Mark Gudesblatt, MD

characteristic brain changes on magnetic resonanceimaging (MRI) are useful. 24 PCR detectionof JCV in CSF has been a gold standard forconfirming PML diagnosis; however, becauseof cART its sensitivity in AIDS-associated PMLmay be low, ranging from 42% to 81%. 25-27 Whilethe PCR method is also useful in diagnosingmonoclonal antibodies- and IRIS-associatedPML, PCR may fail to detect low JCV in CSF ofthese individuals because JCV replication maybe held by a competent immune system in theformer and recovering immune system in thelatter, and a brain biopsy may be necessitated. 8Since only a small fraction of monoclonalantibody–treated individuals are likely todevelop PML, which can lead to long-termneurological sequelae or death, stratifying patientsaccording to risk of PML development isof paramount importance. Indeed, a series ofrecent studies have determined three factorsthat are useful in stratifying monoclonal antibody-treatedMS patients according to theirrisk of PML development. These factors areanti-JCV antibody–positive status, prior immunosuppressantuse, and natalizumab treatmentduration.In a recent editorial, Tyler 5 raised the questionof whether risk can be reduced in patientsreceiving biological immunomodulatorytherapies. “The ability to stratify risk moreaccurately in specific subpopulations wouldobviously be of tremendous utility in guidingtherapeutic decisions,” he wrote. “Diseaseprevention and risk reduction are even morecritical because of the absence of any specificantiviral therapy of proven benefit in the treatmentof PML.”Even though no subjects in their study developedPML, Chen and colleagues 19 suggestedthat surveillance of blood or urine may be usefulin identifying patients potentially at risk ofdeveloping PML after natalizumab treatment.However, a larger prospective study by Rudickand colleagues 20 testing for JCV DNA using acommercially available quantitative PCR assayas well as a more sensitive quantitative PCRassay developed at the National Institutes ofHealth found no difference in the prevalenceof JCV DNA–positive plasma in placebo-treatedor natalizumab-treated patients, nor in theprevalence of similarly positive urine specimensat baseline and at 48 weeks. Furthermore,JCV DNA was not detected prior to diseaseonset in the blood of the five patients whodeveloped PML during the study. Rudick et al 20concluded that “measuring JCV DNA in bloodor urine with currently available methods isunlikely to be useful for predicting PML riskin natalizumab-treated MS patients,” a findingwith which Tyler concurred. 5Pointing to detection of virus-specific antibodiesas the traditional method for establishingpast exposure to viral infection, Tyler 5went on to observe that “A highly sensitive andspecific JCV antibody assay would theoreticallyenable the population to be divided intothose at risk for developing PML (antibodypositive), and those not at risk (antibody negative).”While early studies of JCV serostatus indicatedthat the primary infection happenedin infancy and childhood and that, by adulthood,sero prevalence rates as high as 80%were reported, these findings may have beenconfounded by use of a nonspecific hemagglutination-inhibitionassay, a less accurate butwidely available assay method of that time, aswell as by potential antibody cross-reactivitybetween antibodies against JCV and other humanpolyomaviruses.Two recent studies of note have useddifferent forms of enzyme-linked immunosorbentassay (ELISA) techniques. 7,28 In anevaluation of MS patients treated with natalizumabusing a two-step ELISA to detect antibodiesto the JCV-like particles, Gorelik andcolleagues 28 demonstrated that 100% (17 outof 17) of sera from natalizumab-associatedPML patients obtained 16 to 180 months priorto PML development were JCV-seropositive,whereas only 53.6% of non-PML MS patientstreated with natalizumab were anti-JCV–seropositive.The investigators interpreted theirresults as warranting further research on theclinical utility of the assay as a potential PMLrisk stratification tool for MS patients. Similarly,another ELISA study using baculovirus expressedJCV VP1 showed that 65% of sera from214 MS patients treated with natalizumab andClinical Reviews of JCV and PML • July 2011 S21