Mark Gudesblatt, MD

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TABLE 1 Common clinical features of AIDS-associated PML patients*Clinical features Berenguer et al 32 (2003) Falcó et al 34 (2008) Engsig et al 26 (2009)Cognitive deficits NR NR 27 (57%)Limb weaknesses 82 (69.5) 26 (42.6) 20 (43%)Gait/coordination disorders 76 (64.4) 33 (54.1) 32 (68%)Speech disorders 55 (46.6) 25 (41.0) 20 (43%)Visual impairments 24 (20.3) 16 (26.2) 13 (28%)Seizures 15 (12.7) NR 6 (13%)Cranial nerve palsies 37 (31.4) NR 3 (6%)Sensory affections NR NR 8 (17%)Altered mental status NR 19 (31.1) NRTotal PML cases 118 (100) 61 (100) 47 (100)* Number (percentage) of PML cases. NR = Not rated.PML is a disease of the brain and centralnervous system (CNS) characterized by multifocaldemyelination resulting from lytic infectionof oligodendrocytes by human polyomavirusJC (JCV), 12 a ubiquitous DNA virus namedafter the patient from whom it was first isolated(John Cunningham). 2,8,13 A neurotropic virusthat infects only human beings, JCV is foundin more than 50% of the human populationby adulthood. 8,14 Despite up to 91% of peoplein some smaller, localized population studieshaving detectable serum antibodies againstJCV, PML had remained a relatively rare disease.15 Between 1958 and 1984, only 230 caseswere identified in one comprehensive review. 14During the HIV epidemic, however, the prevalenceincreased significantly, with up to 5% ofAIDS patients developing PML. 8 Mortality associatedwith PML also rose—from 1.5 deathsper 10 million individuals in 1979, before thestart of the epidemic, to 6.1 deaths per 10 millionindividuals in 1987. As a demyelinatingdisorder, PML belongs to the class of opportunisticinfections and occurs predominantly inpatients with severe immunosuppression. 2,13Common presenting symptoms of HIV/AIDSassociatedPML include cognitive deficits, gaitdisorders, limb weaknesses, speech disorders,and visual impairments (Table 1). The naturalcourse of the disease historically is progressive,typically leading to death within months whenthe patient remains immunocompromised. 2In a comprehensive review of clinical featuresand pathogenesis, Tan and Koralnik 8 categorizedPML into three main forms (Table 2):(1) classic PML, which usually affects patientswith severe cellular immunosuppression, includingthose with HIV/AIDS, hematologicalmalignancies, chronic inflammatory disorders,or organ transplant recipients; (2) PMLassociated with the use of therapeutic monoclonalantibodies; and (3) PML-IRIS, which istriggered by a rapid global recovery of the immunesystem after the initiation of cART in patientswith HIV/AIDS or subsequent to discontinuationof immunosuppressive treatment inHIV-negative patients.Although several classes of drugs used tosuppress the host cellular immune responsehave been implicated, monoclonal antibodieshave emerged in recent years as a new categoryof drugs associated with PML. These immunomodulatorydrugs are not broad-spectrum immunesuppressors, but they selectively modulateone or more aspects of the immune systemand have been used in the treatment of autoimmunediseases, including at least four conditionsthat had not been previously implicatedin the risk stratification for PML—MS, Crohn’sdisease, psoriasis, and lupus. Among theS18 July 2011 • Clinical Reviews of JCV and PML
TABLE 2 Different forms of PMLClassic PMLPML associated withmonoclonal antibodies 10PML-IRISOnset Subacute Subacute Immune-recoveryPatientscharacteristicsNeurologicsymptomsMRIDiagnosisSevere immune compromisedeither because of HIV,lymphoproliferative disorders,organ transplant recipients,or on immune-suppressivetherapyBased on location;neurobehavioral, motor,language, visual symptoms,cognitive impairment, seizure;no optic nerve or spinal cordinvolvementAsymmetric, well demarcated,contrast non-enhancingsubcortical white matterlesions, hyperintense in T2and FLAIR, hypointense in T1Suggestive symptoms, JCVdetection in CSF or brainbiopsy, MRIGenerally immune-competentindividuals with autoimmunedisease taking one of immunemodulatingantibodiesSimilar to classic PMLContrast enhancement (43%)may be present, particularly afterdiscontinuation of treatmentAny new neurologic symptomsor signs in patients with monoclonalantibody warrants carefulevaluation, JCV detection inCSF or brain biopsy, MRIHIV+ patients: after initiationof cART; after discontinuationof natalizumabor plasma exchange innatalizumab-associatedPML in MS patientsSimilar to classic PML,appearance of new neurologicsymptoms or rapiddeterioration may occurContrast enhancementand mass effectSuggestive symptoms,JCV detection in CSF orbrain biopsy, MRIHistologyDemyelinating lesions oftenat grey/white junction, JCV inenlarged oligodendrocytes,bizarre astrocytesDemyelination similar to classicPML, with addition of inflammatoryinfiltratesDemyelination similar toclassic PML, with additionof inflammatory infiltratesTreatmentcART for HIV-positivepatients; discontinuation ofimmune-suppressive treatmentfor HIV-negative patientsDiscontinue or decrease immunomodulatingdrugs, plasmaexchange or immunoabsorptionfor natalizumab-treated patients,high-dose corticosteroidsConsider steroids in caseswith notable neurologicworsening or signs ofimpending brainherniationPML = Progressive multifocal leukoencephalopathy; cART = combination antiretroviral therapy; MRI = magnetic resonance imaging,FLAIR = fluid attenuated inversion recovery. (Adapted from Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathyand other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol. 2010;9(4):425-437.)monoclonal antibodies associated with PMLare natalizumab, which is indicated for MS andCrohn’s disease; rituximab, used to treat lupus;and efalizumab, which had been indicated forthe treatment of moderate to severe plaquepsoriasis before being permanently withdrawnfrom the market in April 2009 following diagnosisof PML in three patients receiving thedrug. While the exact mechanism of PML developmentin individuals taking these monoclonalantibodies is debatable, these monoclonalantibodies have been suggested by some tofacilitate JCV reactivation and disseminationor create artificial immune deficiency status inthe CNS (Table 3). Since hematopoietic precursorcells are susceptible to JCV infection, 16 andnatalizumab and efalizumab facilitate releaseof hematopoietic precursor CD34+ cells intoClinical Reviews of JCV and PML • July 2011 S19
Page 1 and 2: A SUPPLEMENT TO NEUROLOGY REVIEWSCl
Page 3 and 4: An Overview of JC Virusand Progress
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Page 9 and 10: 39. Weber F, Goldmann C, Krämer M,
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Page 23 and 24: with HIV-associated PML, recent stu
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Page 27: 22. Lebwohl M, Tyring SK, Hamilton

Mark Gudesblatt, MD

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