Case Report Reversible Cortical Blindness and Convulsions with Cyclosporin a Toxicity in a Patient Undergoing Allogeneic Peripheral Stem Cell Transplantation

Case report Reversible cortical blindness and convulsions with cyclosporin A toxicity in a patient undergoing allogeneic peripheral stem cell transplantation

B Madan and SA Schey

Department of Haematology, Guy’s Hospital, London, UK

Summary: one course each of MACE (mitozantrone on days 1, 3 and 5, cytosine arabinoside on days 1–10, etoposide on days 1– A 40-year-old woman underwent allogeneic peripheral 5) and ICE (idarubicin on days 1 and 2, cytosine arabino- blood stem cell transplantation for relapsed AML-M6. side on days 1–3, etoposide on days 1–3). She achieved She developed graft-versus-host disease on day +15 complete remission after her first induction but relapsed post-transplant, for which she was treated with cyclo- within 1 month of completion of ICE chemotherapy. In sporin A and methyl prednisolone. On day +19 she March 1996 she was given mitoxantrone, cytosine arabino- developed cortical blindness, headache and convulsions side and PSC-833 (a cyclosporin D analogue) as per relapse which were associated with white matter changes on protocol and achieved complete remission. In July 1996, MRI scanning of the head and elevated cyclosporin A she received an allogeneic peripheral stem cell transplant levels. A diagnosis of cyclosporin A encephalopathy was from her HLA-identical sister following conditioning with made and cyclosporin A was discontinued. Her vision cyclophosphamide and total body irradiation. She received recovered completely after 48 h and the other symptoms cyclosporin A as prophylaxis for graft-versus-host disease. resolved. This is the first case of cyclosporin A encepha- She received G-CSF from day +1 to day +10. Her WBC lopathy to be reported in an allogeneic PBSC recipient. count on day +10 following the transplant was 1.7 × 109/l. Keywords: cyclosporin A toxicity; allogeneic peripheral On day +14 she was changed from intravenous to oral blood stem cell transplantation; cyclosporin A encephalo- cyclosporin A. On day +15 she developed acute graft-ver- pathy sus-host disease and was treated with high-dose intravenous methyl prednisolone. On day +19 she complained of blur- ring of vision which started with her noticing difficulty in seeing the digits when dialling the telephone. This rapidly Cyclosporin A is an immunosuppressant that is used for progressed to complete blindness over a period of 3 h. Over the prevention and treatment of graft-versus-host disease the next 12 h she complained of a severe dull generalised 1 following allogeneic organ transplantation. The use of headache and went on to have a generalised tonic clonic cyclosporin A is associated with a multitude of side-effects, seizure. Medications included itraconazole suspension most commonly nephrotoxicity, hepatoxicity and hyperten- 100 mg once daily, amiloride 5 mg once daily, ceftazidime sion.2,3 However, the central nervous system side-effects of 2 g i.v. three times daily, acyclovir 400 mg four times daily, cyclosporin A are not as well known. These include head- lorazepam 2 mg at night, norethisterone 5 mg three times aches, seizures, vomiting, confusion, visual hallucinations, daily, omeprazole 20 mg once daily, loperamide 4 mg three spinal cord and cerebellar-like syndromes, and cortical times daily and cyclosporin A (Neoral) 125 mg twice daily. 4–8 blindness. On physical examination, she was apyrexial, blood pressure was 150/90, pulse 80 per min and there was mild jaundice. The pupils were reactive and there was no afferent pupillary Case report defect. Visual acuity was 0/20 in each eye and confron- tational visual field testing revealed that there was no A 40-year-old woman was diagnosed as having acute response to visually threatening gestures. There was no evi- myeloid leukaemia-FAB classification M6 in October, dence of any nystagmus. Ocular motility and fundoscopic 1995. She was treated on the Medical Research Council examination were normal. The rest of the neurological AML-12 trial and received two courses of ADE chemo- examination was normal. therapy (cytosine arabinoside on days 1–10, daunorubicin A blood count showed haemoglobin of 9.9 g/dl, WBC on days 1, 3 and 5, etoposide on days 1–5) followed by count of 2.8 × 109/l with neutrophils of 2.6 × 109/l, and platelets of 19 × 109/l. Renal function was normal. The only Correspondence: Dr B Madan, Department of Haematology, Greenwich abnormalities in the electrolytes were hypomagnesemia – District General Hospital, Vanbrugh Hill, London SE10 9HE, UK magnesium level 0.30 mmol/l (NR 0.7–1.0 mmol/l), and Received 31 January 1997; accepted 30 June 1997 hypocalcaemia – 1.74 mmol/l (NR 2.10–2.55 mmol). Liver Cyclosporine encephalopathy in a case of allogeneic BMT B Madan and SA Schey 794 mal 48 h later. She complained of drowsiness but was rous- able and oriented. Visual acuity was 20/20 corrected in each eye. Visual field testing did not reveal any defects and fundoscopic examination was normal. The blood pressure was 130/80. A repeat MRI scan done 1 week later showed resolution of the occipital lobe abnormalities but the small focal abnormality in the right frontal white matter persisted. She was discharged on day +41 following the transplant. Currently, she is alive and well at day +200 following the transplant and on no medication.

Discussion

The incidence of cyclosporin A neurotoxicity has been vari- ably reported as being between 10 and 25%.5 A variety of clinical presentations is seen. Generalised motor seizures is one of the more common presentations. Other features that have been reported include altered mental function, confusion, anxiety and visual hallucinations. Atkinson et al4 described spinal cord and cerebellar-like syndromes associated with the use of cyclosporin A in allogeneic bone marrow transplant recipients. Cortical blindness is a rare manifestation of cyclosporin A neurotoxicity observed mainly in patients undergoing liver and bone marrow transplantation. de Groen et al.5 described a syndrome of Figure 1 MRI of the head done on 23 July 1996 (date of onset of encephalopathy, seizures and white matter changes in liver blindness) showing diffuse cortical abnormality in both occiptal lopes and transplant patients. Hinchey et al6 reported on 15 patients a small focal abnormality in the white matter of the right frontal lobe. with reversible posterior encephalopathy due to diverse causes. Rubin and Kang7 reported on acute cortical blindness complicating cyclosporin A toxicity in a BMT patient. function tests showed hyperbilirubinemia – bilirubin 8 120 ␮mol/l (NR 0–22 ␮mol/l) and hypoalbuminemia – Noll and Kulkarni described complex visual hallucinations albumin 30 g/l (NR 35–46 g/l). The remaining tests of liver in a BMT recipient taking cyclosporin A for GVHD. There function were normal. The whole blood cyclosporin A level have been no previous reports of cyclosporin A neurotoxi- was 688 ␮g/l (reference range 100–250 ␮g/l). An MRI scan city in association with peripheral stem cell allografts. of the head showed diffuse subtle cortical abnormality in The central nervous system side-effects of cyclosporin A both occipital lobes and a further small focal abnormality are more frequently seen in patients with high levels of present in the white matter of the right frontal lobe but cyclosporin A in whole blood or plasma. They are more no abnormal enhancement was seen following intravenous frequently seen in association with concurrent high-dose contrast medium (Figure 1). No evidence of acute haemor- methyl prednisolone treatment, hypertension, hypomagnesemia, aluminium overload in renal transplant patients and rhage was present. 4–9 A diagnosis of cyclosporin A toxicity with secondary low serum cholesterol levels in liver transplant patients. encephalopathy and cortical blindness was made. The However, they have also been reported in patients with cyclosporin A and methyl prednisolone were discontinued. therapeutic levels of cyclosporin A and none of the above She was treated with intravenous phenytoin, sublingual risk factors. nifedipine and magnesium replacement. Serial cyclosporin Although the initial cyclosporin A levels were high in A levels were as follows: our patient, she also had other multiple risk factors – concurrent high-dose methyl prednisolone treatment, hyperten- Day +18 22.7.96 526 ␮g/l sion and hypomagnesemia. One unusual feature was the Day +19 23.7.96 688 ␮g/l (date of onset of blindness) nature of the abnormalities on MRI. Other reports have sug- Day +20 24.7.96 449 ␮g/l gested that the abnormalities on neuroimaging have pre- Day +21 25.7.96 388 ␮g/l (date of resolution of blindness) dominantly involved the white matter in the posterior por- + Day 22 26.7.96 261 ␮g/l tions of the cerebral hemispheres, especially bilaterally in + Day 23 27.7.96 164 ␮g/l the parieto-occipital regions.1 The grey matter is addition- Day +24 28.7.96 150 ␮g/l + ally involved in a minority of patients. The changes tend Day 25 29.7.96 103 ␮g/l to be symmetric but the degree of involvement can be Day +26 30.7.96 106 ␮g/l asymmetric. In our patient, however, the changes involved Methotrexate was substituted for cyclosporin A for graft- mainly the occipital cortices bilaterally and the white matter versus-host disease prophylaxis. She was given methotrex- was relatively spared. ate 25 mg/m2 intravenously weekly for 6 weeks. Her vision The mechanism by which cyclosporin A causes central gradually improved over the ensuing 2 days and was nor- nervous system toxicity is not clear. Similar syndromes Cyclosporine encephalopathy in a case of allogeneic BMT B Madan and SA Schey 795 have been reported in quite diverse conditions, eg pre- References eclampsia, hypertension and in patients treated with other immunosuppressive agents such as tacrolimus. This suggests that the cause is multifactorial. The reversible nature 1 Powles RL, Clink HM, Spence D et al. Cyclosporin A to pre- of changes on neuroimaging suggests cortical or subcortical vent graft-versus-host disease in man after allogeneic bone- oedema rather than infarction. The most likely mechanism marrow transplantation. Lancet 1980; i: 327–329. is a perturbation of the blood-brain barrier causing a 2 Hows JM, Chipping PM, Fairhead S et al. Nephrotoxicity in capillary leak syndrome. bone marrow transplant recipients treated with cyclosporin A Hypertension and renal toxicity often form part of the A. Br J Haematol 1983; 54: 69–78. constellation of features seen in cyclosporin A-related neur- 3 Loughran TP Jr, Deeg HJ, Dahlberg S et al. Incidence of hypertension after marrow transplantation among 112 patients otoxicity. The most likely explanation is that ﬂuid overload randomized to either cyclosporin A or methotrexate as graft- associated with hypertension in a patient with an altered versus-host disease prophylaxis. Br J Haematol 1985; 59: blood-brain barrier causes cerebral oedema. 547–553. Another point that warrants highlighting is that many 4 Atkinson K, Biggs J, Darveniza P et al. Spinal cord and cer- other commonly used drugs can affect the bioavailability of ebellar-like syndromes associated with the use of cyclosporin cyclosporin A, eg rifampicin and ketoconazole. Preliminary A in human recipients of allogeneic marrow transplants. rodent data on itraconazole and ketoconazole coadminis- Transplant Proc 1985; 17: 1673–1675. tered with cyclosporin A suggest that there appears to be 5 de Groen PC, Aksamit JA, Rakela J et al. Central nervous an initial slight increase in cyclosporin A levels compared system toxicity after liver transplantation. New Engl J Med to controls with itraconazole but this appears to be a transi- 1987; 317: 861–866. ent observation (personal communication). We and others 6 Hinchey J, Chaves C, Appignani B et al. A reversible pos- have used itraconazole in combination with cyclosporin A terior leukoencephalopathy syndrome. New Engl J Med 1996; in an increasing number of patients without any reports of 334: 494–500. adverse events. 7 Rubin AM, Kang H. Cerebal blindness and encephalopathy in Although the cortical blindness appears to be reversible cyclosporin A toxicity. Neurology 1987; 37: 1072–1076. 8 Noll RB, Kulkarni R. Complex visual hallucinations and and is not life-threatening, its occurrence is dramatic and cyclosporin A. Arch Neurol 1984; 41: 329–330. frightening for both the patient and the clinician. This is 9 Thompson CB, June CH, Sullivan KM, Thomas ED. Associ- the ﬁrst case reported of this complication occurring in a ation between cyclosporin A neurotoxicity and hypomagnesa- PBSCT recipient and illustrates the importance of close emia. Lancet 1984; ii: 1116–1120. monitoring of therapeutic levels of cyclosporin A, especially when used in association with other risk factors.