Mark Gudesblatt, MD

cation. Although PML is generally consideredto be an opportunistic infection in immunocompromisedpatients, such as individualswith acquired immunodeficiency syndrome(AIDS) or individuals taking an immunomodulatoryor immunosuppressant therapy, therehave been a few cases of PML in individualsconsidered to be immuno competent. 25The infection of oligodendrocytes is a lyticprocess that leads to pathological alterationsin the cerebrum, cerebellum, and brain stem.On magnetic resonance imaging (MRI), multiplediffuse asymmetrical lesions are typicallyfound in the subcortical hemispheric whitematter and cerebellar peduncles. 1 Lesionsmay also be found in the grey matter. Reactivegliosis and giant, multinucleated astrocytesare also observed in affected areas. Lesionsare not usually edematous and they can begenerally distinguished from lesions associatedwith MS by a variety of features, such asa low likelihood of enhancement on gadoliniumMRI imaging, configuration, andthe appearance on diffusion-weightedimaging (DWI).PML may manifest in any one ormore of a broad array of neurologicsymptoms, including limb weakness,gait abnormalities, paresis, cognitivedeficits, psychiatric and behavioral changes,and speech or visual deficits. The most commonof these features, limb weakness, is reportedby about half of patients. 26 Patientsmay report sensory disturbances. Headachesare reported by about 10%.Although detection of JCV DNA in a demyelinatedlesion is considered a definitivesign of PML, and presence of JCV DNA in thecerebrospinal fluid (CSF) confirms diagnosisof PML, the correlation between JCV in blood(viremia) and the presence of PML is modesteven with serial measurements. In HIV patientswith PML, for whom there is the greatestexperience in the detection and evaluationof PML, only about half had detectableJCV viremia on serial analyses. 27 A variety oftests have been developed to facilitate diagnosisof PML through detection of JCV, includinga polyclonal antibody test for the JCVagnoprotein, 28 which appears to be presentonly in cases of virulent infection. Enzymelinkedimmunosorbent assays (ELISA) 29 havebeen developed as predictive tools, but somepatients with PML have low or undetectableJCV in the CSF. Even PCR amplification testing,which is generally considered the mostsensitive, has generated false-negative testsin patients with PML. 30 Low serum or CSFJCV titers do not correlate with brain tissuedamage, although they might correlate withsurvival. 31 A diagnosis of presumed PML canbe made on the basis of clinical features,combined with MRI findings, in the absenceof alternative diseases, even in the absence oflaboratory-detectable JCV. 32JCV as Causative Agent of PMLThe events that lead from asymptomatic JCVinfection to overt PML remain controversial.Although immunosuppression is strongly implicatedin the pathway from a quiescent toUltimately, understanding thetransformation of JCV to its virulent formsmay be a more important target of controlthan promoting immune response.an active virus, the role of reactivation is notclear. The reactivation hypothesis is built onthe premise that diminished immune defensespermit a previously dormant virus to replicaterapidly at the sites of latency. In this hypothesis,PML occurs after the virus mutatesinto a virulent form and crosses the bloodbrainbarrier (BBB). However, this is not fullyconsistent with some laboratory and clinicalobservations. In particular, the reactivationof JCV may be less important than a far morecomplex interrelationship between immunedefenses and JCV replication. One argumentagainst reactivation is that fulminant JCV andPML remain very rare events in immunosuppressedindividuals. The trigger for transformationthat confers JCV with virulence andneurotropic properties may be more significantthan an increased rate of replication. Recentevidence suggests that mutations in theClinical Reviews of JCV and PML • July 2011 S5