Conference Coverage
INDIANAPOLIS—Early detection of progressive multifocal leukoencephalopathy (PML) may improve outcomes, according to an update presented at the 2015 CMSC Annual Meeting. When PML results from reversible immunosuppression, as in patients with multiple sclerosis (MS) who are receiving monoclonal antibodies, the immediate cessation of the offending agent is recommended.
The pathogenesis of PML is not well understood, but the initial infection may be oropharyngeal or respiratory, said Joseph R. Berger, MD, Professor of Neurology at the Hospital of the University of Pennsylvania in Philadelphia. The infection spreads to sites of latency and may be re-expressed with circulation in B cells before entering the CNS.
As of March 3, 2015, 541 cases of PML have been reported in patients receiving natalizumab. Of these patients, 538 had MS. The patients’ mean duration of treatment with natalizumab was 42 months. Approximately 8% of patients were a-symptomatic at the time of diagnosis. Data have suggested that exposure to John Cunningham virus (JCV), prior immunosuppressive therapy, and longer treatment duration are risk factors for PML.
Since 2013, New England Journal of Medicine has published three case reports of PML in patients receiving dimethyl fumarate. In one of the cases, the drug had been manufactured by a compounding pharmacy. The literature also contains two cases of PML in patients receiving fingolimod.
To date, 160 cases of PML have been reported in patients receiving rituximab, but none of these cases occurred in patients with MS. Almost all cases of PML related to rituximab were in patients with chronic lymphocytic leukemia or other lymphoproliferative diseases. The drug has a black box warning, but the risk of PML for patients receiving this therapy probably is “vanishingly low,” said Dr. Berger.
A total of 57 patients receiving alemtuzumab have developed PML. Fifty-five of these individuals had chronic lymphocytic leukemia, and two developed PML after a lung transplant. Alemtuzumab depletes B cells, which recover in 27 months, and T cells, which recover in 61 months.
Diagnosis of PML depends on neuropathologic demonstration of demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei. The presence of JCV also must be established by polymerase chain reaction. A two-step Enzyme Linked Immunosorbent Assay can detect JCV antibodies, but it has a significant risk of false seronegativity, said Dr. Berger.
On CT imaging, PML manifests as hypodense lesions and, in less than 10% of cases, as contrast enhancement. PML is visible as hypointense lesions on T1 MRI and as increased signal on T2 MRI and FLAIR. PML is not associated with mass effect on MRI and often affects parieto-occipital and frontal lobes. The condition may affect atypical locations such as the cerebellum, brainstem, basal ganglia, or temporal lobe.
—Erik Greb