Cyclosporine-Associated Central Nervous System Toxicity After Allogeneic Bone Marrow Transplantation

Summary:Two patients with CsA-associated neurotoxicity developed severe cerebellar swelling and thrombotic thrombocytopenic purpura after switching to FK506 and high-dose corticosteroids. The prodrome of CsAassociated neurotoxicity, TTP and hypertension while receiving FK506, and high-dose corticosteroids could all be implicated in the development of this syndrome. Close monitoring of patients receiving FK506 and highdose corticosteroids, for the development of TTP is warranted. Early radiological examination should also be considered in such patients to allow early surgical intervention. Keywords: cerebellar swelling; TTP; FK506; cyclosporine neurotoxicity; steroids Common side-effects of cyclosporin A (CsA) include renal dysfunction, hypertension and tremors.1,2 Rare severe neurotoxicity including ataxia and occipital blindness is also reported. [3][4][5][6] This syndrome resembles thrombotic thrombocytopenic purpura (TTP). There are numerous case reports of TTP following BMT. [7][8][9][10][11][12][13] Clinical manifestations include: hypertension, edema, renal failure, neurologic changes and microangiopathic hemolytic anemia. Although the syndromes are both associated with CsA use, the presence or absence of microangiopathic hemolytic anemia can distinguish them. 14 Treatment of CsA neurotoxicity consists of discontinuing the drug, correcting electrolyte abnormalities and controlling hypertension. 3,13,15 Neurologic changes typically resolve within 48 h of discontinuing CsA. In contrast, patients with TTP have a much poorer outcome despite discontinuing CsA, often requiring intensive support.14 Although ideal management is unclear, it appears that plasma exchange alone 16 or combined with protein immunoadsorption may be effective modes of therapy. and to alter the ratio of thromboxane to prostacyclin production resulting in procoagulant activity. [18][19][20][21][22][23][24] Since patients who develop neurologic symptoms attributable to CsA without microangiopathic changes and those who develop TTP are frequently early post-transplant, discontinuing CsA may be associated with development of severe GVHD. The introduction of FK506 into clinical use has allowed substitution of FK506 for CsA in patients developing TTP following BMT and solid organ transplantation. 25 However, the safety of this approach is not well established as there are now reports of FK506-induced TTP following BMT and solid organ transplantation. 26-28 Case 1A 28-year-old male with Hodgkin's disease received an HLA-matched unrelated donor BMT 2 years after relapsing following an autologous BMT. Conditioning was with thiotepa and carboplatin. He received low-dose intravenous heparin as hepatic veno-occlusive disease (VOD) prophylaxis. GVHD prophylaxis consisted of cyclosporine, methotrexate and methylprednisolone. On day +8, he developed hyperbilirubinemia (primarily direct), associated with an elevated CsA level of 514 (normal range, 250-450). CsA was held and restarted at one-third the previous dose on day +10. On day +11, he developed cort...

show abstract

“…[3][4][5][6] This syndrome resembles thrombotic thrombocytopenic purpura (TTP). There are numerous case reports of TTP following BMT.…”

Section: Discussionmentioning

confidence: 99%

“…14 Treatment of CsA neurotoxicity consists of discontinuing the drug, correcting electrolyte abnormalities and controlling hypertension. 3,13,15 Neurologic changes typically resolve within 48 h of discontinuing CsA. In contrast, patients with TTP have a much poorer outcome despite discontinuing CsA, often requiring intensive support.…”

Section: Discussionmentioning

confidence: 99%

Severe cerebellar swelling and thrombotic thrombocytopenic purpura associated with FK506

Tezcan

Zimmer

Fenstermaker

et al. 1998

Bone Marrow Transplant

View full text Add to dashboard Cite

show abstract

“…All of these patients were included in this study. Mean age was 9.0 years (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Indications for transplantation were acute lymphoblastic leukemia in 31 patients (14 in first complete remission: 1CR), acute myelogenous leukemia in 14 (nine in 1CR), aplastic anemia in nine, non-Hodgkin's lymphoma in seven, myelodysplastic syndrome in four, rhabdomyosarcoma in three, Wiscott-Aldrich syndrome in three, chronic myelogenous leukemia in two, juvenile chronic myelogenous leukemia, neuroblastoma, fibrosarcoma, and yolk sac tumor in one each.…”

mentioning

confidence: 99%

Neurological complications after stem cell transplantation in childhood

Iguchi

Kobayashi

Yoshida

et al. 1999

Bone Marrow Transplant

View full text Add to dashboard Cite

Summary:We analyzed the incidence of neurological complications in 77 patients receiving stem cell transplantation (SCT), and 12 patients (15.8%) had the following symptoms: convulsions, intracranial hemorrhage, and leukoencephalopathy. Although statistically not significant, neurological complications were seen more frequently in patients after allogeneic transplantation, and in those with acute graft-versus-host disease (GVHD) exceeding grade II. The most significant risk factor for neurological complications was identified as unrelated donor allogenic transplantation (P = 0.016). Complications were categorized into three groups, based on time of onset and symptoms: (1) convulsions during the conditioning period, (2) intracranial hemorrhage during the period of granulocyte recovery, and (3) leukoencephalopathy at around 2 months after SCT. We propose awareness of the risks of neurological complications in each period after SCT so that immediate and effective treatment of patients can be instigated.

show abstract

“…22,23 Resolution of neurotoxicity is often seen after temporarily withholding or decreasing the dose of CSP, 39 but symptoms may also recur after a rechallenge with CSP. 41 It is unknown whether these patients would have tolerated rechallenge with CSP without recurrence of neurologic symptoms.…”

Section: Discussionmentioning

confidence: 99%

Clinical outcome after conversion to FK 506 (tacrolimus) therapy for acute graft-versus-host disease resistant to cyclosporine or for cyclosporine-associated toxicities

Furlong

Storb

Anasetti

et al. 2000

Bone Marrow Transplant

View full text Add to dashboard Cite

Summary:This retrospective study describes the outcome in 53 patients who had immunosuppressive treatment changed from cyclosporine (CSP) to tacrolimus for resistant acute GVHD (n = 23), hemolytic uremic syndrome (HUS) (n = 13) or CSP-associated neurotoxicity (n = 17). Tacrolimus was administered at doses of 0.03 mg/kg/day intravenously or 0.12 mg/kg/day orally in divided doses, as tolerated. Median time of conversion to tacrolimus after transplant was day 47. Nineteen patients had treatment changed to tacrolimus for resistant acute GVHD grades III or IV, with the median day of conversion being day 49 after transplant. Two of 20 evaluable patients had a complete resolution of GVHD after changing treatment to tacrolimus, with 18 showing no improvement. Eleven evaluable patients had therapy changed to tacrolimus for CSP-associated neurotoxicity at a median of 36 days after transplant. Eight patients had resolution of neurotoxicity and three had partial improvement. Eleven evaluable patients had therapy changed to tacrolimus for HUS at a median of 46 days after transplant. One patient had complete resolution of HUS and 10 showed no response. Side-effects related to tacrolimus included renal toxicity (34%), neurotoxicity (15%) and HUS (9%). Nine (17%) patients remain alive, including six patients who had therapy changed to tacrolimus for CSP-associated neurotoxicity. While often successful for dealing with neurotoxicity, only a rare patient improved after therapy was changed from CSP to tacrolimus for HUS or resistant acute GVHD. Bone Marrow Transplantation (2000) 26, 985-991.

show abstract

Cyclosporine-Associated Central Nervous System Toxicity After Allogeneic Bone Marrow Transplantation

Cited by 126 publications

References 0 publications

Severe cerebellar swelling and thrombotic thrombocytopenic purpura associated with FK506

Severe cerebellar swelling and thrombotic thrombocytopenic purpura associated with FK506

Neurological complications after stem cell transplantation in childhood

Clinical outcome after conversion to FK 506 (tacrolimus) therapy for acute graft-versus-host disease resistant to cyclosporine or for cyclosporine-associated toxicities

Contact Info

Product

Resources

About