Progressive multifocal leukoencephalopathy (PML) is characterized pathologically by multifocal areas of demyelination of varying size distributed throughout the brain but sparing the spinal cord and optic nerves. In addition to demyelination, there are characteristic cytologic alterations in both astrocytes and oligodendrocytes. Astrocytes are enlarged and contain hyperchromatic, deformed, and bizarre nuclei and frequent mitotic figures. Oligodendrocytes have enlarged, densely staining nuclei that contain viral inclusions formed by crystalline arrays of JC virus (JCV) particles. Patients often present with visual deficits (45%), typically a homonymous hemianopia; mental impairment (38%) (dementia, confusion, personality change); weakness, including hemi- or monoparesis; and ataxia. Seizures occur in ~20% of patients, predominantly in those with lesions abutting the cortex.

Almost all patients have an underlying immunosuppressive disorder or are receiving immunomodulatory therapy. In recent series, the most common associated conditions were AIDS (80%), hematologic malignancies (13%), transplant recipients (5%), and chronic inflammatory diseases (2%). It has been estimated that up to 5% of AIDS patients will develop PML. There have been >700 reported cases of PML occurring in patients being treated for multiple sclerosis and inflammatory bowel disease with natalizumab, a humanized monoclonal antibody that inhibits lymphocyte trafficking into CNS and bowel mucosa by binding to α4 integrins. Overall risk in these patients has been estimated at ~4.2 PML cases per 1000 treated patients, but the risk depends on a variety of factors including anti-JCV antibody serostatus and the magnitude of the JCV antibody response, prior immunosuppressive therapy use, and duration of natalizumab therapy. Patients who lack detectable JCV antibody have a risk of developing PML of <0.1 case/1000 patients, whereas those who are JCV seropositive and have been exposed to prior immunosuppressive therapy and have received >24 months of natalizumab therapy have a risk of >1.3 case/100 treated patients. PML cases have also been reported in patients receiving other humanized monoclonal antibodies with immunomodulatory activity including efalizumab and rituximab, although the relative risks have not been clearly established. The basic clinical and diagnostic features appear to be similar in HIV-associated PML and PML associated with immunomodulatory drugs with the exception of an increased likelihood of MRI enhancement of PML lesions in immunomodulatory cases. In natalizumab-associated PML, patients will also almost invariably develop clinical and radiographic worsening of lesions with discontinuation of therapy, attributed to development of immune reconstitution inflammatory syndrome (IRIS).

Diagnostic Studies

The diagnosis of PML is frequently suggested by MRI. MRI reveals multifocal asymmetric, coalescing white matter lesions located periventricularly, in the centrum semiovale, in the parietal-occipital region, and in the cerebellum. These lesions have increased signal on T2 and FLAIR images and decreased signal on T1-weighted images. HIV-PML lesions are classically nonenhancing (90%), but patients with immunomodulatory drug-associated PML may have peripheral ring enhancement. PML lesions are not typically associated with edema or mass effect. CT scans, which are less sensitive than MRI for the diagnosis of PML, often show hypodense nonenhancing white matter lesions.

The CSF is typically normal, although mild elevation in protein and/or IgG may be found. Pleocytosis occurs in <25% of cases, is predominantly mononuclear, and rarely exceeds 25 cells/μL. PCR amplification of JCV DNA from CSF has become an important diagnostic tool. The presence of a positive CSF PCR for JCV DNA in association with typical MRI lesions in the appropriate clinical setting is diagnostic of PML, reflecting the assay’s relatively high specificity (92–100%); however, sensitivity is variable, and a negative CSF PCR does not exclude the diagnosis. In HIV-negative patients and HIV-positive patients not receiving highly active antiviral therapy (HAART), sensitivity is likely 70–90%. In HAART-treated patients, sensitivity may be closer to 60%, reflecting the lower JCV CSF viral load in this relatively more immunocompetent group. Patients with natalizumab-associated PML have highly variable amounts of JCV DNA in CSF. Some patients may have negative CSF PCRs performed in commercial laboratories where assay detection thresholds are typically >100 JCV DNA copies/μL, but positive results in reference laboratories using supersensitive techniques (detection of 10 JCV copies/μL or less). CSF studies with quantitative JCV PCR indicate that patients with low JCV loads (<100 copies/μL) have a generally better prognosis than those with higher viral loads. Patients with negative CSF PCR studies may require brain biopsy for definitive diagnosis. In biopsy or necropsy specimens of brain, JCV antigen and nucleic acid can be detected by immunocytochemistry, in situ hybridization, or PCR amplification.

Serologic studies are of no utility in diagnosis due to high basal seroprevalence level, but may contribute to risk stratification in patients contemplating therapy with immunomodulatory drugs such as natalizumab

Treatment

No effective therapy for PML is available. There are case reports of potential beneficial effects of the 5-HT2a receptor antagonist mirtazapine, which may inhibit binding of JCV to its receptor on oligodendrocytes. Retrospective non-controlled studies have also suggested a possible beneficial effect of treatment with interferon-α. Neither of these agents has been tested in randomized controlled clinical trials. A prospective multicenter clinical trial to evaluate the efficacy of the antimalarial drug mefloquine failed to show benefit. Intravenous and/or intrathecal cytarabine were not shown to be of benefit in a randomized controlled trial in HIV-associated PML, although some experts suggest that cytarabine may have therapeutic efficacy in situations where breakdown of the blood-brain barrier allows sufficient CSF penetration. A randomized controlled trial of cidofovir in HIV-associated PML also failed to show significant benefit. Because PML almost invariably occurs in immunocompromised individuals, any therapeutic interventions designed to enhance or restore immunocompetence should be considered; a small series of patients treated with the PD-1 inhibitor pembrolizumab demonstrated clinical improvement and stabilization in a subset of subjects. Perhaps the most dramatic demonstration of this is disease stabilization and, in rare cases, improvement associated with the improvement in the immune status of HIV-positive patients with AIDS following institution of HAART. In HIV-positive PML patients treated with HAART, 1-year survival is ~50%, although up to 80% of survivors may have significant neurologic sequelae. HIV-positive PML patients with higher CD4 counts (>300/μL) and low or nondetectable HIV viral loads have a better prognosis than those with lower CD4 counts and higher viral loads. Although institution of HAART enhances survival in HIV-positive PML patients, the associated immune reconstitution in patients with an underlying opportunistic infection such as PML may also result in a severe CNS inflammatory syndrome (IRIS) associated with clinical worsening, CSF pleocytosis, and the appearance of new enhancing MRI lesions. Patients receiving natalizumab or other immunomodulatory antibodies who are suspected of having PML should have therapy immediately halted. Removal of drugs with long pharmacokinetic or biological half-lives, such as natalizumab, with plasma exchange or immunoadsorption is frequently utilized, although whether this improves outcomes has not been definitively established. Patients should be closely monitored for development of IRIS, which is generally treated with intravenous glucocorticoids, although controlled clinical trials of efficacy remain lacking.

References

Harrison's Chapter 132 (Encephalitis)