tacrolimus and Central-Nervous-System-Diseases

Topics: Central Nervous System Diseases; Cerebrovascular Disorders; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Mental Disorders; Neuromuscular Diseases; Seizures; Tacrolimus

Neurotoxicity is a serious complication following orthotopic liver transplantation leading to increased morbidity and mortality. Neurotoxicity may be evoked by various perioperative factors, or may be due to drug-specific toxicity of immunosuppression. In the present study we evaluated the incidence of central nervous system (CNS) toxicity occurring within the early postoperative period of 121 patients, 61 randomly assigned to FK 506- and 60 to CsA-based immunosuppression as part of a multicentre study. The incidence of moderate or severe CNS toxicity was higher in patients treated with FK 506 (21.3%) than in patients receiving CsA (11.7%). The duration of symptoms was also greater in patients treated with FK 506 than in patients receiving CsA. The incidence of moderate or severe neurotoxicity after retransplantation was markedly greater in patients treated with FK 506 (100% of the patients).

Topics: Central Nervous System Diseases; Cyclosporine; Dose-Response Relationship, Drug; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Muromonab-CD3; Postoperative Complications; Reoperation; Tacrolimus; Time Factors

Topics: Animals; Central Nervous System Diseases; Delayed-Action Preparations; Disease Models, Animal; Drug Carriers; Immunosuppressive Agents; Nanofibers; Rats; Tacrolimus

Paraneoplastic neurologic disorders (PND) are autoimmune diseases associated with cancer and ectopic expression of a neuronal antigen in a peripheral tumor. Patients with PND harbor high-titer antibodies and T cells in their serum and cerebrospinal fluid (CSF) that are specific to the tumor antigen, and treatment with the immunosuppressant FK506 (tacrolimus) decreases CSF white blood cell counts. The objective of this study was to determine the effect of FK506 on CSF chemokine levels in PND patients.. CSF samples before and after FK506 treatment were tested by multiplex assay for the presence of 27 cytokines. Follow-up in vitro experiments aimed to determine whether T cells secrete CXCL10 in response to cognate antigen.. Here we report that PND patients harbor high levels of the chemokine CXCL10 in their CSF. CXCL10 is a cytokine that recruits CXCR3(+) cells such as activated T cells, and we found that FK506 treatment specifically decreased CSF CXCL10 from among 27 cytokines tested. In vitro, CXCL10 was only produced during antigen-specific cognate interactions between T cells and antigen-presenting cells (APCs) when interferon-γ (IFNγ) receptors were present on the T cell.. These results support a model in which antigen-specific T cell stimulation by PND APCs triggers IFNγ, followed by CXCL10 production and further lymphocyte recruitment, suggesting that treatments targeting T cells or CXCL10 in the central nervous system (CNS) may interrupt a destructive positive feedback loop present in CNS inflammation.

Topics: Aged; Animals; Biomarkers; Central Nervous System Diseases; Chemokine CXCL10; Feedback, Physiological; Female; Humans; Immunosuppressive Agents; Inflammation; Inflammation Mediators; Male; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Paraneoplastic Syndromes, Nervous System; Tacrolimus

Central nervous system (CNS) complications are common after liver transplantation (LT). According to the literature, the most common causes are infections and the neurotoxicity of immunosuppressive drugs (cyclosporine and tacrolimus). The aim of this study was to evaluate the incidence, clinical presentations, etiologies, and outcomes of CNS complications in a series of 395 consecutive LT recipients whose immunosuppression regimen was designed for low tacrolimus blood levels. An analysis of the 12-hour trough concentrations of tacrolimus in the study population showed that the target drug levels, which were designed to maintain minimal immunosuppression, were usually achieved. In all, 64 patients (16.2%) developed major neurological symptoms (37 within 30 days of LT). None of the observed CNS complications were caused by infections (viral, bacterial, or fungal), and only 3 of the 395 patients (0.8%) received a diagnosis of tacrolimus-related leukoencephalopathy. Cerebrovascular disease was identified in 15 patients (3.8%; 8 had cerebral hemorrhages, 5 had ischemic strokes, and 2 had subdural hemorrhages). Pontine myelinolysis was found in 2 patients (0.5%). Notably, no clear cause was identified for the remaining 44 cases (11.1%): brain imaging was negative for 22 cases, and diffuse hypoxic changes were present for the other 22. CNS complications were significantly associated with a reduction in 3-month patient survival (88.8% versus 95.4%) and 5-year patient survival (57.3% versus 84.1%). Among the pretransplant variables that were analyzed, the incidence of portosystemic encephalopathy, the peak serum bilirubin levels, and the lowest serum total cholesterol levels were significantly different between the 64-patient group with CNS complications and the asymptomatic group of 331 patients.

Topics: Adult; Carcinoid Tumor; Carcinoma, Hepatocellular; Central Nervous System Diseases; Female; Graft Rejection; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis, Autoimmune; Hepatolenticular Degeneration; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis; Liver Cirrhosis, Biliary; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus

Early central nervous complications (CNS) are significant after allogeneic stem cell transplantation; however, the clinical characteristics of early CNS complications have not yet been well described. The medical record of 77 patients who underwent cord blood transplantation (CBT) between March 2001 and November 2005, at 8 centers of the Nagoya Blood and Marrow Transplantation Group were retrospectively reviewed. The preparative regimen included myeloablative CBT (n = 31) or reduced-intensity (RI)-CBT (n = 46). Of the 77 patients, 10 (13%) developed early CNS complications. Causes included Cyclosporine encephalopathy (n = 5), tacrolimus encephalopathy (n = 2), thrombocytic microangiopathy (n = 1), and unknown (n = 3). The median time of onset was 19 days (range: 2-58 days). All of the 10 patients developed impaired consciousness. Seizures developed in 6 patients. Early CNS complications spontaneously subsided in 3 patients. Three patients responded to cyclosporine or tacrolimus discontinuation. The remaining 4 patients died within 30 days of developing of early CNS complications. No relationship was detected between the preparative regimen and the onset of early CNS complications, while an HLA disparity showed borderline significance (hazard ratio, 3.24; 95% confidential interval, 0.94-11.20; P = .06). Early CNS complications are a significant problem after CBT, and the clinician has to be aware of the possibility of these complications.

Topics: Adolescent; Adult; Aged; Central Nervous System Diseases; Consciousness Disorders; Cord Blood Stem Cell Transplantation; Cyclosporine; Female; Histocompatibility; Humans; Male; Middle Aged; Retrospective Studies; Seizures; Tacrolimus; Thrombosis; Transplantation Conditioning; Transplantation, Homologous; Young Adult

Topics: Aquaporin 4; Autoantibodies; Brain; Central Nervous System Diseases; Female; Humans; Immunosuppressive Agents; Middle Aged; Sjogren's Syndrome; Spinal Cord; Tacrolimus; Treatment Outcome

Calcineurin inhibitor-induced central nervous system toxicities are uncommon and often resolve after discontinuation of the offending drug. The long-term outcome of these patients is, however, unknown. Resolution of symptoms occurred in 70% of 30 allografted recipients who developed calcineurin inhibitor-induced neurotoxicity. When patients were rechallenged with the same or a different calcineurin inhibitor, symptoms recurred in 41%, leading to permanent discontinuation of the drug. De novo or progressive acute graft-versus-host disease (GVHD) was observed in 54% of patients at a median of 7 d (range 1-70 d) after initial onset of neurotoxicity. The prognosis was grim, with 24 (80%) of these patients dying a median 33 d after the onset of neurotoxicity (range 2-594 d). GVHD and/or infection occurred in 54% and were the most common primary causes of death. We conclude that calcineurin inhibitor-induced neurotoxicity is frequently reversible but associated with a poor prognosis.

Topics: Adult; Bone Marrow Diseases; Bone Marrow Transplantation; Brain; Calcineurin Inhibitors; Central Nervous System Diseases; Cyclosporine; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Methotrexate; Middle Aged; Prednisone; Retrospective Studies; Tacrolimus; Transplantation, Homologous

Topics: Adult; Central Nervous System Diseases; Cerebrospinal Fluid; Electroencephalography; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Postoperative Complications; Tacrolimus; Transplantation