Curr Neurol Neurosci Rep (2013) 13:408 DOI 10.1007/s11910-013-0408-6

DEMYELINATING DISORDERS (DN BOURDETTE AND V YADAV, SECTION EDITORS)

Progressive Multifocal Leukoencephalopathy in Multiple Sclerosis Joshua J. Chalkley & Joseph R. Berger

Published online: 18 October 2013 # Springer Science+Business Media New York 2013

Abstract AIDS generated a significantly increased interest in the pathogenesis, clinical manifestations, and treatment of progressive multifocal leukoencephalopathy (PML), a disease previously considered to be very rare. Scrutiny increased after a second wave of PML following the introduction of biological agents, in particular, natalizumab and efalizumab. While efalizumab, a lymphocyte function-associated antigen 1 inhibitor marketed for use in psoriasis, has been removed from the market, natalizumab, an α4β1 and α4β7 integrin inhibitor, remains widely used in the treatment of multiple sclerosis (MS). Approximately 400 cases of natalizumab-associated PML have been reported from 2005 to August 2013. Additionally, other therapies currently employed or under development for the treatment of MS may also be associated with PML, such as mycophenolate mofetil, rituximab, and alemtuzumab. Therefore, practitioners using these medications need to understand the risks associated with these agents, ways to mitigate the risk, and treatment of PML and the related condition PML immune reconstitution inflammatory syndrome. PML associated with the use of therapeutic agents, especially, natalizumab, does share similarities with HIV-related PML; however, distinct differences exist. Radiographically isolated PML is seen more commonly with natalizumab-associated PML and the disease appears to be heralded more often by cognitive and behavior disturbances. Furthermore, the mortality of natalizumab-associated PML is substantially lower. Risk mitigation strategies have been developed for the natalizumab-associated PML, which has been convincingly demonstrated to be linked to duration of therapy, JC This Article is part of the Topical Collection on Demyelinating Disorders J. J. Chalkley : J. R. Berger (*) Department of Neurology, University of Kentucky College of Medicine, 740 S. Limestone St., Room L-445, Lexington, KY 40536-0284, USA e-mail: [email protected] J. R. Berger e-mail: [email protected] J. J. Chalkley e-mail: [email protected]

virus seropositivity, and the prior use of immunosuppressive agents. Keywords Multiple sclerosis . Progressive multifocal leukoencephalopathy . JC virus . Natalizumab . Rituximab . Alemtuzumab . Mycophenolate mofetil

Introduction Progressive multifocal leukoencephalopathy (PML) was first described by Aström, Mancall, and Richardson in 1958. The syndrome was characterized by a triad of histopathological features, including demyelination, abnormal oligodendroglial nuclei, and giant astrocytes [1]. Each of the three patients in the seminal publication had underlying B cell lymphoproliferative disorder—either Hodgkin’s disease or chronic lymphocytic leukemia. Through 1981, the inception of the AIDS pandemic, PML remained a disease primarily seen in patients with lymphoproliferative disease, particularly B cell disorders [2–5]. By 1984, only five cases of AIDS-related PML had been reported. However, with rates of PML in HIV-infected persons approaching 5 % [6, 7], the percentage of PML patients with HIV/ AIDS overwhelmed other underlying predisposing causes. The landscape of PML began to change again in the middle part of the last decade with the recognition that natalizumab predisposed to PML. Natalizumab is a monoclonal antibody targeting integrin α4β1 and α4β7 integrin; the former significantly decreases T cell migration into the central nervous system (CNS) and the latter decreases inflammatory cell infiltration of the gut. Natalizumab is highly effective in treating multiple sclerosis (MS). In 2005, three patients were reported to have developed PML while on natalizumab [8–10]. The initial speculation that the combination of natalizumab and interferon (IFN)-β predisposed to the disease was dispelled when additional cases were observed in the absence of IFN therapy. Interest in PML further intensified as it was found in association with other biological agents [11], including efalizumab, an anti-CD11b

408, Page 2 of 7

[12], belatacept [13], brentuximab-vedotin [14, 15], and other therapies, such as mycophenolate mofetil [16]. Given the recent explosion of treatment options for MS targeting the immune system, opportunistic infections, in general, and PML, in particular, have garnered increased attention.

Viral Etiology A year after PML was first described by Aström and colleagues, a viral etiology was proposed by Cavanaugh and Greenbaum [17] on the bases of inclusion body morphology. A more detailed analysis using electron microscopy suggested a papovavirus, a family of double-stranded DNA viruses that are non-enveloped and icosahedral, as the most likely causative agent [18, 19]. Six years later, a viral etiology was confirmed when a novel polyoma virus, JC virus, was isolated from the brain of a patient with PML [20]. JC virus is a non-enveloped, double-stranded DNA virus in the Polyomaviridae virus family. JCV has a DNA genome of 5.1 kilobases in supercoiled form that is encapsulated in an icosahedral protein structure measuring only 40 nm in diameter [21]. JC virus appears to bind to the cell surface by sialic acid receptors that are linked to the serotonin receptor 5HT2a [22]. JC virus causes no identifiable clinical illness at the time of infection; therefore, the exact manner of disease spread remains a mystery. Serological studies indicate that more than 50 % of the adult population has been infected by JC virus. The first serological studies employed the ability of the virus to hemagglutinate type O erythrocytes [23]. Since then, immunoassay techniques have confirmed the ubiquity of the virus in human populations [24]. Exposure for most people appears to be in childhood, as Walker and Padgett demonstrated that more than 50 % of the populations were seropositive by the age of 20 years [20]. In some urban populations, seroconversion rates exceed 90 % [20]. More recent studies show seroprevalence rates in developed countries ranging from 48 % [25] to 91 % [26]. The exact mechanism of viral infection is unknown. Respiratory or oropharyngeal transmission is supported by the presence of JC virus in tonsillar tissues [27]. However, the virus is very rarely present in saliva or oropharyngeal secretions [28]. JC virus is detected in 98 % of sewage in Europe, Africa, and North America, and was found to be stable at 20 °C for more than 70 days [29], and is present in up to 70 % of adult urine in some populations [30], suggesting that this exposure may be the likely source of infection perhaps via an oral route [31].

Pathogenesis PML is a rare disease and the exact pathogenesis is still unknown. There is no animal model to date and data must be gleaned from a limited number of human subjects. Given the prevalence of JC virus infection in the population, the barriers for

Curr Neurol Neurosci Rep (2013) 13:408

the development of PML must be robust. Three factors—the host, the virus, and the immune response—are likely responsible for the low expression of clinical disease. There is strong evidence PML results from the reactivation of a latent infection rather than the result of initial infection. First, IgG against structural proteins is almost always observed in patient with PML [32]. One study found only 1 of 21 patients with IgM specific for JCV in their sera, the remainder had only IgG antibody [20]. Second, PML is almost never seen in the pediatric population, although it has been reported [33]. Third, in one patient, plasma and peripheral blood mononuclear cells collected 8 months before PML onset showed matches in the non-coding control region [34]. Fourth, in six individuals with PML with lymphoid tissue, spleen or bone marrow samples obtained 0.5–4.1 years before PML the JCV isolated from these sites had the same NCCR non-coding control region genetic profile isolated from the brain [35, 36]. Lastly, virtually all patients with natalizumabassociated PML had detectable JC virus antibody in serum 6– 187 months before the diagnosis of PML [36]. The current working explanation for the pathogenesis of PML expression is believed to depend on a number of steps: 1) infection with JC virus; 2) the establishment of latent and or persistent JC virus infection; 3) rearrangement of JC virus into a neurotropic strain if the initial infection has been with the archetype strain; 4) re-activation of the neurotropic JC virus strain from sites of viral persistent/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. (For discussion refer to Berger and Khalili [37].) After initial infection, the virus may become latent or result in a persistent infection of renal tissues. Controversy surrounds what tissues other than uroepithelial tissue are infected; proposed sites include spleen, lung, tonsils, bone marrow, and kidneys [27]. Following the recognition that B cells could be productively infected by JC virus [38], it has been proposed that they are critical to the pathogenesis of PML; however, the precise pathogenesis remains uncertain and the role of infected B cells remains hypothetical at the current time. Nonetheless, it provides a coherent and plausible site for viral replication and viral genome rearrangement from an archetype to prototype (neurotropic) and for viral entry into the CNS [37]. The “B cell” hypothesis is supported by the close correlation of PML with disorders of B cells (lymphoproliferative disorders) or their activation (AIDS, connective tissue disorders, granulomatous disorders, etc.). Natalizumab is associated with hematopoietic stem cell mobilization causing a release of immature cells of B lineage [39, 40]. The mechanism of action of efalizumab is similar. In theory, the maturation of the infected premature B cells leads to increased viral transcription in the perfect cellular milieu for gene rearrangement. Natalizumab abrogates the T cell response to JC virus [41]. Furthermore, its very mechanism of action prevents CNS immunosurveillance

Curr Neurol Neurosci Rep (2013) 13:408

by JCV-specific T cells. Despite the elegance of this theory of PML pathogenesis, it remains to be proven and the absence of an animal model for the disease has, undoubtedly, hampered progress. The role of rituximab, related anti-CD20 monoclonal antibodies and other drugs used or under development for multiple sclerosis in the pathogenesis of PML remains unsettled. These drugs almost certainly do not carry the same risk for PML seen with natalizumab and, to date, none has been associated with PML in MS patients; in fact, virtually all patients reported with PML who had been treated with these agents also had a preexisting disorder that predisposes to PML [42•].

PML in MS Multiple biological agents have been associated with the subsequent development of PML, but natalizumab stands apart for the frequency of the association between its use and PML. Indeed, natalizumab has been associated with more PML cases than any other biological agent; in some populations (JC virus seropositive, history of prior treatment with immunosuppressives, and duration of natalizumab treatment exceeding 24 months), the rate equals or exceeds that seen in HIVinfected persons [43]. As of 2 July 2013, there have been 377 natalizumab-associated PML cases, with 88 fatalities from among 115,315 people who have received this monoclonal antibody [36]. Natalizumab-associated PML has a mortality rate of 23 %, a rate significantly lower than HIV-associated PML. However, patients are often left with severe residual deficits [36]. The risk for developing natalizumab-associated PML correlates with three identified risk factors, namely JC virus seropositivity, prior immunosuppressive therapy, and longer duration of treatment (> 24 months, in particular). One patient with Crohn’s disease developed PML after 8 months of therapy [10], but all natalizumab-associated PML patients have been treated for 12 or more months. It is uncertain when the risk of PML peaks, but when analyzed by treatment epoch it currently appears to be highest after 36 months [36]. With respect to prior immunosuppressive exposure, all seemed to significantly increase the risk of subsequent PML regardless of duration of exposure. Exposure to either glatiramer or IFN-β does not increase the risk of PML. Importantly, JC virus seropositivity confers an increased risk for developing PML. To date, there appear to be no JC virus seronegative individuals who have developed PML within 6 months of testing. The antibody test widely employed is an enzyme-linked immunosorbent assay [24]. A more sensitive test has recently been developed [44]. However, a seronegative status should not be conflated with absence of JC virus infection, as false-negative tests are observed [45, 46]. Although natalizumab-associated PML is more common than in other biological agents the mortality is less than with

Page 3 of 7, 408

AIDS-related PML with most of the deaths occurring with PML immune reconstitution inflammatory syndrome (IRIS) [47•]. The overall mortality in natalizumab-associated PML is 23 % [36]. The sooner PML is recognized and the offending agent stopped, and plasma exchange initiated the better the outcome. The majority of survivors of natalizumab-associated PML are left with a moderate-to-severe disability [36]. The risk for PML with rituximab, an anti-CD20 monoclonal antibody that targets B lymphocytes is more difficult to estimate, but is orders of magnitude lower than the risk with natalizumab. From 1997 to 2008, 52 patients with lymphoproliferative disorders, two with systemic lupus erythematosus, one rheumatoid arthritis, and one with autoimmune pancytopenia developed PML in association with rituximab [48]. All of these patients had received other immunosuppressive therapy and seven underwent hematopoietic stem cell transplantation [49••]. The increased scrutiny of this monoclonal antibody and related agents under development for MS, such as ocrelizumab and

Table 1 Magnetic resonance imaging distinguishing progressive multifocal leukoencephalopathy (PML) from multiple sclerosis (MS) Characteristics

PML

MS

Appearance

Ill-defined, white matter lesions often large (>3 cm), multifocal, sharp borders toward gray matter and ill-defined toward the white matter; often surrounded by smaller T2 punctate lesions Subcortical white matter, parietal, occipital, frontal lobes, can follow white matter tracks cross the corpus callosum, internal capsule, rarely brainstem or cerebellar, no spinal cord involvement Hyperintense, more sensitive for detection of PML lesions in subcortical structures Isointense with progressive hypointensity Hyperintense

Smaller well defined

Location

Flair

T1 T2 Mass effect

Mass effect not typical; PML-immune reconstitution inflammatory syndrome may exhibit edema Contrast 40–50 % of natalizumabenhancement associated PML enhance; pattern may be patchy, punctate, or rim-like (Adapted from [50])

Periventricular to lateral ventricles, Dawson’s fingers, deep white matter, cerebellum, spinal cord

Hyperintense equal to T2

Isotense or mild hypointense Hyperintense, may resolve over months Larger lesions may show slight mass effect

Acute lesions will enhance; C-shaped enhancement or nodular

408, Page 4 of 7

ofatumumab, both anti-CD20 monoclonal antibodies, will provide a more complete assessment of the risk for PML with them. To date, no MS patient has been reported to have developed PML with any CD20 depleting agent.

Diagnosis The 2013 consensus statement [49••] for clinical diagnosis of PML proposed two primary approaches. A clinical presentation and radiological features consistent with the PML and JC virus in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) is sufficient to establish the diagnosis of definite PML. If the clinical presentation is more obscure or if the CSF is negative for JC virus then brain biopsy demonstrating the classic pathological features coupled with identification of the virus confirms the diagnosis [44]. PML can present with a wide variety of neurological symptoms predicated on the area of the brain affected. In contradistinction to PML occurring with other predisposing conditions, natalizumab-associated PML most commonly presented with behavioral and cognitive abnormalities. Hemiparesis, gait disorder, visual field loss, and hemisensory loss, as well as other clinical features, may be either the presenting manifestation or develop during the course of the disease. About 5 % of patients with natalizumab-associated PML are detected during routine screening magnetic resonance imaging (MRI) (“radiographically isolated PML”) and have no clinical manifestations. PML has classic imaging findings, which can aid in the diagnosis. CT typically reveals multiple white matter hypodensities; however, MRI is the imaging modality of choice (Table 1). PML lesions appear hypointense on T1 weighted image (T1WI) and hyperintense on fluid attenuated inversion recovery and T2 weighted imaging. Any region of the brain may be affected in PML, but there is a predilection for the frontal and parieto-occipital

Fig. 1 Magnetic resonance image of progressive multifocal leukoencephalopathy. (A) Fluid attenuated inversion recovery image shows a large hyperintense lesion in left frontal lobe and a smaller lesion in the

Curr Neurol Neurosci Rep (2013) 13:408

regions given their high white matter densities (Fig. 1). However, in natalizumab-associated PML, there does seem to be a predilection for the frontal lobes [36]. Lesions are chiefly subcortical, affecting the U-fibers, are >3 cm in size, have sharp borders towards the gray matter and ill-defined borders toward the white matter, and may be hyperintense on diffusion weighted imaging [50]. Unlike HIV-associated PML in which gadolinium enhancement is seen in

Progressive multifocal leukoencephalopathy in multiple sclerosis.

AIDS generated a significantly increased interest in the pathogenesis, clinical manifestations, and treatment of progressive multifocal leukoencephalo...
262KB Sizes 0 Downloads 0 Views