Bone Marrow Transplantation (2000) 25, 791–795  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Case report MR angiographic diagnosis of cerebral venous sinus thrombosis following allogeneic bone marrow transplantation CJ Harvey1, AJ Peniket2, K Miszkiel1, K Patterson2, AH Goldstone2, S Mackinnon2 and MA Hall-Craggs1 Departments of 1Radiology and 2Haematology, University College London Hospitals Trust, The Middlesex Hospital, London, UK Summary: Allogeneic bone marrow transplantation is frequently associated with neurological complications, particularly intracerebral bleeds and infections. Cerebral venous sinus thrombosis has only rarely been reported following allogeneic transplants. We report three cases of cortical venous thrombosis following allografting for acute lymphoblastic leukaemia. Two patients received marrow from HLA-identical siblings and one from an unrelated donor. Two of the patients presented with grand mal seizures and one presented with a headache. No neurological abnormalities were found upon clinical examination and lumbar puncture was normal in all three cases. In two of the patients computed tomography (CT) of the brain was normal and in the third showed non-specific abnormalities. Magnetic resonance imaging (MRI) with MR angiography (MRA) demonstrated cerebral venous sinus thrombosis in all three patients. In conclusion, cerebral venous sinus thrombosis should be considered in the differential diagnosis when neurological symptoms occur following allogeneic bone marrow transplantation. We therefore advocate the use of MRA for unexplained neurological symptoms post-allograft since without it cerebral venous sinus thrombosis may easily be missed. Bone Marrow Transplantation (2000) 25, 791–795. Keywords: cerebral venous sinus thrombosis; bone marrow transplantation; magnetic resonance angiopathy The use of high-dose therapy and in particular allogeneic bone marrow transplantation in the treatment of haematological malignancies is frequently associated with neurological complications. Among these complications strokes (often haemorrhagic) and CNS infections are frequently severe and contribute significantly to treatment-related mortality.1,2 Cerebral venous sinus thrombosis has rarely been reported following allogeneic bone marrow transplantation.3 The diagnosis of this condition often requires the Correspondence: Dr CJ Harvey at his current address: Department of Imaging, Hammersmith Hospital, Du Cane Rd, London W12 ONN, UK Recceived 8 July 1999; accepted 10 December 1999 use of MRA.4,5 Possible aetiologies of cerebral venous sinus thrombosis include infection,6 venous catheter associated thrombosis,7 vasculitis,8 or prothrombotic conditions.9–11 We report three cases of cerebral venous sinus thrombosis following allogeneic bone marrow transplantation: in all three cases the diagnosis was made using MRA. Case reports Case one A 15-year-old male presented with Philadelphia-positive acute lymphoblastic leukaemia (ALL), was treated according to the Medical Research Council ALL XI protocol12 and proceeded electively to receive an HLA-identical sibling allograft. Conditioning was with cyclophosphamide 60 mg/kg for 2 days (days −6 and −5) and total body irradiation (TBI) 1440 cGy in eight fractions (days −4 to −1). On day −3 he suffered a grand mal seizure. Cyclosporin (as GVHD prophylaxis) and ciprofloxacin (for a fever) had both been introduced approximately 12 h before the seizure. A contrast enhanced CT brain and lumbar puncture were normal. The ciprofloxacin was withdrawn due to clinical concern that this may have precipitated the seizure. Since the fit occurred towards the end of the conditioning regimen it was decided to proceed with the transplant as planned. Neutrophil recovery (⬎0.5 × 109/l) occurred on day 21. On day 25 he suffered a further grand mal seizure. Cranial MR and MRA showed thrombosis of the right transverse and sigmoid sinuses with multiple bilateral parasagittal white matter lesions consistent with venous infarcts (Figure 1). He was treated with phenytoin and the low-dose heparin (100 IU/kg/24 h) (used as prophylaxis against veno-occlusive disease and still being administered at the time of the seizures) was continued until the platelet count rose to ⬎50 × 109/l, following which warfarin was introduced. He remained seizure-free and displayed no neurological deficits. His subsequent course included an early relapse at day +85, but a further remission was induced using donor lymphocytes. This remission lasted a year but he then relapsed locally in the clavicular region and has undergone palliative radiotherapy. MR angiographic diagnosis of cerebral venous sinus thrombosis CJ Harvey et al 792 Figure 1 Patient 1. (a) A coronal T1-weighted MR showing a thrombus (high signal intensity) of the right transverse sinus (straight arrow) associated with a peripheral haemorrhagic venous infarction of the right temporal lobe (arrowhead). (b) An axial T2-weighted MR demonstrating bilateral parasagittal and peripheral white matter venous infarcts (arrowheads). Note the signal void of the patent superior sagittal sinus (straight white arrow). (c) Two dimensional (2D) time-of-flight (TOF) MR venogram demonstrating thrombosis of the right transverse and sigmoid venous sinuses (arrows). Note the patent superior sagittal sinus seen as high signal intensity (curved arrow). Case two A 13-year-old male presented with common ALL 13 months before proceeding to bone marrow transplantation. He was treated according to the MRC UK-ALL XI protocol,12 but relapsed twice at 5 and 11 months following diagnosis. Each relapse was reinduced according to protocol. He received a T cell-depleted matched unrelated donor transplant in his third complete remission. Conditioning was with Campath I-G 10 mg twice a day (day −9 to −5), thiotepa 5 mg/kg (day −8 to −7), cyclophosphamide 60 mg/kg (day −6 to −5) and TBI 1440 cGy (day −4 to −1). Cyclosporin was given as a continuous infusion from day Bone Marrow Transplantation −3. Heparin was given at 100 U/kg/day as a continuous infusion to prevent veno-occlusive disease (day −9). Neutrophil recovery (⬎0.5 × 109/l) occurred on day +32. On day +43 he suffered a severe headache with no neurological deficit. A contrast enhanced CT brain was normal. Cranial MR and an MR venogram (MRV) demonstrated thrombus in the right sigmoid extending into the jugular bulb and proximal internal jugular vein (Figure 2). No focal cerebral abnormalities were present. The cyclosporin level was non-toxic at this stage (181 ␮g/l (normal range 200–500 ␮g/l)) but was nevertheless discontinued in case this had been the precipitating cause for the MR angiographic diagnosis of cerebral venous sinus thrombosis CJ Harvey et al fit responded to intravenous diazepam. At the time of these seizures she had normal blood pressure (130/70) and normal blood electrolytes including calcium and magnesium. A contrast enhanced CT brain was normal. MR of the brain showed poorly defined areas of high signal on T2 weighted images in the white matter of the right frontal lobe, parietal lobe and right corona radiata. An MRV revealed marked paucity of flow in the cortical veins of the right occipital region as compared with the left but the sagittal, transverse and straight sinuses were patent. The cyclosporin level was again non-toxic (385 ␮g/l) and was continued. She was treated with phenytoin and heparin in low dosage (100 IU/kg/24 h). She subsequently recovered well and was started on warfarin when her platelet count exceeded 50 × 109/l (day +37). This was continued for 3 months post seizure and the phenytoin for a further year. She remains well and in complete remission, 18 months post-transplant. 793 Discussion Figure 2 Patient 2. Two dimensional (2D) time-of-flight (TOF) MR venogram showing thrombus in the right sigmoid venous sinus (curved arrow) seen as an area of signal void in contrast to the high signal patent superior sagittal sinus (thick arrow). thrombosis. He received prophylactic phenytoin for 1 week following the diagnosis. The headache resolved over the next 3 days. Low-dose heparin was continued until day +90. He subsequently relapsed on day +150 and salvage therapy was attempted with donor lymphocytes. He became increasingly moribund over the following 5 days and died on day +155. Case three A 21-year-old female presented with ALL (pre-B immunophenotype) with a white blood count of 340 × 109/l. Cytogenetic examination revealed the t(4;11) abnormality. She was treated according to the UK-ALL XII protocol13 and reached a morphological remission after 21 days of induction chemotherapy. She then proceeded to an HLAidentical sibling allograft. Conditioning was with high-dose etoposide (60 mg/kg) and total body irradiation (1440 cGy in eight fractions). Graft-versus-host disease prophylaxis was with methotrexate (days 1, 3, 6 and 11) and cyclosporin as a continuous infusion from day −3. Initially, the transplant was uncomplicated and neutrophil recovery (⬎0.5 × 109/l) occurred on day +18. On day +32 she suffered two grand mal seizures, each lasting 2–3 min within 1 h. The first seizure was self-terminating and the second Intensive therapy of haematological malignancies and particularly the use of allogeneic bone marrow transplantation is frequently disrupted by neurological complications. The nature of these complications is diverse and includes infective complications related to the immunocompromised state, drug side-effects and intracranial haemorrhage.1,2 We describe three cases of cerebral venous sinus thrombosis following allogeneic bone marrow transplantation. The occurrence of such a thrombotic event post-allograft has rarely been reported.3 In all three patients the diagnosis was made using MRA: without the use of this investigation it is likely that the diagnosis would not have been made. The cause of the thrombosis in these three patients remains uncertain. There are several potential causes for venous sinus thrombosis complicating treatment of haematological malignancies. One possible cause of cortical sinus thrombosis is infection.6 There was no evidence of a local sinusitis or mastoiditis and a systemic septic screen was negative. Meningitis or meningeal neoplastic infiltration appear unlikely in our patients in view of the normal lumbar punctures. Prothrombotic states (factor V Leiden, protein S deficiency and protein C deficiency) have been reported in association with cerebral venous sinus thrombosis.9–11 Investigation for these conditions was not possible due to the administration of anticoagulant therapy and/or presence of concurrent conditions. A routine coagulopathy screen was normal although disseminated malignancy may induce a prothrombotic tendency despite normal coagulation indices.14 Dural sinus thrombosis has also been reported in association with subclavian line insertion.9 The use of lasparaginase is well known to be associated with an increase in thrombotic events in patients with ALL.15 None of the patients described here had received this drug during their peri-transplant period. The possibility of a cyclosporin-induced thrombotic aetiology is perhaps most likely. Thrombotic complications associated with cyclosporin have been previously reported.16,17 The mechanism for this thrombotic complication is not fully understood but Vanrenterghem et al18 found that cyclosporin enhanced adenosine-5-diphosphate (ADP) induced platelet aggregation. Bone Marrow Transplantation MR angiographic diagnosis of cerebral venous sinus thrombosis CJ Harvey et al 794 Other procoagulant effects of cyclosporin have been cited.19 Cyclosporin has been associated with numerous neurotoxic side-effects and has been reported as causing fits, coma, cortical blindness,20,21 altered mental state22 and visual hallucinations.23 It is associated with reversible cerebral cortical and white matter changes on CT and MRI.24–28 Cessation or a reduction of cyclosporin has in certain cases led to a resolution of the adverse effects.23,29,30 In our patients reduction or cessation of cyclosporin together with anticoagulation were accompanied by resolution of clinical symptoms. Cerebral venous sinus thrombosis may be diagnosed by conventional angiography or contrast enhanced CT either by direct demonstration of the venous thrombosis (delta sign) or indirect signs such as venous infarction. MRI combined with MRV is the imaging modality of choice.4,5,31 A conventional MR brain usually consists of sagittal T1weighted and axial T1- and T2-weighted spin-echo sequences. With spin-echo sequences, flowing blood typically produces a signal void whilst stationary blood or thrombus produces higher signal intensity (Figure 1a). However, a variety of flow-related artefacts may cause increased intraluminal flow signal mimicking thrombus. Thus any abnormality should be confirmed in multiple planes on both the T1- and T2-weighted images. MRV has been shown to be an accurate, non-invasive method for the diagnosis of dural sinus thrombosis and intravenous contrast medium is not required.4 Good correlation has been demonstrated between MRV and digital subtraction angiography (DSA).4 In contrast to spin-echo sequences MRV demonstrates flow as high signal, with areas of low signal representing thrombus (Figures 1c and 2). The acquisition of cranial MR and MRV sequences takes approximately 25 min. It should be noted that without the use of MRA in the patients reported here it is likely that the diagnosis would not have been made: two of the three patients had normal CT brains and the third had non-specific abnormalities, emphasising the limitations of the CT in this context. In the only other report of cortical sinus thrombosis complicating allogeneic bone marrow transplantation, all three patients described required MRA to confirm the diagnosis.3 It is interesting to speculate how commonly the diagnosis of cortical sinus thrombosis is missed: it is possible that some patients may remain asymptomatic with this condition. This matter can only be resolved through research studies involving the use of MRI angiography in both symptomatic and asymptomatic patients undergoing allogeneic bone marrow transplantation. Therapy of cerebral venous sinus thrombosis is with intravenous heparin,32,33 local thrombolytic therapy34 and/or oral anticoagulants.33 Anticoagulation in thrombocytopaenic patients may be hazardous with the risks outweighing the benefits because of haemorrhage. In two of the patients described here, warfarin was introduced when the platelet count rose to greater than 50 × 109/l; in the third patient, extremely delayed platelet regeneration precluded the introduction of warfarin. Anticonvulsants may be necessary for seizure control and prophylaxis.35 In summary, we report three cases of cerebral venous sinus thrombosis following allogeneic bone marrow trans- Bone Marrow Transplantation plantation. Cerebral venous sinus thrombosis should be considered in the differential diagnosis when neurological symptoms occur following bone marrow transplantation. In all three cases, diagnosis was made using MRA when other investigations including CT brain were unhelpful. We therefore advocate more frequent use of MRA following allogeneic bone marrow transplantation for unexplained neurological symptoms. References 1 Gallardo D, Ferra C, Berlanga JJ et al. Neurologic complications after allogeneic bone marrow transplantation. 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