Optic Disc Edema after Bone Marrow Transplantation Possible Role of Cyclosporine Toxicity ROBERT AVERY, MD, DOUGLAS A. JABS, MD, JOHN R. WINGARD, MD GEORGIA VOGELSANG, MD, REIN SARAL, MD, GEORGE SANTOS, MD
Abstract: Bone marrow transplantation has become widely used in the treatment of aplastic anemia and leukemia. Cyclosporine is used as prophylaxis against graft-versus-host disease. The authors report on eight cases of optic disc edema in patients taking cyclosporine after allogenic bone marrow transplant. Thorough evaluation revealed a possible alternate cause in two cases. In all cases, the optic disc edema resolved after discontinuing or decreasing the cyclosporine. Although cyclosporine has not previously been associated with optic disc edema, it has been implicated as the cause of a variety of neurologic side effects. Bone marrow transplant patients taking cyclosporine should be followed for the development of optic disc edema. Ophthalmology 1991; 98: 1294-130 1
Bone marrow transplantation has become the treatment of choice for severe aplastic anemia, when a donor exists, and is widely used in the treatment of leukemia and lymphoma when treatment with chemotherapy has failed or is expected to fail. l - 6 Bone marrow transplantation uses ablation of the patient's own marrow using cytoreductive chemotherapy and total body irradiation, followed by transplantation of donor bone marrow to reconstitute the patient's hematologic function. A major complication of allogenic marrow transplantation is graft-versus-host disease (GVHD) in which the transplanted marrow mounts a lymphocyte-mediated immunologic attack on the host, which is perceived as foreign by the donor marrow. 7- 13 Cyclosporine, also known as cyclosporin A, is a potent immunosuppressive drug now used routinely for the proOriginally received: November 9. 1990. Revision accepted: February 28, 1991. From the Wilmer Ophthalmological Institute, The Department of Ophthalmology, and the Bone Marrow Transplant Unit, The Johns Hopkins University School of Medicine, Baltimore. Presented in part as a poster at the American Academy of Ophthalmology Annual Meeting, New Orleans, Oct/Nov 1989. Supported in part by NIH grant P01 CA 153960 from the National Cancer Institute/NIH, Bethesda, Maryland. Reprint requests to Douglas A. Jabs, MD, The Wilmer Ophthalmological Institute, 550 N Broadway, Suite 700, Baltimore, MD 21205.
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phylaxis of and treatment of GVHD. 14-16 Because cyclosporine lacks myelotoxicity, its use allows for more rapid engraftment than does myelosuppressive immunosuppressants. 15 However, cyclosporine demonstrates several toxicities, the most frequent and dose-limiting of which is nephrotoxicity.17-19 More recently, cyclosporine has been implicated in a wide variety of neurotoxicities, including seizures, encephalopathy, cerebellar and spinal cord syndromes, dysarthria, tremor, coma, cortical blindness, increased intracranial pressure, and increased cerebral spinal fluid protein.20 - 31 We report eight patients who underwent allogenic bone marrow transplantation and in whom optic disc edema subsequently developed. Of these, two patients had possible alternate causes: one, an eosinophilic meningitis of unknown etiology, and the second, a previous intracranial hemorrhage. Of the remaining six patients, no alternative etiology of the optic disc edema could be determined, and in all cases the disc edema improved after decreasing or discontinuing the cyclosporine. We suggest that optic disc edema may be another manifestation of cyclosporine neurotoxicity.
SUBJECfS AND METHODS All patients in this series underwent transplant at the Bone Marrow Transplantation Unit of the Johns Hopkins
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Oncology Center between July 1984 and July 1990 and had regular ophthalmologic examinations as part of an ongoing evaluation of the ocular complications of marrow transplantY All patients included in this report received transplants according to standardized protocols used by the Unit. Informed consent was obtained for the transplant, as well as for all transplant-related procedures. The preparative regimens were standardized according to pretransplant diagnosis and have been described elsewhere. 3,4,33,34 The usual cyclosporine dose for GYRO prophylaxis was 5 mg/kg/day intravenously for the 2 days before and the first 3 days after transplant. The dose of cyclosporine was then slowly tapered to 3.75 mg/kg orally twice daily by day 50 and continued at that dose until discontinuation at day 170. The dose of cyclosporine was altered depending on the clinical course of GYRO or on the development of renal impairment.
RESULTS Ouring this period, 323 patients underwent allogenic marrow transplant using cyclosporine prophylaxis. Of these 323 patients, optic disc edema developed in 8 (2.5%). Unexplained disc edema was not seen in any of 52 patients undergoing allogenic transplant using alternative methods of GYRO prophylaxis during this period or that of our previous study.32,34 Only one patient among 399 patients undergoing an autologous transplant developed papilledema, and this occurred in association with a Streptococcus viridans meningitis and resolved with successful antibiotic treatment of the meningitis. None offour patients undergoing syngeneic bone marrow transplant developed optic disc edema. One patient (case 2) developed disc edema in association with an eosinophilic meningitis of unknown etiology, which resolved with corticosteroid therapy, and one patient (case 4) had suffered a previous intracerebral bleed. Of the remaining six patients, no alternative etiology was found, and discontinuing or decreasing the cyclosporine dose was associated with resolution of the disc edema in all eight cases. The clinical courses of the eight patients with optic disc edema on cyclosporine are summarized in Table 1.
CASE REPORTS Case 1. A 14-year-old boy with acute myelogenous leukemia underwent an allogeneic bone marrow transplant on May 12, 1986. Despite cyclosporine prophylaxis, he developed acute GVHD of the skin, which was successfully treated with methylprednisolone. The patient was seen at 175 days after transplant for routine ophthalmologic examination, at which time he had no evidence of GVHD. He had no visual symptoms. His medications included cyclosporine at a dosage of 145 mg daily, trimethoprim/sulfamethoxazole, clonidine, and magnesium oxide. Results of examination showed a visual acuity of 20/20 bilaterally, color vision of 10/10 Ishihara plates bilaterally, and normal pupillary responses, extraocular motility, slit-lamp examination, and intraocular pressures. Results of Goldmann perimetry showed enlarged blind spots. Results of ophthalmoscopy
showed bilateral optic disc edema. Results of a neurologic examination and computed tomogram of the head were unremarkable. Results of a lumbar puncture showed an opening pressure of240 mm of water, protein level of 53 mg/dl, glucose level of 33 mg/dl, and a cell count of 8 mononuclear cells/JlJ. Cerebrospinal fluid cultures for bacteria, fungi, and viruses were negative, and cytology was normal. The patient's cyclosporine was discontinued, and by day 412 after transplant his papilledema had completely resolved. At last follow-up, 4 years after transplant, the patient was taking no medication and had a normal eye examination. Case 2. A 33-year-old woman with chronic myelogenous leukemia underwent an allogeneic T cell depleted bone marrow transplant on September 5, 1986. She was not placed on cyclosporine prophylaxis and developed acute GVHD, which was successfully treated with methylprednisolone. However, on day 56, she was readmitted to the hospital for headache and fever, and a computed tomogram showed a communicating hydrocephalus. On day 61, results of a lumbar puncture showed an opening pressure of 260 mm of water, glucose level of 52 mg/ dl, protein level of 31 mg/dl, and no cells. At this time, her graft had failed, and she was aplastic. Papilledema was not present. On day 74, she underwent a second transplant from the same donor after a preparative regimen of cyclosporine, cyclophosphamide, and OKT3. Her course was complicated by biopsyproven pulmonary aspergillosis, mild hypertension, and peripheral eosinophilia with a leukocyte count of 28,000/JLI and up to 40% eosinophils. Evaluation of the eosinophilia, including stool samples for parasites, HCTH skin test, muscle biopsy, serum and cerebrospinal fluid toxoplasma titers and connective tissue disease serologies was negative. On day 102 after transplant, results of an ophthalmic examination showed a visual acuity of 20/25 in the right eye and 20/20 in the left. The rest of the eye examination was normal except for bilateral optic disc edema. Medications at that time were cyclosporine at a dosage of 480 mg daily, amphotericin, megestrol acetate, 5-flucytosine, replacement immunoglobulin, vancomycin, doxepin, nifedipine, and trimethoprim/sulfamethoxazole. A repeat computed tomogram of the head showed hydrocephalus. Results of a lumbar puncture showed an opening pressure of 380 mm of water with 99 leukocytes!J.d. The cerebrospinal fluid differential was 23% mononuclear cells and 77% polymorphonuclear cells, with a predominance of eosinophils. Cerebrospinal fluid cultures for bacteria and fungi were negative, and cytology showed only reactive leukocytes. Results of an indium scan showed no evidence of cerebrospinal fluid outflow obstruction. The cyclosporine dose was subsequently tapered and discontinued. Acetazolamide 500 mg sequels orally twice daily and repeated lumbar punctures were started. The eosinophilic meningitis was treated with oral methylprednisolone. The disc edema resolved over I month. At last ophthalmic follow-up, I year after transplant, eye examination was unremarkable with no papilledema. Case 3. A 5-year-old boy underwent allogeneic bone marrow transplant on April 10, 1987 for chronic myelogenous leukemia. Despite cyclosporine prophylaxis, he developed acute and chronic GVHD requiring treatment with prednisone, azathioprine, and thalidomide. On day 332 after transplant, sinus films taken for recurrent sinusitis showed bony erosions consistent with increased intracranial pressure. Ophthalmologic examination showed a visual acuity in the right eye of 20/40 and 20/ 30 in the left; a color vision of 8/8 Ishihara plates bilaterally; enlarged blind spots on Goldmann perimetry; and moderately severe bilateral optic disc edema on ophthalmoscopy (Fig I). His medications at that time were cyclosporine at a dosage of 190 mg daily, thalidomide, magnesium oxide, clotrimazole, dicloxacillin, and replacement immunoglobulin. He denied any 1295
IV \0 0\
52 31 0
175 240
33 53 8 mono
Lumbar puncture (day) Opening pressure (mmH 2O) Glucose (mg/dl) Protein (mg/dl) White cells (per ILl)
137 Unexplained eosinophilia responded to MePred started day 118
113
5M CML
323 >500
Normal CT
35F CML
Patient 4
C/O 324 D/C 818 361 490 HTN and status epilepticus on CSA resolved after D/C of CSA on day 818
115 181 1 mono
818 330
Normal CT
67 188 442 Normal cysternogram
80 139 8 (38% polys)
Parietal hematoma, unchanged 31 230
BU Cy VP 16 Cy TBI CSA CSA Acute Acute 31 20/20, 20/20 8.5/10, 8.5/10 Normal
#2 (day 79)
Patient 3
Cy TBI CSA Acute and chronic 323 20/40, 20/20 8/8, 8/8 Enlarged BS
#1
44 55 118 22 99 (77% polys, mostly 1 mono eos)
Hydrocephalus Day (103) 103 380
Normal
102 20/25, 20/20
Cy OKT3 CSA CSA
#2 (day 74)
33F CML
Patient 2
Bu Cy CSA None
#1
515
136, D/C 395
51 143 73 mono
135 230
Normal MRI
Cy ATG CSA Acute 134 20/20, 20/20 10/10, 10/10 Normal
#2 (day 94)
19M AML
Patient 5
43M CML
Patient 7
Normal cysternogram
34, D/C 191 65/191
60 45 0
34 320
350
173
Va 20/20, 20/30 on day 173
D/C 196
50 60 0
196 140
Normal CT
Bu Cy CSA Acute 196 20/20, 20/20 10/10,10/10 Enlarged bS
43M AML
Patient 8
D/C 130
66 61 1 poly
130 180
Cy TBI CSA None 130 20/25, 20/100 10/10, 10/10 Paracentral scotoma L>R Normal CT, MRI Normal CT, MRI
Bu Cy CSA Acute 34 20/25, 20/25 6.5/10, 7/10 Enlarged BS
46M AML
Patient 6
AML = acute myelogenous leukemia; CML = chronic myelogenous leukemia; GVHD = graft vs. host disease; CSA = cyclosporine; ODE = optic disc edema; BS = blind spot; CT = computerized tomogram; MRI = magnetic resonance imaging; Poly = polymorphonuclear leukocyte; Eos = eosinophil; Mono = mononuclear leukocyte; D/C = discontinued; MePred = methylprednisolone; HTN = hypertension; VA = visual acuity; Bu = busulfan; Cy = cytoxan; TBI = total body irradiation; ATG = anti thymocyte globulin.
Course CSA decreased (day) D/C 175 ODE improved (day) ODE resolved (day) 412 Comment:
Hydrocephalus Day (56) 61 260
Normal CT
Neuroimaging
Cy TBI None Acute
Bu Cy CSA Acute 175 20/20, 20/20 10/10, 10/10 Enlarged BS
BMT preparation GVHD prophylaxis GVHD Day ODE Ox Visual acuity Color vision Visual fields
#1
14M AML
Patient 1
Age (yr)/sex Diagnosis
Case
Table 1. Patients wth Optic Disc Edema after Bone Marrow Transplant
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neurologic symptoms. His blood pressure was 106170, and his physical examination was unremarkable except for the papilledema. A computed tomogram of the head was normal, but results of a lumbar puncture showed an opening pressure of greater than 500 mm of water, glucose level of 55 mg/dl, protein level of 22 mg/dl, and cell count of one mononuclear cell/loLl. Cultures of the cerebrospinal fluid for bacteria and fungi were negative. The serum cyclosporine level was 20 ng/ml. The cyclosporine was discontinued, and the patient was treated with repeated lumbar punctures and acetazolamide 500 mg sequels orally twice daily. By day 361 after transplant, the disc edema had decreased, and by day 490 after transplant, it had completely resolved (Fig 2). Two years after the transplant, his leukemia relapsed, and the patient underwent a second allogeneic marrow transplant on June 16, 1989. He developed severe acute GVHD, which was treated with cyclosporine 5 mg/kg/day and methylprednisolone 2 mg/kg/day in four equal doses. Nineteen days after the second transplant, the methylprednisolone was decreased to 1.5 mg/ kg/day. The following day he developed hypertension to 180/ 120 mmHg and suffered seizures. A computed tomogram of the head was normal, but results of a lumbar puncture showed an opening pressure of 330 mm of water, glucose level of 115 mg/ dl, protein level of 181 mg/dl, and a cell count of 849 erythrocytes/loLl. He became hypoxic due to continued seizure activity and required a brief period of intubation. Cyclosporine was discontinued, the seizures ceased, the patient improved, and he was extubated the following day. The seizures were believed to be a manifestation of cyclosporine toxicity. Results of ophthalmologic examination showed no recurrence of the optic disc edema. Case 4. A 35-year-old woman with chronic myelogenous leukemia underwent an allogeneic bone marrow transplant on July 17, 1987. Despite cyclosporine prophylaxis, she developed acute GVHD, successfully treated with methylprednisolone. On day 19, she suffered a left posterior parieto-occipital intraparenchymal cerebral hemorrhage, while the platelet count was 20,000/IoLI, complicated by confusion, a single generalized tonicclonic seizure, subsequent right hemiplegia, a right visual field defect, and speech difficulties. The patient's neurologic deficits quickly resolved, but on day 31, asymptomatic bilateral optic disc edema was observed. Visual acuity was 20/20 bilaterally; color vision was 8IJ2 of 10 Ishihara plates bilaterally, and Goldmann perimetry was normal. Her medications were cyclosporine at dosage of 540 mg daily, Phenergan, phenytoin, ranitidine, methylprednisolone, and megestrol acetate. A computed tomogram of the head showed a resolving intracerebral bleed without new pathology or hydrocephalus. On day 48, the patient experienced transient right eye visual obscurations, presumed to be related to papilledema. Intracranial pressure monitoring showed a maximum intracranial pressure of 230 mm of water. Results of cerebrospinal fluid examination showed a glucose level of 80 mg/dl, protein level of 139 mg/dl, and 8 leukocytes/loLl, of which 38% were polymorphonuclear leukocytes and 62% were mononuclear cells. Cerebrospinal fluid cultures for bacteria, fungi, and viruses were negative, and cytology was normal. The serum cyclosporine level was 493 ng/ml. On day 67, the cyclosporine dose was decreased from 350 mg twice daily orally to 240 mg daily and subsequently tapered to 135 mg twice daily by day 188. The bilateral disc edema remained unchanged at eye examination on days 67 and 94. However, the optic disc edema was markedly decreased in the right eye and resolved in the left on examination on day 188. At last ophthalmic followup, 422 days after transplant, the eye examination was normal with no disc edema. Case 5. A 19-year-old man with acute myelogenous leukemia and a history of central nervous system relapse received an al-
logenic one antigen mismatched bone marrow transplant on October 28, 1987. The immediate post-transplant course was complicated by a superior vena cava syndrome, sinusitis, erosive gastritis, and ultimately failure of engraftment. He underwent a second transplant on December II, 1987 from the same donor using cyclosporine prophylaxis. Mild acute GVHD developed and responded well to treatment with methylprednisolone. On day 90 after transplant, asymptomatic bilateral papilledema was noted on routine ophthalmologic examination. The visual acuity was 20/20 bilaterally, the color vision 10/10 Ishihara plates bilaterally, and Goldmann perimetry was normal. His medications were cyclosporine at a dosage of 500 mg daily, erythromycin, magnesium oxide, ranitidine, and pseudoephedrine. A neurologic examination and a magnetic resonance imaging scan of the head were normal. Results of a lumbar puncture showed an opening pressure of 230 mm of water, glucose level of 51 mg/ dl, protein level of 143 mg/d!, and 73 leukocytes/loLl, mostly lymphocytes, which were normal by cytology. Cultures of the cerebrospinal fluid for bacteria and fungi were negative. The serum cyclosporine level was 684 ng/ml. On day 92, the patient's cyclosporine dose was lowered from 250 mg orally twice daily to 150 mg twice daily. On day 97, he developed cutaneous herpes zoster and was readmitted to the hospital for intravenous acyclovir therapy. His skin lesions resolved with intravenous acyclovir therapy. The optic disc edema was still present on examination at day 145. The cyclosporine was tapered and ultimately discontinued on day 395, and the optic disc edema completely resolved by day 515 after transplant. Case 6. A 46-year-old man with acute myelogenous leukemia underwent an allogeneic transplant on October 4, 1988. Graftversus-host disease prophylaxis was cyclosporine, and very mild cutaneous GVHD developed, which did not require therapy. The patient was referred for ophthalmologic examination 34 days after transplant for complaints of blurred vision. Results of examination showed a visual acuity of 20/25 bilaterally, a color vision of 6 112 of 10 Ishihara plates on the right and 7 of 10 plates on the left. Results of Goldmann perimetry showed an enlarged blind spot in both eyes. Optic disc edema was present bilaterally (Fig 3). Medications were cyclosporine at a dosage of 600 mg daily, trimethoprim/sulfamethoxazole, magnesium oxide, Mycostatin, and verapamil. Results of medical examination showed mild hypertension, which was well controlled by medication. A computed tomogram of the head was normal. A lumbar puncture showed an opening pressure of 320 mm of water, protein level of 45 mg/dl, glucose level of 60 mg/dl, and no cells. Cerebrospinal fluid cultures were negative, and cytology was normal. The serum cyclosporine level was 163 ng/ml. The patient's cyclosporine dose was decreased from 300 mg twice daily orally to 200 mg twice daily, and treatment with acetazolamide, 500 mg sequels twice daily, was begun to lower the increased intracranial pressure. By day 65, the optic disc edema had started to resolve. The cyclosporine was tapered and discontinued, and by day 191, there was only minimal optic disc edema present (Fig 4). Case 7. A 43-year-old man with chronic myelogenous leukemia underwent an allogeneic bone marrow transplant on December 19, 1988. He received cyclosporine prophylaxis and did not develop GVHD. His course was uncomplicated until day 123 after transplant, when he noticed blurred vision in the left eye. Results of an ophthalmologic examination on day 130 showed a visual acuity of 20/25 in the right eye and 20/100 in the left, a left afferent pupillary defect, and bilateral optic disc edema, greater on the left eye than on the right. Results of Goldmann perimetry showed bilateral enlarged blind spots and temporal paracentral scotomata. Medications were cyclosporine at a dosage of 230 mg daily, magnesium oxide, ranitidine, and sucralfate. A computed tomogram of the head, a magnetic res1297
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Fig 1. Top, case 3. Left, right eye and right, left eye, at day 332 after bone marrow transplant, shows bilateral optic disc edema. Fig 2. Second row, case 3. Left, right eye and right, left eye, at day 490 post-transplant, showing resolution of the optic disc edema. Fig 3. Third row, case 6. Left, right eye and right, left eye, at day 34 after transplant shows bilateral optic disc edema. Fig 4. Bottom, case 6. Left, right eye and right, left eye, at day 191 post-transplant shows dramatic improvement in the disc edema. (
onance imaging scan, and a neurologic examination were all normal. Results oflumbar puncture showed an opening pressure of 180 mm of water, glucose level of 66 mg/dl, protein level of 61 mg/dl, and one polymorphonuclear leukocyte/JLI. Cerebrospinal fluid cultures for bacteria and fungi were negative, and cytology was normal. The serum cyclosporine level was 333 ng/ml. The cyclosporine was discontinued, and the patient was treated with acetazolamide 500 mg sequels twice daily. By day 139, his visual acuity improved to 20/25 in the right and 20/50 in the left. There was a mild decrease in the optic disc edema. By day 173, the acuity had improved to 20/20 in the right eye and 20/30 in the left, and the disc edema had resolved. Case 8. A 43-year-old man with acute myelogenous leukemia underwent an allogeneic bone marrow transplant on June 27, 1989. He received cyclosporine prophylaxis but developed acute GVHD. This was successfully treated with corticosteroids and intravenous Xomazyme. He was seen for routine follow-up at day 196 after transplant. At that time, he had no visual symptoms. His only medications were cyclosporine at a dosage of 130 mg daily, magnesium oxide, and trimethoprim/sulfamethoxazole. Visual acuity was 20/20 in both eyes. Color vision was 10/10 Ishihara plates bilaterally, and results of Goldmann perimetry showed mildly enlarged blind spots bilaterally. The ophthalmologic examination was unremarkable except for bilateral optic disc edema. Computed tomogram of the head and a neurologic examination were normal. Results oflumbar puncture showed an opening pressure of 140 mm of water, glucose level of 50 mg/dl, protein level of 60 mg/dl, and no leukocytes. Cerebrospinal fluid cultures were negative. The cyclosporine was discontinued. The patient was subsequently seen on day 350 after transplant, at which time the optic disc edema had resolved.
DISCUSSION Cyclosporine has become widely used in the field of organ transplantation. However, with widespread use, a increasing number of side effects have been ascribed to it. Neurologic side effects ascribed to cyclosporine are usually central instead of peripheral and are reversible with reduction or discontinuation of the drug. 18 ,22-29 Up to 20% of liver and kidney transplant patients have been reported to develop signs of cyclosporine neurotoxicity.19,30 The severity of the effects ranges from paresthesia, headaches, and tremors, which may be relatively benign, to paresis, encephalopathy, coma, and seizures, which may be fatal. 30 Seizures have been reported to occur in up to 2% of patients taking cyclosporine. 18 ,20,23,30 Cortical blindness and encephalopathy was noted in one patient with a toxic serum cyclosporine level (1704 ng/ml) and resolved after discontinuation of the cyclosporine. 28 Similar resolution of paresis, mental status changes, and even coma has been described. 22 ,24,29 Despite several reports of cyclosporine neurotoxicities, we are unaware of any previous report of papilledema, optic disc edema, or optic
neuropathy related to cyclosporine, Several patients with cyclosporine-related seizures have been reported to have elevated cerebrospinal fluid pressure, but no reference is made of the presence of disc edema.2o,24 We report the cases of eight patients undergoing bone marrow transplant in whom optic disc edema developed, which resolved or improved after decreasing or eliminating the dose of cyclosporine, No definite alternate cause for the disc edema was determined in six of these cases despite extensive evaluation. Case 1 had papilledema, detected on routine ophthalmologic examination, associated with a mild elevation of his intracranial pressure. An evaluation for alternative causes was unsuccessful, and his papilledema resolved with discontinuation of his cyclosporine. Asymptomatic papilledema also developed in the patient in case 3 and resolved with discontinuation of the cyclosporine, lumbar puncture, and oral acetazolamide therapy, In connection with his second transplant, he suffered seizures, believed to be related to cyclosporine and which necessitated discontinuation of the cyclosporine, Papilledema did not develop in association with this event, but the patient was taking cyclosporine only briefly and had only a brief elevation of his intracranial pressure. Presumably, there was insufficient time available during this second challenge for papilledema to develop once again. Case 5 is similar to case 1 in that optic disc edema was asymptomatic and detected only on ophthalmologic examination. The neurologic evaluation and neuroimaging were normal. Results oflumbar puncture showed a mildly elevated intracranial pressure with elevated protein and pleocytosis levels. Despite lowering of the cyclosporine dose, the disc edema persisted. However, the disc edema resolved after cyclosporine was discontinued, The patient in case 6 complained of blurred vision and decreased color vision but had good visual acuity. Neurologic examination and neuroimaging were normal, but results of lumbar puncture showed moderately elevated intracranial pressure, Decrease in the dose of cyclosporine and the institution of acetazolamide therapy led to improvement in the optic disc edema. Case 7 presented with definite impairment of his visual acuity and an optic neuropathy rather than straightforward papilledema. Neuroimaging was normal, but results of lumbar puncture showed mild elevation of the cerebrospinal fluid protein level. Discontinuation of the cyclosporine and treatment to lower the intracranial pressure resulted in rapid improvement of the optic neuropathy and disc edema, Case 8 was similar to case 1 in that the patient presented with asymptomatic bilateral optic edema, which resolved after discontinuation of the cyclosporine. Elevation of the intracranial pressure was not detected in this case, although there was a mild elevation of the cerebrospinal fluid protein. 1299
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Two additional cases present a slightly more complicated picture. Case 2 did not receive cyclosporine in conjunction with her first transplant but did develop a communicating hydrocephalus and elevated intracranial pressure. No papilledema was seen at that time. She was prescribed cyclosporine in conjunction with her second transplant and papilledema was noted only after the institution of cyclosporine therapy. At that time, she had a peripheral eosinophilia and an eosinophilic meningitis. Treatment of the elevated intracranial pressure and the use of steroids to treat the eosinophilic meningitis led to improvement in an ocular condition. Case 4 developed papilledema while taking cyclosporine but had suffered a previous intracranial bleed. The papilledema was noted at a time when her bleed was resolving and at a time when results of neuroradiologic studies showed no evidence for outflow obstruction from the previous intracranial bleed. It was the opinion of the neurologists at that time that the optic disc edema could not be explained on the basis of the previous intracranial bleed and was due to the cyclosporine therapy. The one constant in all eight of these cases is the use of cyclosporine and improvement in the optic disc edema when the cyclosporine was either discontinued or the dose was substantially decreased. Seven of the eight cases presented with a picture of papilledema with asymptomatic or minimally symptomatic optic disc edema and no evidence for visual impairment other than an enlarged blind spot on visual fields. In six of the seven cases the intracranial pressure was elevated, although often modestly. Case 7 had more of a picture of an optic neuropathy with decreased visual acuity and an afferent pupillary defect. In all cases, the ocular abnormalities rapidly resolved after cyclosporine was discontinued, strongly suggesting that cyclosporine was the cause of the disc edema. The serum concentration of cyclosporine was measured in five patients and found to range from less than 20 ng/ ml to 684 ng/ml. The relationship between serum levels of cyclosporine, therapeutic efficacy, and toxicity is inconsistent, particularly in relation to toxicity. However, some authors l6 have suggested that "therapeutic" serum levels of cyclosporine are approximately 100 ng/ml to 300 ng/ml. Thus, three of our patients had mildly "elevated" levels, while one was in the "therapeutic" range and one was in the "subtherapeutic" range. The inconsistency in serum levels and the fact that none of the patients had excessively high levels suggest that the optic disc edema is an idiosyncratic response to cyclosporine. If the optic disc edema is due to cyclosporine, one cannot tell whether it represents a direct toxic effect of the drug, papilledema due to increased intracranial pressure, or some other mechanism. It is also possible that both mechanisms could be operative, accounting for the different clinical pictures seen. Patients undergoing bone marrow transplantation represent a complex medical situation in which there are often mUltiple organ system abnormalities and multiple therapies used. Treatment of patients undergoing bone marrow transplant usually requires mUltiple drugs, making it difficult to implicate any one as the cause of a pathologic process. However, given 1300
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the large number of neurotoxic effects already ascribed to cyclosporine, we believe that it also may have a role in the development of optic disc edema in patients who have undergone bone marrow transplant.
REFERENCES 1. Thomas ED, Storb R, Clift RA, et al. Bone marrow transplantation (first of two parts). N Engl J Med 1975; 292:832-43. 2. Thomas ED, Storb R, Clift RA, et al. Bone marrow transplantation (second of two parts). N Engl J Med 1975; 292:895-902. 3. Santos GW, Tutschka PJ, Brookmeyer R, et aI. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med 1983; 309:1347-53. 4. Wingard JR, Piantadosi S, Santos GW, et al. Allogeneic bone marrow transplantation for patients with high·risk acute lymphoblastic leukemia. J Clin Onco11990; 8:820-30. 5. Elfenbein GJ, Mellits ED, Santos GW. Patients with aplastic anemia. Engraftment and survival after allogenic bone marrow transplantation for severe aplastic anemia. Transplant Proc 1983; 15:1412-16. 6. Goldman JM, Apperley JF, Jones L, et al. Bone marrow transplantation for patients with chronic myeloid leukemia. N Engl J Med 1986; 314: 202-7. 7. Slavin RE, Santos GW. The graft versus host reaction in man after bone marrow transplantation: pathology, pathogenesis, clinical fea· tures, and implication. Clin Immunollmmunopathol1973; 1:472-98. 8. Glucksberg H, Storb R, Fefer A, et al. Oinical manifestations of graft· versus-host disease in human reCipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18:295-304. 9. Shulman HM, Sullivan KM, Weiden PL, et al. Chronic graft-versushost syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980; 69:204-17. 10. Sullivan KM, Shulman H, Storb R, et al. Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood 1981; 57:267-76. 11. Storb R, Prentice RL, Buckner CD, et al. Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings. Beneficial effects of a protective environment. N Engl J Med 1983; 308:302-7. 12. Champlin RE, Gale RP. The early complications of bone marrow transplantation. Semin Hematol1984; 21:101-8. 13. Sullivan KM, Deeg HJ, Sanders JE, et al. Late complications after marrow transplantation. Semin Hematol 1984; 21 :53-63. 14. Tutschka PJ, Beschorner WE, Hess AD, Santos GW. Cyclosporin-A to prevent graft-versus-host disease: a pilot study in 22 patients rec\living allogeneic marrow transplants. Blood 1983; 61 :318-25. 15. Deeg HJ, Storb R, Thomas ED, et al. Cyclosporine as prophylaxis for graft-versus-host disease: a randomized study on patients undergoing marrow transplantation for acute non lymphoblastic leukemia. Blood 1985; 65:1325-34. 16. Kahan BD. Cyclosporine. N Engl J Med 1989; 321: 1725-38. 17. Shulman H, Striker G, Deeg HJ, et al. Nephrotoxicity of cyclosporin A after allogeneic marrow transplantation: glomerular thromboses and tubular injury. N Engl J Med 1981; 305:1392-5. 18. Palestine AG, Austin HA III, Ballow JE, et al. Renal histopathologic alterations in patients treated with cyclosporine for uveitis. N Engl J Med 1986;314:1293-8. 19. Kahan BD, Flechner SM, Lorber MI, et al. Complications of cyclosporine-prednisone immunosuppression in 402 renal allograft recipients exclusively followed at a single center for from one to five years. Transplantation 1987; 43:197-204. 20. Durrant S, Chipping PM, Palmer S, Gordon-Smith EC. Cyclosporin A, methylprednisolone, and convulsions. [letter]. Lancet 1982; 2:82930.
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21. Kennedy MS, Yee GC, Deeg HJ, et al. Pharmacokinetics and toxicity of cyclosporine in marrow transplant patients. Transplant Proc 1983; 15:2416-8. 22. Atkinson K, Biggs J, Darveniza P, et al. Cyclosporin-associated central nervous system toxicity after allogeneic bone marrow transplantation. Transplantation 1984; 38:34-7. 23. Thompson CB, June CH, Sullivan KM, Thomas ED. Association be· tween cyclosporin neurotoxicity and hypomagnesaemia. Lancet 1984; 2:1116-20. 24. Beaman M, Parvin S, Veitch PS, Walls J. Convulsions associated with cyclosporin A in renal transplant recipients. Br Med J 1985; 290: 13940. 25. Wilczek H, Ringden 0, Tyden G. Cyclosporine·associated central nervous system toxicity after renal transplantation. Transplantation 1985; 39:110. 26. Velu Th, Debusscher L, Stryckmans PA. Cyclosporine-associated fatal convulsions [Letter). Lancet 1985; 1:219. 27. Labar B, Bogdanic V, Plavsic F, et al. Cyclosporin neurotoxicity in patients treated with allogeneic bone marrow transplantation. Biomed Pharmacother 1986; 40:148-50.
28. Rubin AM, Kang H. Cerebral blindness and encephalopathy with cyclosporin A toxicity. Neurology 1987; 37:1072-6. 29. de Groen PC, Aksamit AJ, Rakela J, et al. Central nervous system toxicity after liver transplantation. The role of cyclosporine and cho· lesterol. N Engl J Med 1987; 317:861-6. 30. Lane RJM, Roche SW, Leung AAW, et al. Cyclosporin neurotoxicity in cardiac transplant reCipients. J Neurol Neurosurg Psychiatry 1988; 51 :1434-7. 31. Noll RB, Kulkami R. Complex visual hallucinations and cyclosporine. Arch Neurol 1984; 41 :329-30. 32. Jabs DA, Wingard J, Green WR, et al. The eye in bone marrow transplantation. III. Conjunctival graft-versus-host disease. Arch Ophthalmol 1989; 107:1343-8. 33. Santos GW, Tutschka PJ, Brookmeyer R, et al. Cyclosporine plus methylprednisolone versus cyclophosphamide plus methylprednisolone as prophylaxis for graft-versus-host disease: a randomized doubleblind study in patients undergoing allogeneic marrow transplantation. Clin Transplant 1987; 1:21-8. 34. Hirst LW, Jabs DA, Tutschka PJ, et al. The eye in bone marrow transplantation. I. Clinical study. Arch Ophthalmol1983; 101 :580-84.
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Abstract: Bone marrow transplantation has become widely used in the treatment of aplastic anemia and leukemia. Cyclosporine is used as prophylaxis against graft-versus-host disease. The authors report on eight cases of optic disc edema in patients taking cyclosporine after allogenic bone marrow transplant. Thorough evaluation revealed a possible alternate cause in two cases. In all cases, the optic disc edema resolved after discontinuing or decreasing the cyclosporine. Although cyclosporine has not previously been associated with optic disc edema, it has been implicated as the cause of a variety of neurologic side effects. Bone marrow transplant patients taking cyclosporine should be followed for the development of optic disc edema. Ophthalmology 1991; 98: 1294-130 1
Bone marrow transplantation has become the treatment of choice for severe aplastic anemia, when a donor exists, and is widely used in the treatment of leukemia and lymphoma when treatment with chemotherapy has failed or is expected to fail. l - 6 Bone marrow transplantation uses ablation of the patient's own marrow using cytoreductive chemotherapy and total body irradiation, followed by transplantation of donor bone marrow to reconstitute the patient's hematologic function. A major complication of allogenic marrow transplantation is graft-versus-host disease (GVHD) in which the transplanted marrow mounts a lymphocyte-mediated immunologic attack on the host, which is perceived as foreign by the donor marrow. 7- 13 Cyclosporine, also known as cyclosporin A, is a potent immunosuppressive drug now used routinely for the proOriginally received: November 9. 1990. Revision accepted: February 28, 1991. From the Wilmer Ophthalmological Institute, The Department of Ophthalmology, and the Bone Marrow Transplant Unit, The Johns Hopkins University School of Medicine, Baltimore. Presented in part as a poster at the American Academy of Ophthalmology Annual Meeting, New Orleans, Oct/Nov 1989. Supported in part by NIH grant P01 CA 153960 from the National Cancer Institute/NIH, Bethesda, Maryland. Reprint requests to Douglas A. Jabs, MD, The Wilmer Ophthalmological Institute, 550 N Broadway, Suite 700, Baltimore, MD 21205.
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phylaxis of and treatment of GVHD. 14-16 Because cyclosporine lacks myelotoxicity, its use allows for more rapid engraftment than does myelosuppressive immunosuppressants. 15 However, cyclosporine demonstrates several toxicities, the most frequent and dose-limiting of which is nephrotoxicity.17-19 More recently, cyclosporine has been implicated in a wide variety of neurotoxicities, including seizures, encephalopathy, cerebellar and spinal cord syndromes, dysarthria, tremor, coma, cortical blindness, increased intracranial pressure, and increased cerebral spinal fluid protein.20 - 31 We report eight patients who underwent allogenic bone marrow transplantation and in whom optic disc edema subsequently developed. Of these, two patients had possible alternate causes: one, an eosinophilic meningitis of unknown etiology, and the second, a previous intracranial hemorrhage. Of the remaining six patients, no alternative etiology of the optic disc edema could be determined, and in all cases the disc edema improved after decreasing or discontinuing the cyclosporine. We suggest that optic disc edema may be another manifestation of cyclosporine neurotoxicity.
SUBJECfS AND METHODS All patients in this series underwent transplant at the Bone Marrow Transplantation Unit of the Johns Hopkins
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Oncology Center between July 1984 and July 1990 and had regular ophthalmologic examinations as part of an ongoing evaluation of the ocular complications of marrow transplantY All patients included in this report received transplants according to standardized protocols used by the Unit. Informed consent was obtained for the transplant, as well as for all transplant-related procedures. The preparative regimens were standardized according to pretransplant diagnosis and have been described elsewhere. 3,4,33,34 The usual cyclosporine dose for GYRO prophylaxis was 5 mg/kg/day intravenously for the 2 days before and the first 3 days after transplant. The dose of cyclosporine was then slowly tapered to 3.75 mg/kg orally twice daily by day 50 and continued at that dose until discontinuation at day 170. The dose of cyclosporine was altered depending on the clinical course of GYRO or on the development of renal impairment.
RESULTS Ouring this period, 323 patients underwent allogenic marrow transplant using cyclosporine prophylaxis. Of these 323 patients, optic disc edema developed in 8 (2.5%). Unexplained disc edema was not seen in any of 52 patients undergoing allogenic transplant using alternative methods of GYRO prophylaxis during this period or that of our previous study.32,34 Only one patient among 399 patients undergoing an autologous transplant developed papilledema, and this occurred in association with a Streptococcus viridans meningitis and resolved with successful antibiotic treatment of the meningitis. None offour patients undergoing syngeneic bone marrow transplant developed optic disc edema. One patient (case 2) developed disc edema in association with an eosinophilic meningitis of unknown etiology, which resolved with corticosteroid therapy, and one patient (case 4) had suffered a previous intracerebral bleed. Of the remaining six patients, no alternative etiology was found, and discontinuing or decreasing the cyclosporine dose was associated with resolution of the disc edema in all eight cases. The clinical courses of the eight patients with optic disc edema on cyclosporine are summarized in Table 1.
CASE REPORTS Case 1. A 14-year-old boy with acute myelogenous leukemia underwent an allogeneic bone marrow transplant on May 12, 1986. Despite cyclosporine prophylaxis, he developed acute GVHD of the skin, which was successfully treated with methylprednisolone. The patient was seen at 175 days after transplant for routine ophthalmologic examination, at which time he had no evidence of GVHD. He had no visual symptoms. His medications included cyclosporine at a dosage of 145 mg daily, trimethoprim/sulfamethoxazole, clonidine, and magnesium oxide. Results of examination showed a visual acuity of 20/20 bilaterally, color vision of 10/10 Ishihara plates bilaterally, and normal pupillary responses, extraocular motility, slit-lamp examination, and intraocular pressures. Results of Goldmann perimetry showed enlarged blind spots. Results of ophthalmoscopy
showed bilateral optic disc edema. Results of a neurologic examination and computed tomogram of the head were unremarkable. Results of a lumbar puncture showed an opening pressure of240 mm of water, protein level of 53 mg/dl, glucose level of 33 mg/dl, and a cell count of 8 mononuclear cells/JlJ. Cerebrospinal fluid cultures for bacteria, fungi, and viruses were negative, and cytology was normal. The patient's cyclosporine was discontinued, and by day 412 after transplant his papilledema had completely resolved. At last follow-up, 4 years after transplant, the patient was taking no medication and had a normal eye examination. Case 2. A 33-year-old woman with chronic myelogenous leukemia underwent an allogeneic T cell depleted bone marrow transplant on September 5, 1986. She was not placed on cyclosporine prophylaxis and developed acute GVHD, which was successfully treated with methylprednisolone. However, on day 56, she was readmitted to the hospital for headache and fever, and a computed tomogram showed a communicating hydrocephalus. On day 61, results of a lumbar puncture showed an opening pressure of 260 mm of water, glucose level of 52 mg/ dl, protein level of 31 mg/dl, and no cells. At this time, her graft had failed, and she was aplastic. Papilledema was not present. On day 74, she underwent a second transplant from the same donor after a preparative regimen of cyclosporine, cyclophosphamide, and OKT3. Her course was complicated by biopsyproven pulmonary aspergillosis, mild hypertension, and peripheral eosinophilia with a leukocyte count of 28,000/JLI and up to 40% eosinophils. Evaluation of the eosinophilia, including stool samples for parasites, HCTH skin test, muscle biopsy, serum and cerebrospinal fluid toxoplasma titers and connective tissue disease serologies was negative. On day 102 after transplant, results of an ophthalmic examination showed a visual acuity of 20/25 in the right eye and 20/20 in the left. The rest of the eye examination was normal except for bilateral optic disc edema. Medications at that time were cyclosporine at a dosage of 480 mg daily, amphotericin, megestrol acetate, 5-flucytosine, replacement immunoglobulin, vancomycin, doxepin, nifedipine, and trimethoprim/sulfamethoxazole. A repeat computed tomogram of the head showed hydrocephalus. Results of a lumbar puncture showed an opening pressure of 380 mm of water with 99 leukocytes!J.d. The cerebrospinal fluid differential was 23% mononuclear cells and 77% polymorphonuclear cells, with a predominance of eosinophils. Cerebrospinal fluid cultures for bacteria and fungi were negative, and cytology showed only reactive leukocytes. Results of an indium scan showed no evidence of cerebrospinal fluid outflow obstruction. The cyclosporine dose was subsequently tapered and discontinued. Acetazolamide 500 mg sequels orally twice daily and repeated lumbar punctures were started. The eosinophilic meningitis was treated with oral methylprednisolone. The disc edema resolved over I month. At last ophthalmic follow-up, I year after transplant, eye examination was unremarkable with no papilledema. Case 3. A 5-year-old boy underwent allogeneic bone marrow transplant on April 10, 1987 for chronic myelogenous leukemia. Despite cyclosporine prophylaxis, he developed acute and chronic GVHD requiring treatment with prednisone, azathioprine, and thalidomide. On day 332 after transplant, sinus films taken for recurrent sinusitis showed bony erosions consistent with increased intracranial pressure. Ophthalmologic examination showed a visual acuity in the right eye of 20/40 and 20/ 30 in the left; a color vision of 8/8 Ishihara plates bilaterally; enlarged blind spots on Goldmann perimetry; and moderately severe bilateral optic disc edema on ophthalmoscopy (Fig I). His medications at that time were cyclosporine at a dosage of 190 mg daily, thalidomide, magnesium oxide, clotrimazole, dicloxacillin, and replacement immunoglobulin. He denied any 1295
IV \0 0\
52 31 0
175 240
33 53 8 mono
Lumbar puncture (day) Opening pressure (mmH 2O) Glucose (mg/dl) Protein (mg/dl) White cells (per ILl)
137 Unexplained eosinophilia responded to MePred started day 118
113
5M CML
323 >500
Normal CT
35F CML
Patient 4
C/O 324 D/C 818 361 490 HTN and status epilepticus on CSA resolved after D/C of CSA on day 818
115 181 1 mono
818 330
Normal CT
67 188 442 Normal cysternogram
80 139 8 (38% polys)
Parietal hematoma, unchanged 31 230
BU Cy VP 16 Cy TBI CSA CSA Acute Acute 31 20/20, 20/20 8.5/10, 8.5/10 Normal
#2 (day 79)
Patient 3
Cy TBI CSA Acute and chronic 323 20/40, 20/20 8/8, 8/8 Enlarged BS
#1
44 55 118 22 99 (77% polys, mostly 1 mono eos)
Hydrocephalus Day (103) 103 380
Normal
102 20/25, 20/20
Cy OKT3 CSA CSA
#2 (day 74)
33F CML
Patient 2
Bu Cy CSA None
#1
515
136, D/C 395
51 143 73 mono
135 230
Normal MRI
Cy ATG CSA Acute 134 20/20, 20/20 10/10, 10/10 Normal
#2 (day 94)
19M AML
Patient 5
43M CML
Patient 7
Normal cysternogram
34, D/C 191 65/191
60 45 0
34 320
350
173
Va 20/20, 20/30 on day 173
D/C 196
50 60 0
196 140
Normal CT
Bu Cy CSA Acute 196 20/20, 20/20 10/10,10/10 Enlarged bS
43M AML
Patient 8
D/C 130
66 61 1 poly
130 180
Cy TBI CSA None 130 20/25, 20/100 10/10, 10/10 Paracentral scotoma L>R Normal CT, MRI Normal CT, MRI
Bu Cy CSA Acute 34 20/25, 20/25 6.5/10, 7/10 Enlarged BS
46M AML
Patient 6
AML = acute myelogenous leukemia; CML = chronic myelogenous leukemia; GVHD = graft vs. host disease; CSA = cyclosporine; ODE = optic disc edema; BS = blind spot; CT = computerized tomogram; MRI = magnetic resonance imaging; Poly = polymorphonuclear leukocyte; Eos = eosinophil; Mono = mononuclear leukocyte; D/C = discontinued; MePred = methylprednisolone; HTN = hypertension; VA = visual acuity; Bu = busulfan; Cy = cytoxan; TBI = total body irradiation; ATG = anti thymocyte globulin.
Course CSA decreased (day) D/C 175 ODE improved (day) ODE resolved (day) 412 Comment:
Hydrocephalus Day (56) 61 260
Normal CT
Neuroimaging
Cy TBI None Acute
Bu Cy CSA Acute 175 20/20, 20/20 10/10, 10/10 Enlarged BS
BMT preparation GVHD prophylaxis GVHD Day ODE Ox Visual acuity Color vision Visual fields
#1
14M AML
Patient 1
Age (yr)/sex Diagnosis
Case
Table 1. Patients wth Optic Disc Edema after Bone Marrow Transplant
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neurologic symptoms. His blood pressure was 106170, and his physical examination was unremarkable except for the papilledema. A computed tomogram of the head was normal, but results of a lumbar puncture showed an opening pressure of greater than 500 mm of water, glucose level of 55 mg/dl, protein level of 22 mg/dl, and cell count of one mononuclear cell/loLl. Cultures of the cerebrospinal fluid for bacteria and fungi were negative. The serum cyclosporine level was 20 ng/ml. The cyclosporine was discontinued, and the patient was treated with repeated lumbar punctures and acetazolamide 500 mg sequels orally twice daily. By day 361 after transplant, the disc edema had decreased, and by day 490 after transplant, it had completely resolved (Fig 2). Two years after the transplant, his leukemia relapsed, and the patient underwent a second allogeneic marrow transplant on June 16, 1989. He developed severe acute GVHD, which was treated with cyclosporine 5 mg/kg/day and methylprednisolone 2 mg/kg/day in four equal doses. Nineteen days after the second transplant, the methylprednisolone was decreased to 1.5 mg/ kg/day. The following day he developed hypertension to 180/ 120 mmHg and suffered seizures. A computed tomogram of the head was normal, but results of a lumbar puncture showed an opening pressure of 330 mm of water, glucose level of 115 mg/ dl, protein level of 181 mg/dl, and a cell count of 849 erythrocytes/loLl. He became hypoxic due to continued seizure activity and required a brief period of intubation. Cyclosporine was discontinued, the seizures ceased, the patient improved, and he was extubated the following day. The seizures were believed to be a manifestation of cyclosporine toxicity. Results of ophthalmologic examination showed no recurrence of the optic disc edema. Case 4. A 35-year-old woman with chronic myelogenous leukemia underwent an allogeneic bone marrow transplant on July 17, 1987. Despite cyclosporine prophylaxis, she developed acute GVHD, successfully treated with methylprednisolone. On day 19, she suffered a left posterior parieto-occipital intraparenchymal cerebral hemorrhage, while the platelet count was 20,000/IoLI, complicated by confusion, a single generalized tonicclonic seizure, subsequent right hemiplegia, a right visual field defect, and speech difficulties. The patient's neurologic deficits quickly resolved, but on day 31, asymptomatic bilateral optic disc edema was observed. Visual acuity was 20/20 bilaterally; color vision was 8IJ2 of 10 Ishihara plates bilaterally, and Goldmann perimetry was normal. Her medications were cyclosporine at dosage of 540 mg daily, Phenergan, phenytoin, ranitidine, methylprednisolone, and megestrol acetate. A computed tomogram of the head showed a resolving intracerebral bleed without new pathology or hydrocephalus. On day 48, the patient experienced transient right eye visual obscurations, presumed to be related to papilledema. Intracranial pressure monitoring showed a maximum intracranial pressure of 230 mm of water. Results of cerebrospinal fluid examination showed a glucose level of 80 mg/dl, protein level of 139 mg/dl, and 8 leukocytes/loLl, of which 38% were polymorphonuclear leukocytes and 62% were mononuclear cells. Cerebrospinal fluid cultures for bacteria, fungi, and viruses were negative, and cytology was normal. The serum cyclosporine level was 493 ng/ml. On day 67, the cyclosporine dose was decreased from 350 mg twice daily orally to 240 mg daily and subsequently tapered to 135 mg twice daily by day 188. The bilateral disc edema remained unchanged at eye examination on days 67 and 94. However, the optic disc edema was markedly decreased in the right eye and resolved in the left on examination on day 188. At last ophthalmic followup, 422 days after transplant, the eye examination was normal with no disc edema. Case 5. A 19-year-old man with acute myelogenous leukemia and a history of central nervous system relapse received an al-
logenic one antigen mismatched bone marrow transplant on October 28, 1987. The immediate post-transplant course was complicated by a superior vena cava syndrome, sinusitis, erosive gastritis, and ultimately failure of engraftment. He underwent a second transplant on December II, 1987 from the same donor using cyclosporine prophylaxis. Mild acute GVHD developed and responded well to treatment with methylprednisolone. On day 90 after transplant, asymptomatic bilateral papilledema was noted on routine ophthalmologic examination. The visual acuity was 20/20 bilaterally, the color vision 10/10 Ishihara plates bilaterally, and Goldmann perimetry was normal. His medications were cyclosporine at a dosage of 500 mg daily, erythromycin, magnesium oxide, ranitidine, and pseudoephedrine. A neurologic examination and a magnetic resonance imaging scan of the head were normal. Results of a lumbar puncture showed an opening pressure of 230 mm of water, glucose level of 51 mg/ dl, protein level of 143 mg/d!, and 73 leukocytes/loLl, mostly lymphocytes, which were normal by cytology. Cultures of the cerebrospinal fluid for bacteria and fungi were negative. The serum cyclosporine level was 684 ng/ml. On day 92, the patient's cyclosporine dose was lowered from 250 mg orally twice daily to 150 mg twice daily. On day 97, he developed cutaneous herpes zoster and was readmitted to the hospital for intravenous acyclovir therapy. His skin lesions resolved with intravenous acyclovir therapy. The optic disc edema was still present on examination at day 145. The cyclosporine was tapered and ultimately discontinued on day 395, and the optic disc edema completely resolved by day 515 after transplant. Case 6. A 46-year-old man with acute myelogenous leukemia underwent an allogeneic transplant on October 4, 1988. Graftversus-host disease prophylaxis was cyclosporine, and very mild cutaneous GVHD developed, which did not require therapy. The patient was referred for ophthalmologic examination 34 days after transplant for complaints of blurred vision. Results of examination showed a visual acuity of 20/25 bilaterally, a color vision of 6 112 of 10 Ishihara plates on the right and 7 of 10 plates on the left. Results of Goldmann perimetry showed an enlarged blind spot in both eyes. Optic disc edema was present bilaterally (Fig 3). Medications were cyclosporine at a dosage of 600 mg daily, trimethoprim/sulfamethoxazole, magnesium oxide, Mycostatin, and verapamil. Results of medical examination showed mild hypertension, which was well controlled by medication. A computed tomogram of the head was normal. A lumbar puncture showed an opening pressure of 320 mm of water, protein level of 45 mg/dl, glucose level of 60 mg/dl, and no cells. Cerebrospinal fluid cultures were negative, and cytology was normal. The serum cyclosporine level was 163 ng/ml. The patient's cyclosporine dose was decreased from 300 mg twice daily orally to 200 mg twice daily, and treatment with acetazolamide, 500 mg sequels twice daily, was begun to lower the increased intracranial pressure. By day 65, the optic disc edema had started to resolve. The cyclosporine was tapered and discontinued, and by day 191, there was only minimal optic disc edema present (Fig 4). Case 7. A 43-year-old man with chronic myelogenous leukemia underwent an allogeneic bone marrow transplant on December 19, 1988. He received cyclosporine prophylaxis and did not develop GVHD. His course was uncomplicated until day 123 after transplant, when he noticed blurred vision in the left eye. Results of an ophthalmologic examination on day 130 showed a visual acuity of 20/25 in the right eye and 20/100 in the left, a left afferent pupillary defect, and bilateral optic disc edema, greater on the left eye than on the right. Results of Goldmann perimetry showed bilateral enlarged blind spots and temporal paracentral scotomata. Medications were cyclosporine at a dosage of 230 mg daily, magnesium oxide, ranitidine, and sucralfate. A computed tomogram of the head, a magnetic res1297
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Fig 1. Top, case 3. Left, right eye and right, left eye, at day 332 after bone marrow transplant, shows bilateral optic disc edema. Fig 2. Second row, case 3. Left, right eye and right, left eye, at day 490 post-transplant, showing resolution of the optic disc edema. Fig 3. Third row, case 6. Left, right eye and right, left eye, at day 34 after transplant shows bilateral optic disc edema. Fig 4. Bottom, case 6. Left, right eye and right, left eye, at day 191 post-transplant shows dramatic improvement in the disc edema. (
onance imaging scan, and a neurologic examination were all normal. Results oflumbar puncture showed an opening pressure of 180 mm of water, glucose level of 66 mg/dl, protein level of 61 mg/dl, and one polymorphonuclear leukocyte/JLI. Cerebrospinal fluid cultures for bacteria and fungi were negative, and cytology was normal. The serum cyclosporine level was 333 ng/ml. The cyclosporine was discontinued, and the patient was treated with acetazolamide 500 mg sequels twice daily. By day 139, his visual acuity improved to 20/25 in the right and 20/50 in the left. There was a mild decrease in the optic disc edema. By day 173, the acuity had improved to 20/20 in the right eye and 20/30 in the left, and the disc edema had resolved. Case 8. A 43-year-old man with acute myelogenous leukemia underwent an allogeneic bone marrow transplant on June 27, 1989. He received cyclosporine prophylaxis but developed acute GVHD. This was successfully treated with corticosteroids and intravenous Xomazyme. He was seen for routine follow-up at day 196 after transplant. At that time, he had no visual symptoms. His only medications were cyclosporine at a dosage of 130 mg daily, magnesium oxide, and trimethoprim/sulfamethoxazole. Visual acuity was 20/20 in both eyes. Color vision was 10/10 Ishihara plates bilaterally, and results of Goldmann perimetry showed mildly enlarged blind spots bilaterally. The ophthalmologic examination was unremarkable except for bilateral optic disc edema. Computed tomogram of the head and a neurologic examination were normal. Results oflumbar puncture showed an opening pressure of 140 mm of water, glucose level of 50 mg/dl, protein level of 60 mg/dl, and no leukocytes. Cerebrospinal fluid cultures were negative. The cyclosporine was discontinued. The patient was subsequently seen on day 350 after transplant, at which time the optic disc edema had resolved.
DISCUSSION Cyclosporine has become widely used in the field of organ transplantation. However, with widespread use, a increasing number of side effects have been ascribed to it. Neurologic side effects ascribed to cyclosporine are usually central instead of peripheral and are reversible with reduction or discontinuation of the drug. 18 ,22-29 Up to 20% of liver and kidney transplant patients have been reported to develop signs of cyclosporine neurotoxicity.19,30 The severity of the effects ranges from paresthesia, headaches, and tremors, which may be relatively benign, to paresis, encephalopathy, coma, and seizures, which may be fatal. 30 Seizures have been reported to occur in up to 2% of patients taking cyclosporine. 18 ,20,23,30 Cortical blindness and encephalopathy was noted in one patient with a toxic serum cyclosporine level (1704 ng/ml) and resolved after discontinuation of the cyclosporine. 28 Similar resolution of paresis, mental status changes, and even coma has been described. 22 ,24,29 Despite several reports of cyclosporine neurotoxicities, we are unaware of any previous report of papilledema, optic disc edema, or optic
neuropathy related to cyclosporine, Several patients with cyclosporine-related seizures have been reported to have elevated cerebrospinal fluid pressure, but no reference is made of the presence of disc edema.2o,24 We report the cases of eight patients undergoing bone marrow transplant in whom optic disc edema developed, which resolved or improved after decreasing or eliminating the dose of cyclosporine, No definite alternate cause for the disc edema was determined in six of these cases despite extensive evaluation. Case 1 had papilledema, detected on routine ophthalmologic examination, associated with a mild elevation of his intracranial pressure. An evaluation for alternative causes was unsuccessful, and his papilledema resolved with discontinuation of his cyclosporine. Asymptomatic papilledema also developed in the patient in case 3 and resolved with discontinuation of the cyclosporine, lumbar puncture, and oral acetazolamide therapy, In connection with his second transplant, he suffered seizures, believed to be related to cyclosporine and which necessitated discontinuation of the cyclosporine, Papilledema did not develop in association with this event, but the patient was taking cyclosporine only briefly and had only a brief elevation of his intracranial pressure. Presumably, there was insufficient time available during this second challenge for papilledema to develop once again. Case 5 is similar to case 1 in that optic disc edema was asymptomatic and detected only on ophthalmologic examination. The neurologic evaluation and neuroimaging were normal. Results oflumbar puncture showed a mildly elevated intracranial pressure with elevated protein and pleocytosis levels. Despite lowering of the cyclosporine dose, the disc edema persisted. However, the disc edema resolved after cyclosporine was discontinued, The patient in case 6 complained of blurred vision and decreased color vision but had good visual acuity. Neurologic examination and neuroimaging were normal, but results of lumbar puncture showed moderately elevated intracranial pressure, Decrease in the dose of cyclosporine and the institution of acetazolamide therapy led to improvement in the optic disc edema. Case 7 presented with definite impairment of his visual acuity and an optic neuropathy rather than straightforward papilledema. Neuroimaging was normal, but results of lumbar puncture showed mild elevation of the cerebrospinal fluid protein level. Discontinuation of the cyclosporine and treatment to lower the intracranial pressure resulted in rapid improvement of the optic neuropathy and disc edema, Case 8 was similar to case 1 in that the patient presented with asymptomatic bilateral optic edema, which resolved after discontinuation of the cyclosporine. Elevation of the intracranial pressure was not detected in this case, although there was a mild elevation of the cerebrospinal fluid protein. 1299
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Two additional cases present a slightly more complicated picture. Case 2 did not receive cyclosporine in conjunction with her first transplant but did develop a communicating hydrocephalus and elevated intracranial pressure. No papilledema was seen at that time. She was prescribed cyclosporine in conjunction with her second transplant and papilledema was noted only after the institution of cyclosporine therapy. At that time, she had a peripheral eosinophilia and an eosinophilic meningitis. Treatment of the elevated intracranial pressure and the use of steroids to treat the eosinophilic meningitis led to improvement in an ocular condition. Case 4 developed papilledema while taking cyclosporine but had suffered a previous intracranial bleed. The papilledema was noted at a time when her bleed was resolving and at a time when results of neuroradiologic studies showed no evidence for outflow obstruction from the previous intracranial bleed. It was the opinion of the neurologists at that time that the optic disc edema could not be explained on the basis of the previous intracranial bleed and was due to the cyclosporine therapy. The one constant in all eight of these cases is the use of cyclosporine and improvement in the optic disc edema when the cyclosporine was either discontinued or the dose was substantially decreased. Seven of the eight cases presented with a picture of papilledema with asymptomatic or minimally symptomatic optic disc edema and no evidence for visual impairment other than an enlarged blind spot on visual fields. In six of the seven cases the intracranial pressure was elevated, although often modestly. Case 7 had more of a picture of an optic neuropathy with decreased visual acuity and an afferent pupillary defect. In all cases, the ocular abnormalities rapidly resolved after cyclosporine was discontinued, strongly suggesting that cyclosporine was the cause of the disc edema. The serum concentration of cyclosporine was measured in five patients and found to range from less than 20 ng/ ml to 684 ng/ml. The relationship between serum levels of cyclosporine, therapeutic efficacy, and toxicity is inconsistent, particularly in relation to toxicity. However, some authors l6 have suggested that "therapeutic" serum levels of cyclosporine are approximately 100 ng/ml to 300 ng/ml. Thus, three of our patients had mildly "elevated" levels, while one was in the "therapeutic" range and one was in the "subtherapeutic" range. The inconsistency in serum levels and the fact that none of the patients had excessively high levels suggest that the optic disc edema is an idiosyncratic response to cyclosporine. If the optic disc edema is due to cyclosporine, one cannot tell whether it represents a direct toxic effect of the drug, papilledema due to increased intracranial pressure, or some other mechanism. It is also possible that both mechanisms could be operative, accounting for the different clinical pictures seen. Patients undergoing bone marrow transplantation represent a complex medical situation in which there are often mUltiple organ system abnormalities and multiple therapies used. Treatment of patients undergoing bone marrow transplant usually requires mUltiple drugs, making it difficult to implicate any one as the cause of a pathologic process. However, given 1300
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the large number of neurotoxic effects already ascribed to cyclosporine, we believe that it also may have a role in the development of optic disc edema in patients who have undergone bone marrow transplant.
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