with fractionated total body irradiation of 13.2 Gy and cyclophosphamide 120 ... cranial neoplasia, paraneoplastic syndrome or intoxi- cations. Neurotoxicity is a ... GVHD were observed and prophylactic immunosuppres- with marrow from an ...
Bone Marrow Transplantation, (1997) 20, 255–256 1997 Stockton Press All rights reserved 0268–3369/97 $12.00
Case report Cyclosporin A-induced ocular flutter after marrow transplantation R Apsner1, A Schulenburg2, N Steinhoff3, F Keil2, K Janata4 , P Kalhs2 and H Greinix2 1
Universita¨tsklinik fu¨r Innere Medizin III, Abteilung fu¨r Nephrologie und Dialyse; 2Universita¨tsklinik fu¨r Innere Medizin I, Abteilung fu¨r Knochenmarktransplantation; 3Universita¨tsklinik fu¨r Neurologie; and 4 Abteilung fu¨r Notfallmedizin der Universita¨tskliniken, Vienna, Austria
Summary: Ocular flutter is a rare neurologic condition occurring in patients suffering from viral encephalitis, intracranial neoplasia, paraneoplastic syndrome or intoxications. Neurotoxicity is a recognized complication of cyclosporin A (CsA) therapy, but ocular flutter has not been reported in association with CsA administration to date. We describe a 17-year-old female patient who developed ocular flutter 51 days after transplantation with marrow from an unrelated donor, for acute myeloid leukemia. After discontinuation of cyclosporin, which was given for prophylaxis of graft-versus-host disease, the clinical symptoms resolved within 3 weeks, but a slightly abnormal electrooculogram persisted for more than 10 months. Keywords: cyclosporin; neurotoxicity; ocular flutter
Cyclosporin A (CsA) is widely used for immunosuppression in solid organ transplantation 1 and for prevention and treatment of graft-versus-host disease (GVHD) after allogeneic marrow transplantation (BMT).2 Minor adverse neurologic effects are frequent, and severe and potentially life-threatening central nervous complications may require the discontinuation of the drug. Ocular flutter is a burst of involuntary saccadic horizontal oscillations without an intersaccadic interval. Ocular flutter is thought to be a pontocerebellar disorder, but the exact pathomechanism is unknown. It has been observed in patients suffering from viral encephalitis, intracranial neoplasia, paraneoplastic syndrome and after intoxication with thallium, lithium, haloperidol, toluene, insecticides and organophosphates,3–4 but not in association with CsA administration. Here, a case of severe CsA-induced ocular flutter after BMT is reported.
second remission was referred for BMT. After conditioning with fractionated total body irradiation of 13.2 Gy and cyclophosphamide 120 mg/kg body weight, she received a marrow allograft from a phenotypically matched unrelated donor. For CNS prophylaxis, methotrexate (MTX) at a dose of 12 mg was given intrathecally once prior to bone marrow infusion. For prophylaxis of GVHD, CsA and intravenous MTX were given according to the Seattle protocol. The patient recovered without serious complications and was discharged 25 days after transplantation. No signs of acute GVHD were observed and prophylactic immunosuppression with oral CsA adjusted to serum levels of around 200 ng/ml was maintained. Antiviral prophylaxis and Pneumocystis carinii prophylaxis were given (famcyclovir 500 mg twice a day, cotrimoxazole 4 tablets/week). Due to poor gastrointestinal tolerance, cotrimoxazole was replaced with pentamidine inhalations every 4 weeks. On day 51 after BMT, the patient experienced attacks of panic that rapidly worsened leading to hospitalisation 5 days later. She presented with drop attacks, vertigo, vomiting and blurred vision. She was unable to stand or walk, but had no complaints when her eyes were closed. The patient was normotensive. Neurologic examination revealed symmetric rapid conjugated horizontal eye movements. Electrooculography (EOG) confirmed the clinical diagnosis of ocular flutter. Electroencephalography showed diffuse slowing consistent with a metabolic or encephalitic process. Cerebrospinal fluid and magnetic resonance imaging of the brain were unremarkable as were blood and urine tests, except for a slight hypomagnesaemia of 0.64 mmol/l (normal 0.7–1.0 mmol/l). Although CsA levels were within the therapeutic range (249 ng/ml) CsA toxicity was suspected and CsA was replaced by steroids. The clinical symptoms completely resolved within 3 weeks, but a slight abnormality of the EOG has remained. No episodes of acute GVHD was observed after CsA withdrawal.
Case report
Discussion
In November 1995, a 17-year-old Caucasian female with PML-RAR alpha positive acute myeloid leukemia in
Tremor, paraesthesias/hyperaesthesias, confusion, fatigue and seizures are well known symptoms of CsA neurotoxicity.5,6 Tetra- and paraparesis, spinal demyelination, coma, cortical blindness, transient loss of speech, cerebellar syndrome, Parkinsonism and – as in the above case – ocular flutter are occasional features of CsA toxicity.7–11
Correspondence: Dr R Apsner, Allgemeines Krankenhaus der Stadt Wien, Universita¨tskliniken, Wa¨hringergu¨rtel 18-20, A-1090 Vienna, Austria Received 16 December 1996; accepted 19 April 1997
Cyclosporin-induced ocular flutter R Apsner et al
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After exclusion of other causes for the neurological symptoms, we assumed CsA-related toxicity. Since neurologic improvement was achieved after discontinuation of CsA our diagnosis seems likely, although CsA levels were in the therapeutic range. However, metabolites usually not assessed in clinical practice may be neurotoxic, even at low CsA concentrations.12 The clinical symptoms of central nervous toxicity related to CsA mostly resolve without sequelae after modification or cessation of the drug. In our patient, subtle neurologic abnormalities with a pathologic EOG have now persisted for 10 months. However it remains uncertain whether CsA caused irreversible neurologic damage, or revealed preexisting minimal brain dysfunction. References 1 Faulds D, Goa KL, Benfield P. Cyclosporin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders. Drugs 1993; 45: 953–1040. 2 Atkinson K. Cyclosporin in bone marrow transplantation. Bone Marrow Transplant 1987; 1: 265–270. 3 Bergenius J. Saccade abnormalities in patients with ocular flutter. Acta Otolaryngol 1986; 102: 228–233.
4 Zangemeister WH, Mu¨ller-Jensen A. Benign encephalitis: EOG analysis of opsoclonus. J Neurol 1979; 222: 95–108. 5 Reece DE, Frei LD, Shepherd JD et al. Neurologic complications in allogeneic bone marrow transplant patients receiving cyclosporin. Bone Marrow Transplant 1991; 8: 393–401. 6 Beaman M, Parvin S, Veitch PS et al. Convulsions associated with cyclosporin A in renal transplant recipients. Br Med J 1985; 290: 139–140. 7 Adams DH, Gunson B, Honigsberger L et al. Neurological complications following liver transplantation. Lancet 1987; 1: 949–951. 8 Atkinson K, Biggs J, Darveniza P et al. Spinal cord and cerebellar-like syndromes associated with the use of cyclosporine in human recipients of allogeneic bone marrow transplants. Transplant Proc 1985; 2: 1673–1675. 9 Katirji MB. Visual hallucinations and cyclosporine. Transplantation 1987; 43: 768–769. 10 Bird GLA, Meadows J, Gogka J et al. Cyclosporin-associated akinetic mutism and extrapyramidal syndrome after liver transplantation. J Neurol Neurosurg Psych 1990; 53: 1068– 1071. 11 Wasserstein PH, Honig LS. Parkinsonism during cyclosporin treatment. Bone Marrow Transplant 1996; 18: 649–650. 12 Kunzendorf U, Brockmo¨ller J, Jochimsen F et al. Neurotoxicity caused by a high cyclosporine metabolite level. Transplantation 1989; 48: 531–532.
