Progressive Multifocal Leukoencephalopathy
Section snippets
Epidemiology
Before the AIDS pandemic the incidence of PML was at 0.15 cases per million. With AIDS, the incidence rose to 0.6 cases per million [25]. By far the most common immunosuppressive drugs related to the development of PML are corticosteroids, which appear to account for about 40% while chemotherapy accounts or about 16%; in almost half of all patients no causative drug can be identified [9]. Second to AIDS, lympho- and myeloproliferative disorders, solid tumors, and congenital immunodeficiency
Clinical signs and symptoms
Clinical symptoms and signs of PML are nonspecific. In about 25% of cases, PML is the initial AIDS-defining illness [19]. Due to the small number of series and the retrospective character of all studies published to date, a broad range of symptoms and signs has been variously described as initial or presenting manifestation of PML (Table 2, Table 3) [19], [22], [23], [54], [55], [56], [57], [58]. The most common presenting symptom is limb weakness in 52% of cases. In approximately 45%,
Diagnosis
Until recently, PML had never been described in the course of or as differential diagnosis to multiple sclerosis (MS), but the unexpected development of PML in two patients treated for MS has led to the need to establish criteria and means of detecting PML in MS patients treated with natalizumab, a monoclonal antibody to VLA-4, an a4/b1 integrin [12], [13], [49]. Seizures, speech disorders or frank aphasia are rare new symptoms in MS patients with a frequency of 2.3% to 4% and about 0.8%,
Biology
JCV is a double-stranded circular DNA virus and a member of the polyomaviridae. A virus particle has a diameter of about 45 nm and forms an icosaheder. The viral capsid contains three proteins designated as virus particle (VP) VP1, VP2, and VP3. VP1 accounts for about 75% of the capsid protein, the remaining two proteins are designated as VP2 and VP3. VP1 forms virus-like particles (VLPs) independently of VP2 and VP3 [81], [82]. VP1 is an efficient transporter or drug delivery system and may be
Pathogenesis
The pathogenesis of PML may be divided into three phases. The first phase is that of primary, inapparent infection. Possible routes of infection are by respiratory and/or fecal-oral route [122]. The second phase is latency in the human host. The long-known urinary excretion of JCV points to the kidney as one place of latency [123], [124], [125]. The genomic structure of the form of JCV most frequently found in the kidney has been designated as archetype [124]. Other likely places of viral
Humoral immunity
Infection with JCV induces a humoral IgG response, predominantly directed toward the major capsid protein VP1 [75], [112], [127]. It appears that there is also an IgM response toward JCV. Its role is still unknown and could either be an indication of active JCV antigenic stimulation in healthy adults or be the result of nonspecific serologic crossreactivity [128]. All patients with PML investigated so far had detectable serum IgG antibodies [75], [129], [130]. Antibodies are not protective in
Cellular immunology
Richardson [131] speculated in 1961 on an altered or suppressed immunity as cause of PML. Substantiation of his idea came from case reports showing anergy to delayed type hypersensitivity reactions to antigens such as tetanus toxoid and 2,4-dinitrofluorobenzene in PML patients [132], [133]. In 1980, Willoughby and colleagues [134] could demonstrate a reduced proliferation of lymphocytes in the presence of mitogens such as phytohemagglutinin or concanavalin A in 7 PML patients. Further, clinical
Therapy
The first drug initially thought to be effective but later proven in a well-designed clinical trial to lack any efficiency in PML was cytarabine or ARA-C [32], [142]. Clinical benefit in patients with genital warts treated with either interferon alpha, beta, or gamma initiated a pilot study with alpha 2a interferon in 13 PML patients without any relevant benefit [143], [144]. These findings were disputed by some case reports and one retrospective analysis but weighted evidence points to the
Prognosis
A CD4 count of 100/mm3 or higher, a low JC viral load in CSF of 100 copies/μL or less, and the presence of JCV-specific cytotoxic T cells in HLA-A2+ HIV-1–positive patients have all been shown to be associated with a prolonged survival [71], [139], [164], [165], [166]. Up to 10% of patients with PML and newly treated with HAART for HIV develop an immune restitution inflammatory syndrome (IRIS) [17], [167], [168]. It is characterized by rapid clinical deterioriation in conjunction with a massive
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