title: Infectious and non-infectious neurologic complications in heart transplant recipients.
abstract: Neurologic complications are important causes of morbidity and mortality in heart transplant (HT) recipients. New immunomodulating agents have improved survival rates, although some have been associated with a high rate of neurologic complications (infectious and non-infectious). We conducted this study to analyze the frequency of these complications, before and after the use of daclizumab induction therapy. We reviewed all neurologic complications in our HT cohort, comparing infectious with non-infectious complications over 2 periods of time in which different induction therapies were used (316 patients with OKT3 or antithymocyte globulin from 1988 to 2002, and 68 patients with daclizumab from 2003 to 2006). Neurologic complications were found in 75/384 patients (19.5%) with a total of 78 episodes. Non-infectious complications accounted for 68% of the 78 episodes of neurologic complications. A total of 51 patients and 53 episodes were detailed as follows: 25 episodes of stroke (25 of 78 total episodes, 32%; 19 ischemic, 6 hemorrhagic); 7 neuropathies; 6 seizures; 4 episodes of transient ischemic attack (TIA); 3 anoxic encephalopathy; 2 each brachial plexus palsy and metabolic encephalopathy; and 1 each myoclonia, central nervous system (CNS) lymphoma, subdural hematoma, and Cotard syndrome. Mean time to presentation of stroke, TIA, and encephalopathy was 1 day (range, 1-19 d) posttransplant. Mortality rate among non-infectious complications was 12/53 (22.6%). Infectious complications accounted for 32% of the 78 total episodes. We found 25 episodes in 24 patients: 17 herpes zoster (median, 268 d after HT), 3 CNS aspergillosis (median, 90 d after HT), 1 CNS toxoplasmosis and tuberculosis (51 d after HT), 1 pneumococcal meningitis (402 d after HT), and 2 Listeria meningitis (median, 108 d after HT). The 3 patients with CNS aspergillosis died. The mortality rate among patients with infectious neurologic complications was 12% (42.8% if the CNS was involved). When we compared the OKT3-ATG and daclizumab groups, we found that the incidence of non-infectious complications was 15.1% vs. 7.3%, respectively, and the incidence of infectious complications was 7.5% vs. 1.4%, respectively. All but 1 opportunistic infection occurred in the OKT3-ATG time period. In conclusion, a wide variety of neurologic complications affected 19.5% of HT recipients. Non-infectious causes clearly predominated, but infections still accounted for 32% of the episodes. New monoclonal induction therapies have contributed to diminished CNS opportunistic infections in our program.
authors.affiliation: From Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Muñoz
authors.forename: Maricela
authors.initials: M
authors.lastname: Valerio
authors.forename: Jesús
authors.initials: J
authors.lastname: Palomo
authors.forename: Juan
authors.initials: J
authors.lastname: Fernández-Yáñez
authors.forename: Ana
authors.initials: A
authors.lastname: Fernández-Cruz
authors.forename: Jesús
authors.initials: J
authors.lastname: Guinea
authors.forename: Emilio
authors.initials: E
authors.lastname: Bouza
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D002493:Central Nervous System Diseases / Q000453:epidemiology*; D000077561:Daclizumab; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology*; D006562:Herpes Zoster / Q000453:epidemiology; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008584:Meningitis, Listeria / Q000453:epidemiology; D008586:Meningitis, Pneumococcal / Q000453:epidemiology; D008875:Middle Aged; D016853:Muromonab-CD3 / Q000627:therapeutic use; D020953:Neuroaspergillosis / Q000453:epidemiology; D009894:Opportunistic Infections / Q000453:epidemiology*; D015995:Prevalence; D012189:Retrospective Studies; D016781:Toxoplasmosis, Cerebral / Q000453:epidemiology; D020306:Tuberculosis, Central Nervous System / Q000453:epidemiology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D016853:Muromonab-CD3; D000077561:Daclizumab
references.citation: Aguado JM, Torre-Cisneros J, Fortun J, Benito N, Meije Y, Doblas A, Munoz P. Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clin Infect Dis. 2009;48:1276-1284.
references.citation: Andrews BT, Hershon JJ, Calanchini P, Avery GJ II, Hill JD. Neurologic complications of cardiac transplantation. West J Med. 1990;153:146-148.
references.citation: Ang LC, Gillett JM, Kaufmann JC. Neuropathology of heart transplantation. Can J Neurol Sci. 1989;16:291-298.
references.citation: Bashir RM. Neurologic complications of organ transplantation. Curr Treat Options Neurol. 2001;3:543-554.
references.citation: Beniaminovitz A, Itescu S, Lietz K, Donovan M, Burke EM, Groff BD, Edwards N, Mancini DM. Prevention of rejection in cardiac transplantation by blockade of the interleukin-2 receptor with a monoclonal antibody. N Engl J Med. 2000;342:613-619.
references.citation: Cemillan CA, Alonso-Pulpon L, Burgos-Lazaro R, Millan-Hernandez I, del Ser T, Liano-Martinez H. [Neurological complications in a series of 205 orthotopic heart transplant patients]. Rev Neurol. 2004;38:906-912.
references.citation: Ernst ME, Franey RJ. Acyclovir- and ganciclovir-induced neurotoxicity. Ann Pharmacother. 1998;32:111-113.
references.citation: Hershberger RE, Starling RC, Eisen HJ, Bergh CH, Kormos RL, Love RB, Van Bakel A, Gordon RD, Popat R, Cockey L, Mamelok RD. Daclizumab to prevent rejection after cardiac transplantation. N Engl J Med. 2005;352:2705-2713.
references.citation: Hotson JR, Enzmann DR. Neurologic complications of cardiac transplantation. Neurol Clin. 1988;6:349-365.
references.citation: Hotson JR, Pedley TA. The neurological complications of cardiac transplantation. Brain. 1976;99:673-694.
references.citation: Hovens MM, Vaessen N, Sijpkens YW, de Fijter JW. Unusual presentation of central nervous system manifestations of varicella zoster virus vasculopathy in renal transplant recipients. Transpl Infect Dis. 2007;9:237-240.
references.citation: Jarquin-Valdivia AA, Wijdicks EF, McGregor C. Neurologic complications following heart transplantation in the modern era: decreased incidence, but postoperative stroke remains prevalent. Transplant Proc. 1999;31:2161-2162.
references.citation: Kobashigawa J, David K, Morris J, Chu AH, Steffen BJ, Gotz VP, Gordon RD. Daclizumab is associated with decreased rejection and no increased mortality in cardiac transplant patients receiving MMF, cyclosporine, and corticosteroids. Transplant Proc. 2005;37:1333-1339.
references.citation: Loire R, Tabib A, Bastien O. [Fatal aspergillosis after cardiac transplantation. About 26 cases]. Ann Pathol. 1993;13:157-163.
references.citation: Malheiros SM, Almeida DR, Massaro AR, Castelo A, Diniz RV, Branco JN, Carvalho AC, Gabbai AA. Neurologic complications after heart transplantation. Arq Neuropsiquiatr. 2002;60:192-197.
references.citation: Montero CG, Martinez AJ. Neuropathology of heart transplantation: 23 cases. Neurology. 1986;36:1149-1154.
references.citation: Munoz P, Palomo J, Munoz R, Rodriguez-Creixems M, Pelaez T, Bouza E. Tuberculosis in heart transplant recipients. Clin Infect Dis. 1995;21:398-402.
references.citation: Munoz P, Rodriguez C, Bouza E, Palomo J, Yanez JF, Dominguez MJ, Desco M. Risk factors of invasive aspergillosis after heart transplantation: protective role of oral itraconazole prophylaxis. Am J Transplant. 2004;4:636-643.
references.citation: Perez-Miralles F, Sanchez-Manso JC, Almenar-Bonet L, Sevilla-Mantecon T, Martinez-Dolz L, Vilchez-Padilla JJ. Incidence of and risk factors for neurologic complications after heart transplantation. Transplant Proc. 2005;37:4067-4070.
references.citation: Peterson LR, Ferguson RM. Fatal central nervous system infection with varicella-zoster virus in renal transplant recipients. Transplantation. 1984;37:366-368.
references.citation: Petrikovits E, Bedanova H, Necas J, Studenik P, Cerny J. Daclizumab in the induction phase of immunosuppression in heart transplant recipients. Ann Transplant. 2005;10:5-10.
references.citation: Reyes G, Fernandez-Yanez J, Rodriguez-Abella H, Palomo J, Pinto A, Duarte J. [Ventricular assist devices as a bridge to transplantation]. Rev Esp Cardiol. 2007;60:72-75.
references.citation: Sarmiento E, Rodriguez-Hernandez C, Rodriguez-Molina J, Fernandez-Yanez J, Palomo J, Anguita J, Perez JL, Lanio N, Fernandez-Cruz E, Carbone J. Impaired anti-pneumococcal polysaccharide antibody production and invasive pneumococcal infection following heart transplantation. Int Immunopharmacol. 2006;6:2027-2030.
references.citation: Schober R, Herman MM. Neuropathology of cardiac transplantation. Survey of 31 cases. Lancet. 1973;1:962-967.
references.citation: Schwechheimer K, Hashemian A. Neuropathologic findings after organ transplantation. An autopsy study. Gen Diagn Pathol. 1995;141:35-39.
references.citation: Torre-Cisneros J, Doblas A, Aguado JM, San Juan R, Blanes M, Montejo M, Cervera C, Len O, Carratala J, Cisneros JM, Bou G, Munoz P, Ramos A, Gurgui M, Borrell N, Fortun J, Moreno A, Gavalda J. Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort. Clin Infect Dis. 2009;48:1657-1665.
references.citation: Torre-Cisneros J, Lopez OL, Kusne S, Martinez AJ, Starzl TE, Simmons RL, Martin M. CNS aspergillosis in organ transplantation: a clinicopathological study. J Neurol Neurosurg Psychiatry. 1993;56:188-193.
references.citation: Zierer A, Melby SJ, Voeller RK, Guthrie TJ, Al-Dadah AS, Meyers BF, Pasque MK, Ewald GA, Moon MR, Moazami N. Significance of neurologic complications in the modern era of cardiac transplantation. Ann Thorac Surg. 2007;83:1684-1690.