Handbook of Clinical Neurology, Vol. 123 (3rd series) Neurovirology A.C. Tselis and J. Booss, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 17

Progressive multifocal leukoencephalopathy JOSEPH R. BERGER* Department of Neurology and Department of Medicine, University of Kentucky College of Medicine, Lexington, KY, USA

INTRODUCTION The recognition of three cases of progressive multifocal leukoencephalopathy (PML) attending the use of natalizumab, a monoclonal antibody directed against a4b1 and a4b7 integrin for the treatment of multiple sclerosis (MS) and Crohn disease, in 2005 heightened interest in this formerly rare disease (Berger and Koralnik, 2005; Kleinschmidt-DeMasters and Tyler, 2005; LangerGould et al., 2005; Van Assche et al., 2005). Interest in this neurologic disorder was further magnified by the observation of PML with other biologic agents (Berger, 2010), including efalizumab (Bechtel et al., 2009) belatacept (Grinyo et al., 2010; Mengelle et al., 2011; Yamamura, 2009), rituximab (Nived et al., 2008), and alemtuzumab (Waggoner et al., 2009), as well as immunomodulatory agents that were not monoclonal antibodies, such as mycophenolate mofetil (Neff et al., 2008). This heightened interest has resulted in an expansion of the investigation of the pathobiology of the disease, risk mitigation strategies, and potential treatments. However, PML ceased being a rare disorder with the advent of the human immunodeficiency virus (HIV) pandemic. First described as a distinct entity by Astrom et al. in 1958, the syndrome was identified chiefly on the basis of a triad of unique histopathologic features which included demyelination, abnormal oligodendroglial nuclei, and giant astrocytes. Each of the three patients they described had an underlying B-cell lymphoproliferative disorder, namely, Hodgkin’s disease and chronic lymphocytic leukemia. In the 26 years from 1958 through 1984, a comprehensive review of PML by Brooks and Walker (1984) was able to identify 230 published and unpublished cases, of which 69 cases were pathologically confirmed and 40 cases both virologically and pathologically confirmed. In this series, only 5 of the 230 patients

had HIV/acquired immunodeficiency syndrome (AIDS) , an illness first described in 1981, and only two of these AIDS-associated PML cases had been previously reported (Miller et al., 1982; Bedri et al., 1983). HIV/AIDS accounted for only 2.1% of the underlying illnesses in that series; however, by the end of the 20th century, the spectrum of predisposing illnesses for PML changed dramatically. In some locales, HIV/AIDS accounted for more than 90% of the predisposing disorders associated with PML (Berger et al., 1998b). HIV/AIDS had resulted in a remarkable increase in the frequency of PML, an incidence now declining with effective combined antiretroviral therapy. We are currently entering a new era with respect to PML, namely, one in which PML is observed with the use of biologic agents for diseases that may not be illnesses that necessarily predispose to the development of PML by themselves.

MOLECULAR BIOLOGY OF JC VIRUS Following its initial description, the etiology of PML remained a mystery. In the seminal paper describing the disease, Astrom et al. (1958) stated that “We do not know the cause of this condition . . . most frequently a complication of chronic lymphatic leukemia or Hodgkin’s . . . Whether there is some factor shared in common between these diseases and sarcoidosis and tuberculosis . . . remains unknown.” However, in 1959, the year following this description, Cavanaugh et al. suggested the possibility of a viral etiology based on the electron microscopic appearance of inclusion bodies in the enlarged oligodendroglial nuclei. The specific nature of these inclusion bodies on electron microscopic study appeared to be consistent with papovavirus(SilvermanandRubinstein,1965;ZuRhein,1965),avirus not previously known to result in central nervous system (CNS) disorders. Viral isolation in glial cell cultures by

*Correspondence to: Joseph R. Berger, M.D., Ruth L. Works Professor and Chairman, Department of Neurology, University of Kentucky College of Medicine, Kentucky Clinic L-445, 740 S. Limestone St., Lexington KY 40536-0284, USA. Tel: þ1-859-2185039, Fax: þ1-859-323-5943, E-mail: [email protected]



Padgett at the University of Wisconsin from the brain of a patient with PML confirmed that a papovavirus was responsible (Padgett et al., 1971). The virus was labeled the JC virus (JCV), using the initials of the person from whom it was isolated. JCV is in the genus Polyomavirus in the family Papovavirus. Previous descriptions of PML occurring in association with other polyomaviruses, e.g., BK virus and SV40, are now believed to have been incorrect. The cases attributed to SV40 have been poorly characterized and, in some instances, re-examination of these brain tissues by in situ DNA hybridization has revealed JCV, not SV40 (Stoner and Ryschkewitsch, 1991). BK virus, another human polyomavirus and an important cause of renal transplant rejection(Gardner etal.,1971;Tooze,1980),not surprisingly, can be isolated from the urine of some patients with PML, but has not been proven to be neuropathogenic. BK virus shares more than 70% nucleotide homology with JCV (Frisque et al., 1979). Our understanding of PML has increased greatly over the past 50 years. First, as there is no animal model for the disease, it can only be studied in humans. With the increased incidence of PML due to HIV/AIDS and now newer biologic therapies, there is more opportunity to study the disease. Second, there has been development of highly sensitive molecular techniques that allow detection of very few copies of a viral genome, including advances in in situ hybridization and amplification of viral genomes using polymerase chain reaction (PCR) (Arthur et al., 1989; Weber et al., 1990). The application of these techniques to tissues available from PML patients has, among other studies, enabled investigations of the mechanisms of viral multiplication (Lynch and Frisque, 1990, 1991; Major et al., 1990), the cellular control over viral gene expression (Amemiya et al., 1989, 1992; Tada et al., 1989), and the delivery of virus to the CNS (Houff et al., 1988; Weber et al., 1990). Third, the recognition of a risk for PML with newer therapies for cancer, solid-organ and hematologic transplantation, MS, and other autoimmune disease has expanded the research in this disorder. JCV has a simple DNA genome of 5.1 kilobases in a double-stranded, supercoiled form, encapsidated in an icosahedral protein structure measuring 40 nm in diameter (Fig. 17.1). The DNA codes for three non-structural proteins and three capsid proteins (VP1, VP2, VP3) (Fig. 17.1). The T protein, a non-structural but multifunctional protein, is a DNA-binding protein responsible for initiation of viral DNA replication and transcription of the capsid proteins which are transcribed from opposite strands of the DNA genome. In certain rodent and non-human primate cells, JCV T-protein expression is consistent with a malignant transformation or tumor induction, particularly of astroglial cells into astrocytomas (ZuRhein, 1967; Walker et al., 1973; London et al., 1978). In these cells only the T protein, named for its

Regulatory region

Early region – T and t antigen (highly conserved)

Late region – structural proteins (highly conserved)

Fig. 17.1. The JC virus genome.

tumor-promoting function, is expressed. The role of JCV and its protein products in the pathogenesis of human glial and other tumors remains controversial. A smaller t protein has not been considered important for pathogenicity. There are approximately 200 nucleotide basepairs of non-coding sequence, referred to as the regulatory or non-coding control region. It is located between the two coding sequence areas, the early and late genes. This region of the genome contains the signals for DNA replication as well as for promotion and enhancement of transcription (ZuRhein, 1967; Walker et al., 1973; London et al., 1978; Frisque et al., 1979, 1984). This region is responsible for the cellular tropism of JCV (Khalili et al., 1988). This region of the viral genome demonstrates the most sequence variability in the brains of patients with PML as a consequence of deletions and rearrangements perhaps acquired during propagation in brain or in extraneural host tissues (Dorries, 1984; Martin et al., 1985). Initial studies of JCV in cultures of human fetal brain cells indicated an exclusive neurotropism for glial cells (ZuRhein, 1965; Padgett et al., 1971; Dorries, 1984; Martin et al., 1985). Although JCV does not routinely infect neurons, it does infect both oligodendrocytes and astrocytes (Wroblewska et al., 1980; Aksamit and Proper, 1988). Recent studies prompted by the appearance of a unique disorder characterized by ataxia and cerebellar atrophy in AIDS patients revealed that JCV could also infect the granular cells of the cerebellum (Koralnik et al., 2005). Rarely, the causative virus may infect cortical pyramidal cells and result in a fulminant encephalopathy in immunosuppressed individuals (Wuthrich et al., 2009). Elphick and colleagues (2004) demonstrated that JCV uses serotonin receptor 5-HT2a for binding to the cell surface. In vitro, antibodies directed against this receptor (Elphick et al., 2004) and serotonin antagonists (Nukuzuma et al., 2009) inhibit JCV propagation. However, the importance of the serotonin HT2a receptor for


Cell surface receptor 5HT2a (mirtazipine)

Clathirin dependent endocytosis (chlorpromazine) Caveosome from which transported to ER

Endoplasmic reticulum from which transported to nucleus

Intranuclear DNA binding region NF1 class X (binds JCV promotor)

Fig. 17.2. Steps to viral entry and transfer to the nucleus. ER, endoplasmic reticulum.

infection is not without controversy (Chapagain et al., 2008). The sialic acid component of the receptor is important. JCV uses both alpha(2,3)-linked and alpha(2,6)-linked sialic acids on N-linked glycoproteins to infect cells. The sialic acid linkages required for cell surface binding directly correlate with the linkages required for infection (Dugan et al., 2008). It is quite possible that other receptors, which remain yet to be identified, can also permit JCV binding. Following binding, the virus enters the cell through clathrin and eps15dependent pathways (Pho et al., 2000; Querbes et al., 2004) following which it is transported to the endoplasmic reticulum through caveosomes. From there, it enters the nucleus (Fig. 17.2). Nuclear DNA-binding proteins that selectively interacted with the regulatory region of the genome are critical to the tropism of the virus. In particular, binding of nuclear factor 1 (NF-1), a protein that functions in both transcriptional control and replication of DNA, is important to JCV replication (Tamura et al., 1988; Amemiya et al., 1989, 1992; Ahmed et al., 1990). Cells that are not permissive to JCV infection probably do not have these same protein factors and/or have other proteins that bind the JCV regulatory sequences and block transcription (Tada et al., 1989; Amemiya et al., 1992).

PATHOGENESIS OF PML Despite a high prevalence of JCV infection in the world’s population, PML remains rare, indicating that there must be enormous barriers to the development of the disease. Currently, it is believed that these barriers exist in three major spheres: host factors, the virus itself, and an abnormality of the host’s immunologic response. Host factors predisposing to the disease are poorly understood and have not been well studied. There is a better appreciation of the underlying viral factors and the nature of the immune deficiencies that predispose to the disease. A number of lines of evidence strongly suggest that PML typically results from reactivation of a latent


infection rather than occurring as a consequence of primary infection. For instance, antibody directed to JCV in PML patients is almost exclusively IgG, not IgM (Weber et al., 2001). In one study addressing the nature of the immunoglobulin response, only 1 of 21 patients with PML had IgM specific for JCV in their sera, whereas 20 of 21 had IgG antibody specific for JCV (Padgett and Walker, 1983). Some investigators have argued that the latter study does not exclude the possibility of PML resulting from acute JCV infection as many of these patients were studied late in the course of their disease. Although PML has been reported in children (Berger et al., 1992b), it is very rare, reflecting the decreased percentage of children who have been exposed to the virus. Plasma and peripheral blood mononuclear cells (PBMCs) obtained 8 months before the onset of PML showed the same genetic makeup of the non-coding control region (NCCR) (Fedele et al., 2003). There have been six individuals with PML from whom lymphoid tissue, spleen, or bone marrow had been obtained 0.5–4.1 years before PML, and the JCV isolated from these sites have all had the same NCCR genetic profile as that isolated from the brain (E. O. Major, personal communication). Lastly, at least 17 patients with natalizumab-associated PML from whom blood had been collected 16–180 months before the diagnosis all demonstrated JCV antibody (Gorelik et al., 2010). The development of PML is a stochastic event. For PML to develop, a number of steps must ensue: (1) infection with JCV; (2) latent and/or persistent JCV infection in extraneural tissues; (3) rearrangement of JCV into a neurotropic strain if the initial infection has been with the archetype strain; (4) reactivation of the neurotropic JCV strain from sites of viral latency; (5) entry into the brain; (6) establishment of productive infection of oligodendrocytes; and (7) an ineffective immune system that prevents immunosurveillance from eliminating the infection. Following the initial infection of JCV, the virus enters latency in selected tissues. The precise sites of viral latency have not been systematically investigated; however, known sites of viral latency include the tonsils (Monaco et al., 1998), lung, spleen, bone marrow, and kidney (Caldarelli-Stefano et al., 1999). Between 25% (Rudick et al., 2010) and 40% (Rossi et al., 2007) of non-immunocompromised patients have detectable JCV in their urine by PCR and, in select populations, that number may be higher (Berger et al., 2006). These observations suggest that the kidney and components of the renal system are sites of viral infection, but it is unlikely that this is the site of viral infection that leads to the development of PML as the DNA sequence of the regulatory region from kidney or urine in these individuals is markedly different from the sequence found in the brain of PML patients (Yogo et al., 1991). The JCV isolated



from the kidney is referred to as the archetype sequence (Yogo et al., 1990) and contains 187 nucleotide pairs with no tandem repeats, as is observed in the PML brain isolates (Martin et al., 1985; Henson et al., 1992). To convert the archetype sequence to that most often found in PML brain tissue requires deletions, substitutions, and duplications in the NCCR, regulatory region, of the virus (Yogo et al., 1991; Tominaga et al., 1992). The neurotropic form of JCV contains a 98-basepair tandem repeat in the NCCR (Major et al., 1992). Current evidence implicates the importance of viral latency in B lymphocytes in bone marrow or other lymphoid tissues that can be activated during immune suppression and enter the peripheral blood (Major et al., 1992). Importantly, several regulatory region sequences have been identified from JCV DNA in peripheral blood of PML patients that are not related to the archetype but closely related to sequences found in PML brain (Tornatore et al., 1992a). Circulating infected lymphocytes may be able to cross the blood–brain barrier and pass infection to astrocytes at the border of vessels, which in turn augments infection through multiplication to eventually infect oligodendrocytes. Using in situ DNA hybridization, JCV-infected cells are frequently found near blood vessels in the brain, in B lymphocytes in bone marrow (Houff et al., 1988), and in the brain (Major et al., 1990). In a report of 19 patients with biopsy-proven PML, over 90% had JCV DNA in peripheral blood lymphocytes using the PCR technology (Tornatore et al., 1992b). Data derived from other groups of individuals without PML revealed that 60% of HIV-1-seropositive individuals, 30% of renal transplant recipients, and approximately 5% of normal healthy volunteers also had JCV DNA in their peripheral circulation (Tornatore et al., 1992b). In relatively immunologically healthy HIV-infected persons on highly active antiretroviral therapy (HAART), the likelihood of finding JCV DNA in circulating lymphocytes appears to parallel that of the normal population (Berger et al., 2005). However, any group whose immune system is compromised, either by immunosuppressive regimen or by disease, would be considered to be at risk for the development of PML. Other lines of evidence pointing to the importance of the B cell in the pathogenesis of PML are the high frequency with which the disorder is observed in B-cell malignancies, such as chronic lymphocytic leukemia and Hodgkin’s disease and illnesses associated with B-cell activation, such as systemic lupus erythematosus (SLE) and AIDS. Additionally, the monoclonal antibody natalizumab, which appears to carry the highest risk for the development of the disease of any of the biologic agents, results in hematopoietic stem cell mobilization (Neumann et al., 2009), in particular a release of immature cells of B lineage, CD34 þ progenitor cells

(Krumbholz et al., 2008), from the bone marrow. Natalizumab has also been shown to upregulate host cell nuclear transcription factors associated with JCV expression (Lindberg et al., 2008), leading to the suggestion that JCV expression, replication, and perhaps even genetic mutation to a neurotropic strain in the B cell is in part responsible for the increased risk for PML. However, a study of JCV expression in CD34 þ cells in patients under treatment with natalizumab failed to detect the virus: two plasma samples from this study sample were positive for JCV (Warnke et al., 2011). The proposed pathogenesis remains conjectural and will need to be rethought if studies (Tan et al., 2010) that demonstrate rearranged JCV sequences in non-PML brain tissue are confirmed.

EPIDEMIOLOGY OF JC VIRUS The ability of JCV to cause hemagglutination of type O erythrocytes has enabled the performance of antibody studies to determine evidence of prior infection. To date, no disease has been convincingly associated with acute infection. The mechanism of viral spread remains speculative. Respiratory transmission has been postulated. The presence of JCV in tonsillar tissues (Monaco et al., 1998) suggested that saliva and oropharyngeal secretions may be a means of transmission. However, recent studies of these fluids in HIV-infected persons and healthy controls indicate that the virus is rarely demonstrated in them and, when present, is there in very low titer (Berger et al., 2006). Between the ages of 1 and 5 years, approximately 10% of children demonstrate antibody to JCV, and by age 10, it can be observed in 40–60% of the population (Taguchi et al., 1982; Walker and Padgett, 1983a, b). By late adulthood, this figure rises almost sevenfold, although between the ages of 20 and 50 approximately 50–60% of individuals demonstrate positivity using a hemagglutination inhibition assay and an increase thereafter (Walker and Padgett, 1983a) (Fig. 17.3). Seroconversion rates to JCV have exceeded 90% in some urban areas (Walker and Padgett, 1983a). The high incidence of JCV antibody seropositivity has been largely predicated on the use of the hemagglutination assay. This assay likely overestimates the frequency of antibody positivity due to cross-reactivity with another common polyomavirus, BK virus. Other studies employing an immunoassay for JCV show rates varying between 35% (Knowles et al., 2003) and 91% (Matos et al., 2010) among adults.

HOST FACTORS AND UNDERLYING DISEASES With rare exception (Gheuens et al., 2010), a significant underlying immunosuppressive condition is recognized




100 80 60 40

JC Antibody BK Antibody

20 0









AGE (years)

Fig. 17.3. Seroepidemiology of JC virus. (Reproduced from Brooks and Walker, 1984.)

in all individuals with PML. Typically, the abnormality is one of cell-mediated immunity, more specifically, a general impairment of the Th1-type T-helper cell function (Weber et al., 2001). The first 3 patients described by Astrom et al. (1958) had either chronic lymphocytic leukemia or lymphoma as the underlying illness. In the large review of Brooks and Walker published in 1984, lymphoproliferative diseases were the most common underlying disorders, accounting for 62.2% of cases. Other predisposing illnesses in that series included myeloproliferative diseases in 6.5%, carcinoma in 2.2%, granulomatous and inflammatory diseases, such as tuberculosis and sarcoidosis, in 7.4%, and other immune deficiency states in 16.1%. Although AIDS was included in the latter category, it accounted for only five of the 230 cases (2.1%) (Brooks and Walker, 1984). Indeed, until the AIDS epidemic, PML remained a rare disease. To most practicing neurologists, it remained a medical curiosity about which one learned from the textbooks. However, the AIDS pandemic changed the incidence of this formerly rare illness quite remarkably. While only 230 cases were identified in a review from 1958 to 1984 (Brooks and Walker, 1984), 156 cases were identified from the University of Miami Medical Center and the Broward County Medical Examiner’s Office in south Florida during the 14-year interval 1980–1994 (Berger et al., 1998b). All but two of these cases were associated with HIV/AIDS, indicating how dramatically the AIDS pandemic had changed the epidemiology of PML. A 20-fold increase was observed in the disease frequency when comparing the 5-year intervals 1980–1984 to 1990–1994 (Berger et al., 1998b). In the United States, AIDS has been estimated to be the underlying cause of immunosuppression in 55% to more than 85% of all cases of PML (Major et al., 1992). Data accumulated from death certificates reported to the Centers for Disease Control and Prevention (CDC) indicated that 87% of all cases of reported cases PML in 1993 were associated with HIV infection (Selik et al., 1997).

The first description of PML complicating AIDS was published in 1982, 1 year after the initial description of AIDS (Miller et al., 1982). In less than a decade, HIV/AIDS became the most common underlying disorder predisposing to the development of PML at institutions in New York (Krupp et al., 1985) and Miami (Berger et al., 1987). The epidemiology of PML changed dramatically with HIV/AIDS. Gillespie and colleagues (1991), studying the prevalence of AIDS-related illnesses in the San Francisco Bay area, estimated a prevalence for PML of 0.3% and opined that this figure may have significantly underestimated the true prevalence. Death certificate reporting of AIDS to the CDC between 1981 and June 1990 revealed that 971 (0.72%) of 135 644 individuals dying with AIDS also had PML (Holman et al., 1991). Due to the notorious inaccuracies in death certificate reporting (Messite and Stellman, 1996) and the requirement of pathologic confirmation for inclusion in this study, it, too, likely significantly underestimated the true prevalence of this disorder. Other studies have suggested that the prevalence of PML at this time in the AIDS pandemic was substantially higher, with most estimates ranging between 1% and 5% in clinical studies and as high as 10% in pathologic series (Krupp et al., 1985; Berger et al., 1987; Lang et al., 1989; Kure et al., 1991; Kuchelmeister et al., 1993). In 1987, a large, retrospective, hospital-based clinical study (Berger et al., 1987) found PML in approximately 4% of patients hospitalized with AIDS. Four percent of all patients dying with AIDS had PML in a combined series of seven separate neuropathologic studies comprising a total of 926 patients with AIDS (Kure et al., 1991). Two other large neuropathologic series found PML in 7% (Lang et al., 1989) and 9.8% (Kuchelmeister et al., 1993) of autopsied AIDS patients. The authors of the latter study acknowledged that an unusually high estimate may have resulted from numerous referral cases from outside the study center and the inherent bias imposed (Kuchelmeister et al., 1993). However, a study of 548 consecutive, unselected autopsies between 1983 and 1991 performed on HIVseropositive individuals by the Broward County (Florida) Medical Examiner revealed that 29 (5.3%) had PML confirmed at autopsy (Whiteman et al., 1993). Similarly, the Multicenter AIDS Cohort Study (MACS) also identified a dramatic rise in the incidence of PML over a similar time period. Specifically, the MACS identified 22 cases of PML among the cohort of AIDS cases studied from 1985 to 1992: the average annual incidence of PML was 0.15 per 100 person-years with a yearly rate of increase of 24% between 1985 and 1992 (Bacellar et al., 1994). Although these estimates



may be susceptible to selection and other biases, there is an indisputable markedly increased incidence and prevalence of PML since the inception of the AIDS pandemic. Indeed, it appears that the incidence of PML complicating HIV/AIDS is higher than that of any other immunosuppressive disorder relative to their frequency. A number of possible explanations have been proposed (Berger, 2003), including: (1) differences in the degree and duration of the cellular immunosuppression in HIV infection; (2) facilitation of the entry into the brain of JCV-infected B lymphocytes by alterations in the blood–brain barrier due to HIV; (3) facilitation of the entry of these infected cells by the upregulation of adhesion molecules on the brain vascular endothelium due to HIV infection; (4) transactivation of JCV by the HIV proteins, particularly, tat; and (5) transactivation of JCV by the cytokines and chemokines elaborated by the microglial cells of HIV-infected brains. Concomitant with the increase in PML in association with AIDS has been the not unexpected alteration in the demographics of the affected population. Prior to the AIDS epidemic, PML was chiefly a disease of the elderly, with males and females virtually equally affected (Brooks and Walker, 1984). Currently, in the United States, PML occurs chiefly in men between the ages of 20 and 50 (Berger et al., 1998b), reflective of the demographics of the HIV-infected population. As the demographics of the HIV-infected population changes in the United States or in countries in which transmission of HIV is by means other than homosexual relationships, the demographics of PML will undoubtedly mirror that of the HIV-infected population at large. Regardless of the cause of underlying immunosuppression, children rarely develop PML. As exposure to JCV occurs some time during childhood, a minority of young children are at risk for the disease. However, it has been observed in HIV-infected children (Berger et al., 1992b; Singer et al., 1993; Morriss et al., 1997). Curiously, there seems to be a higher degree of prevalence of PML in white males compared to African American males (Holman et al., 1998). Additionally, there may be some geographic differences in the prevalence of PML. For example, PML is considered rare in Africa and a neuropathologic study from Southern India suggests an incidence of 1% (Satishchandra et al., 2000). The population differences observed may be the consequence of the nature of medical care rendered as PML is typically observed in advanced HIV infection, and therefore, patients succumbing to other AIDS-related disorders early in the course of their infection may not live sufficiently long to develop PML. In 1996, there was an expansion of available antiretroviral therapies with the development of HAART. Opportunistic infections, e.g., cytomegalovirus (Verbraak

et al., 1999; Baril et al., 2000), toxoplasmosis (Maschke et al., 2000), and primary CNS lymphomas (Sparano et al., 1999) have been reported to have declined significantly following their introduction. D’Arminio Monforte and colleagues (2000) detected a 95% risk reduction in all CNS AIDS-related conditions following the adoption of HAART in their cohort. Twenty cases of PML were identified in this study, but a specific analysis for PML was not undertaken. Others (Maschke et al., 2000) have similarly noted a decline in HIV-related CNS disorders, but have had too few cases to comment specifically about PML. Data from the MACS suggest that the incidence of PML has declined in the HAART era (Sacktor, 2002). However, the survival of patients with PML on HAART has increased substantially (Albrecht et al., 1998; Miralles et al., 1998; Clifford et al., 1999; De Luca et al., 2000; Antinori et al., 2003) and the prevalence of the disease may actually be relatively unaffected. A nationwide Danish study of HIV-associated PML found that the incidence rates declined from 3.3 per 1000 person-years in 1995–1996 (pre-HAART era) to 1.8 per 1000 person-years in 1997–1999 (early HAART era) and, even more, to 1.3 per 1000 person-years in 2000–2006 (late HAART era), confirming the decline in incidence of PML following the introduction of effective combination antiretroviral therapy (Engsig et al., 2009). Similarly, a national multiple-cause-of-death database for the United States from 1979 to 2005 confirmed a decline in death rate from HIV-associated PML deaths from 1992 to 1995 when compared to 2002–2005 and attributed the decline to HAART (Christensen et al., 2010). A Swiss study found this overall decline in HIV-associated PML mortality was dependent on combined antiretroviral therapy and baseline CD4 T-lymphocyte counts (Khanna et al., 2009). Despite the observed decline in incidence, PML remains a significant CNS complication of HIV/AIDS. A study from Brazil found that PML was only exceeded in frequency by cerebral toxoplasmosis, cryptococcal meningoencephalitis, and CNS tuberculosis among other neurologic opportunistic infections (Vidal et al., 2008).

PML IN OTHER POPULATIONS PML incidence in diseases other than HIV was recently calculated from a review of a large US health insurer database for the time period January 2000 through June 2008 (Amend et al., 2010). The database included 138 469 patients with autoimmune disease, 25 706 patients with non-Hodgkin’s lymphoma or chronic lymphocytic leukemia, and 8778 transplant patients. In this population,

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY the incidence rate for PML per 100 000 patient-years was 2.4 for SLE, 10.8 for autoimmune vasculitis, 8.3 for nonHodgkin’s lymphoma, 11.1 for chronic lymphocytic leukemia, and 35.4 for bone marrow transplantation (Amend et al., 2010). No cases of PML in MS, rheumatoid arthritis, Sj€ ogren’s syndrome, and solid-organ transplantation were noted in this database (Amend et al., 2010). Another study employing the Nationwide Inpatient Sample database for the years 1998–2005 inclusively attempted to determine the incidence of PML among patients with rheumatologic diseases (Molloy and Calabrese, 2009). This study identified 9675 cases of PML, of which 80% were associated with HIV, 8.4% with hematologic malignancies, and 2.83% with solid cancers (Molloy and Calabrese, 2009). Forty-three cases (0.44%) were seen with SLE, 24 (0.25%) with rheumatoid arthritis, and 25 (0.26%) with other connective tissue disorders (Molloy and Calabrese, 2009). Rates of PML per 100 000 discharges were 4 for SLE, 0.4 for rheumatoid arthritis, and 2 for other connective tissue disorders, indicating that PML was more common with SLE than any other rheumatologic condition (Molloy and Calabrese, 2009). With respect to biologic agents, natalizumab has been associated with more PML cases than any other monoclonal antibody. Natalizumab is a combined a4b1 and a4b7 integrin inhibitor that has proven substantial therapeutic efficacy in MS and inflammatory bowel disorders. The a4b1 integrin inhibition prevents the entry of inflammatory cells into the CNS and it is this activity that is believed to be responsible for the increased risk of PML seen with this agent. As of December 2, 2010, 79 confirmed cases of natalizumab-associated PML have been recognized in the postmarketing phase (BiogenIdec, 2010). Unlike the seminal three reported cases in which one patient had Crohn disease (Van Assche et al., 2005), all have had MS. Although no cases have been unequivocally diagnosed before 12 months of natalizumab therapy, several individuals have manifested symptoms before that time (Clifford et al., 2010). The incidence estimates by treatment duration are 1.54 (confidence interval (CI) 1.22–1.92) for  12 monthly infusions, 1.76 (CI 1.38–2.22) for  18 monthly infusions, and 2.05 (CI 1.58–2.61) for  24 monthly infusions (BiogenIdec, 2010). The rates appear to plateau or decline thereafter, although the small sample size with more than 30 infusions renders this observation uncertain. The prior use of immunosuppressive therapy in this population, including mitoxantrone, methotrexate, and azathioprine, appears to quadruple the risk of subsequent development of PML, even for durations of therapy of as little as 4 months and with last use


up to 5 years before the institution of natalizumab (BiogenIdec, 2010). The incidence of PML with rituximab, an anti-CD20 monoclonal antibody that targets B lymphocytes, is used in the treatment of lymphoproliferative disorders and autoimmune diseases, including SLE, rheumatoid arthritis, and MS. Unlike natalizumab, estimating the risk of PML with rituximab is more difficult as PML has been linked to most of the illnesses for which it is used. From 1997 to 2008, 52 patients with lymphoproliferative disorders (generally B-cell malignancies), 2 with SLE, 1 with rheumatoid arthritis, and 1 with autoimmune pancytopenia have been reported with PML after rituximab therapy (Carson et al., 2009). All had been treated with other immunosuppressive regimens, including hematopoietic stem cell transplantation in 7 (Carson et al., 2009). Garcia-Suarez and colleagues (2005) have even argued that the use of rituximab after high-dose therapy and hematopoietic stem cell transplantation delays the onset of PML. However, it is likely that the number of cases of PML reported with rituximab is an underestimate of the true incidence. Efalizumab is an anti-CD11a IgG1 antibody with demonstrated efficacy in moderate to severe plaque psoriasis (Gordon et al., 2003; Leonardi, 2004). It targets psoriasis pathogenesis at multiple levels, importantly by inhibiting the initial T-cell activation in lymph nodes, preventing binding of T cells to endothelial cells, and blocking trafficking of T cells from the circulation into the psoriatic skin, preventing their reactivation in the dermal and epidermal layer (Lebwohl et al., 2003). More than 6000 patients had been treated with efalizumab before its removal from the European and US markets in the spring of 2009; of these, only 166 patients had received more than 3 years of therapy. Four patients, ranging in age from 47 to 73 years old, treated with efalizumab for more than 3 years for psoriasis have developed PML. PML was confirmed in three cases and suspected in one. As with MS and Crohn disease, PML had not previously been observed complicating psoriasis. Other monoclonal antibodies that have been connected with PML, albeit very rarely, include alemtuzumab (Martin et al., 2006; Gallamini et al., 2007), an anti-CD52 antibody that depletes both B and T cells and is used chiefly in treating hematologic malignancies and in preventing organ rejection, and belatacept (Grinyo et al., 2010), a fusion protein Fc fragment of IgG1 linked to CTLA4 which is crucial for T-cell costimulation used in renal transplantation. Alemtuzumab is also being studied for the treatment of MS (Fox, 2010), but no cases of PML have been reported in these study cohorts. A summary of risk stratification may be found in Table 17.1 (Zaheer and Berger, 2012).



Table 17.1 Classes of agents associated with progressive multifocal leukoencephalopathy (PML) Therapeutic agent

Underlying condition previously associated with PML?

Latency from initiation of Risk of developing PML? therapeutic agent to PML?

Class 1 Natalizumab

No MS, Crohn’s disease

Long >8 months, peaking at 24 months

High Depends on JC virus antibody status, duration of administration, and prior immunosuppressants. Ranges from 1:1000 in 1–24 months in JC virus-seropositive subjects and no prior immunosuppressants, to >1:100 after 24 months in JC virus-seropositive subjects with prior immunosuppressant use

Efalizumab Class 2

Psoriasis Yes



No latency. PML arises stochastically after beginning drug None

Lymphoproliferative disorders, rheumatoid arthritis, systemic lupus erythematosus, AIDS Solid-organ transplants, systemic None lupus erythematosus, and other autoimmune diseases Hodgkin’s disease None

Mycophenolate mofetil Brentuximab vedotin

1:30 000



Adapted from Zaheer and Berger (2012). AIDS, acquired immunodeficiency syndrome.

Table 17.2

CLINICAL DISEASE PML heralds AIDS in approximately 1% of all HIVinfected persons (Berger et al., 1998a). Therefore, the occasional patient is seen with neurologic features antedating knowledge of HIV infection. This may lead to significant diagnostic confusion in the otherwise healthy individual with unsuspected HIV infection. A high index of suspicion for underlying HIV infection is required when confronted with unusual neurologic illnesses. Diagnostic confusion is also to be anticipated when PML arises in patients with MS as many of the clinical and radiographic manifestations may overlap. The most common symptoms (Table 17.2) reported by patients with PML or their caregivers are weakness and disturbances (Berger et al., 1998a). Other common symptoms include cognitive abnormalities, headaches, gait disorders, visual impairment, and sensory loss. In a large series with more than 150 AIDS-related PML patients (Berger et al., 1998a), each of these symptoms was seen in more than 15% of patients. In general, these symptoms are similar to those identified in a series of non-HIVassociated PML cases. In comparison to the series of Brooks and Walker (1984), headaches were significantly more common in the HIV-infected population and visual

Signs and symptoms of AIDS-associated PML Symptoms


Weakness Cognitive impairment Speech abnormalities Headache Gait impairment Visual abnormalities Sensory loss

Hemiparesis Gait disturbance Cognitive impairment Dysarthria Dysphasia Hemisensory loss Visual field defect Ocular palsy

Reproduced from Berger et al. (1998b). AIDS, acquired immunodeficiency syndrome; PML, progressive multifocal leukoencephalopathy.

disturbances were more common in the non-HIVinfected. Seizures are seen in up to 10% of patients and are usually focal in nature, although secondary generalization may occur. Seizures in AIDS-associated PML may reflect involvement of the cortical astrocytes by the JCV (Sweeney et al., 1994) or may be secondary to some other process or HIV infection of the brain itself (Wong et al., 1990).

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY Limb weakness is the most common sign observed with HIV-associated PML (Table 17.2) (Berger et al., 1998a). It was observed in over 50% (Berger et al., 1998b). Cognitive disturbances and gait disorders are seen in approximately one-quarter to one-third of patients (Berger et al., 1998b). Diplopia, noted by 9% of patients, is usually the consequence of involvement of the third, fourth, or sixth cranial nerves and is typically observed in association with other brainstem findings (Berger et al., 1998b). Visual field loss due to involvement of the retrochiasmal visual pathways is significantly more common than diplopia or other visual disturbances (Brooks and Walker, 1984; Omerud et al., 1996; Berger et al., 1998a, b). Optic nerve disease does not occur with PML and, although the lesions of PML confirmed by JCV antigen presence were detected in the spinal cord of one of 138 HIV-infected patients dying with AIDS (Henin et al., 1992), clinical myelopathy secondary to PML must be vanishingly rare. PML does not involve the peripheral nervous system. Subtle differences in the clinical presentation may be noted in PML that has arisen as a consequence of different underlying disorders, as noted when the Brooks and Walker (1984) cohort, in which lymphoroliferative disorders constituted more than 60% of the patient pool, in comparison to the Berger et al. (1998b) cohort of HIVassociated PML. Natalizumab-associated PML also appears to differ. Natalizumab-associated PML most frequently presents with cognitive embarrassment (48%), motor abnormalities (37%), language disorders (31%), and visual disturbances (26%).

NEUROIMAGING In the appropriate clinical context, radiographic imaging may strongly support the diagnosis of PML. Computed tomography (CT) of the brain in PML reveals hypodense lesions of the affected white matter (Fig. 17.4). On CT scan, the lesions of PML exhibit no mass effect and infrequently contrast enhance. A “scalloped” appearance beneath the cortex is noted when there is involvement of the subcortical arcuate fibers (Whiteman et al., 1993). Cranial magnetic resonance imaging (MRI) is far more sensitive to the presence of the white-matter lesions of PML than CT scan (Whiteman et al., 1993). MRI shows a hyperintense lesion on T2-weighted images and fluid attenuated with inversion recovery (FLAIR) images in the affected regions (Fig. 17.5). On T1-weighted images, these lesions are hypointense. With CT scan, faint, typically peripheral, contrast enhancement may be observed in 5–10% of cases (Whiteman et al., 1993; Berger et al., 1998b). As many as 15% of HIV-associated PML patients may exhibit gadolinium enhancement on MRI (Berger et al., 1998b). However, gadolinium enhancement has


Fig. 17.4. Computed tomography scan showing hypointense lesions within the right hemisphere.

been observed in 30–40% of natalizumab-associated PML at the time of diagnosis (BiogenIdec, 2010). The lesions of PML may occur virtually anywhere in the brain and, although characteristically multifocal, they need not be. Indeed, natalizumab-associated PML is often monofocal, with frontal lobe lesions predominating (BiogenIdec, 2010). In every radiographic series of PML, the frontal lobes and parieto-occipital regions are the regions that appear to be most commonly affected, presumably as a consequence of their volume. However, isolated or associated involvement of the basal ganglia, external capsule, and posterior fossa structures (cerebellum and brainstem) may be seen as well (Whiteman et al., 1993). Other diseases may affect the white matter in a similar manner in association with HIV infection. Particularly notable in this regard are AIDS dementia and cytomegalovirus infection. With respect to AIDS dementia, radiographic distinctions include a greater propensity of PML lesions to involve the subcortical white matter, hypointensity on T1W1 images, and occasional contrast enhancement (Whiteman et al., 1993). Cytomegalovirus lesions are typically located in the periventricular white matter and centrum semiovale (Kalayjian et al., 1993; Miller et al., 1997). Subependymal enhancement is often observed as a consequence of CMV infection (Miller et al., 1997). Other potentially HIV-associated disorders that may result in



Fig. 17.5. (A) Magnetic resonance imaging (MRI) of progressive multifocal leukoencephalopathy. T2-weighted MRI showing extensive hyperintense signal affecting the white matter of the right hemisphere. (B) Fluid attenuated inversion recovery (FLAIR) MRI showing extensive hyperintense signal abnormality involving the left middle cerebellar peduncle and adjacent pons and cerebellum.

hyperintense signal abnormalities of the white matter resembling PML include varicella-zoster leukoencephalitis (Gray et al., 1994), an MS-like illness (Berger et al., 1992b), acute disseminated encephalomyelitis (Chetty et al., 1997; Bhigjee et al., 1999), CNS vasculitis (Scaravilli et al., 1989), varicella-zoster leukoencephalitis (Gray et al., 1994), a reversible leukoencephalopathy associated with nucleoside analog antiretrovirals (Church, 2002), and white-matter edema associated with primary or metastatic brain tumors. Almost always, the clinical features, laboratory findings, and associated radiographic features enable the correct diagnosis. Magnetization transfer MRI studies have been suggested as an effective means of monitoring the degree of demyelination in PML (Brochet and Dousset, 1999). Magnetic resonance spectroscopy reveals a decrease in N-acetylaspartate and creatine and increased choline products, myoinositol, and lactate in the lesions of PML (Chang et al., 1997). These changes likely reflect neuronal loss and cell membrane and myelin breakdown consequent to PML (Chang et al., 1997). Cerebral angiography is not routinely performed, but it exhibited arteriovenous shunting and a parenchymal blush in the absence of contrast enhancement on MRI in 4 of 6 patients in one study (Nelson et al., 1999). Pathologic studies suggested that small-vessel proliferation and perivascular inflammation were the explanation for these unexpected angiographic features (Nelson et al., 1999). Thallium-201 single photon emission computed tomography (Tl201 SPECT)

generally reveals no uptake in the lesions of PML (Iranzo et al., 1999); however, a single case report of a contrastenhancing lesion with a positive Tl201 SPECT has been reported (Port et al., 1999).

LABORATORY STUDIES In the overwhelming majority of HIV-infected patients with PML, severe cellular immunosuppression, as defined by CD4 lymphocyte counts 95%. Although amplification of the virus from the CSF in the absence of PML has been considered very unlikely, a low copy number of JCV may be detected in the CSF of MS patients without PML using these ultrasensitive techniques (Iacobaeus et al., 2009) and it is not unlikely that the same pertains to other disorders.

PATHOLOGY The cardinal feature of PML is demyelination, which is apparent both macroscopically and microscopically. Demyelination may, on rare occasions, be monofocal, but it typically occurs as a multifocal process, suggesting a hematologic spread of the virus. These lesions may occur in any location in the white matter and range in size from 1 mm to several centimeters (Astrom et al., 1958; Richardson, 1970); larger lesions are not infrequently the result of coalescence of multiple smaller lesions. The histopathologic hallmarks of PML are a triad (Astrom et al., 1958; Richardson, 1970) of multifocal demyelination (Fig. 17.3), hyperchromatic, enlarged oligodendroglial nuclei (Fig. 17.4), and enlarged bizarre astrocytes with lobulated hyperchromatic nuclei (Fig. 17.5). The latter may be seen to undergo mitosis and appear to be malignant. This has resulted in a mistaken diagnosis of glioma on occasion (Van Assche et al., 2005). Electron microscopic examination or immunohistochemistry will reveal the JCV in the oligodendroglial cells. These virions measure 28–45 nm in diameter and appear singly or in dense crystalline arrays (Astrom et al., 1958; Richardson, 1970). Less frequently, the virions are detected in reactive astrocytes, and they are uncommonly observed in macrophages that are engaged in removing the affected oligodendrocytes (Mazlo and Herndon, 1977; Mazlo and Tariska, 1982). The virions are generally not seen in the large, bizarre astrocytes (Mazlo and Tariska, 1982). In situ hybridization and in situ PCR for JCV antigen allow for detection of the virion in the infected cells even in formalin-fixed archival tissue (Samorei et al., 2000).


DIAGNOSIS The gold standard for diagnosing PML remains the demonstration of the characteristic histopathologic triad coupled with evidence of the virus either by electron microscopy or the appropriate immunocytochemical studies. Diagnosis is more often established when the following criteria are applied: (1) a compatible clinical picture; (2) a typical brain MRI; and (3) PCR detection of JCV in the CSF.

PML-IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME By definition, the immune reconstitution inflammatory syndrome (IRIS) is paradoxic worsening of symptoms and/or radiographic manifestations generally of an opportunistic infection that occur upon recovery of a suppressed immune system. It was first recognized with AIDS patients who had been started on antiretroviral therapy and experience both a decline in their HIV viral load as well as an improvement in their CD4 T-lymphocyte counts; however, it may be seen in conditions other than AIDS. PML-IRIS has been most commonly observed in HIV-associated disease and is characterized by new or increased neurologic deficits, an increased number or size of lesions observed by neuroimaging, contrast enhancement of these lesions, and brain edema (Cinque et al., 2001, 2003; Thurnher et al., 2001; Safdar et al., 2002; Du Pasquier and Koralnik, 2003; Hoffmann et al., 2003). Fatal outcomes have been reported (Safdar et al., 2002; Di Giambenedetto et al., 2004) and the development of this syndrome with infratentorial PML may be especially dangerous (Kastrup et al., 2005). PML-IRIS may occur in 18% of HIV-associated PML patients (Cinque et al., 2001). Among 54 patients with HIV-associated PMLIRIS, 36 developed PML and IRIS simultaneously and 18 had worsening of pre-existing PML after the initiation of combined antiretroviral therapy (Tan et al., 2009). PML-IRIS is also reported with natalizumab and may accompany the majority of these cases (BiogenIdec, 2010).

PROGNOSIS Prior to the HAART era, the median survival of PML complicating AIDS was 6 months and the mode was 1 month (Berger et al., 1998b). In the absence of effective antiretroviral therapy, the survival of AIDS patients with PML is not significantly different than PML occurring with any other immunosuppressive condition. However, even in the pre-HAART era, recovery of neurologic function, improvement of PML lesions in radiographic imaging, and survival exceeding 12 months had been

368 J.R. BERGER observed in as many as 10% of patients with AIDSMajor, 1998). The survival of PML in the era of HAART associated PML (Berger et al., 1998b). Factors that has changed quite considerably, however, with as many appear to be associated with prolonged survival include as 50% of patients demonstrating long-term survival PML as the presenting manifestation of AIDS (Berger (>12 months) (Albrecht et al., 1998; Miralles et al., et al., 1998a), higher CD4 lymphocyte counts (>300 1998; Clifford et al., 1999; Inui et al., 1999; cells/mm3) (Berger et al., 1998a), presence of a perivasTantisiriwat et al., 1999; De Luca et al., 2000; Antinori cular inflammatory infiltrate in the PML lesions et al., 2001). The benefit of HAART in AIDS-associated (Richardson, 1974), and contrast enhancement on radioPML has not been universally observed, however graphic imaging (Berger et al., 1998a; Arbusow et al., (De Luca et al., 1998), as the benefit seems to be chiefly 2000), although another study failed to link any radioconfined to treatment-naı¨ve patients (Wyen et al., 2004) logic features with prognosis (Post et al., 1999). Addior those individuals who have been non-compliant with tionally, a correlation between low titers of JC viral their antiretroviral therapy. The reversal of immunosupDNA load in the CSF and prolonged survival has been pression with HAART in HIV-associated PML has its demonstrated (Taoufik et al., 1998; De Luca et al., parallel with the discontinuation of natalizumab and 1999; Yiannoutsos et al., 1999). The longest survival the initiation of plasma exchange in natalizumabhas been 92 months from onset of illness (Berger associated PML. et al., 1998b). Nucleoside analogs have been employed because they The cellular immune response against JCV appears to impede the synthesis of DNA (Goodman et al., 1985). be tightly correlated with a favorable clinical outcome in In vitro studies (Hou and Major, 1998) have clearly demPML (Du Pasquier et al., 2001; Koralnik et al., 2001; onstrated the ability of cytosine arabinoside (cytarabine, Koralnik, 2002). The presence of JCV-specific cytotoxic ARA-C), a cytosine analog, to inhibit JCV replication T lymphocytes (CTL) in these patients is likely related to and anecdotal reports of intravenous and intrathecal the presence of inflammatory infiltrates in the PML administration suggested the value of this therapy in lesions which are responsible for the alterations of the PML (Bauer et al., 1973; Conomy et al., 1974; Van blood–brain barrier and marginal contrast enhancement Horn et al., 1978; Tashiro et al., 1987; O’Riordan et al., seen on imaging studies. These JCV-specific CTLs are 1990; Lidman et al., 1991). However, a carefully conprobably instrumental in destroying infected oligodenducted clinical trial of AIDS-related PML failed to show drocytes, preventing further disease progression, and any value of either intravenous or intrathecal administradecreasing CSF JC viral load. The lack of recurrence tion of ARA-C when compared to placebo (Hall et al., of PML in some of the patients exhibiting long-term sur1998). Theoretically, neither method of administration vival and recovery reflects clearance of the JCV from the permitted adequate concentrations of the drug to reach CSF (De Luca et al., 2000). the disease sites, and trials with novel intraparenchymal Survival with natalizumab-associated PML is signifidelivery systems have been suggested. Alternatively, cantly better. The mortality of this disorder is 20% and higher doses of ARA-C than those employed in the ranmost deaths have occurred with PML-IRIS domized study may prove beneficial. Despite anecdotal (BiogenIdec, 2010; Clifford et al., 2010). The earlier that reports of the value of other nucleoside analogs in PML, PML is diagnosed, natalizumab discontinued, and such as, adenine arabinoside (vidarabine, ARA-A) plasma exchange initiated, the better the prognosis. (Wolinsky et al., 1976; Rand et al., 1977; Tashiro et al., Among this group, approximately one-third of survivors 1987), none has been convincingly demonstrated to amehave a mild neurologic deficit, one-third a moderate defliorate the disease course. icit, and one-third a severe neurologic deficit at 6 months Interferons have also had occasional positive results, (BiogenIdec, 2010; Clifford et al., 2010). both subcutaneously (Steiger et al., 1993) and intrathecally (Tashiro et al., 1987), when used in conjunction with ARA-C. The antiretroviral activity of the interferons TREATMENT may be the consequence of their ability to stimulate natTo date there are no unequivocally successful therapeuural killer cells. In a pilot study of 17 patients with AIDS tic modalities for PML. Most of the extant literature and PML treated with alpha 2a interferon and zidovuconsists of anecdotal reports. In the pre-HAART era, dine, two had long-term clinical stabilization, though zidovudine (AZT) and other antiretrovirals had been pronone improved (Berger et al., 1992a). A retrospective posed as adjunctive therapy for AIDS-associated PML. study, comparing patients with AIDS-associated PML Anecdotal responses to antiretroviral therapy (Conway receiving a minimum treatment of 3 weeks of 3 million et al., 1990) led to the suggestion to administer zidovuunits of alpha-IFN daily to untreated historic condine. However, in vitro assays failed to demonstrate trols, suggested that alpha-IFN treatment delayed the an effect of zidovudine on JCV replication (Hou and progression of the disease, palliated symptoms, and

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY significantly prolonged survival (Huang et al., 1998). However, re-examination of that data indicated that the improved survival could be explained by the concomitant administration of HAART (Geschwind et al., 2001). The antineoplastic drug camptothecin, a DNA topoisomerase I inhibitor, has been demonstrated to block JCV replication in vitro when administered in pulsed doses in amounts non-toxic to cells (Kerr et al., 1993). Its therapeutic usefulness in PML has been entirely anecdotal (O’Reilly, 1997; Vollmer-Haase et al., 1997). Another antineoplastic drug, topotecan, may also inhibit JCV replication (Kerr et al., 1993). However, both these drugs display significant systemic toxicity and their value in the treatment of PML remains open to question. Cidofovir (HPMPC: (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine) and its cyclic counterpart have demonstrated selective antipolyomavirus activity (Andrei et al., 1997). The 50% inhibitory concentrations for HPMPC were in the range of 4–7 mg/mL, and its selectivity index varied from 11 to 20 for mouse polyomavirus and from 23 to 33 for SV40 strains in confluent cell monolayers (Andrei et al., 1997). It has been proposed as an agent for the treatment of PML (Sadler et al., 1998) and there is anecdotal evidence to support its use (Blick et al., 1998; Brambilla et al., 1999; De Luca et al., 1999; Dodge, 1999; Meylan et al., 1999). However, a well-designed AIDS clinical trials group study addressing the value of cidofovir in the same fashion as it had ARA-C failed to show any benefit (Marra et al., 2002). Furthermore, the drug has serious sideeffects, including ocular hypotony, bone marrow depression, and renal disorders. Increased understanding of the molecular biology of JCV and new technologies will likely result in novel strategies. The observation that JCV binding is dependent on the serotonin receptor, 5HT2a, has led to the use of serotonin receptor antagonists, such as risperidone, zipradsidone, and mirtazapine, as a potential therapeutic modality (Kast et al., 2007; Verma et al., 2007). The experience has been entirely anecdotal and not likely to be very effective. Systematic screening of 2000 approved drugs and biologically active molecules for anti-JCV activity demonstrated that mefloquine, an anitmalarial agent, inhibits JC viral replication (Brickelmaier et al., 2009). The success of this strategy is limited to anecdote (Gofton et al., 2011; Kishida and Tanaka, 2010; Schroder et al., 2010) and it has certainly not proven to be universally effective. One possibility is the use of antisense oligonucleotides. An antisense oligonucleotide that is properly designed with a specific complementary base sequence that binds selectively to a targeted region of mRNA can prevent the translation of the mRNA into protein.


Antisense oligonucleotide directed to JCV T antigen may reduce viral expression by 80% (K. Khalili, personal communication). Antisense oligonucleotides that target other sites of the viral genome, such as transcription sites, may prove to be effective therapeutic strategies. As a strong JCV-specific cellular immunity has been associated with a favorable clinical outcome of PML (Du Pasquier et al., 2001; Koralnik et al., 2001; Koralnik, 2002), the enrichment of an autologous population of JCV-specific CTL populations using tetrameric major histocompatibility complex class I–JCV peptide complexes may be demonstrated to be a therapeutic option. Koralnik (2002) demonstrated the ability to boost immunity to JCV with a vaccine based on a newly discovered JCV-specific CTL epitope. Conceivably, this approach, too, may have some therapeutic merit. Treatment of PML-IRIS should include high-dose steroids. In the study cited above of HIV-associated PML-IRIS, 12 patients were treated with steroids, of whom 5 died and 7 survived with good neurologic recovery (Tan et al., 2009). While not reaching statistical significance, the investigators argue that steroids have a salutary effect on PML-IRIS. Survival also appeared to be better in natalizumab-associated PML-IRIS patients treated with steroids. While the consensus of expert opinion favors the use of steroids for PML-IRIS, they are not without potential risk (Berger, 2009).

RISK MITIGATION STRATEGIES With the observation that certain monoclonal antibody therapy may predispose to PML, attempts to identify methods to mitigate the risk of developing PML have assumed increasing importance. As PML appears to be almost always a reactivation of latent infection, identifying those individuals that have never been infected with the virus would distinguish a subset of individuals with little or no risk of developing the disease. Towards those ends, Gorelik and colleagues (2010) have developed an enzyme-linked immunosorbent assay to detect JCVspecific antibodies that appears to be 95% sensitive. In theory, JCV antibody-seronegative individuals could be treated with biologic or other agents that increase the risk for PML with impunity. Alternative strategies, such as monitoring blood or urine for JCV expression, discontinuing an offending biologic agent for limited time periods, use of the Cylex immune cell function assay (Helantera and Koskinen, 2010), or co-administration of serotonin receptor antagonists, are not likely to be very effective. Early diagnosis may be facilitated by frequent periodic cranial MRIs and may improve prognosis; however, this approach remains unproven.



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