Eur J Haematoll996: 56: 95-97 Printed in Belgium - 011 rights reserved Copyright 0 Munksguard 1996 I S S N 0902-4441 - Letters to the Editor Acute ischaemic cerebrovascular accident after autologous bone marrow transplantation To the Editor: When a patient with thrombocytopenia after highdose chemotherapy develops an acute hemiparesis, the first diagnostic consideration is an intracerebral haemorrhage. We describe such a patient in whom a cerebral infarction appeared to be the cause. We postulate a direct relationship with the chemotherapy . A 46-yr-old woman underwent an autologous bone marrow transplantation because of relapsed Hodgkin's disease. She had no hypertension or cardiovascular disease, did not smoke and had no diabetes mellitus. There was no family history of cardioor cerebrovascular events. Hodgkin's disease had been diagnosed 3 yr earlier as stage IVB and successfully treated with 8 cycles of MOPPABV chemotherapy (Mitoxin, Oncovin, Procarbazin, Prednison, Adriamycin, Bleomycin and Vinblastin). She relapsed after 2.5 yr in abdominal lymph nodes and spleen. She again responded favourably to MOPPABV chemotherapy. Autologous bone marrow was harvested and cryopreserved. After four cycles a complete remission was documented by CT scanning. She then received ablative chemotherapy consisting of cyclophosphamide 1500 mg/m2 daily on d - 6 to -3, BCNU (carmustine) 300mg/m2 on d - 6, and VP16 (etoposide) 125 mg/m2 every 12 h for a total of six doses on d - 6 to - 4. On d 0 the autologous bone marrow was reinfused. The course was uneventful until d 6 when she developed an acute left-sided paresis. Blood pressure was l20/80 mm Hg, the pulse was regular at 80 b.p.m., temperature 36.4"C. At neurological examination she was conscious, vision and speech were undisturbed. She had a left-sided hemiparesis, hemihypaesthesia and hypalgesia. Tendon reflexes were low, and asymmetrical. There was a Babinski reflex on the left-, plantar flexion on the right side. Laboratory investigation showed a haemoglobin of 6.6 mmol/l, WBC 0.1 x 109/1,and a platelet count of 20 x 109/l. The prothrombin time (12.8 s) and activated prothrombin time (27.0 s) were normal. On the immediately made CT brain scan no abnormalities were seen. The MRI 9 d later showed a hyperintense triangu- lar lesion in the territory of supply of the anterior cerebral artery (Fig. 1). An echocardiogram was normal and showed no valvular lesions. Seventeen h after the first symptoms she developed generalized seizures that were treated with phenytoin. On d 25 there was bone marrow recovery. The neurological symptoms improved gradually. On d 62 she was discharged with only minor neurological symptoms. She was functionally independent in her daily activities. This patient developed a cerebral infarction 12 d after the start of chemotherapy and 6 d after autologous bone marrow reinfusion. We assume that this event is directly related to the pretransplant chemotherapy; no other risk factors for cerebrovascular disease were present. Similar cases, occurring within days after chemotherapy, have been described in patients treated with cisplatin, bleomycin and vinblastine or etoposide for testicular cancer and cancer of the upper aerodigestive tract (1-3). An increased incidence of ischaemic cerebral infarctions has also been found in adjuvant chemotherapy for breast cancer (4). Stroke-like ischaemic manifestations have further been described in children treated with chemotherapy for acute lymphoblastic leukaemia or lymphoma (5). Seizures and visual hallucinations were the most prominent symptoms. The typical CT and MRI findings were infarct-like triangular lesions involving both the cortex and the subcortical white matter. In a recent study (6) on neurologic complications after high-dose chemotherapy and autologous bone marrow transplantation for Hodgkin's disease with the same regimen used as in our patient there was a high incidence of early neurologic symptoms (in 65 of 168 patients). These were considered to be mainly metabolic encephalopathies. However, in autopsy series of patients dying after bone marrow transplantation there seems to be rather a high incidence of ischaemic cerebral infarctions (7). What could be the pathogenetic mechanism of the cerebral infarction in these patients? One possibility is hypercoagulability. After autologous bone marrow transplantation temporary decreases of the anticoagulants protein C and antithrombin I11 with a 95 Letters to the Editor Fig. 1. T2-weighted image of the brain showing a hyperintense lesion in the territory of supply of the anterior cerebral artery. concomitent increase in fibrinogen have been found (8). The cerebral infarction may result from a local thrombosis or an embolus from a non-bacterial thrombotic endocarditis (7). A second possibility is chemotherapy-induced vasospasm leading to vascular occlusion (2). A third possibility is chemotherapyinduced endothelial activation or damage leading to a vascular occlusion. Increased levels of Von Willebrand factor as a marker for endothelial damage following bone marrow transplantation have been reported (9), fitting with this hypothesis. The incidence of chemotherapy-induced vascular complications may increase because haematopoietic growth factors and peripheral blood stem cell transplantation lead to a higher dose intensity of chemotherapy, making extramedullary toxicities including vascular events more probable. References 1. DOLLDC, LISTAF, GRECO A, HAINSWORTH JD, HANDE KR, JOHNSON DH. Acute vascular ischemic events after cisplatin-based combination chemotherapy for germ-cell tumors of the testis. Ann Int Med 1986: 105: 48-51. 2. I ~ L F, I KARAOGUZ H, D I N ~ OD, L et al. Severe vascular toxicity associated with cis-platin based chemotherapy. Cancer 1993: 72: 587-593. Letters to the Editor 3. KUKLALJ, MCGUIREWP, LAD T, SALTIELM. Acute vascular episodes associated with therapy for carcinomas of the upper aerodigestive tract with bleomycin, vincristine, and cisplatin. Cancer Treat Rep 1982: 66: 369-370. 4. SAPHNER T, TORMEY DC, GRAYR. Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol 1991: 286-294. 5. PIHKOH, TYNIT, VIRKOLA K, et al. Transient ischemic cerebral lesions during induction chemotherapy for acute lymphoblastic leukemia. J Pediatr 1993: 123: 718-724. 6. SNIDERS, BASHIRR, BIERMANP. Neurologic complications after high-dose chemotherapy and autologous bone marrow transplantation for Hodgkin's disease. Neurology 1994: 44: 681-684. 7. MOHRMAN RL, MAH V, VINTERSHV. Neuropathologic findings after bone marrow transplantation: an autopsy study. Hum Pathol 1990: 21: 630-639. 8. GORDON B, HAIREW, KESSINGER A, DUGGAN M, ARMIT- AGE J. High frequency of antithrombin I11 and protein C deficiency following autologous bone marrow transplantation for lymphoma. Bone Marrow Trans 1991: 8: 497-502. 9. COLLINS PW, GUTTERIDGE CN, O'DRISCOLL A, et al. Von Willebrand factor as marker of endothelial cell activation following BMT. Bone Marrow Trans 1992: 10: 499-506. Correspondence: J. van der Lelie', E.S. Louwerse', L.L.M. Thomas', M.H.J. van Oers' and A.E.G.Kr. von dem Borne' Department of Internal Medicine, Division of 'Haematology and 'Department of Neurology, Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, the Netherlands 97