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1
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Bugallo-Carrera C, Facal D, Domínguez-Lenogue C, Álvarez-Vidal V, Gandoy-Crego M, Caamaño-Ponte J. Neuropsychiatric Symptoms after Liver Transplantation in a 65-Year-Old Male Patient. Brain Sci 2022; 12:1721. [PMID: 36552180 PMCID: PMC9776108 DOI: 10.3390/brainsci12121721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 12/07/2022] [Accepted: 12/10/2022] [Indexed: 12/23/2022] Open
Abstract
The development of immunosuppressants has been key for the advancement of solid organ transplant surgery. Specifically, cyclosporine, tacrolimus, or everolimus have significantly increased the survival rate of patients by reducing the risk of a rejection of the transplanted organ and limiting graft-versus-host disease. We report the case of a 65-year-old man who, after undergoing a liver transplantation and receiving an immunosuppressive treatment with cyclosporine and everolimus, presented severe obsessive, psychotic, and behavioral symptoms over the past three years, and describe the pharmacological and non-pharmacological interventions implemented against these symptoms. In this case, the immunosuppressants used have been cyclosporine and, preferably, everolimus. On the other hand, potential adverse reactions to the treatment have been observed, including neuropsychiatric symptoms such as tremor, anxiety, dysthymia, psychosis, and behavioral disorders, which make it necessary to use corrective psychoactive drugs such as benzodiazepines, antidepressants, and antipsychotics, combined with non-pharmacological interventions. A transversal approach, from the medical and psychosocial disciplines, facilitates success in managing neuropsychiatric symptoms after soft organ transplants.
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Affiliation(s)
- Cesar Bugallo-Carrera
- Asociación de Familiares de Enfermos de Alzheimer de Fisterra e Soneira—Afafes. Cee, 15270 A Coruña, Spain
- Department of Developmental Psychology, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - David Facal
- Department of Developmental Psychology, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Cristina Domínguez-Lenogue
- Asociación de Familiares de Enfermos de Alzheimer de Fisterra e Soneira—Afafes. Cee, 15270 A Coruña, Spain
| | - Vanessa Álvarez-Vidal
- Hospital de Día de Procesos, Servicio de Geriatría, Hospital Universitario Lucus Augusti, 27003 Lugo, Spain
| | - Manuel Gandoy-Crego
- Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
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2
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Aksoy F, Dundar HZ, Bican Demir A, Kiyici M, Kaya E. Myelitis After Liver Transplant: A Case Report. EXP CLIN TRANSPLANT 2021. [PMID: 34085919 DOI: 10.6002/ect.2020.0278] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
We report a case of neurotoxicity as a side effect of a calcineurin inhibitor (tacrolimus), which is used as an immunosuppressive drug after liver transplant. Our patient had chronic hepatic failure due to Budd-Chiari syndrome and underwent a liver transplant after an appropriate deceased donor organ was obtained. After organ transplant surgery, he was kept under the effect of an immunosuppressive drug (tacrolimus) with daily control of the level of drug in his blood to avoid drug toxicity. Despite the level of drug in his blood being within the ideal range, the patient developed neurotoxicity that presented as weakness of his extremities. Appropriate diagnostic tests were done, and all proved that these signs and symptoms were related to the use of tacrolimus. Therefore, the drug was changed to cyclosporine. After a few months, the patient regained normal neurological functions of his extremities. We should take precautions to monitor neurological symptoms and signs while we administer calcineurin inhibitors.
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Affiliation(s)
- Fuat Aksoy
- From the Department of General Surgery, Bursa Uludag University, Bursa, Turkey
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3
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Coe CL, Horst SN, Izzy MJ. Neurologic Toxicities Associated with Tumor Necrosis Factor Inhibitors and Calcineurin Inhibitors. Neurol Clin 2020; 38:937-951. [PMID: 33040870 DOI: 10.1016/j.ncl.2020.07.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The calcineurin inhibitors cyclosporine and tacrolimus are used for their immunosuppressive effects. Neurotoxic side effects include tremor, paresthesia, and headache. Rarer neurotoxicities include seizure, posterior reversible encephalopathy syndrome, and encephalopathy. Tacrolimus tends to be more neurotoxic than cyclosporine. Management of toxicities associated with calcineurin inhibitors includes dose reduction, switching between calcineurin inhibitors, or switching to a calcineurin-free regimen. Tumor necrosis factor (TNF) inhibitors are used in autoimmune diseases. Management of demyelinating conditions among patients treated with anti-TNF should follow standard of care and withdrawal of the anti-TNF. This drug class should be avoided in patients with a history of demyelinating conditions.
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Affiliation(s)
- Christopher L Coe
- Department of Medicine, Section of Hospital Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232, USA. https://twitter.com/ccoemd
| | - Sarah N Horst
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 1211 21st Avenue South, Medical Arts Building, Suite 220, Nashville, TN 37232, USA. https://twitter.com/HorstIBDDoc
| | - Manhal J Izzy
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Transplant Hepatology, 1660 The Vanderbilt Clinic, Nashville, TN 37232, USA.
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4
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Abstract
Neurologic disturbances including encephalopathy, seizures, and focal deficits complicate the course 10-30% of patients undergoing organ or stem cell transplantation. While much or this morbidity is multifactorial and often associated with extra-cerebral dysfunction (e.g., graft dysfunction, metabolic derangements), immunosuppressive drugs also contribute significantly. This can either be through direct toxicity (e.g., posterior reversible encephalopathy syndrome from calcineurin inhibitors such as tacrolimus in the acute postoperative period) or by facilitating opportunistic infections in the months after transplantation. Other neurologic syndromes such as akinetic mutism and osmotic demyelination may also occur. While much of this neurologic dysfunction may be reversible if related to metabolic factors or drug toxicity (and the etiology is recognized and reversed), cases of multifocal cerebral infarction, hemorrhage, or infection may have poor outcomes. As transplant patients survive longer, delayed infections (such as progressive multifocal leukoencephalopathy) and post-transplant malignancies are increasingly reported.
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5
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Joshi P, Rymowicz R, Kennedy CA, Schwartz MR. Acute psychosis associated with immunosuppressive agent use years after liver transplantation. Asian J Psychiatr 2019; 43:65-66. [PMID: 31085439 DOI: 10.1016/j.ajp.2019.05.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 04/19/2019] [Accepted: 05/06/2019] [Indexed: 11/25/2022]
Affiliation(s)
- Pallavi Joshi
- Department of Psychiatry and Behavioral Sciences, Northwell Health - Staten Island University Hospital, 376 Seguine Ave, Staten Island, NY 10309, United States.
| | - Robert Rymowicz
- Department of Psychiatry, Rutgers New Jersey Medical School, 183 South Orange Ave, Newark, NJ 07103, United States
| | - Cheryl A Kennedy
- Department of Psychiatry, Rutgers New Jersey Medical School, 183 South Orange Ave, Newark, NJ 07103, United States
| | - Matthew R Schwartz
- Department of Psychiatry and Behavioral Sciences, Northwell Health - Staten Island University Hospital, 376 Seguine Ave, Staten Island, NY 10309, United States
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6
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Weiss N, Thabut D. Neurological Complications Occurring After Liver Transplantation: Role of Risk Factors, Hepatic Encephalopathy, and Acute (on Chronic) Brain Injury. Liver Transpl 2019; 25:469-487. [PMID: 30697911 DOI: 10.1002/lt.25420] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Accepted: 12/19/2018] [Indexed: 02/06/2023]
Abstract
Orthotopic liver transplantation (LT) remains the only way to definitively cure patients with the most severe liver diseases. Because the survival rate is now fairly high, important questions about neurological sequelae or quality of life after LT have emerged. Indeed, LT represents a peculiar situation because up to 30% of patients present with neurological symptoms after LT compared with only 4% after cardiac transplant and 0.5% after renal transplant. These postoperative neurological symptoms have long been interpreted as sequelae of hepatic encephalopathy (HE). However, postoperative decompensation of an unknown cerebral condition due to the pathophysiology of cirrhosis or undiagnosed neurodegenerative disorders or aging constitute other possibilities that are underrecognized. Some patients who undergo LT for acute liver failure and patients with cirrhosis without episodes of HE and without any previous cerebral alteration also display post-LT neurological symptoms. This latter situation speaks in favor of a direct adverse effect of either general anesthesia, the surgical procedure, or factors related to the postoperative intensive care unit (ICU) environment. The role of inflammation, which has been described in the ICU setting, could also be a crucial determinant. In this review, we will discuss the neurological complications associated with LT, the neurocognitive complications after LT, and how to assess the LT-related neurological or neurocognitive complications. Furthermore, we will review the various hypotheses surrounding post-LT neurocognitive impairment and will conclude with recommendations for future directions.
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Affiliation(s)
- Nicolas Weiss
- Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, Assistance Publique - Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière-Charles Foix, Département de Neurologie, Unité de Réanimation Neurologique, Sorbonne Université, Paris, France.,Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université, INSERM, Paris, France
| | - Dominique Thabut
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université, INSERM, Paris, France.,Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, Assistance Publique - Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière-Charles Foix, Service d'Hépato-Gastroentérologie, Unité de Soins Intensifs d'Hépato-Gastroentérologie, Sorbonne Université, Paris, France
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7
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Sen A, Callisen H, Libricz S, Patel B. Complications of Solid Organ Transplantation: Cardiovascular, Neurologic, Renal, and Gastrointestinal. Crit Care Clin 2018; 35:169-186. [PMID: 30447778 DOI: 10.1016/j.ccc.2018.08.011] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Despite improvements in overall graft function and patient survival rates after solid organ transplantation, complications can lead to significant morbidity and mortality. Cardiovascular complications include heart failure, arrhythmias leading to sudden death, hypertension, left ventricular hypertrophy, and allograft vasculopathy in heart transplantation. Neurologic complications include stroke, posterior reversible encephalopathy syndrome, infections, neuromuscular disease, seizure disorders, and neoplastic disease. Acute kidney injury occurs from immunosuppression with calcineurin inhibitors or as a result of graft failure after kidney transplantation. Gastrointestinal complications include infections, malignancy, mucosal ulceration, perforation, biliary tract disease, pancreatitis, and diverticular disease. Immunosuppression can predispose to infections and malignancy.
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Affiliation(s)
- Ayan Sen
- Department of Critical Care Medicine, Mayo Clinic Arizona, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA.
| | - Hannelisa Callisen
- Department of Critical Care Medicine, Mayo Clinic Arizona, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA
| | - Stacy Libricz
- Department of Critical Care Medicine, Mayo Clinic Arizona, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA
| | - Bhavesh Patel
- Department of Critical Care Medicine, Mayo Clinic Arizona, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA
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9
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Kang HG, Park SK, Wang SJ, Oh SY, Ryu HU. Opsoclonus-myoclonus syndrome following long-term use of cyclosporine. Clin Toxicol (Phila) 2017; 56:373-376. [PMID: 28905654 DOI: 10.1080/15563650.2017.1375511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
BACKGROUND Cyclosporine A (CsA) is a widely used immunosuppressive agent that may provoke unexpected neurologic complications. The mechanism is unclear and variable intervals have been reported between CsA administration and onset of the related side effects. Here, we describe a case of delayed-onset CsA neurotoxicity presenting as opsoclonus-myoclonus syndrome (OMS). CASE DETAILS A 37-year-old woman with a two-week period of opsoclonus and upper extremity myoclonus was admitted to our hospital. The patient had been taking CsA for 17 years after receiving a kidney transplant. Further evaluation did not reveal any other abnormalities. Seven days after switching from CsA to tacrolimus, in the absence of additional immune-modulating therapy, her neurologic symptoms improved considerably. CONCLUSION This is the case of delayed, long-term complications of CsA presenting as OMS. Symptoms resolved by substituting CsA with another immunomodulating drug. The etiology of the neurologic complications may involve paradoxically-enhanced delayed-type hypersensitivity.
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Affiliation(s)
- Hyun Goo Kang
- a Department of Neurology , Chosun University Hospital , Gwang-ju , South Korea
| | - Sung Kwang Park
- b Department of Internal Medicine , Chonbuk National University Hospital , Jeonju , South Korea
| | - Su Jeong Wang
- c Department of Neurology , Chonbuk National University Hospital , Jeonju , South Korea
| | - Sun-Young Oh
- c Department of Neurology , Chonbuk National University Hospital , Jeonju , South Korea
| | - Han Uk Ryu
- c Department of Neurology , Chonbuk National University Hospital , Jeonju , South Korea
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10
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Kapoor A, Birks E, Lenneman A, McCants K. Posterior Reversible Encephalopathy Syndrome after Heart Transplantation: Diagnosis and Immunosuppressive Therapy. Tex Heart Inst J 2017; 44:205-208. [PMID: 28761402 DOI: 10.14503/thij-15-5007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Posterior reversible encephalopathy syndrome, an infrequent neurotoxicity associated with the use of tacrolimus, was first described in 1996, as a reversible syndrome manifested by headache, altered mental function, seizures, and visual disturbances. We describe the case of a 37-year-old woman who developed neurologic symptoms consistent with encephalopathy after treatment with tacrolimus, which was prescribed to maintain immunosuppression after orthotopic heart transplantation. This report also discusses the imaging methods used in the diagnosis of posterior reversible encephalopathy and highlights the difficulty of maintaining immunosuppression and managing medication-related adverse effects, while taking into account the risk of acute rejection after transplantation.
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11
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Wang P, Que W, Li H, Yan L, Fu Z, Ye Q, Chen G, Dou K, Lu S, Yang Z, Zhu Z, Peng Z, Zhong L. Efficacy and safety of a reduced calcineurin inhibitor dose combined with mycophenolate mofetil in liver transplant patients with chronic renal dysfunction. Oncotarget 2017; 8:57505-57515. [PMID: 28915690 PMCID: PMC5593662 DOI: 10.18632/oncotarget.15490] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 02/08/2017] [Indexed: 02/05/2023] Open
Abstract
Calcineurin inhibitors (CNIs) are frequently given at a reduced dose in combination with mycophenolate mofetil (MMF) to avoid nephrotoxicity, but the optimal reduction in CNI dose has not been established. In this prospective, open-label, multicenter study, liver transplant recipients with chronic renal dysfunction who were administered a CNI-based immunosuppressive regimen were included in the intent-to-treat (ITT) population. The primary endpoint was declination in renal function, which was defined as a ≥ 20% decrease in the glomerular filtration rate during the year following regimen adjustment. In the ITT population, renal function declined after regimen adjustment in three patients (7%) in the MMF plus 50% CNI reduction group. Additionally, three of 40 patients (7.5%) in the MMF plus 75% CNI reduction group experienced at least one clinically suspected or biopsy-proven acute rejection. There were no differences between the two groups. The corrected mean improvement in creatinine clearance at week 52 was 6.551 mL/min in the MMF plus 50% CNI reduction group and 6.442 mL/min in the MMF plus at least 75% CNI reduction group. Thus, a regimen of MMF combined with a 50% or at least 70% reduction in CNI dose could improve renal function and was both tolerable and safe.
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Affiliation(s)
- Pusen Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weitao Que
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao Li
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lvnan Yan
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Zhiren Fu
- Organ Transplantation Institute of Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Qifa Ye
- Engineering and Technology Research Center for Transplantation Medicine of the National Ministry of Health, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Guihua Chen
- Department of Liver Transplantation, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xian, China
| | - Shichun Lu
- Department of Liver Transplantation, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Zhanyu Yang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Zhijun Zhu
- Department of Transplantation, Tianjin First Central Hospital, Tianjin Medical University, Tianjin, China
| | - Zhihai Peng
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin Zhong
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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12
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Abstract
Major neurologic morbidity, such as seizures and encephalopathy, complicates 20-30% of organ and stem cell transplantation procedures. The majority of these disorders occur in the early posttransplant period, but recipients remain at risk for opportunistic infections and other nervous system disorders for many years. These long-term risks may be increasing as acute survival increases, and a greater number of "sicker" patients are exposed to long-term immunosuppression. Drug neurotoxicity accounts for a significant proportion of complications, with posterior reversible leukoencephalopathy syndrome, primarily associated with calcineurin inhibitors (i.e., cyclosporine and tacrolimus), being prominent as a cause of seizures and neurologic deficits. A thorough evaluation of any patient who develops neurologic symptoms after transplantation is mandatory, since reversible and treatable conditions could be found, and important prognostic information can be obtained.
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Affiliation(s)
- R Dhar
- Division of Neurocritical Care, Department of Neurology, Washington University, St. Louis, MO, USA.
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13
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Kulbe JR, Hill RL, Singh IN, Wang JA, Hall ED. Synaptic Mitochondria Sustain More Damage than Non-Synaptic Mitochondria after Traumatic Brain Injury and Are Protected by Cyclosporine A. J Neurotrauma 2016; 34:1291-1301. [PMID: 27596283 DOI: 10.1089/neu.2016.4628] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Currently, there are no Food and Drug Administration (FDA)-approved pharmacotherapies for the treatment of those with traumatic brain injury (TBI). As central mediators of the secondary injury cascade, mitochondria are promising therapeutic targets for prevention of cellular death and dysfunction after TBI. One of the most promising and extensively studied mitochondrial targeted TBI therapies is inhibition of the mitochondrial permeability transition pore (mPTP) by the FDA-approved drug, cyclosporine A (CsA). A number of studies have evaluated the effects of CsA on total brain mitochondria after TBI; however, no study has investigated the effects of CsA on isolated synaptic and non-synaptic mitochondria. Synaptic mitochondria are considered essential for proper neurotransmission and synaptic plasticity, and their dysfunction has been implicated in neurodegeneration. Synaptic and non-synaptic mitochondria have heterogeneous characteristics, but their heterogeneity can be masked in total mitochondrial (synaptic and non-synaptic) preparations. Therefore, it is essential that mitochondria targeted pharmacotherapies, such as CsA, be evaluated in both populations. This is the first study to examine the effects of CsA on isolated synaptic and non-synaptic mitochondria after experimental TBI. We conclude that synaptic mitochondria sustain more damage than non-synaptic mitochondria 24 h after severe controlled cortical impact injury (CCI), and that intraperitoneal administration of CsA (20 mg/kg) 15 min after injury improves synaptic and non-synaptic respiration, with a significant improvement being seen in the more severely impaired synaptic population. As such, CsA remains a promising neuroprotective candidate for the treatment of those with TBI.
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Affiliation(s)
- Jacqueline R Kulbe
- Spinal Cord & Brain Injury Research Center (SCoBIRC) and Department of Anatomy & Neurobiology, University of Kentucky College of Medicine , Lexington, Kentucky
| | - Rachel L Hill
- Spinal Cord & Brain Injury Research Center (SCoBIRC) and Department of Anatomy & Neurobiology, University of Kentucky College of Medicine , Lexington, Kentucky
| | - Indrapal N Singh
- Spinal Cord & Brain Injury Research Center (SCoBIRC) and Department of Anatomy & Neurobiology, University of Kentucky College of Medicine , Lexington, Kentucky
| | - Juan A Wang
- Spinal Cord & Brain Injury Research Center (SCoBIRC) and Department of Anatomy & Neurobiology, University of Kentucky College of Medicine , Lexington, Kentucky
| | - Edward D Hall
- Spinal Cord & Brain Injury Research Center (SCoBIRC) and Department of Anatomy & Neurobiology, University of Kentucky College of Medicine , Lexington, Kentucky
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14
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A Review of Lung Transplantation and Its Implications for the Acute Inpatient Rehabilitation Team. PM R 2016; 9:294-305. [DOI: 10.1016/j.pmrj.2016.09.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Revised: 09/21/2016] [Accepted: 09/23/2016] [Indexed: 12/12/2022]
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15
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Abstract
This chapter reviews the neurologic complications of medications administered in the hospital setting, by class, introducing both common and less common side effects. Detail is devoted to the interaction between pain, analgesia, sedation, and their residual consequences. Antimicrobials are given in nearly every hospital setting, and we review their capacity to produce neurologic sequelae with special devotion to cefepime and the antiviral treatment of human immunodeficiency virus. The management of hemorrhagic stroke has become more complex with the introduction of novel oral anticoagulants, and we provide an update on what is known about reversal of the new oral anticoagulants. Both central and peripheral nervous system complications of immunosuppressants and chemotherapies are reviewed. Because diagnosis is generally based on clinical acumen, alone, neurotoxic syndromes resulting from psychotropic medications may be easily overlooked until severe dysautonomia develops. We include a practical approach to the diagnosis of serotonin syndrome and neuroleptic malignant syndrome.
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Affiliation(s)
- Elliot T Dawson
- Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Sara E Hocker
- Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
- Department of Neurology, Division of Critical Care Neurology, Mayo Clinic, Rochester, MN, USA.
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16
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Abstract
Transplantation is the rescue treatment for end-stage organ failure with more than 110,000 solid organs transplantations performed worldwide annually. Recent advances in transplantation procedures and posttransplantation management have improved long-term survival and quality of life of transplant recipients, shifting the focus from acute perioperative critical care needs toward long-term chronic medical problems. Neurologic complications affect up to 30-60 % of solid organ transplant recipients. Common etiologies include opportunistic infections and toxicities of antirejection medications, and wide spectrum of toxic and metabolic disturbances. Most complications are common to all allograft types, but some are relatively specific for individual allograft types (e.g., central pontine myelinolysis in liver transplant recipients). Close collaboration between neurologists and other transplant team members is essential for effective management. Early recognition of complications and accurate diagnosis leading to timely treatment is essential to reduce the morbidity and improve the overall transplant outcome.
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17
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Rompianesi G, Montalti R, Cautero N, De Ruvo N, Stafford A, Bronzoni C, Ballarin R, De Pietri L, Di Benedetto F, Gerunda GE. Neurological complications after liver transplantation as a consequence of immunosuppression: univariate and multivariate analysis of risk factors. Transpl Int 2015; 28:864-869. [PMID: 25790037 DOI: 10.1111/tri.12564] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 12/30/2014] [Accepted: 03/15/2015] [Indexed: 12/17/2022]
Abstract
Neurological complications (NCs) can frequently and significantly affect morbidity and mortality of liver transplant (LT) recipients. We analysed incidence, risk factors, outcome and impact of the immunosuppressive therapy on NC development after LT. We analysed 478 LT in 440 patients, and 93 (19.5%) were followed by NCs. The average LOS was longer in patients experiencing NCs. The 1-, 3- and 5-year graft survival and patient survival were similar in patients with or without a NC. Multivariate analysis showed the following as independent risk factors for NC: a MELD score ≥20 (OR = 1.934, CI = 1.186-3.153) and an immunosuppressive regimen based on calcineurin inhibitors (CNIs) (OR = 1.669, CI = 1.009-2.760). Among patients receiving an everolimus-based immunosuppression, the 7.1% developed NCs, vs. the 16.9% in those receiving a CNI (P = 0.039). There was a 1-, 3- and 5-year NC-free survival of 81.7%, 81.1% and 77.7% in patients receiving a CNI-based regimen and 95.1%, 93.6% and 92.7% in those not receiving a CNI-based regimen (P < 0.001). In patients undergoing a LT and presenting with nonmodifiable risk factors for developing NCs, an immunosuppressive regimen based on CNIs is likely to result in a higher rate of NCs compared to mTOR inhibitors.
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Affiliation(s)
- Gianluca Rompianesi
- Liver Transplant Centre, Azienda Ospedaliero-Universitaria di Modena Policlinico, Modena, Italy
| | - Roberto Montalti
- Liver Transplant Centre, Azienda Ospedaliero-Universitaria di Modena Policlinico, Modena, Italy
| | - Nicola Cautero
- Liver Transplant Centre, Azienda Ospedaliero-Universitaria di Modena Policlinico, Modena, Italy
| | - Nicola De Ruvo
- Liver Transplant Centre, Azienda Ospedaliero-Universitaria di Modena Policlinico, Modena, Italy
| | | | - Carolina Bronzoni
- General Surgery, Azienda Ospedaliero-Universitaria di Modena Policlinico, Modena, Italy
| | - Roberto Ballarin
- Liver Transplant Centre, Azienda Ospedaliero-Universitaria di Modena Policlinico, Modena, Italy
| | - Lesley De Pietri
- Division of Anaesthesiology and Intensive Care Unit, Azienda Ospedaliero-Universitaria di Modena Policlinico, Modena, Italy
| | - Fabrizio Di Benedetto
- Liver Transplant Centre, Azienda Ospedaliero-Universitaria di Modena Policlinico, Modena, Italy
| | - Giorgio E Gerunda
- General Surgery, Azienda Ospedaliero-Universitaria di Modena Policlinico, Modena, Italy
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18
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Hemin protects against hippocampal damage following orthotopic autologous liver transplantation in adult rats. Life Sci 2015; 135:27-34. [PMID: 26092480 DOI: 10.1016/j.lfs.2015.05.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 04/13/2015] [Accepted: 05/23/2015] [Indexed: 02/08/2023]
Abstract
AIMS Induction of heme oxygenase-1 (HO-1) has been widely accepted to be neuro-protective. This study aimed to examine whether hemin (a HO-1 inducer) attenuates neuronal damage in the hippocampus induced by orthotopic autologous liver transplantation (OALT) in adult rats. MAIN METHODS Rats were randomly allocated into four groups (n=8 each): (i) Sham control group; (ii) OALT model group; (iii) Hemin+OALT group, with intra-peritoneal (i.p.) injection of hemin (5 mg/kg) 24 hours (h) before the OALT; and (iv) ZnPP (a HO-1 inhibitor)+OALT group, with i.p. injection of ZnPP (32 mg/kg) 24h before the OALT. Twenty four hours after the surgery, the hippocampal tissues were collected for electron microscopic examination and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) analysis. The levels of hippocampal HO-1 protein and serum S-100β, the concentrations of regional tumor necrosis factor-α (TNF-α) and interleukins (IL-6, IL-10), as well as the status of malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) in the hippocampus were assessed. KEY FINDINGS Rats suffered severe neuronal damage in the hippocampus after OALT, mainly in apoptosis. Pre-treatment with hemin obviously alleviated the damage; up-regulated the HO-1 protein level; inhibited the release of TNF-α, IL-6 and MDA; and promoted the activities of SOD, CAT and IL-10; however, pre-treatment with ZnPP did not exhibit the opposite effect, except that a marked increase in serum S-100β level was detected. SIGNIFICANCE Hemin up-regulated the expression of HO-1 and attenuated hippocampal neuronal damage induced by OALT.
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Wei WC, Liu CP, Yang WC, Shyur LF, Sheu JH, Chen SS, Yang NS. Mammalian target of rapamycin complex 2 (mTORC2) regulates LPS-induced expression of IL-12 and IL-23 in human dendritic cells. J Leukoc Biol 2015; 97:1071-80. [PMID: 25877925 DOI: 10.1189/jlb.2a0414-206rr] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 03/03/2015] [Indexed: 11/24/2022] Open
Abstract
IL-12 p40, a common subunit for both IL-12 p70 and IL-23, plays a critical role in the development of Th1 and Th17 cells and autoimmune diseases. Regulation of IL-12 p40 expression is thus considered to be a strategy for developing therapies for Th1- and Th17-mediated autoimmune diseases. The mTOR protein is a subunit mTORC1 and mTORC2. Although mTORC1 has been shown to mediate IL-12 p40 expression in DCs and relevant signaling, the role of mTORC2 in IL-12 p40 expression remains largely unclear. In the present study, we demonstrate that blocking mTORC2 activity using the phytochemical cytopiloyne can specifically inhibit LPS-induced expression of IL-12 p70, IL-23, and IL-12 p40 in human DCs. This regulation by mTORC2 involving Akt activation and the persistent phase of NF-κB activation is further confirmed by siRNA knockdown of Rictor and Sin1 gene expression and the use of alternative inhibition approaches. In terms of IL-12 p40 expression, our findings reveal a new role for the mTORC2 pathway that is antagonistic to that of mTORC1. Our study provides new insight into mTOR regulation of IL-12 p40-mediated Th1 (IFN-γ) and Th17 (IL-17) responses and suggests that the phytochemical cytopiloyne might have useful applications in therapies for Th1 and Th17 cell-mediated inflammatory diseases.
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Affiliation(s)
- Wen-Chi Wei
- *Agricultural Biotechnology Research Center, Academia Sinica, Taiwan, ROC; Department of Diabetes and Metabolic Diseases Research, Department of Immunology, Beckman Research Institute, City of Hope Duarte, California, USA; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC; Department of Allergy and Immunology, IgE Therapeutics, Inc., San Diego, California, USA; and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA; Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC; and Department of Life Science, National Central University, Taoyuan County, Taiwan, ROC
| | - Chih-Pin Liu
- *Agricultural Biotechnology Research Center, Academia Sinica, Taiwan, ROC; Department of Diabetes and Metabolic Diseases Research, Department of Immunology, Beckman Research Institute, City of Hope Duarte, California, USA; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC; Department of Allergy and Immunology, IgE Therapeutics, Inc., San Diego, California, USA; and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA; Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC; and Department of Life Science, National Central University, Taoyuan County, Taiwan, ROC
| | - Wen-Chin Yang
- *Agricultural Biotechnology Research Center, Academia Sinica, Taiwan, ROC; Department of Diabetes and Metabolic Diseases Research, Department of Immunology, Beckman Research Institute, City of Hope Duarte, California, USA; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC; Department of Allergy and Immunology, IgE Therapeutics, Inc., San Diego, California, USA; and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA; Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC; and Department of Life Science, National Central University, Taoyuan County, Taiwan, ROC
| | - Lie-Fen Shyur
- *Agricultural Biotechnology Research Center, Academia Sinica, Taiwan, ROC; Department of Diabetes and Metabolic Diseases Research, Department of Immunology, Beckman Research Institute, City of Hope Duarte, California, USA; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC; Department of Allergy and Immunology, IgE Therapeutics, Inc., San Diego, California, USA; and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA; Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC; and Department of Life Science, National Central University, Taoyuan County, Taiwan, ROC
| | - Jyh-Horng Sheu
- *Agricultural Biotechnology Research Center, Academia Sinica, Taiwan, ROC; Department of Diabetes and Metabolic Diseases Research, Department of Immunology, Beckman Research Institute, City of Hope Duarte, California, USA; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC; Department of Allergy and Immunology, IgE Therapeutics, Inc., San Diego, California, USA; and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA; Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC; and Department of Life Science, National Central University, Taoyuan County, Taiwan, ROC
| | - Swey-Shen Chen
- *Agricultural Biotechnology Research Center, Academia Sinica, Taiwan, ROC; Department of Diabetes and Metabolic Diseases Research, Department of Immunology, Beckman Research Institute, City of Hope Duarte, California, USA; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC; Department of Allergy and Immunology, IgE Therapeutics, Inc., San Diego, California, USA; and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA; Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC; and Department of Life Science, National Central University, Taoyuan County, Taiwan, ROC
| | - Ning-Sun Yang
- *Agricultural Biotechnology Research Center, Academia Sinica, Taiwan, ROC; Department of Diabetes and Metabolic Diseases Research, Department of Immunology, Beckman Research Institute, City of Hope Duarte, California, USA; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC; Department of Allergy and Immunology, IgE Therapeutics, Inc., San Diego, California, USA; and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA; Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC; and Department of Life Science, National Central University, Taoyuan County, Taiwan, ROC
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Rimkus CDM, Andrade CS, Leite CDC, McKinney AM, Lucato LT. Toxic leukoencephalopathies, including drug, medication, environmental, and radiation-induced encephalopathic syndromes. Semin Ultrasound CT MR 2014; 35:97-117. [PMID: 24745887 DOI: 10.1053/j.sult.2013.09.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Toxic leukoencephalopathies can be secondary to the exposure to a wide variety of exogenous agents, including cranial irradiation, chemotherapy, antiepileptic agents, drugs of abuse, and environmental toxins. There is no typical clinical picture, and patients can present with a wide array of signs and symptoms. Involvement of white matter is a key finding in this scenario, although in some circumstances other high metabolic areas of the central nervous system can also be affected. Magnetic resonance (MR) imaging usually discloses bilateral and symmetric white matter areas of hyperintense signal on T2-weighted and fluid-attenuated inversion recovery images, and signs of restricted diffusion are associated in the acute stage. In most cases, the changes are reversible, especially with prompt recognition of the disease and discontinuation of the noxious agent. Either the MR or clinical features may be similar to several nontoxic entities, such as demyelinating diseases, leukodystrophies, hepatic encephalopathy, vascular disease, hypoxic-ischemic states, and others. A high index of suspicion should be maintained whenever a patient presents recent onset of neurologic deficit, searching the risk of exposure to a neurotoxic agent. Getting to know the most frequent MR appearances and mechanisms of action of causative agents may help to make an early diagnosis and begin therapy, improving outcome. In this review, some of the most important causes of leukoencephalopathies are presented; as well as other 2 related conditions: strokelike migraine attacks after radiation therapy syndrome and reversible splenial lesions.
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Affiliation(s)
| | - Celi Santos Andrade
- Department of Radiology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Claudia da Costa Leite
- Department of Radiology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Alexander M McKinney
- Department of Radiology/Neuroradiology, University of Minnesota and Hennepin County Medical Centers, Minneapolis, MN
| | - Leandro Tavares Lucato
- Department of Radiology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
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Westover MB, Shafi MM, Bianchi MT, Moura LMVR, O'Rourke D, Rosenthal ES, Chu CJ, Donovan S, Hoch DB, Kilbride RD, Cole AJ, Cash SS. The probability of seizures during EEG monitoring in critically ill adults. Clin Neurophysiol 2014; 126:463-71. [PMID: 25082090 DOI: 10.1016/j.clinph.2014.05.037] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 03/25/2014] [Accepted: 05/11/2014] [Indexed: 10/25/2022]
Abstract
OBJECTIVE To characterize the risk for seizures over time in relation to EEG findings in hospitalized adults undergoing continuous EEG monitoring (cEEG). METHODS Retrospective analysis of cEEG data and medical records from 625 consecutive adult inpatients monitored at a tertiary medical center. Using survival analysis methods, we estimated the time-dependent probability that a seizure will occur within the next 72-h, if no seizure has occurred yet, as a function of EEG abnormalities detected so far. RESULTS Seizures occurred in 27% (168/625). The first seizure occurred early (<30min of monitoring) in 58% (98/168). In 527 patients without early seizures, 159 (30%) had early epileptiform abnormalities, versus 368 (70%) without. Seizures were eventually detected in 25% of patients with early epileptiform discharges, versus 8% without early discharges. The 72-h risk of seizures declined below 5% if no epileptiform abnormalities were present in the first two hours, whereas 16h of monitoring were required when epileptiform discharges were present. 20% (74/388) of patients without early epileptiform abnormalities later developed them; 23% (17/74) of these ultimately had seizures. Only 4% (12/294) experienced a seizure without preceding epileptiform abnormalities. CONCLUSIONS Seizure risk in acute neurological illness decays rapidly, at a rate dependent on abnormalities detected early during monitoring. This study demonstrates that substantial risk stratification is possible based on early EEG abnormalities. SIGNIFICANCE These findings have implications for patient-specific determination of the required duration of cEEG monitoring in hospitalized patients.
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Affiliation(s)
- M Brandon Westover
- Department of Neurology, Epilepsy Service, Massachusetts General Hospital, Wang 720, Boston, MA 02114, USA.
| | - Mouhsin M Shafi
- Department of Neurology, Epilepsy Service, Massachusetts General Hospital, Wang 720, Boston, MA 02114, USA; Department of Neurology, Epilepsy Service, Beth Israel Deaconess Medical Center, West/Baker 5, Boston, MA 02214, USA.
| | - Matt T Bianchi
- Department of Neurology, Epilepsy Service, Massachusetts General Hospital, Wang 720, Boston, MA 02114, USA.
| | - Lidia M V R Moura
- Department of Neurology, Epilepsy Service, Massachusetts General Hospital, Wang 720, Boston, MA 02114, USA.
| | - Deirdre O'Rourke
- Department of Neurology, Epilepsy Service, Massachusetts General Hospital, Wang 720, Boston, MA 02114, USA.
| | - Eric S Rosenthal
- Department of Neurology, Epilepsy Service, Massachusetts General Hospital, Wang 720, Boston, MA 02114, USA.
| | - Catherine J Chu
- Department of Neurology, Epilepsy Service, Massachusetts General Hospital, Wang 720, Boston, MA 02114, USA.
| | - Samantha Donovan
- Department of Neurology, Epilepsy Service, Massachusetts General Hospital, Wang 720, Boston, MA 02114, USA
| | - Daniel B Hoch
- Department of Neurology, Epilepsy Service, Massachusetts General Hospital, Wang 720, Boston, MA 02114, USA.
| | - Ronan D Kilbride
- Department of Neurology, Epilepsy Service, Massachusetts General Hospital, Wang 720, Boston, MA 02114, USA.
| | - Andrew J Cole
- Department of Neurology, Epilepsy Service, Massachusetts General Hospital, Wang 720, Boston, MA 02114, USA.
| | - Sydney S Cash
- Department of Neurology, Epilepsy Service, Massachusetts General Hospital, Wang 720, Boston, MA 02114, USA.
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Hodzic E, Brcic M, Atic M, Halilcevic A, Jasarevic A, Aleckovic-Halilovic M, Trojak D, Atic N, Zulic S, Mehmedovic Z, Iveljic I. Posterior Reversible Encephalopathy Syndrome (PRES) as a Complication of Immunosuppressive Therapy in Renal Transplantation in Children. Med Arch 2014; 68:218-20. [PMID: 25568539 PMCID: PMC4240331 DOI: 10.5455/medarh.2014.68.218-220] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2014] [Accepted: 05/25/2014] [Indexed: 11/03/2022] Open
Abstract
Although kidney transplantation is by far the best method of renal replacement therapy, organ receiver is still not spared of eventual toxic consequences of drugs that are in charge of keeping the transplanted kidney functional. Both calcineurin inhibitors, of which tacrolimus more often, occasionally lead to neurotoxic side effects, mostly mild and reversible and dose-dependent in nature, but they can also be very severe or even fatal. It is very important to be aware of possible neurotoxic effects, to confirm them radiologically, and to prevent or reduce drug effects on nervous system. Sometimes the reduction of dose or substitution with another drug with similar mechanism effect is sufficient to terminate the neurotoxic effects of the drug and still not jeopardize the function of transplanted organ.
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Affiliation(s)
- Emir Hodzic
- University Clinical Center Tuzla, Clinic for Internal Diseases, Tuzla, Bosnia and Herzegovina
| | - Majda Brcic
- University Clinical Center Tuzla, Clinic for Internal Diseases, Tuzla, Bosnia and Herzegovina
| | - Mirza Atic
- University Clinical Center Tuzla, Clinic for Internal Diseases, Tuzla, Bosnia and Herzegovina
| | - Alma Halilcevic
- University Clinical Center Tuzla, Clinic for Internal Diseases, Tuzla, Bosnia and Herzegovina
| | - Amila Jasarevic
- University Clinical Center Tuzla, Clinic for Internal Diseases, Tuzla, Bosnia and Herzegovina
| | | | - Davor Trojak
- University Clinical Center Tuzla, Clinic for Internal Diseases, Tuzla, Bosnia and Herzegovina
| | - Nedima Atic
- University Clinical Center Tuzla, Clinic for Diseases of Children, Tuzla, Bosnia and Herzegovina
| | - Snezana Zulic
- University Clinical Center Tuzla, Clinic for Diseases of Children, Tuzla, Bosnia and Herzegovina
| | - Zlatan Mehmedovic
- University Clinical Center Tuzla, Clinic for Surgery, Tuzla, Bosnia and Herzegovina
| | - Ivana Iveljic
- University Clinical Center Tuzla, Clinic for Internal Diseases, Tuzla, Bosnia and Herzegovina
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Abstract
Inflammatory bowel diseases (IBD) are chronic, relapsing and remitting inflammatory conditions affecting the digestive system, comprising two main distinctive diseases, ulcerative colitis (UC) and Crohn's disease (CD). Besides the classic gastrointestinal manifestations, a variable number of IBD patients present with extraintestinal manifestations, including central and peripheral nervous system involvement. Peripheral neuropathy is one of the most common complications. An inflammatory myopathy has also been found. Cranial neuropathies include the Melkersson-Rosenthal syndrome, optic neuritis, and sensorineural hearing loss. Patients with IBD have a remarkable thromboembolic tendency and are at increased risk of both venous and arterial thrombotic complications. The prothrombotic state in IBD has multiple contributors. Ischemic stroke occurs through several mechanisms, including large artery disease, small vessel disease, paradoxical embolism, endocarditis, vasculitis, and associated with anti-TNF-α therapy. Thrombosis of the dural sinus and cerebral veins are at least as frequent as arterial stroke in IBD. Multiple sclerosis has been repeatedly associated with IBD. Up to 50% of IBD present asymptomatic white matter lesions. Other central nervous system complications include a slowly progressive myelopathy, epidural and subdural spinal empyema secondary to fistulous extension from the rectum, seizures, and encephalopathy.
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Wijdicks EF, Hocker SE. Neurologic complications of liver transplantation. HANDBOOK OF CLINICAL NEUROLOGY 2014; 121:1257-66. [DOI: 10.1016/b978-0-7020-4088-7.00085-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/12/2023]
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Transplantation of Encapsulated Pancreatic Islets as a Treatment for Patients with Type 1 Diabetes Mellitus. Adv Med 2014; 2014:429710. [PMID: 26556410 PMCID: PMC4590955 DOI: 10.1155/2014/429710] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 11/30/2013] [Indexed: 12/19/2022] Open
Abstract
Encapsulation of pancreatic islets has been proposed and investigated for over three decades to improve islet transplantation outcomes and to eliminate the side effects of immunosuppressive medications. Of the numerous encapsulation systems developed in the past, microencapsulation have been studied most extensively so far. A wide variety of materials has been tested for microencapsulation in various animal models (including nonhuman primates or NHPs) and some materials were shown to induce immunoprotection to islet grafts without the need for chronic immunosuppression. Despite the initial success of microcapsules in NHP models, the combined use of islet transplantation (allograft) and microencapsulation has not yet been successful in clinical trials. This review consists of three sections: introduction to islet transplantation, transplantation of encapsulated pancreatic islets as a treatment for patients with type 1 diabetes mellitus (T1DM), and present challenges and future perspectives.
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Abstract
Neurologic complications are common side-effects of immunosuppressive medications used in the prevention of graft rejection after organ transplantation. The medications most commonly encountered include the calcineurin inhibitors and mycophenolate mofetil. Depression is the most commonly encountered neurotoxicity; however, severe but rare adverse neurological effects related to these therapies have been reported. Interferons, ribavirin, and protease inhibitors are therapeutic options commonly encountered in the treatment of hepatitis. Nucleoside analogs such as adefovir dipivoxil and entecavir carry significant risks for the development of lactic acidosis and hepatic dysfunction; however, most common adverse effects to these therapies in general are mild. While the mechanisms of action are poorly elucidated, they are discussed along with treatment strategies.
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Affiliation(s)
| | - Edward M Manno
- Neurological Intensive Care Unit, Cleveland Clinic, Cleveland, OH, USA.
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27
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Pruitt AA, Graus F, Rosenfeld MR. Neurological complications of solid organ transplantation. Neurohospitalist 2013; 3:152-66. [PMID: 24167649 DOI: 10.1177/1941874412466090] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Solid organ transplantation (SOT) is the preferred treatment for an expanding range of conditions whose successful therapy has produced a growing population of chronically immunosuppressed patients with potential neurological problems. While the spectrum of neurological complications varies with the type of organ transplanted, the indication for the procedure, and the intensity of long-term required immunosuppression, major neurological complications occur with all SOT types. The second part of this 2-part article on transplantation neurology reviews central and peripheral nervous system problems associated with SOT with clinical and neuroimaging examples from the authors' institutional experience. Particular emphasis is given to conditions acquired from the donated organ or tissue, problems specific to types of organs transplanted and drug therapy-related complications likely to be encountered by hospitalists. Neurologically important syndromes such as immune reconstitution inflammatory syndrome (IRIS), posterior reversible encephalopathy syndrome (PRES), and posttransplantation lymphoproliferative disorder (PTLD) are readdressed in the context of SOT.
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Affiliation(s)
- Amy A Pruitt
- Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA
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Corbett C, Armstrong MJ, Parker R, Webb K, Neuberger JM. Mental health disorders and solid-organ transplant recipients. Transplantation 2013; 96:593-600. [PMID: 23743726 DOI: 10.1097/tp.0b013e31829584e0] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Depression affects up to 60% of solid-organ recipients and is independently associated with both mortality (hazard ratio for death of ~2) and de novo malignancy after transplantation, although the mechanism is not clear. Both pretransplantation psychosis and depression occurring more than 2 years after transplantation are associated with increased noncompliance and graft loss. It remains to be shown that effective treatment of depression is associated with improved outcomes and quality of life. Immunosuppressive drugs (especially corticosteroids and calcineurin inhibitors) and physiologic challenges can precipitate deterioration in mental health. All potential transplant candidates should be assessed for mental health problems and preexisting medical conditions that can mimic mental health problems, such as uremic, hepatic, or hypoxic encephalopathy, should be identified and treated appropriately. Expert mental health review of those with identified risk factors (such as previous suicide attempts, history of mental illness or noncompliance with medications) is advisable early in the transplant assessment process to mitigate risk and support the patient. Patients with mental health disorders, when adequately controlled and socially supported, have outcomes similar to the general transplant population. Therefore, exclusion from transplantation based on the diagnosis alone is neither ethically nor medically justified. However, it is ethically and clinically justifiable to deny access to transplantation to those who, despite full support, would have a quality of life that is unacceptable to the candidate or are likely to be noncompliant with treatment or follow-up, which would lead to graft loss.
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Affiliation(s)
- Chris Corbett
- 1 NIHR Birmingham Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK. 2 Liver Unit, Queen Elizabeth Hospital, Birmingham, UK. 3 Organ Donation and Transplantation, NHS Blood and Transplant, Bristol, UK. 4 Address correspondence to: Chris Corbett, M.B.B.S., M.R.C.P., NIHR Birmingham Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, 5th Floor IBR Building, Birmingham B152TT, UK
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Živković SA. Neurologic complications after liver transplantation. World J Hepatol 2013; 5:409-416. [PMID: 24023979 PMCID: PMC3767839 DOI: 10.4254/wjh.v5.i8.409] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Revised: 06/21/2013] [Accepted: 07/13/2013] [Indexed: 02/06/2023] Open
Abstract
Neurologic complications are relatively common after solid organ transplantation and affect 15%-30% of liver transplant recipients. Etiology is often related to immunosuppressant neurotoxicity and opportunistic infections. Most common complications include seizures and encephalopathy, and occurrence of central pontine myelinolysis is relatively specific for liver transplant recipients. Delayed allograft function may precipitate hepatic encephalopathy and neurotoxicity of calcineurin inhibitors typically manifests with tremor, headaches and encephalopathy. Reduction of neurotoxic immunosuppressants or conversion to an alternative medication usually result in clinical improvement. Standard preventive and diagnostic protocols have helped to reduce the prevalence of opportunistic central nervous system (CNS) infections, but viral and fungal CNS infections still affect 1% of liver transplant recipients, and the morbidity and mortality in the affected patients remain fairly high. Critical illness myopathy may also affect up to 7% of liver transplant recipients. Liver insufficiency is also associated with various neurologic disorders which may improve or resolve after successful liver transplantation. Accurate diagnosis and timely intervention are essential to improve outcomes, while advances in clinical management and extended post-transplant survival are increasingly shifting the focus to chronic post-transplant complications which are often encountered in a community hospital and an outpatient setting.
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30
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Kawahara T, Asthana S, Kneteman NM. m-TOR inhibitors: what role in liver transplantation? J Hepatol 2011; 55:1441-51. [PMID: 21781947 DOI: 10.1016/j.jhep.2011.06.015] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Revised: 06/28/2011] [Accepted: 06/29/2011] [Indexed: 12/11/2022]
Abstract
The development of calcineurin inhibitors (CNIs) led to marked improvements in patient and graft survival after liver transplantation (LTx). We have been left, however, with a dependence on immunosuppressive agents with nephrotoxicity, neurotoxicity, adverse impacts on cardiac risk profile, and risk for malignancy. These challenges need to be met against a dominance of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) as indications for liver transplant. Unmet needs for immunosuppression (IS) in LTx include: (1) Effective drugs that avoid CNIs toxicities. (2) Agents without adverse impact on HCV recurrence. (3) Compounds that minimize risk of HCC recurrence. New immunosuppressives will need to address the above needs while supporting patient and graft survival equivalent to those achievable with CNIs, ideally without important new toxicities. Two new classes of agents are currently in advanced clinical development: belatacept, and the mammalian target of rapamycin inhibitors (m-TORi). This manuscript will review evidence for a role for m-TORi in LTx in a range of clinical scenarios including patients with CNI nephrotoxicity or neurotoxicity, patients at risk of (or with) HCV recurrence, and patients at risk of HCC recurrence.
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Affiliation(s)
- Toshiyasu Kawahara
- Division of Transplantation, Department of Surgery, University of Alberta, Canada
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Chauhan A, Sharma U, Jagannathan N, Reeta K, Gupta YK. Rapamycin protects against middle cerebral artery occlusion induced focal cerebral ischemia in rats. Behav Brain Res 2011; 225:603-9. [DOI: 10.1016/j.bbr.2011.08.035] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Revised: 08/21/2011] [Accepted: 08/24/2011] [Indexed: 11/28/2022]
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32
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Vizzini G, Asaro M, Miraglia R, Gruttadauria S, Filì D, D'Antoni A, Petridis I, Marrone G, Pagano D, Gridelli B. Changing picture of central nervous system complications in liver transplant recipients. Liver Transpl 2011; 17:1279-85. [PMID: 21770016 DOI: 10.1002/lt.22383] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
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.
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Affiliation(s)
- Giovanni Vizzini
- Mediterranean Institute for Transplantation and High Specialization Therapies, University of Pittsburgh Medical Center in Italy, Palermo, Italy.
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Kriss M, Sotil EU, Abecassis M, Welti M, Levitsky J. Mycophenolate mofetil monotherapy in liver transplant recipients. Clin Transplant 2011; 25:E639-46. [PMID: 22007615 DOI: 10.1111/j.1399-0012.2011.01512.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
INTRODUCTION Complete conversion of calcineurin inhibitor (CNI) immunosuppressant therapy to non-nephrotoxic agents such as mycophenolate mofetil (MMF) is controversial, but may be safe in selected patients, although appropriate protocols and long-term benefits of conversion are not well reported. METHODS We analyzed all liver transplant (LT) recipients at our institution who were converted from CNI-based therapy to MMF monotherapy because of renal dysfunction (n = 23) and compared them with patients remaining on CNI-based therapy (n = 23). Renal function, rejection episodes, and markers of CNI-related comorbidities (lipid profile, blood pressure, and glycosylated hemoglobin) were noted. RESULTS Overall, serum creatinine (SCr) and calculated glomerular filtration rate improved on MMF monotherapy. This improvement was significant when compared with patients who remained on CNI-based therapy. Improvement was most pronounced in patients with milder renal dysfunction (SCr <2.2 mg/dL prior to conversion) (n = 14) with decrease in SCr from 1.63 ± 0.29 to 1.34 ± 0.26 mg/dL (p = 0.02) at last follow-up. Five patients on MMF monotherapy (21.7%) progressed to end-stage renal disease (ESRD), while only two (8.7%) had rejection episodes following conversion. Clinical markers of CNI-related comorbidities also improved. MMF monotherapy was well tolerated. CONCLUSION In summary, our data support the safety and efficacy of CNI to MMF monotherapy conversion.
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Affiliation(s)
- Michael Kriss
- Department of Medicine, Northwestern University, Chicago, IL 60611, USA
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Pustavoitau A, Bhardwaj A, Stevens R. Analytic Review: Neurological Complications of Transplantation. J Intensive Care Med 2011; 26:209-22. [DOI: 10.1177/0885066610389549] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Recipients of solid organ or hematopoietic cell transplants are at risk of life-threatening neurological disorders including encephalopathy, seizures, infections and tumors of the central nervous system, stroke, central pontine myelinolysis, and neuromuscular disorders—often requiring admission to, or occurring in, the intensive care unit (ICU). Many of these complications are linked directly or indirectly to immunosuppressive therapy. However, neurological disorders may also result from graft versus host disease, or be an expression of the underlying disease which prompted transplantation, as well as injury induced during radiation, chemotherapy, surgery, and ICU stay. In rare cases, neuroinfectious pathogens may be transmitted with the transplanted tissue or organ. Diagnosis may be a challenge because clinical symptoms and findings on neuroimaging lack specificity, and a biological specimen or tissue diagnosis is often needed for definitive diagnosis. Management is centered on preventing further neurological injury, etiology-targeted therapy, and balancing the benefits and toxicities of specific immunosuppressive agents.
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Affiliation(s)
- Aliaksei Pustavoitau
- Departments of Anesthesiology Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Anish Bhardwaj
- Departments of Neurology and Neurological Surgery, Tufts University School of Medicine, Boston, MA, USA,
| | - Robert Stevens
- Departments of Anesthesiology Critical Care Medicine, Neurology, Neurosurgery, and Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Toxic Leukoencephalopathy following Fludarabine-Associated Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 2011; 17:300-8. [DOI: 10.1016/j.bbmt.2010.04.003] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2010] [Accepted: 04/02/2010] [Indexed: 11/18/2022]
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Sullivan PG, Sebastian AH, Hall ED. Therapeutic window analysis of the neuroprotective effects of cyclosporine A after traumatic brain injury. J Neurotrauma 2011; 28:311-8. [PMID: 21142667 DOI: 10.1089/neu.2010.1646] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Mitochondrial dysfunction plays a pivotal role in secondary cell death mechanisms following traumatic brain injury (TBI). Several reports have demonstrated that inhibition of the mitochondrial permeability transition pore with the immunosuppressant drug cyclosporine A (CsA) is efficacious. Accordingly, CsA is being moved forward into late-stage clinical trials for the treatment of moderate and severe TBI. However, several unknowns exist concerning the optimal therapeutic window for administering CsA at the proposed dosages to be used in human studies. The present study utilized a moderate (1.75 mm) unilateral controlled cortical impact model of TBI to determine the most efficacious therapeutic window for initiating CsA therapy. Rats were administered an IP dose of CsA (20 mg/kg) or vehicle at 1, 3, 4, 5, 6, and 8 h post-injury. Immediately following the initial IP dose, osmotic mini-pumps were implanted at these time points to deliver 10 mg/kg/d of CsA or vehicle. Seventy-two hours following the initiation of treatment the pumps were removed to stop CsA administration. Quantitative analysis of cortical tissue sparing 7 days post-injury revealed that CsA treatment initiated at any of the post-injury initiation times out to 8 h resulted in significantly less cortical damage compared to animals receiving vehicle treatment. However, earlier treatment begun in the first 3 h was significantly more protective than that begun at 4 and 8 h. Treatment initiated at 1 h post-injury (∼68% decrease) was not significantly different than that seen at 3 h (∼46% decrease), but resulted in significantly greater cortical tissue sparing compared to CsA treatment initiated at least 4 h post-injury (28% decrease). Together these results illustrate the importance of initiating therapeutic interventions such as CsA as soon as possible following TBI, preferably within 4 h post-injury, to achieve the best possible neuroprotective effect. However, the drug appears to retain some protective efficacy even when initiated as late as 8 h post-injury.
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Affiliation(s)
- Patrick G Sullivan
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky 40536-0305, USA.
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Campagna F, Biancardi A, Cillo U, Gatta A, Amodio P. Neurocognitive-neurological complications of liver transplantation: a review. Metab Brain Dis 2010; 25:115-24. [PMID: 20204483 DOI: 10.1007/s11011-010-9183-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2009] [Accepted: 01/28/2010] [Indexed: 12/20/2022]
Abstract
Neurological complications are common after liver transplantation (LT) and they are associated with a significant morbidity. Long-term effects of LT on cognitive and psychological outcomes are not clear. The objective of this study was to summarize the present knowledge on the neurological and cognitive complications of LT, resulting from a systematic review of the literature in the last 10 years. Several studies have investigated the incidence and the pathophysiology of neurological complications; in contrast, the knowledge of cognitive and psychological status after LT is poor. Currently, the effect of LT on mental performance is debated. Some studies have shown an improvement of cognitive function after OLTX and, at the same time, a persistence of different cognitive deficits. In addition, the quality of life (QoL) and the psychological status after LT seem to improve but LT recipients have significant deficiencies in most QoL domains. Consequently, future studies are necessary in order to investigate cognitive alterations and QoL in LT recipients.
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Affiliation(s)
- Francesca Campagna
- Department of Clinical and Experimental Medicine, University of Padova, Clinica Medica 5, Via Giustiniani, 35128, Padova, Italy.
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Abstract
Neurologic complications affect posttransplant recovery of more than 20% of transplant recipients. Etiology is usually related to surgical procedure of transplantation, primary disorders causing failure of transplanted organ, opportunistic infections, and neurotoxicity of immunosuppressive medications. Risk of opportunistic infections and immunosuppressant neurotoxicity is greatest within the first six months, but it persists along with long-term maintenance immunosuppression required to prevent graft rejection. Neurotoxicity may require alteration of immunosuppressive regimen, and prompt therapy of opportunistic infections improves outcomes.
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Affiliation(s)
- Sasa A Zivković
- Neurology Service, VA Pittsburgh Healthcare System, University Drive C, Pittsburgh, PA 15240, USA.
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41
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Friedman D, Claassen J, Hirsch LJ. Continuous electroencephalogram monitoring in the intensive care unit. Anesth Analg 2009; 109:506-23. [PMID: 19608827 DOI: 10.1213/ane.0b013e3181a9d8b5] [Citation(s) in RCA: 196] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Because of recent technical advances, it is now possible to record and monitor the continuous digital electroencephalogram (EEG) of many critically ill patients simultaneously. Continuous EEG monitoring (cEEG) provides dynamic information about brain function that permits early detection of changes in neurologic status, which is especially useful when the clinical examination is limited. Nonconvulsive seizures are common in comatose critically ill patients and can have multiple negative effects on the injured brain. The majority of seizures in these patients cannot be detected without cEEG. cEEG monitoring is most commonly used to detect and guide treatment of nonconvulsive seizures, including after convulsive status epilepticus. In addition, cEEG is used to guide management of pharmacological coma for treatment of increased intracranial pressure. An emerging application for cEEG is to detect new or worsening brain ischemia in patients at high risk, especially those with subarachnoid hemorrhage. Improving quantitative EEG software is helping to make it feasible for cEEG (using full scalp coverage) to provide continuous information about changes in brain function in real time at the bedside and to alert clinicians to any acute brain event, including seizures, ischemia, increasing intracranial pressure, hemorrhage, and even systemic abnormalities affecting the brain, such as hypoxia, hypotension, acidosis, and others. Monitoring using only a few electrodes or using full scalp coverage, but without expert review of the raw EEG, must be done with extreme caution as false positives and false negatives are common. Intracranial EEG recording is being performed in a few centers to better detect seizures, ischemia, and peri-injury depolarizations, all of which may contribute to secondary injury. When cEEG is combined with individualized, physiologically driven decision making via multimodality brain monitoring, intensivists can identify when the brain is at risk for injury or when neuronal injury is already occurring and intervene before there is permanent damage. The exact role and cost-effectiveness of cEEG at the current time remains unclear, but we believe it has significant potential to improve neurologic outcomes in a variety of settings.
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Affiliation(s)
- Daniel Friedman
- Department of Neurology, Comprehensive Epilepsy Center, Columbia University, NewYork City, New York, USA
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Dzudie A, Boissonnat P, Roussoulieres A, Cakmak, Mosbah K, Bejui FT, Obadia JF, Sebbag L. Cyclosporine-related posterior reversible encephalopathy syndrome after heart transplantation: should we withdraw or reduce cyclosporine?: case reports. Transplant Proc 2009; 41:716-20. [PMID: 19328965 DOI: 10.1016/j.transproceed.2009.01.041] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Cyclosporine (CsA) related encephalopathy has not been well documented after heart transplantation. We report 2 cases of posterior reversible encephalopathy syndrome (PRES). The first case was a 68-year-old woman who underwent heart transplantation and received immunosuppression with mycophenolate mofetil, prednisone, and CsA. On day 14, she developed arterial hypertension, headache, visual disturbances, and generalized seizures. Fluid-attenuated inversion recovery magnetic resonance imaging (MRI) of the brain showed diffuse and bilateral high signals in the frontal posterior and the occipital areas. The second case was a 19-year-old man with a heart transplant receiving immunosuppression with prednisone and CsA. On day 44, he developed acute headache and generalized seizures. T2-weighted MRI of the brain showed diffuse high signals in the cerebellum, right lenticular and occipital areas. In both cases blood CsA concentration was therapeutic. Both cases recovered but in the first case neurologic findings were reversed only after CsA withdrawal.
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Affiliation(s)
- A Dzudie
- Heart Transplant Unit, Louis Pradel's Cardiovascular Hospital, Hospices civils Lyon, Lyon, France
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Rauch MC, San Martín A, Ojeda D, Quezada C, Salas M, Cárcamo JG, Yañez AJ, Slebe JC, Claude A. Tacrolimus causes a blockage of protein secretion which reinforces its immunosuppressive activity and also explains some of its toxic side-effects. Transpl Immunol 2009; 22:72-81. [PMID: 19628039 DOI: 10.1016/j.trim.2009.07.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2009] [Revised: 07/06/2009] [Accepted: 07/13/2009] [Indexed: 11/29/2022]
Abstract
BACKGROUND Tacrolimus (FK506) is a macrolide immunosuppressant drug from the calcineurin inhibitor family, widely used in solid organ and islet cell transplantation, but produces significant side-effects. OBJECTIVE This study examined the effect of FK506 on interleukin-2 (IL-2) and insulin secretion, establishing a novel characteristic of this drug that could explain its diverse adverse effects, and developed an experimental model for the simultaneous analysis of mRNA expression and protein secretion affected by this drug. METHODS The IL-2 levels when tacrolimus was administered were analysed by Western blot, immunocytochemistry and RT-PCR in a T lymphocyte cellular line (Jurkat) 24 h post-stimulation. The insulin levels when tacrolimus was administered were analysed 4 h after stimulation of glucose-induced insulin secretion in a pancreatic cellular line (MIN6). RESULTS The previously published information describes tacrolimus as only capable of partially blocking IL-2 mRNA expression. In our hands, the cellular content of IL-2 is almost undetectable in stimulated Jurkat cells and can be detected in cellular extracts only when the secretory pathway is blocked by brefeldin A (BFA). BFA added 2 h after the beginning of stimulation was able to inhibit IL-2 secretion, without affecting IL-2 mRNA expression. Therefore BFA utilization allowed us to establish a model to analyze the effect on IL-2 secretion, separately from its expression. Tacrolimus added before stimulation inhibits only IL-2 synthesis, but blocks IL-2 protein secretion when added 2 h after stimulation. Similarly, tacrolimus is also capable of blocking the glucose-stimulated secretion of insulin by MIN6 cells. An increase of the intracellular content can be detected concomitantly with a decrease of the hormone measured in the culture medium. CONCLUSIONS Results of this study indicate that tacrolimus possesses another important effect in addition to the inhibition of IL-2 gene transcription, namely the ability to act as a general inhibitor of the protein secretory pathway. These results strongly suggest that the diabetogenic effect of the immune suppressant FK506 could be caused by the blockade of insulin secretion. This novel effect also provides an explanation for other side-effects observed in immunosuppressive treatment.
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Affiliation(s)
- M C Rauch
- Instituto de Bioquímica, Universidad Austral de Chile, Chile
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Farkas SA, Schnitzbauer AA, Kirchner G, Obed A, Banas B, Schlitt HJ. Calcineurin inhibitor minimization protocols in liver transplantation. Transpl Int 2009; 22:49-60. [PMID: 19121146 DOI: 10.1111/j.1432-2277.2008.00796.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Liver transplant recipients are at increasingly high risk for suffering from impaired renal function and probable need of renal replacement therapy. Extended criteria organs and transplantation of patients with higher model for end-stage liver disease scores further increase this problem. Acute and chronic nephrotoxicity are the trade-off in immunosuppression with potent calcineurin inhibitors (CNIs). As a good renal function is associated with better graft and patient survival, CNI minimization protocols have been developed. Current strategies to overcome CNI toxicity include reduction or withdrawal of CNIs concurrently with switching over to mammalian target of rapamycin inhibitor or mycophenolate mofetil (MMF)-based regimens. This strategy caused an improvement in renal function in a significant number of liver transplantation patients according to several studies. However, total CNI avoidance seems to result in higher rejection rates. To prevent chronic renal dysfunction in patients prone to or with acute renal failure, CNI delay - with induction therapy for bridging - followed by low-dose CNI in combination with MMF are proven strategies without risking higher rejection rates. An individualized, tailor-made immunosuppressive regime, with a special focus on renal function is recommended. This review gave an overview on CNI minimization protocols in liver transplantation also focusing on recently analyzed studies.
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Affiliation(s)
- Stefan A Farkas
- Department of Surgery, University Hospital Regensburg, Germany.
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Updates in the Management of Seizures and Status Epilepticus in Critically Ill Patients. Neurol Clin 2008; 26:385-408, viii. [DOI: 10.1016/j.ncl.2008.03.017] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Sternthal MB, Murphy SJ, George J, Kornbluth A, Lichtiger S, Present DH. Adverse events associated with the use of cyclosporine in patients with inflammatory bowel disease. Am J Gastroenterol 2008; 103:937-43. [PMID: 18177449 DOI: 10.1111/j.1572-0241.2007.01718.x] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Intravenous cyclosporine (i.v. CsA) is an effective therapy for patients with inflammatory bowel disease (IBD). However, data regarding its adverse events in these patients are limited. METHODS A retrospective chart review of the initial 111 consecutive patients with IBD treated with i.v. CsA followed by a predetermined duration of oral therapy. RESULTS One hundred eleven patients (64 UC, 47 CD; mean age 33 yr, range 16-68) received i.v. CsA at 4 mg/kg/day, then oral CsA at 8 mg/kg/day, with dose adjustment based on serum creatinine. The mean treatment duration was 9.3 months (range 1 wk to 34 months). Major adverse events occurred in 17 (15.3%) patients. Nephrotoxicity (serum creatinine > or = 1.4 mg/dL [123 micromol/L] or a rise by at least 33% over baseline not responding to dose adjustment) sufficiently severe to warrant discontinuation of therapy occurred in 6 (5.4%) patients. Serious infection occurred in 7 (6.3%) patients, seizures in 4 (3.6%) patients, anaphylaxis in 1 (0.9%) patient, and death in 2 (1.8%) patients. Minor adverse events (transient effects with complete resolution either spontaneously or with dose adjustment) comprised: paresthesias (51%), hypomagnesemia (42%), hypertension (39%), hypertrichosis (27%), headache (23%), minor nephrotoxicity (defined as above but with restoration of normal serum creatinine with dose adjustment; 19% of patients), abnormal liver function tests (19%), minor infections (15%), hyperkalemia (13%), and gingival swelling (4%). CONCLUSIONS In our initial experience, limited duration CsA therapy was frequently associated with adverse events although the majority of these were minor and responded to dose adjustment. Although not all severe adverse events can be clearly attributed to CsA use alone, its high incidence suggests that vigorous monitoring by experienced clinicians at tertiary care centers may be required.
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Affiliation(s)
- Michael B Sternthal
- The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Mount Sinai Medical Center, New York, New York 10028, USA
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Metabolische Störungen. NEUROINTENSIV 2008. [PMCID: PMC7121226 DOI: 10.1007/978-3-540-68317-9_39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Bei fortgeschrittenem Organversagen von Niere, Herz, Leber oder Lunge stellt eine Organtransplantation meist das einzige kurative Therapieverfahren dar. Auch eine Knochenmarktransplantation wird bei sonst unheilbaren Leukämien oder Lymphomen eingesetzt. Nach Organtransplantation treten bei 30–60% der Patienten neurologische Komplikationen auf. Differenzialdiagnostisch müssen vorbestehende, durch die Grunderkrankung bedingte, Störungen von intraoperativen Komplikationen, von metabolisch bedingten neurologischen Störungen und von Nebenwirkungen der notwendigen immunsuppressiven Medikation abgegrenzt werden. Immunsuppressiva können dabei sowohl eine direkte Neurotoxizität als auch indirekt vermehrt Infektionen des Zentralnervensystems (ZNS) und sekundäre ZNS-Malignome verursachen. Während metabolische Enzephalopathien oder opportunistische ZNS-Infektionen bei allen Patienten nach Transplantation etwa gleich häufig auftreten können, sind andere neurologische Syndrome für bestimmte Organtransplantationen typisch.
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Amodio P, Biancardi A, Montagnese S, Angeli P, Iannizzi P, Cillo U, D'Amico D, Gatta A. Neurological complications after orthotopic liver transplantation. Dig Liver Dis 2007; 39:740-7. [PMID: 17611177 DOI: 10.1016/j.dld.2007.05.004] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2006] [Revised: 05/08/2007] [Accepted: 05/08/2007] [Indexed: 12/11/2022]
Abstract
BACKGROUND The number of orthotopic liver transplantation performed each year is increasing due to increased safety and logistic facilities. Therefore, the importance of reducing adverse events is progressively growing. AIM To review present knowledge on the neurological complications of orthotopic liver transplantation. METHODS The epidemiology, the clinical features and the pathophysiology of the neurological complications of orthotopic liver transplants, resulting from a systematic review of the literature in the last 25 years, are summarized. RESULTS AND CONCLUSIONS The review highlights that a relevant variety of neurological adverse events can occur in patients undergoing orthotopic liver transplantation. The knowledge of neurological complications of orthotopic liver transplantation is important for transplantation teams to reduce their prevalence and improve their management. In addition, the likelihood of neurological adverse effects provides evidence for the need of a careful cognitive and neurological work up of patients in the orthotopic liver transplantation waiting list, in order to recognize and interpret neurological dysfunction occurring after orthotopic liver transplantation.
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Affiliation(s)
- P Amodio
- Clinical Medicine 5 and Veneto Regional Reference Centre for Hepatic Diseases, University of Padova, Padova, Italy.
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Abou Khaled KJ, Hirsch LJ. Advances in the management of seizures and status epilepticus in critically ill patients. Crit Care Clin 2007; 22:637-59; abstract viii. [PMID: 17239748 DOI: 10.1016/j.ccc.2006.06.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Seizures and status epilepticus are common in critically ill patients. They can be difficult to recognize because most are non-convulsive and require electroencephalogram monitoring to detect; hence, they are currently underdiagnosed. Early recognition and treatment are essential to obtain maximal response to first-line treatment and to prevent neurologic and systemic sequelae. Anti-seizure medication should be combined with management of the underlying cause and reversal of factors that can lower the seizure threshold, including many medications, fever, hypoxia, and metabolic imbalances. This article discusses specific treatments and specific situations, such as hepatic and renal failure patients and organ transplant patients.
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Affiliation(s)
- Karine J Abou Khaled
- Comprehensive Epilepsy Center, Department of Neurology, Columbia University Neurological Institute, New York, NY 10032, USA
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50
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Taylor JL, Palmer SM. Critical care perspective on immunotherapy in lung transplantation. J Intensive Care Med 2006; 21:327-44. [PMID: 17095497 DOI: 10.1177/0885066606292876] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Lung transplantation is now a viable therapeutic option in the care of patients with advanced pulmonary parenchymal or pulmonary vascular disease. Lung transplantation, however, with chronic posttransplant immunosuppression, creates a uniquely vulnerable population of patients likely to experience significant life-threatening complications requiring intensive care. The introduction of several novel immunosuppressive agents, such as sirolimus and mycophenolate mofetil, in conjunction with more established agents such as cyclosporine and tacrolimus, has greatly increased treatment options for lung transplant recipients and likely contributed to improved short-term transplant outcomes. Modern transplant immunosuppression, however, is associated with a host of complications such as opportunistic infections, renal failure, and thrombotic thrombocytopenic purpura. The main focus of this review is to provide a comprehensive summary of modern immunotherapy in lung transplantation and to increase awareness of the serious and potentially life-threatening complications of these medications.
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