Progressive Multifocal Leukoencephalopathy in a Heart Transplant Recipient Following Rituximab Therapy for Antibody-Mediated Rejection

We report the case of a male heart transplant recipient who developed acute antibody-mediated rejection and was treated with 5 weeks of a rituximab-containing regimen. Two months later he presented with progressive motor and cognitive impairments and was diagnosed with progressive multifocal leukoencephalopathy (PML). He was treated with reduction of his immunosuppressive medications, mirtazapine, IVIG and plasmapheresis. He died within weeks. We reviewed the current literature on PML and its association with immunosuppression, highlighting its impact in the setting of solid organ transplantation and considering the potential effect of newer biologic drugs on the incidence of this devastating disease in the transplant population. We report the case of a male heart transplant recipient who developed acute antibody-mediated rejection and was treated with 5 weeks of a rituximab-containing regimen. Two months later he presented with progressive motor and cognitive impairments and was diagnosed with progressive multifocal leukoencephalopathy (PML). He was treated with reduction of his immunosuppressive medications, mirtazapine, IVIG and plasmapheresis. He died within weeks. We reviewed the current literature on PML and its association with immunosuppression, highlighting its impact in the setting of solid organ transplantation and considering the potential effect of newer biologic drugs on the incidence of this devastating disease in the transplant population. The patient was a 48-year-old Caucasian male who underwent heart transplantation in 1998 for dilated cardiomyopathy. In 2002 he developed acute cellular rejection (ACR), grade 3B and C4d+ antibody-mediated rejection (AMR) treated with pulse steroids, increased daily cyclosporine dose to 275 mg and mycophenolate mofetil (MMF). Due to persistent rejection he was transitioned from cyclosporine to tacrolimus. In November 2008 he developed coronary artery vasculopathy (CAV) and received percutaneous coronary interventions. He remained well on prednisone 7.5 mg daily, tacrolimus 0.5 mg two times a day and MMF 750 mg two times a day. In October 2011 he missed several MMF doses while on a business trip. He subsequently developed shortness of breath and weight gain and was admitted with acute heart failure and probable rejection (tacrolimus level was 8.9 mg/dL). This was initially treated with methyl-prednisolone. An echocardiogram demonstrated preserved left ventricular ejection fraction with restrictive diastolic filling. Cardiac catheterization showed elevated cardiac filling pressures and preserved cardiac index and no obstructive coronary disease. Luminex assay showed donor specific antibodies (DSA) to HLA-I and HLA-II. An endomyocardial biopsy (EMB) showed AMR based on C4d positivity by immunostain with no ACR. His AMR was treated with eight cycles of plasmapheresis and intravenous immunoglobulin (IVIG). In spite of clinical improvement he still had elevated DSA and C4d+ on follow-up EMB. Four cycles of 780 mg rituximab were administered over 5 weeks and immunosuppressives were adjusted to MMF 1000 mg two times a day, prednisone 20 mg daily with slow tapering, and tacrolimus 1 mg two times a day (goal 10–12 mg/dL). Two months later, he presented with confusion, forgetfulness, mild tremors and difficulty with balance. On physical exam he was hemodynamically stable and afebrile. He was awake, alert and oriented. Cranial nerves, motor strength, sensation, reflexes and coordination were normal, and there was bilateral intention tremor. The Montreal cognitive assessment showed deficits in attention, language, abstraction and visuospatial areas, with intact naming, recall and orientation. An MRI of the brain showed multiple confluent subcortical white matter lesions most suggestive of progressive multifocal leukoencephalopathy (PML). Cerebrospinal fluid (CSF) analysis demonstrated zero WBC, 265 RBC/mm3, 77 mg/dL protein, 102 mg/dL glucose. Qualitative polymerase chain reaction (PCR) was positive for JC virus (JCV), considered diagnostic for PML in this context. The importance of reducing immunosuppressives to allow for immunologic control of the virus was discussed extensively, though it remained a therapeutic dilemma due to his high risk for rejection. Ultimately, MMF was stopped, tacrolimus was reduced to 0.5 mg twice daily and prednisone was increased back to 20 mg daily. He received five cycles of plasma exchange (PLEX), one dose of IVIG 30 g and mirtazapine 30 mg daily. He deteriorated neurologically and was discharged 18 days after admission to home hospice nearly mute and unable to walk without assistance. He died 1 week after discharge. PML is a progressive demyelinating disease of the cortical and subcortical white matter, classically in a multifocal distribution. As with our patient, neurologic symptoms occur subacutely, often presenting with altered behavior, cognitive dysfunction, motor deficits, ataxia, visuospatial deficits and seizures. Lesions are usually asymmetric, involving the deep and juxtacortical white matter with relative sparing of the immediate periventricular regions (1Krupp LB Lipton RB Swerdlow ML Leeds NE Llena J Progressive multifocal leukoencephalopathy: Clinical and radiographic features.Ann Neurol. 1985; 17: 344-349Crossref PubMed Scopus (145) Google Scholar). Involvement of parieto-occipital white matter and the corpus callosum is common. Lesions are seen as hypodense on computed tomography (CT) and as increased signal on T2-weighted MRI images. Characteristic findings are present on diffusion-weighted MRI but these may change over the course of the disease. Mass effect is rare and there is classically no enhancement with contrast, although variable enhancement has been noted in natalizumab-affected cases. The constellation of MRI findings are highly suggestive of PML; however they could also be found with acute disseminated encephalomyelitis, the mitochondrial encephalopathies, vasculitis, HIV encephalitis, multiple sclerosis (2Sahraian MA Radue EW Eshaghi A Besliu S Minagar A Progressive multifocal leukoencephalopathy: A review of the neuroimaging features and differential diagnosis.Euro J Neurol. 2012; 19: 1060-1069Crossref PubMed Scopus (94) Google Scholar) or immunosuppressive-associated leukoencephalopathy (3Singh N Bonham A Fukui M Immunosuppressive-associated leukoencephalopathy in organ transplant recipients.Transplantation. 2000; 69: 467-472Crossref PubMed Scopus (162) Google Scholar). Definitive diagnosis is by brain biopsy but the finding of JC virus by PCR in cerebrospinal fluid is both sensitive and specific in the appropriate clinical context and has become the most commonly used diagnostic test for the disease. In the absence of immune reconstitution PML is fatal, with prognosis ranging from weeks to months. JC virus was identified as the etiologic agent of PML in 1971 (4Padgett BL Walker DL ZuRhein GM Eckroade RJ Dessel BH Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy.Lancet. 1971; 1 (Epub 1971/06/19. eng.): 1257-1260Abstract PubMed Scopus (1246) Google Scholar). JCV is a polyoma virus with a circular double stranded DNA (5Dorries K Progressive multifocal leucoencephalopathy: Analysis of JC virus DNA from brain and kidney tissue.Virus Res. 1984; 1 (Epub 1984/01/01. eng.): 25-38Crossref PubMed Scopus (50) Google Scholar). Primary infection is asymptomatic. After initial viremia JCV remains latent in the kidney (6Yogo Y Kitamura T Sugimoto C et al.Isolation of a possible archetypal JC virus DNA sequence from nonimmunocompromised individuals.J Virol. 1990; 64 (Epub 1990/06/01. eng.): 3139-3143Crossref PubMed Google Scholar), circulating white blood cells (5Dorries K Progressive multifocal leucoencephalopathy: Analysis of JC virus DNA from brain and kidney tissue.Virus Res. 1984; 1 (Epub 1984/01/01. eng.): 25-38Crossref PubMed Scopus (50) Google Scholar,7Jing D Oelschlaegel U Ordemann R et al.CD49d blockade by natalizumab in patients with multiple sclerosis affects steady-state hematopoiesis and mobilizes progenitors with a distinct phenotype and function.Bone Marrow Transplant. 2010; 45 (Epub 2010/01/26. eng.): 1489-1496Crossref PubMed Scopus (51) Google Scholar) and the brain (8Cettomai D McArthur JC Mirtazapine use in human immunodeficiency virus-infected patients with progressive multifocal leukoencephalopathy.Arch Neurol. 2009; 66 (Epub 2009/02/11. eng.): 255-258Crossref PubMed Scopus (101) Google Scholar). Under appropriate conditions, and facilitated by serotonin receptors, active infection of the glial cells of the central nervous system (CNS) occurs (9Sabath BF Major EO Traffic of JC virus from sites of initial infection to the brain: The path to progressive multifocal leukoencephalopathy.J Infect Dis. 2002; 186 (Epub 2002/11/09. eng.): S180-S186Crossref PubMed Scopus (126) Google Scholar). Infection proliferates in the setting of immunodeficiency, particularly T cell impairments, leading to the typical white matter degeneration of PML. Thus, the development of PML is a multistep process requiring infection, reactivation, neural invasion and viral proliferation in the setting of immunodeficiency (10Kedar S Berger JR The changing landscape of progressive multifocal leukoencephalopathy.Curr Infect Dis Rep. 2011; 13 (Epub 2011/05/24. eng.): 380-386Crossref Scopus (8) Google Scholar). The seroprevalence of JCV ranges from 10% in children to 60% in adults (10Kedar S Berger JR The changing landscape of progressive multifocal leukoencephalopathy.Curr Infect Dis Rep. 2011; 13 (Epub 2011/05/24. eng.): 380-386Crossref Scopus (8) Google Scholar, 11Taguchi F Kajioka J Miyamura T Prevalence rate and age of acquisition of antibodies against JC virus and BK virus in human sera.Microbiol Immunol. 1982; 26 (Epub 1982/01/01. eng.): 1057-1064Crossref PubMed Scopus (131) Google Scholar, 12Knowles WA Pipkin P Andrews N et al.Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40.J Med Virol. 2003; 71 (Epub 2003/07/15. eng.): 115-123Crossref PubMed Scopus (464) Google Scholar). Prior to the human immunodeficiency virus (HIV) epidemic PML was considered a rare disease seen in patients with hematological malignancies (13Astrom KE Mancall EL Richardson Jr, EP Progressive multifocal leuko-encephalopathy; a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin’s disease.Brain. 1958; 81 (Epub 1958/03/01. eng.): 93-111Crossref PubMed Scopus (706) Google Scholar) and associated with autoimmune disorders (14Amend KL Turnbull B Foskett N Napalkov P Kurth T Seeger J Incidence of progressive multifocal leukoencephalopathy in patients without HIV.Neurology. 2010; 75 (Epub 2010/10/13. eng.): 1326-1332Crossref PubMed Scopus (91) Google Scholar) (Table 1). HIV was associated with a 50-fold increase in the incidence of PML, affecting 1–7% of HIV-infected individuals in clinical and pathological studies (15Berger JR Kaszovitz B Post MJ Dickinson G Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. A review of the literature with a report of sixteen cases.Ann Intern Med. 1987; 107: 78-87Crossref PubMed Scopus (446) Google Scholar,16Lang W Miklossy J Deruaz JP et al.Neuropathology of the acquired immune deficiency syndrome (AIDS): A report of 135 consecutive autopsy cases from Switzerland.Acta Neuropathol. 1989; 77: 379-390Crossref PubMed Scopus (178) Google Scholar). PML was an acquired immunodeficiency syndrome (AIDS) defining illness and invariably lethal once diagnosed (17Berger JR Pall L Lanska D Whiteman M Progressive multifocal leukoencephalopathy in patients with HIV infection.J Neurovirol. 1998; 4 (Epub 1998/04/08. eng.): 59-68Crossref PubMed Scopus (302) Google Scholar). With the advent of highly active antiretroviral therapy (HAART) in the mid 1990s and resultant immune reconstitution, PML became less frequent (18Khanna N Elzi L Mueller NJ et al.Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study.Clin Infect Dis. 2009; 48 (Epub 2009/04/08. eng.): 1459-1466Crossref PubMed Scopus (115) Google Scholar) as well as less fatal (19Clifford DB Yiannoutsos C Glicksman M et al.HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy.Neurology. 1999; 52 (Epub 1999/02/20. eng.): 623-625Crossref PubMed Google Scholar).Table 1:Comparative incidence of PML in different conditions associated with immunosuppressionIncidenceCondition(100 000 patient year)Multiple sclerosis + natalizumab202+Heart or lung transplant124!HIV with HAART60¥HIV prior to HAART240¥Bone marrow transplant35.4*Chronic lymphocytic leukemia11.1*Autoimmune vasculitis10.8*Non-Hodgkin’s lymphoma8.3*Systemic lupus erythematous2.4*Data obtained from references *(14Amend KL Turnbull B Foskett N Napalkov P Kurth T Seeger J Incidence of progressive multifocal leukoencephalopathy in patients without HIV.Neurology. 2010; 75 (Epub 2010/10/13. eng.): 1326-1332Crossref PubMed Scopus (91) Google Scholar), !(38Mateen FJ Muralidharan R Carone M et al.Progressive multifocal leukoencephalopathy in transplant recipients.Ann Neurol. 2011; 70 (Epub 2011/08/09. eng.): 305-322Crossref PubMed Scopus (134) Google Scholar), ¥(18Khanna N Elzi L Mueller NJ et al.Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study.Clin Infect Dis. 2009; 48 (Epub 2009/04/08. eng.): 1459-1466Crossref PubMed Scopus (115) Google Scholar) and +(21Rudick RA Multiple sclerosis, natalizumab, and PML: Helping patients decide.Cleveland Clin J Med. 2011; 78 (Epub 2011/12/14. eng.): S18-S23Crossref PubMed Scopus (9) Google Scholar). Open table in a new tab Data obtained from references *(14Amend KL Turnbull B Foskett N Napalkov P Kurth T Seeger J Incidence of progressive multifocal leukoencephalopathy in patients without HIV.Neurology. 2010; 75 (Epub 2010/10/13. eng.): 1326-1332Crossref PubMed Scopus (91) Google Scholar), !(38Mateen FJ Muralidharan R Carone M et al.Progressive multifocal leukoencephalopathy in transplant recipients.Ann Neurol. 2011; 70 (Epub 2011/08/09. eng.): 305-322Crossref PubMed Scopus (134) Google Scholar), ¥(18Khanna N Elzi L Mueller NJ et al.Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study.Clin Infect Dis. 2009; 48 (Epub 2009/04/08. eng.): 1459-1466Crossref PubMed Scopus (115) Google Scholar) and +(21Rudick RA Multiple sclerosis, natalizumab, and PML: Helping patients decide.Cleveland Clin J Med. 2011; 78 (Epub 2011/12/14. eng.): S18-S23Crossref PubMed Scopus (9) Google Scholar). An increase in the incidence of PML occurred again after the introduction of biological drugs (monoclonal antibodies) (20Major EO History and current concepts in the pathogenesis of PML.Cleveland Clin J Med. 2011; 78 (Epub 2011/12/14. eng.): S3-S7Crossref PubMed Scopus (13) Google Scholar). In 2004, natalizumab, a humanized monoclonal antibody directed against VLA-4, was approved in the United States for use in patients with multiple sclerosis (MS). By 2006, the association between natalizumab and PML led to a black box warning. The incidence of PML in patients who received natalizumab was 2.02 per 1000 patient years (21Rudick RA Multiple sclerosis, natalizumab, and PML: Helping patients decide.Cleveland Clin J Med. 2011; 78 (Epub 2011/12/14. eng.): S18-S23Crossref PubMed Scopus (9) Google Scholar). Seropositivity for JCV, concomitant use of immunosuppression and the length of the natalizumab treatment were identified as risk factors for the development of PML (22Sorensen PS Bertolotto A Edan G et al.Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab.Mult Scler. 2012; 18 (Epub 2012/02/09. eng.): 143-152Crossref PubMed Scopus (205) Google Scholar), and algorithms based on these were developed to minimize PML in the MS population (23Thompson JP Noyes K Dorsey ER Schwid SR Holloway RG Quantitative risk-benefit analysis of natalizumab.Neurology. 2008; 71 (Epub 2008/07/30. eng.): 357-364Crossref PubMed Scopus (42) Google Scholar). 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