Progressive multifocal leukoencephalopathy (PML) after transplantation

Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal opportunistic demyelinating disorder related to a viral infection of the central nervous system that was initially described in immunocompromised patients. It has commonly been reported in patients with hematologic malignancies, systemic lupus erythematosus, and chronic inflammatory diseases and is recognized as an AIDS-defining illness. No effective treatment is available at present for PML, and the article by Weber et al. is one of the first to describe successful treatment of PML in a pediatric renal transplant recipient.

PML is rarely seen in adult renal transplant recipients; it was first described in the 1970s. Until the publication of this article, no cases in pediatric transplant recipients were reported in the literature. The etiologic agent is the polyomavirus JC (named after the patient in whom it was first described), an unenveloped DNA virus for which the majority of the human population is seropositive, with seroconversion occurring during adolescence. JC virus belongs to the Polyomaviridae family that includes the more commonly known opportunistic BK virus, which affects the transplanted kidney predominantly. JC virus has limited tissue tropism, infecting the kidney, and oligodendrocytes and astrocytes in the central nervous system. In healthy individuals, the virus is silent. But in an immunocompromised host, reactivation of the latent JC virus in the bone marrow results in a disseminated lytic infection in the brain (1). The signs and symptoms of the disease are often subtle, making the diagnosis difficult in adults and more so in children. Symptoms can include cognitive and personality disturbances, motor weakness, visual disturbances, and seizures. The lesions occur within the first 17 months after transplantation, with a tendency for later presentation in renal transplant recipients (2). Cytotoxic CD8+ T lymphocytes are the primary inflammatory cell seen in PML lesions. The destruction of infected oligodendrocytes is a critical step in the stabilization of PML, and T lymphocytes are found in the cerebrospinal fluid of patients who survive. There is demyelinization, giant astrocytosis, and nuclear inclusion bodies in the oligodendrocytes of the brain (1). The gold standard for diagnosis is a brain biopsy, but neuroimaging studies will demonstrate pathologic changes. Computed tomography scans will reveal hypodense, non-enhancing lesions of the cerebral white matter. Magnetic resonance imaging appears to be more sensitive, appearing as increased signal intensity on proton density and T2-weighted images. A complicating factor in the transplant population is that immunosuppression-associated leukoencephalopathy can mimic the findings (2).

Transplant immunosuppressive therapies vary throughout the United States and the world, including both induction agents and post-transplant immunosuppression. Long-term post-transplant immunosuppressives include tacrolimus, cyclosporine, mycophenolate mofetil (MMF), mycophenolate sodium, azathioprine, sirolimus, and corticosteroids. PML has been reported in the context of organ transplantation with the use of cyclosporine, azathioprine, corticosteroids, tacrolimus, and MMF (2). There are little data regarding the incidence of PML in transplant patients because most of the literature is confined to case reports. Neff et al. conducted a study to examine the incidence in 2008. They noted nine cases of post-transplant PML out of nearly 32 750 (0.03%) renal transplant recipients, with five deaths during the study period, based on the USRDS report from January 2000 to July 2004. All patients diagnosed with PML were on MMF at the time of discharge from the hospital, but it is unclear if they were on MMF at the time of the diagnosis of PML (3).

The association of biologic immunomodulatory drugs and PML is not new. In 2009, efalizumab was withdrawn for the United States and European markets after three confirmed cases of PML were identified in 1200 patients treated for psoriasis, and natalizumab was transiently withdrawn in 2005 after three cases of PML occurred in patients treated for multiple sclerosis and Crohn’s disease (4). MMF use rose rapidly in United States after it was approved by the FDA in 1995, and between January 2000 and July 2004 was used in more than 75% of patients at the time of hospital discharge, based on USRDS Medicare reports (3). Although Neff et al. reported that 100% of the patients during their study period were thought to be using MMF, Shitrit et al. reviewed 24 cases of PML, and of the nine kidney transplant recipients, none were on MMF (2, 3). Ultimately in 2008, the FDA released a safety report regarding the potential association between MMF and PML.

The case that Weber et al. present is the first report of PML in a pediatric renal transplant patient. In addition to the patient’s transplant immunosuppression, the patient also had an underlying immunodeficiency. Common variable immune deficiency (CVID) is a heterogenous condition of hypogammaglobinemia with varying phenotypes and is the most common cause of primary antibody deficiencies (5). Recent research, however, indicates that some patients with CVID have T-cell proliferation and secretory defects (6). MMF is an irreversible inhibitor of inosine monophosphate dehydrogenase in lymphocytes and affects lymphocytic proliferation and activation. Knowing that the lymphocyte plays a critical role in the pathogenesis of PML, it is plausible that MMF use may contribute to its development.

Treatment options for JC virus activation are limited. Cytosine arabinoside, IL-2, and alpha-interferon have been reported as treatment modalities for PML in the past, but the condition has routinely continued to progress. Withdrawal of immunosuppressive therapy was also attempted in other case reports, but the progression of PML persisted (2). Cidofovir, a nucleoside analog, has emerged as the most selective anti-polyoma virus agent and has been used successfully to treat patients with transplant nephropathy related to another polyoma virus, BK. This is the first case where the combination of cidofovir and cessation of MMF have been successful in treating PML.

With the low incidence of PML recognized in transplant recipients, understanding the risk factors for developing PML is difficult. The exact relationship between the immune system and pathogenesis of JC virus in PML remains elusive, although great strides are being made in further understanding the intrinsic actions of this virus. Preemptive screening for JC virus serologies will not be beneficial, as most people are seropositive for the virus. For now, diligence in screening and monitoring patients for this rare opportunistic infection will be critical. It is always necessary to have a healthy respect for the immunosuppressive agents utilized in transplantation, with routine attempts to minimize their use. The prognosis remains poor in PML, but the success of Weber et al. has offered new hope in the treatment of an otherwise fatal disease.