Tacrolimus-Related Encephalopathy following Allogeneic Stem Cell Transplantation in Children

Abstract

Tacrolimus is a potent immunosuppressive drug widely used to prevent and treat graft-versus-host disease (GVHD) in stem cell transplantation (SCT). Among 49 patients receiving tacrolimus who underwent SCT from January 2000 to July 2003, 10 patients (20%) developed encephalopathy. The commonly observed symptoms were convulsions and drowsiness, and most patients complained of signal symptoms such as headache, nausea, and cortical blindness before onset. The most common abnormality on neuroimages was high-intensity lesions in white matter on magnetic resonance imaging T2-weighted or fluid-attenuated inversion recovery images. At onset, all patients were receiving treatment for acute GVHD (grade II/III) or extensive chronic GVHD and demonstrated an abrupt increase in blood pressure from baseline levels. The serum tacrolimus concentration was generally within acceptable levels at onset. Symptoms gradually improved in all patients when the blood pressure was lowered with antihypertensive medication, regardless of continued tacrolimus administration following a short-term suspension. The pathogenesis of tacrolimus-related encephalopathy is multifactorial, although refractory GVHD and a sudden increase in blood pressure seem to be major predisposing factors. Because the withdrawal of tacrolimus or switching to less potent anti-GVHD agents usually worsens the GVHD, the administration of tacrolimus should be managed by closely monitoring serum levels and controlling blood pressure.

Tacrolimus‐associated posterior reversible encephalopathy syndrome in hematopoietic allogeneic stem cell transplantation

“…Another PRES study which had a higher number of HLA-mismatched donors reported a high incidence of severe GVHD. The patients in that study subsequently had a higher incidence of PRES than in our study or the Wong study [8].…”

“…GVHD leads to the release of endothelial activators, such as TNF-a and interleukin-1, which leads to system-wide vasoconstriction, including the CNS [4,7,8]. In our study, 7 of the 19 patients had active GVHD at the time of PRES onset.…”

“…The available literature comments on the basics of managing PRES including withdrawal or dose reduction of the offending agent, blood pressure control, and anticonvulsants in those with seizures [2][3][4]. More specifically, in terms of tacrolimus management, case reports and retrospective reviews report their experience and collectively, these hardly define a trend to a successful management strategy [1][2][3]7,8,10,13]. In our study, there did not seem to be a trend in favor of one strategy over another since the survival percentages to discharge were similar.…”

Cerebral complications induced by calcineurin inhibitors in children after haematopoietic stem cell transplantation

“…As far as the pathogenesis of tacrolimus-related encephalopathy is concerned, several factors should be considered [15,16]. The toxic effects of tacrolimus have not been defined yet, but a direct neurotoxicity may be the cause of the white matter oedema [17].…”

Prophylactic and therapeutic treatment of graft-versus-host disease in Japan

“…It has been suggested that calcineurin inhibitors are involved in the development of intestinal thrombotic microangiopathy, a life-threatening complication after allogeneic transplantation, in humans and rats [38][39][40]. The blood concentration of Tac was not necessarily high in patients who developed Tac-related encephalopathy [41]. Genetic polymorphisms of cytochrome P450 may affect the serum concentration of calcineurin inhibitors in transplant patients [42].…”