Bone Marrow Transplantation, (1999) 23, 959–962  1999 Stockton Press All rights reserved 0268–3369/99 $12.00 http://www.stockton-press.co.uk/bmt Case report Cortical blindness and in a patient receiving FK506 after bone marrow transplantation

RE Steg1, A Kessinger2 and ZK Wszolek3

1Department of , Creighton University School of Medicine; 2Section of Hematology and Oncology, 3Section of Neurology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA

Summary: accompanied by acute dyspnea, thready pulse, low oxygen saturation and hypotension. These symptoms reversed with A 54-year-old woman with a myelodysplastic syndrome corticosteroid administration. The suspected but uncon- treated with high-dose chemotherapy and an allogenic firmed allergen was polyoxyethylated castor oil, a vehicle, bone marrow transplant developed acute cortical blind- in addition to alcohol, in the commercial cyclosporine pro- ness while receiving tacrolimus (FK506). MRI showed duct for injection. Tacrolimus (FK506) was substituted. white matter abnormalities. After discontinuation of Eleven days after the allogenic transplant, she developed FK506, the patient’s vision returned within 8 days. acute renal failure following a period of sepsis and hypoten- FK506 neurotoxicity is similar to cyclosporine neurotox- sion from which she gradually recovered without requiring icity and can occur in allogenic bone marrow transplant dialysis. However, on day 22, she developed a slight patients treated with FK506. worsening of her recovering renal function and FK506 tox- Keywords: cortical blindness and seizures; FK506 neuro- icity was suspected. On day 23, the blood level of FK506 toxicity; bone marrow transplantation was 50 ng/ml, exceeding the target level of 10–20 ng/ml, and FK506 dosage was reduced to one attenuated dose on day 28 and then was discontinued. Renal function slowly improved over the next few days but on day 27, when the FK506 (tacrolimus), a fungal metabolite produced by Strep- FK506 level was 20 ng/ml, she complained of confusion tomyces tsukubaenis, is an effective immunosuppressive and spatial disorientation. Her blood pressure was 156/82 agent used for bone marrow and organ transplantation mm Hg. Clinical examination revealed cortical blindness patients. A case of FK506 neurotoxicity is discussed. with visual defects and a of light perception only. An MRI of the brain, the first that had been perfor- med, demonstrated abnormal signals in the posterior par- Case report ietal and temporal areas bilaterally (Figure 1). A spinal tap was not performed. Thrombotic thrombocytopenic purpura A 54-year-old woman had been diagnosed 11 years earlier was considered since occasional schistocytes were seen on with extensive low-grade non-Hodgkin’s lymphoma. She the peripheral blood smear. She was platelet transfusion was treated with chemotherapy and achieved a complete independent after day 19 with a platelet count of 74 000/␮l remission. However, 2 years later her disease recurred and on day 30. An elevation in the LDH was noted from day she received salvage chemotherapy. One year later, she had 25 to day 31 which then fell to normal limits. No plasma- high-dose therapy and an autologous peripheral blood stem pheresis was performed. Creatinine levels reached an apex cell transplant. Her post-transplant course was essentially on day 24 and returned to normal by day 28. An EEG per- uneventful until 6 years later when she developed a myelo- formed on day 28 showed frequent right occipital subclin- dysplastic syndrome and underwent a matched, unrelated ical discharges (Figure 2). The patient received bone marrow transplant (BMT). Cyclophosphamide and prednisone and an intravenous loading dose of fospheny- total body irradiation were used as conditioning. She had toin. On day 29 she continued to experience light percep- never received intrathecal chemotherapy or brain irradiation tion only and was showing denial of blindness, character- prior to this conditioning. Three days prior to her allogenic istic of the Anton syndrome. A repeat EEG revealed transplant, cyclosporine was first given as prophylaxis for subclinical seizure discharges over both occipital regions, graft-versus-host disease. During intravenous infusion of most pronounced on the right. A pattern-shift visual evoked this drug she developed chest tightness and wheezing potential (VEP) performed on day 29 showed no reproduc- ible responses following stimulation of the right eye, and a poorly defined response following stimulation of the left Correspondence: Dr RE Steg, Department of Neurology, Creighton Uni- versity School of Medicine, Suite 5300, 601 North 30th Street, Omaha, eye with a markedly prolonged P100 latency of 198 ms, NE 68131–2197, USA indicating conduction defects in the visual pathways bilater- Received 5 May 1998; accepted 3 December 1998 ally. Bilateral visual pathway conduction defects remained Cortical blindness and seizures after BMT RE Steg et al 960

Figure 1 MRI of the head without contrast demonstrating white matter lesions in (a) the posterior temporal-occipital head regions bilaterally, and (b) the centrum semiovale. The adjacent cortex is also involved.

evident on a repeat VEP 4 days later which showed bilateral of the blood–brain barrier, and that the breakdown of the prolongation of the P100 latency of 191 ms following left blood–brain barrier may allow for increased passage of eye stimulation and 205 ms following right eye stimulation. lipophilic agents such as FK506 and cyclosporine. The Subsequently, her confusion cleared and her vision con- mechanism of neurotoxicity associated with FK506 is not tinued to gradually improve. Within 8 days of the onset of clear, however, and our reported case occurred in a bone cortical blindness, the corrected visual acuity was 20/30 in marrow transplant recipient with normal liver function. the right eye and 20/20 in the left eye. MRI was not Devine et al9 described three bone marrow transplant repeated. Placing the patient on oral cyclosporine for graft- recipients who developed cerebral blindness while receiv- versus-host disease prophylaxis was considered, and ing FK506. In each case FK506 was discontinued and the although a trial dose resulted in no anaphylaxis, the visual symptoms reversed within 1–2 weeks of onset. decision was made to use azathioprine for long-term man- MRI easily demonstrates the white matter lesions caused agement. Eight months after transplantation she was receiv- by FK506 and cyclosporine toxicity which may not be ing low doses of prednisone for mild chronic graft-versus- apparent on CT. Seizures are a well known complication host disease of the skin, had no discernable visual defects of cyclosporine neurotoxicity and may occur in combi- and was fully alert and oriented. nation with cortical blindness in patients with FK506 neuro-toxicity. As the seizures may be subclinical, EEG may be necessary for their detection. Discussion When toxicity is suspected, based upon MRI findings and clinical features, discontinuation of the drug should be con- FK506 is an effective immunosuppressive agent for bone sidered. In our case, FK506 was discontinued, and follow- marrow and organ transplantation.1 It has a similar side- ing a brief course of corticosteroids, azathioprine was sub- effect profile to the older and more widely used immuno- stituted without recurrence of neurotoxicity. Azathioprine suppressive agent, cyclosporine. Cyclosporine can produce was chosen instead of cyclosporine because cyclosporine white matter changes leading to cortical blindness and seiz- has also been associated with cortical blindness.2–7 It is ures in different transplant populations including kidney, unknown if a reduction in the FK506 dosage would have heart, liver, and bone marrow.2–7 There is less known about resulted in a similar outcome. In the three bone marrow FK506 neurotoxicity. Cortical blindness and white matter transplant recipients reported by Devine and colleagues9 lesions have been previously reported in a liver transplant who developed cortical blindness while receiving FK506, recipient receiving FK506.8 The investigators suggested two subsequently received cyclosporine without sequelae. that hepatic may contribute to neurotoxicity However, it was noted that patients have been described via elevated ammonia levels, which increase permeability with cerebral blindness secondary to FK506 which recurred Cortical blindness and seizures after BMT RE Steg et al 961 a Fp1-F3

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Figure 2 Digitalized EEG segment obtained on the same day as the MRI showing generalized slowing of the background rhythms with asymmetry between the homologous head regions. (a) A repetitive sharp wave discharge is seen over the right occipital head region (P4-02 and T6-02 channels). (b) Twenty seconds later: repetitive sharp waves remain present over the right occipital head region with no apparent clinical manifestations. Cortical blindness and seizures after BMT RE Steg et al 962 after switching to cyclosporine.10 Azathioprine was system toxicity after liver transplantation. New Engl J Med subsequently given to our patient as its use has not been 1987; 317: 861–866. associated with cortical blindness. 4 Lane RJM, Roche SE, Leung AAW et al. Cyclosporine neuro- toxicity in cardiac transplant recipients. J Neurol Neurosurg Psychiat 1988; 51: 1434–1437. 5 Rubin AM. Transient cortical blindness and occipital seizures Acknowledgements with cyclosporine toxicity. Transplantation 1989; 47: 572–573. 6 Scheinman SJ, Reinitz ER, Petro G et al. Cyclosporine central neurotoxicity following renal transplantation. Transplantation We would like to acknowledge the assistance of Mr Joseph 1990; 49: 215–216. Edwards in preparation of the figures. 7 Casanova B, Prieto M, Deye E et al. Persistent cortical blind- ness after cyclosporine leukoencephalopathy. Liver Transplant Surg 1997; 3: 638–640. 8 Shutter LA, Green JP, Newman NJ et al. Cortical blindness References and white matter lesions in a patient receiving FK506 after liver transplantation. Neurology 1993; 43: 2417–2418. 1 Neuberger J, Elias E. Immunosuppressive agents. In: Maddrey 9 Devine SM, Newman NJ, Siegel JL et al. Tacrolimus (FK506)- WC, Sorrell MF (eds). Transplantation of the Liver, 2nd edn. induced cerebral blindness following bone marrow transplan- Appleton and Lange: Norwalk, 1995, pp 247–265. tation. Bone Marrow Transplant 1996; 18: 569–572. 2 Rubin AM, Kang H. Cerebral blindness and encephalopathy 10 Eidelman BH, Abu-Elmagd K, Wilson J et al. Neurologic with cyclosporin A toxicity. Neurology 1987; 37: 1072–1076. complications of FK506. Transplant Proc 1991; 23: 3175– 3 De Groen PC, Aksamit AJ, Rakela J et al. Central nervous 3178.