British Journal of Radiology (2005) 78, 575-577
© 2005 British Institute of Radiology
doi: 10.1259/bjr/85140104
Seizures following bone marrow transplantation
M Bratby, MA, MB BS, MRCP
and
D MacVicar, MA, MRCP, FRCR
Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK
Correspondence: Dr David MacVicar, Consultant Radiologist
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Introduction
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A 19-year-old male presented to our institution for bone marrow transplantation (BMT) from a matched unrelated donor. 5 years previously he had been diagnosed with acute lymphoblastic leukaemia, treated with chemotherapy according to a high-risk protocol. Remission was achieved, but CNS relapse was confirmed 2 years later. Further treatment included craniospinal irradiation. A further 2 and a half years had elapsed when further relapse was confirmed by the presence of blasts in the peripheral blood. Over the following 6 months, further remission was achieved, and the patient was referred for BMT.
Conditioning chemotherapy of busulphan, cyclophosphamide and Campath (an anti-lymphocyte monoclonal antibody) was given. Following transplantation, cyclosporin A and methotrexate were commenced for graft versus host disease prophylaxis. Immediately post-transplant, neutropenic sepsis developed and was treated with anti-microbial agents. At day 30 post-transplant he suffered tonic–clonic seizures and subsequently a reduced level of consciousness. CT scan was performed which was within normal limits. MRI of the brain was subsequently undertaken (Figures 1 and 2
).
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Figure 1. Axial fluid attenuated inversion recovery (FLAIR) sequences of brain at level of (a) pons and (b) lateral ventricles.
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What abnormality is shown? What is the diagnosis? What is the advice to the clinical team and prognosis of the condition?
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Diagnosis
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Axial fluid attenuated inversion recovery (FLAIR) images (Figure 1a, b
) demonstrate symmetrical abnormal high signal most marked in the parietal and occipital regions. Abnormal signal is present in both grey and white matter and the changes are predominantly in the posterior part of the brain. Asymmetrical focal areas of abnormal signal can also be detected in the left frontal lobe and the posterior part of the right frontal lobe. The T2 weighted sequence (Figure 2) also demonstrates high signal in the posterior part of the brain, although the changes are less conspicuous on this pulse sequence.
From the clinical presentation and the MRI study a diagnosis of reversible posterior leukoencephalophathy syndrome (RPLS) was made. The likely aetiological factor was identified as cyclosporin A, and the patient was converted to mycophenylate. The neurological syndrome recovered over a 2-week period. Follow-up MRI scan (Figure 3) showed complete resolution of the high signal abnormalities.
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Figure 3. Follow-up MRI study. Fluid attenuated inversion recovery (FLAIR) sequence shows no abnormality in previously affected areas.
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Discussion
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RPLS was described in a series of patients in 1996 [1]. The clinical findings include headache, decreased level of consciousness and seizures, and focal neurology including cortical blindness and paralysis. The imaging findings in our patient were typical of RPLS. CT may show hypodensity in white and grey matter of the parietal and occipital lobes, but is frequently considered normal. MRI is more sensitive, and the observed changes appear to reflect oedema in certain areas of the brain. Focal and diffuse areas of high signal intensity are observed on T2 weighted and FLAIR imaging, while abnormal areas are of low signal on T1 weighted imaging, do not enhance following contrast and do not exhibit mass effect. Abnormalities are predominantly posterior, especially involving parietal and occipital lobes, but the cerebellum, brain stem, basal ganglia, subcortical white matter and frontal lobes may also be affected [2, 3]. Diffusion-weighted imaging [4, 5] can help to distinguish between areas of vasogenic oedema (free diffusion), which is potentially reversible, and areas of established infarction, which will show cytotoxic oedema (restricted diffusion). Diffusion-weighted imaging was performed in our patient and was interpreted as showing no evidence of restricted diffusion. In many cases, as in our patient, MRI changes resolve completely, but it is well recognised that clinical and imaging abnormalities can persist.
Neurological presentations following BMT are not uncommon, and cyclosporin A has increasingly been identified as a major aetiological factor. Cyclosporin related neurotoxicity was first identified in 1984 in a patient post-BMT [6]. The mechanism by which cyclosporin causes neurotoxicity is less well known. The distribution of the lesions suggests a vascular process. In many patients with the clinical syndrome of RPLS a transient or sustained increase in blood pressure is noted, and hypertensive encephalopathy associated with renal disease and eclampsia gives similar imaging findings. Our patient experienced a blood pressure rise to a level of 160/100 from a baseline of 110/70. This rise in blood pressure resolved on withdrawal of cyclosporin. The diagnosis of RPLS is presumed in the presence of a characteristic history and imaging findings, and biopsy is rarely undertaken. Resolution of abnormalities following withdrawal of cyclosporin is usually considered confirmatory. RPLS may be seen following transplantation of liver and kidney, but appears especially frequent following BMT. In this clinical context, there is a wide differential diagnosis, given that neurological complications are frequent following BMT. The differential diagnosis includes cerebral infarction, of which the main pattern to be differentiated is that of bilateral posterior cerebral artery infarction secondary to basilar tip embolism. Immunosuppressed patients are also susceptible to acute encephalomyelitis and progressive multifocal leukoencephalopathy. The distribution of abnormalities on MRI may help to discriminate these entities [7]. An autopsy study of neuropathological findings after BMT in 180 patients identified intraparenchymal brain haemorrhage and subarachnoid haemorrhage as the most common observed abnormalities. In all, neuropathological abnormalities were demonstrated in over 90% of patients dying following BMT [8]. The incidence of severe neurological complications appears slightly higher in patients receiving transplants from matched unrelated donors compared with matched sibling donors [9]. A cerebral vasculopathy characterized by increased cerebral blood flow velocities has been proposed as a cause of cyclosporin related toxicity [10].
Despite the uncertainty surrounding the causation, RPLS comprises a recognisable set of clinical and imaging findings. Following transplantation, it is important for the radiologist to recognise these findings as patients on High Dependency Units following seizures may be attended by a variety of clinicians including anaesthetists and others without direct experience of BMT. Treatment is conservative and should include control of blood pressure and withdrawal or reduction of cyclosporin dose, which should result in resolution of abnormalities and a favourable outcome.
Received for publication February 1, 2005.
Accepted for publication February 25, 2005.
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References
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- Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, et al. A reversible posterior leukoencephalopathy syndrome. New Engl J Med 1996;334:494–500.[Abstract/Free Full Text]
- Casey SO, Sampaio RC, Michel E, Truwit CL. Posterior reversible encephalopathy syndrome: utility of fluid-attenuated inversion recovery MR imaging in the detection of cortical and subcortical lesions. AJNR Am J Neuroradiol 2000;21:1199–206.[Abstract/Free Full Text]
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- Port JD, Beauchamp NJ Jr. Reversible intracerebral pathologic entities mediated by vascular autoregulatory function. Radiographics 1998;18:353–67.[Abstract]
- Bleggi-Torres LF, de Medeiros BC, Werner B, Neto JZ, Loddo G, Pasquini R, et al. Neuropathological findings after bone marrow transplantation: an autopsy study of 180 cases. Bone Marrow Transplant 2000;25:301–7.[CrossRef][Medline]
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Introduction
Diagnosis
