visual-evoked potentials suggesting optic nerve dysfunction. Generally, the condition is reversible upon cessation of the chelating agent. Lakhanpal, Schocket, and [iji'? described eight patients who had developed ocular toxicity with visual loss within days of initial exposure to deferoxamine; six cases were due to presumed retrobulbar neuropathy, and two to pigmentary retinopathy. All showed improved vision after cessation of the drug. In another study of 89 patients receiving subcutaneous deferoxamine, 13 had acute onset of visual loss or deafness, or both. Four of these showed optic neuropathy, with marked loss of visual acuity, defective color vision, and delayed visual-evoked potentials. These four patients had been taking the drug for an average of nine months (range, four months to one year) before detection of the visual loss. All four patients
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showed improved vision within several weeks after discontinuation of deferoxamine, but all had residual optic atrophy. 11 The mechanism of deferoxamine ocular toxicity is unknown. By measuring serum concentrations of trace metals in 26 dialysis patients before and after intravenous infusion of deferoxamine, Simon and associates" showed that the toxicity is not likely a result of depletion of essential trace metals (Zn, Cu, Mn), They described a patient who had acute visual loss with dyschromatopsia after the first deferoxamine infusion. Visual recovery occurred within 48 hours. They argued that the almost immediate visual loss is incompatible with depletion of trace metals, and more suggestive of direct deferoxamine toxicity. Others have described similar cases. 14 In our Patient 2, the initial diagnosis was uremic optic neuropathy, but the pattern of visual field loss and the failure to respond to the therapeutic regimen advocated by Knox and associates! were more consistent with idiopathic intracranial hypertension. The association of the latter condition with uremia is supported by others. Larsson15 described 11 uremic patients with systemic and intracranial hypertension. The systolic blood pressure ranged from 170 to 270 mm Hg (mean, 220 mm Hg), the diastolic pressure from 80 to 170 mm Hg (mean, 135 mm Hg), and the intracranial pressure from 200 to 600 mm H 20 (mean, 350 mm H 20). Sudden impairment of vision was an initial symptom in most of these patients. Bar and Savir" described four uremic patients with similar clinical findings, but the intracranial pressures were not reported. They attributed these cases to renal retinopathy, that is, severe hypertensive retinopathy in the presence of mild to moderate systemic hypertension, the discrepancy explained by a synergistic effect of the concurrent uremia. One patient described by Hilton and coworkers" required placement of a shunt to treat idiopathic hydrocephalus with papilledema. The pathogenesis of intracranial hypertension in uremia is unknown. It has been speculated that it is related to systemic hypertension." Alteration of the blood-brain barrier has been reported to occur frequently in patients with uremia of diverse origins. IS Meningeal signs, cerebrospinal fluid pleocytosis, and increased cerebrospinal fluid protein and urea levels are frequently associated findings,19,2O and may be confused with chronic meningitis in the immunosuppressed patient. The profound loss of vision in our Patient 3
(visual acuity of R.E.: light perception and L.E.: no light perception), and the subsequent, albeit minimal, improvement is inconsistent with typical bilateral, consecutive nonarteritic ischemic optic neuropathy. However, in the setting of uremia, anemia, systemic hypertension, and other yet unknown factors associated with severe azotemia, it is possible that even a young patient may suffer an atypical and unusually severe episode of nonarteritic ischemic optic neuropathy. Visual loss in patients with uremia may be caused by a variety of associated conditions: uremic encephalopathy with brain edema and cortical blindness (uremic amaurosis)": related hematologic and vasculopathic conditions (anemia, hypertension, disseminated intravascular coagulation) predisposing to ischemic optic neuropathy, maculopathy, or uveal effusions; chronic papilledema; deferoxamine toxicity; and opportunistic infections in immunocompromised patients after renal transplantation. The possible role of uremic toxins including parathyroid hormone, urea, creatinine, myoinositol, transketolase, guanidine derivatives, and middle molecules is not estabIished.l-" Our report as well as those of others underscore the heterogeneity of pathophysiologic processes afflicting the optic nerve in patients with uremia in a manner analogous to the diverse central and peripheral nervous system disorders in this condition. Obviously, not all uremia-associated nervous system disorders, including optic neuropathies, are responsive to dialysis or corticosteroid therapy. The group described by Knox and associates' represents a subset in a larger spectrum of optic neuropathies associated with uremia.
References 1. Fraser, C. L., and Arieff, A. I.: Nervous system complications in uremia. Ann. Intern. Med. 109:143, 1988. 2. Raskin, N. H., and Fishman, R. A.: Neurologic disorders in renal failure (two parts). N. Eng!. J. Med. 294:143, 204, 1976. 3. Tyler, H. R.: Neurologic disorders in renal failure. Am. J. Med. 44:734, 1968. 4. Knox, D. L., Hanneken, A. M., Hollows, F. c.. Miller, N. R., Schick, H. L., Jr., and Gonzales, W. L.: Uremic optic neuropathy. Arch. Ophthalmol. 106:50, 1988. 5. Bloomfield, S. E., Markenson, A. L., Miller,
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D. R., and Peterson, C. M.: Lens opacities in thalassemia. J. Pediatr. Ophthalmol. 15:154, 1978. 6. Arden, G. B., Wonke, B., Kennedy, c., and Huehns, E. R.: Ocular changes in patients undergoing long-term deferoxamine treatment. Br. J. Ophthalmol. 68:873, 1984. 7. Davies, S. G., Marcus, R. E., Hungerford, J. L., Miller, M. H., Arden, G. B., and Huehns, E. R.: Ocular toxicity of high dose intravenous deferoxamine. Lancet 2:181, 1983. 8. Easterbrook, M., and Mortimer, G. B.: Ocular signs in chronic renal failure. Br. J. Ophthalmol.
54:724, 1970.
9. Rubinstein, M., Dupont, P., Doppee, J. P., Dehon, C., Ducobu, J., and Hainaut, J.: Ocular toxicity of deferoxamine. Lancet 1:817, 1985. 10. Lakhanpal, V., Schocket, S. S., and Jiji, R.: Deferoxamine (Desferal)-induced toxic retinal pigmentary degeneration and presumed optic neuropathy. Ophthalmology 91:443,1984. 11. Olivieri, N. F., Buncic, R. J., Chew, E., Gallant, T., Harrison, R. V., Keenan, N., Logan, W., Mitchell, D., Ricci, G., Skarf, B., Taylor, M., and Freedman, M. H.: Visual and auditory neurotoxicity in patients receiving subcutaneous deferoxamine infusions. N. Engl. J. Med. 314:869, 1986. 12. Taylor, M. J., Keenan, N. K., Gallant, T., Skarf, B., Freedman, M. H., and Logan, W. J.: Subclinical VEP abnormalities in patients on chronic deferoxamine therapy. Longitudinal studies. Electroencephalogr. Clin. Neurophysiol. 68:81, 1987. 13. Simon, P., Ang, K. 5., Meyrier, A., Allain, P.,
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and Mauras, Y.: Deferoxamine, ocular toxicity, and trace metals. Lancet 2:512, 1983. 14. Pengloan, J., Dantal, J., Rossazza, c.. Abazza, M., and Nivet, H.: Ocular toxicity after a single intravenous dose of deferoxamine in two hemodialyzed patients. Nephron 46:211, 1987. 15. Larsson, S. W.: Choked disc in nephritis. Acta Ophthalmol. 1:193, 1923. 16. Bar, S., and Savir, H.: Renal retinopathy. The renewed entity. Metab. Pediatr. Syst. Ophthalmol. 6:33, 1982. 17. Hilton, A. F., Harrison, J. D., Lamb, A. M.,
Petrie, J. J. B., and Hardie, I.: Ocular complications in haemodialysis and renal transplant patients. Aust. J. Ophthalmol. 10:247, 1982. 18. Freeman, R. B., Sheff, M. F., Maher, J. F., and Schreiner, G. E.: The blood-cerebrospinal fluid barrier in uremia. Ann. Intern. Med. 56:233, 1962. 19. Madonick, M. J., Berke, K., and Schiffer, 1.: Pleocytosis and meningeal signs in uremia. Report on sixty-two cases. Arch. Neurol. Psychiatry 64:431, 1950. 20. Schreiner, G., and Maher,
J. F.: Uremia. Biochemistry, Pathogenesis and Treatment. Springfield, Illinois, Charles C Thomas, 1961, pp. 256-269. 21. Walsh, F. B., and Brown, A. B.: Bilateral blindness of sudden onset. Trans. Ophthalmol. Soc. Aust, 23:13, 1963. 22. Bab, A. L., Ahmad, S., Bergstrom, J., 'and
Scribner, B. H.: The middle molecule hypothesis in perspective. Am. J. Kidney Dis. 1:46, 1981.
OPHTHALMIC MINIATURE
"You must be nervous about your cataract operation on Tuesday. I would be. It's not so much what they're going to do-that's almost certain to improve things-but the thinking about it beforehand. The eye calls forth imaginings in a way that most other organs don't. I wonder why that is; I wonder if it's because the eye has been used so often as a symbol. The window of the soul ... the 'power behind the eye' Emerson said could charm down insanity or wild beasts ... 'if thine eye offend thee ... ' Maybe that's it: the whole thing'S too graphic for comfort." Gail Godwin, A Southern Family New York, William Morrow and Company, Inc., 1987, p. 466.