American Journal of Hematology 77:72–76 (2004)
Reversible Posterior Leukoencephalopathy Syndrome Complicating Cytotoxic Chemotherapy for Hematologic Malignancies C.S. Tam,1 J. Galanos,1 J.F. Seymour,1 A.G. Pitman,2 R.J. Stark,1,3,4 and H.M. Prince1* 1 Hematology Service, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia Department of Diagnostic Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia 3 Department of Neurology, Monash University, The Alfred Hospital, Commercial Road, Melbourne, Victoria, Australia 4 Department of Medicine, Monash University, The Alfred Hospital, Commercial Road, Melbourne, Victoria, Australia 2
Reversible posterior leukoencephalopathy syndrome (RPLS) is an uncommon but distinctive clinicoradiological entity comprising of headache, seizures, visual disturbance, and altered mental function, in association with posterior cerebral white matter edema. With appropriate management, RPLS is reversible in the majority of cases. Previous reported associations of RPLS include hypertension, eclampsia, renal failure, and use of immunosuppressive drugs; reports in the adult hematology setting are rare. We report two cases of adults undergoing treatment for hematological malignancies who developed RPLS, and we emphasize the importance of early recognition and institution of appropriate management in reducing the risk of development of permanent neurological disability. Am. J. Hematol. 77:72–76, 2004. ª 2004 Wiley-Liss, Inc. Key words: posterior leukoencephalopathy; hypertensive encephalopathy; eclampsia; cyclosporine encephalopathy; cytotoxic chemotherapy
INTRODUCTION
Reversible posterior leukoencephalopathy syndrome (RPLS) is a term first used by Hinchey et al. [13] to describe an uncommon but distinct clinicoradiological entity of headache, seizures, visual disturbance, and altered mental function associated with symmetrical posterior hemispheric edema. The syndrome is characterized by its reversibility upon control of hypertension and other primary instigating factors [13]. Imaging demonstrates evidence of white matter edema, usually affecting the parieto-occipital region in a strikingly symmetrical distribution [13,21]. The etiology of RPLS is not fully understood but is believed to be related to failure of cerebral autoregulation leading to development of vasogenic edema [13,21,23]. RPLS is most commonly seen in patients with hypertensive encephalopathy, eclampsia, renal failure, or use of cyclosporine or tacrolimus [13]. Despite increasing awareness of RPLS as a complication of treatment of childhood cancers [8,22,24,25], this syndrome is rarely reported in the adult oncology setting. We report two patients who developed ª 2004 Wiley-Liss, Inc.
RPLS during cytotoxic chemotherapy for hematological malignancies. CASE ONE
A 65-year-old man was admitted for management of advanced-stage multiple myeloma, with rapid progression of disease after brief response to previous therapy with high-dose cyclophosphamide (4 g/m2). Salvage chemotherapy with DT-PACE (dexamethasone, thalidomide, cisplatin, adriamycin, cyclophosphamide, and etoposide) [20] was commenced, *Correspondence to: Associate Professor H. Miles Prince, Hematology Service, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, Victoria 8006, Australia. E-mail:
[email protected] Received for publication 6 November 2003; Accepted 31 March 2004 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.20147
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Fig. 1. (Top) Fluid-attenuated inversion recovery (FLAIR) magnetic resonance sequences of Patient 1, showing widespread hyperintense signals in occipital white matter and left hippocampus at presentation (left, arrows). Repeat scan 2 weeks later (right) showing complete resolution of occipital white matter abnormality and persistence of left hippocampal infarct. (Bottom) FLAIR magnetic sequences of Patient 2, showing multiple symmetrical foci of hyperintense signal within occipital white matter at presentation (left, arrows). Repeat scan 4 months later (right) showing complete resolution of white matter abnormalities.
with intravenous fluids for tumor lysis prophylaxis. The patient developed significant fluid overload despite regular administration of frusemide, with weight gain of 10% above admission body weight and moderate elevation of blood pressure (150/80 mmHg, from baseline of 120/70 mmHg). On day 8, the patient developed sudden onset headache, cortical blindness, and ocular paresis, in association with hypertension of 180/100 mmHg. Computerized tomography (CT) scan of the brain revealed widespread bilateral occipital lobe white matter edema; diagnostic lumbar puncture was not performed at this time because of the risk of cerebral herniation. The patient’s conscious state rapidly deteriorated, and he became comatose 2 hr post headache onset, with recurrent left-sided focal seizures. Medical control of hypertension was instituted, and the patient’s conscious state improved rapidly. By the third day post onset, all neurological deficits had resolved completely, with no recurrence of seizure activity. A magnetic resonance (MR) scan of the
head revealed bilateral posterior white matter edema characteristic of RPLS (Fig. 1). Repeat MR scan of the head 2 weeks later showed near-complete resolution of previous extensive abnormalities. The patient remained free of recurrent neurological symptoms but died from sepsis 2 months later. CASE TWO
A 60-year-old man was admitted for management of relapsed lymphoblastic lymphoma. Chemotherapy with high-dose methotrexate (1 g/m2 over 24 hr) and cytarabine (1.5 g/m2 every 12 hr 4 doses) was administered, complicated by acute renal failure and severe methotrexate toxicity. Use of intravenous hydration resulted in significant fluid overload (weight gain of 12% body weight). Serum creatinine peaked at 0.34 mmol/L on day 4 and remained between 0.15 and 0.25 mmol/L over the subsequent week.
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On day 8, the patient developed headache and blurring of vision, in association with hypertension of 150/90 mmHg. On day 9, he deteriorated with increasing vagueness, dysarthria, and gait unsteadiness; that evening he had a generalized tonic–clonic seizure. MR scan showed symmetric occipital white matter abnormalities consistent with RPLS (Fig. 1). Medical control of hypertension and correction of fluid overload was instituted, with rapid resolution of the patient’s neurological deficits. Diagnostic lumbar puncture performed 24 hr post RPLS onset showed normal opening pressure and normal cerebral spinal fluid microscopy and biochemistry. A repeat MR scan performed 4 months later showed complete resolution of changes. The subsequent clinical course was complicated by recurrent lymphoma requiring further chemotherapy. Meticulous attention to blood pressure control and fluid management resulted in no recurrence of RPLS, despite development of severe tumor lysis syndrome, multiple episodes of septic shock, and eventual progression to dialysis-dependent end-stage renal failure. Five months post RPLS, the patient underwent autologous stem cell transplantation complicated by severe neutropenic sepsis and eventual death from multiorgan failure. Five days before death, the patient developed confusion progressing to coma, in association with severe hypertension refractory to intravenous antihypertensive therapy with atenolol, glycerine trinitrate, and hydralazine. Although there was a strong clinical suspicion for recurrent RPLS, no neuroimaging was obtained at the time and the patient’s family declined a postmortem examination. DISCUSSION
RPLS is characterized by subacute onset of headache, altered conscious state and behavior, and visual disturbance ranging from blurred vision to total cortical blindness; seizures are common and may herald the onset [13]. Focal deficits of cranial nerves and limbs are uncommon [10,13,15,21]. Characteristic radiological changes are those of white matter edema, with often strikingly symmetrical hyperintense signals predominantly in the posterior hemispheres on T2-weighted MR scanning; this is best visualized on fluid-attenuated inversion recovery (FLAIR) sequences [13,21]. The majority of patients previously reported have complete or near-complete resolution of clinical and radiological changes within days to weeks [13]. RPLS is typically seen in patients with hypertensive encephalopathy, eclampsia, renal failure, and use of immunosuppressant drugs [13]. Many other
associations have been reported, including microangiopathy [2], sickle cell disease [10], intravenous immunoglobulin use [28], large-volume red cell transfusion [16], stem cell re-infusion [12], use of erythropoietin or G-CSF [5,17], hypercalcemia [18], and acute intermittent porphyria [19,26]. In the pediatric oncology literature, there is increasing awareness of RPLS as a complication of cancer treatment [22,24,25], particularly in the setting of hematopoietic stem cell transplantation where it is the most common severe neurological complication [8]. In adult oncology literature, however, RPLS is rarely recognized outside the hematopoietic stem cell transplantation setting. No single chemotherapeutic agent or therapeutic regimen has been identified to date as being consistently associated with RPLS. Implicated drugs have included single-agent cisplatin [15] or cytarabine [27], as well as combinations of adriamycin [4,7, 9,11,14], cyclophosphamide [4,7,9,11,14], vincristine [4,7,9,11], corticosteroids [4,7,9,11,14], ifosfamide [9], etoposide [9], and cytarabine [9]. Most published reports of RPLS complicating combination chemotherapy for adult hematological malignancies involved the use of intrathecal chemotherapy, with methotrexate, cytarabine, or both [7,9,11,14]; there is therefore previous uncertainty about the contributory role of intrathecal chemotherapy in RPLS development. Neither of our patients, however, received intrathecal chemotherapy. Furthermore, in the pediatric literature there are examples of continued administration of intrathecal chemotherapy to patients who developed RPLS following initial regimens that involved intrathecal treatment, with no recurrence of neurological symptoms [24]. There is therefore little evidence of etiologic link between RPLS and intrathecal administration of cytotoxic drugs. One constant feature in all reported cases of RPLS complicating cytotoxic chemotherapy is the presence of systemic hypertension [4,7,9,11,14,15]. Hypertension is also a feature in the vast majority of RPLS reported [5,7,9–11,13–16,19,21,23–26]. In contrast to encephalopathy caused by isolated malignant hypertension, patients with RPLS often present with only moderate levels of hypertension (systolic blood pressure 130–200 mmHg, diastolic blood pressure generally > 90 mmHg); in the majority of cases this still represents a significant increase above baseline levels. One hypothesis for the pathogenesis of RPLS consistent with this observation involves dysfunction of cerebral vascular autoregulation. Under normal circumstances, sympathetic innervation of cerebral vessels assists in regulating intracerebral blood flow against fluctuations in systemic perfusion pressure [3]; in RPLS, failure of autoregulation due to unknown
Case Report: Posterior Leukoencephalopathy in Hematology
mechanisms result in hyperperfusion of the brain following only modest rises in blood pressure, with resultant breakdown of blood–brain barrier and interstitial edema [3,13,26]. Posterior hemispheric predilection may be explained by poor sympathetic innervation of vertebrobasilar system relative to the carotid system [6]. Evidence supporting vascular pathogenesis of RPLS includes demonstrations of vasospasm during acute-phase RPLS [11,16] and MR brain–water diffusion studies suggesting that white matter edema in RPLS is largely vasogenic in origin [21,23,25]. In the majority of reported cases, RPLS is fully reversible within a period of days to weeks, with removal of the inciting factor and control of the blood pressure [13]. However, permanent neurological disability can occur, often in association with complicating cerebral infarction or hemorrhage [1,11]; fatalities have also been reported [4,9]. The MR findings of hyperintense signals on diffusion-weighted images and restricted diffusion on apparent diffusion coefficient map are occasionally seen and are suggestive of cytotoxic edema; these findings may be predictive of irreversible infarction [1,10,11,25]. As a result of our experience, our institution now considers patients with one or more of (i) significant fluid overload (>10% baseline weight), (ii) mean blood pressure >25% of baseline, and (iii) creatinine >0.16 mmol/L to be at high risk for RPLS; all such patients receive early neuroimaging to evaluate any unexplained neurological change. In addition, meticulous attention is paid to changes in weight and blood pressure in any patient who receives a regimen requiring more than 3 L of intravenous fluid daily. RPLS may be an under-appreciated complication of cytotoxic therapy; early diagnosis requires a high clinical index of suspicion, appreciation that initial neurological deficits are variable and often subtle, and timely evaluation of cerebral white matter with neuroimaging.
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