Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system (CNS). Although originally associated with broad-based immunosuppression (human immunodeficiency virus infection, lymphoproliferative disorders, and immunosuppressive medications), recognition of PML in patients with selective immunosuppression is growing. This restricted immunodeviation can arise from autoimmune disorders such as systemic lupus erythematosus, selective immunosuppressive therapies (eg, rituximab, leflunomide, and efalizumab), or immunosuppression limited to the CNS (eg, treatment with natalizumab).
This article reviews approaches to the management of PML, with specific recommendations regarding PML associated with natalizumab therapy.
APPROACH TO PML TREATMENT
The ideal approach to PML treatment is generally two-pronged: antiviral therapies to directly reduce viral replication and immune reconstitution that empowers the immune system to attack the JC virus (JCV). Challenges to treatment are the difficulty in culturing JCV for in vitro studies, lack of an animal model of PML, and infrequency of PML cases.
At present, no antiviral agent has confirmed efficacy in PML. Nucleoside analogues, serotonin 5-hydroxytryptamine receptor antagonists (to block the JCV receptor), and several cytokines provided exciting prospects in preclinical studies for treatment of PML in humans. Unfortunately, subsequent clinical studies of cytarabine, cidofovir, and interferon alfa all yielded disappointing results. A derivative of cidofovir, CMX001, is also being evaluated for efficacy in PML. Mefloquine was identified through a broad pharmaceutical screening study to have strong antiviral effects in vitro, but a clinical trial to assess its effects was stopped. It remains unclear whether the failure of clinical studies after successful in vitro studies is secondary to low drug penetration into the CNS, treatment initiation too late in the course of PML, or other differences not yet fully understood.
Given the widespread failure of antiviral regimens, the mainstay of PML treatment is immune reconstitution. When immunosuppression is secondary to a medical disorder, efforts are pursued to reverse the primary disorder. For example, highly active antiretroviral therapy significantly prolongs survival in antiretroviral-naïve acquired immunodeficiency syndrome patients.1,2 Decreasing the intensity of immunosuppressive therapy in solid organ transplant may improve survival with PML. When PML is associated with biologic therapies for autoimmune diseases, early diagnosis and immediate suspension of therapy is thought to improve outcomes.
EXPERIENCE WITH NATALIZUMAB
PML in the setting of natalizumab therapy is related to cumulative exposure to natalizumab. As of August 4, 2011, there had been 150 cases of natalizumab-related PML documented in more than 88,000 patients exposed to natalizumab worldwide3 (see page S18, “Multiple sclerosis, natalizumab, and PML: Helping patients decide”). The incidence of PML in natalizumab-treated patients varies according to the number of infusions received, but the incidence of PML by each epoch of treatment exposure (1 to 24 infusions, 25 to 36 infusions, 37 to 48 infusions) appears to have remained stable over time.3
The mortality associated with natalizumab-related PML was 19% (29 deaths among the 150 confirmed cases) as of August 4, 2011.3 In cases with at least 6 months of follow-up, mortality has remained at about 20%. Many who survived were left with serious morbidity and permanent disability, although interpretation of disability is difficult because functional impairment is a hallmark of multiple sclerosis (MS) irrespective of PML. Survival in patients with natalizumab-associated PML appears to be better than with PML associated with other conditions, possibly because of early diagnosis achieved through clinical vigilance and swift immune reconstitution through natalizumab discontinuation and either plasmapheresis or immunoabsorption. Predictors of survival include younger age at diagnosis, less disability prior to onset of PML, more localized disease on magnetic resonance imaging (MRI) of the brain, and shorter time from symptom onset to PML diagnosis.
Clinical characteristics of natalizumab-associated PML
Several clinical observations should increase suspicion of natalizumab-associated PML.3–5 For example, the most common presenting symptoms are cognitive, motor, language, and visual impairment. Gadolinium-enhancing lesions are observed at presentation in about one-half of patients. Seizures and paroxysmal events can occur at presentation, which helps to differentiate PML from an MS relapse.
Approximately one-half of patients with natalizumab-associated PML have an initial viral load of less than 500 copies/mL, underscoring the need for ultrasensitive polymerase chain reaction (PCR) testing. An ultrasensitive JCV assay (Focus Diagnostics, Cypress, California) is available that can detect less than 50 copies/mL of JCV DNA. Because the viral copy numbers in the cerebrospinal fluid (CSF) may be low in patients treated with natalizumab, the CSF PCR may be falsely negative. In several cases of PML, JCV was undetectable in the CSF by PCR, identified only later by repeat PCR or brain biopsy.4 Serum JCV PCR is not useful in the screening or diagnosis of PML.
Natalizumab-associated PML has not been observed with therapy of 6 months’ or less duration. After 6 months of natalizumab therapy, new MRI lesions are rare in patients who are negative for neutralizing antibodies. A new MRI lesion in such a patient should be considered suspicious for PML. Our standard protocol is to check for neutralizing antibodies at 6 months in all patients treated with natalizumab. Symptoms of PML develop in affected patients whose duration of therapy ranges from 6 to 81 infusions. Symptoms often develop well before PML is diagnosed.4,5
Forty-six percent of patients treated with natalizumab who develop PML have received previous autologous bone marrow transplantation or chemo therapy, including mitoxantrone, azathioprine, methotrexate, and mycophenolate mofetil. In comparison, up to 25% of MS patients who were treated with natalizumab (13% in the United States, 24% in Europe) have had prior chemotherapy treatment. Prior immunosuppressive therapy increases the risk of PML by two- to fourfold, which may explain the higher rate of PML in Europe compared with that of the United States.4,5
Testing for immune response to JCV
A JCV enzyme-linked immunosorbent assay (ELISA) test has been developed that identifies patients with an immune response to JCV. Among MS patients, 55% test positive for JCV through this assay.6 The false-negative rate of the test is 5%, and the overall annual seroconversion rate is estimated to be about 2%, necessitating repeat testing.
Based on results of this assay, the estimated risk of PML in seropositive patients is about 1 in 500.6 The test was positive in 28 of 28 patients who developed PML. The probability of this relationship occurring by chance is 0.5528, which suggests that this assay is useful to stratify risk for development of PML. Although the rate of false negatives makes the test an imperfect predictor, it is still useful in clinical practice. The test became available clinically in late summer 2011. Further longitudinal observation studies (STRATIFY-1 and STRATIFY-2) on the use of the JCV ELISA to detect anti-JCV antibodies in the blood of natalizumab-treated patients with MS are under way.