Mark Gudesblatt, MD

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The marked difference in survival in thatmulticenter analysis points to the progress thathas been made in altering the prognosis of patientswith PML. Prior to the advent of HAART/cART, only about 10% of HIV-positive patientssurvived at least one year following PML diagnosis.9,41 In an evaluation of the clinical and radiographicfeatures of PML in a cohort of 154AIDS patients, median survival was six monthsand 9% of patients were alive more than oneyear after PML was diagnosed. 3 With the introductionof cART, however, the one-year survivalrate has risen to approximately 50%. 8,9,31 TheItalian Registry Investigative Neuro AIDS StudyGroup found, for example, that patients startingHAART at diagnosis of PML who had previouslyreceived antiretrovirals demonstrateda significantly higher one-year survival probability(58%) versus those continuing HAART(24%) or who never received it (0%). 31Clinical vigilance, early diagnosis, andprompt treatment (discontinuation ofnatalizumab, initiation of plasmaexchange) were associated withimproved survival.More recent data from the United Statesare even more promising and suggest that, foran increasing number of HIV-positive patients,PML has become a chronic disorder ratherthan a relentlessly and rapidly progressive fataldisease. 9 In a study of the clinical outcomeof long-term survivors of PML, investigatorsfollowed 24 patients who survived more thanfive years from disease onset, with a meanfollow-up period of 94.2 months. All but oneof the patients were HIV-positive and receivedHAART, and the remaining patient had non-Hodgkin’s lymphoma and was HIV-negative.<strong>Mark</strong>ed improvement of neurological functionoccurred in 4 of 24 patients (17%), partial improvementwas observed in 11 of 24 (46%), and9 of 24 (37%) remained stable. At the end of theobservation period, one-third of patients (8 of24) had no significant disability despite persistentsymptoms, one-quarter (6 of 24) hadslight disability and could live independently,and equal numbers of the remainder (5 of 24,21%, in each group) either were moderatelydisabled or had moderately severe disabilityrequiring constant help or institutionalization.Survival in the study was linked to the patients’ability to initiate a cellular immune responseto the JCV. 8,9 The 23 HIV-positive patients had amedian CD4 count of 389/mL at the end of theobservation period, and 19 of 23 (83%) had undetectableHIV RNA in their plasma. 9 Nineteenof 20 patients (95%) tested in this series haddetectable JCV-specific CD8+ CTLs in theirperipheral blood. The authors argued that improvedprognosis of HIV-positive patients withPML resulted from HAART-associated immunerecovery:In fact, PML is becoming a chronic disease—ratherthan a fatal disease—in agrowing number of HIV-infected patients.For this reason, it is important to understandthe clinical outcome of long-termsurvivors of PML in HIV-infected patients….Interestingly, the overwhelmingmajority of tested subjects [in our cohort]had a detectable cellular immuneresponse against JCV, which confirmsprevious studies on the role of T lymphocytesin PML survival. 9Interestingly, one-year survival rates betweenpatients with PML-IRIS (54%) and PMLpatients without IRIS (49%) were comparable,suggesting that the inflammatory reaction associatedwith IRIS does not alter the survivalrate of patients with PML—in contrast to whathas been observed for classic PML in otherstudies.Recent evidence indicates that survival ofmonoclonal antibody–associated PML patientsis improving. In one of the largest series reportedin MS patients who had natalizumabassociatedPML, 20 of 28 patients (71%) werestill living at the time of reporting. 10 Clinicalvigilance, early diagnosis, and prompt treatment(discontinuation of natalizumab, initiationof plasma exchange) were associatedwith improved survival. 10 Vermersch and colleagues11 reported a similar survival rate (71%)in a study of clinical outcomes in 35 cases ofnatalizumab-associated PML.S24 July 2011 • Clinical Reviews of JCV and PML
Natalizumab, the first monoclonal antibodyapproved for the treatment of relapsingforms of MS, was voluntarily withdrawn fromthe US and European markets in February 2005after three patients undergoing therapy withthe drug in combination with other immunoregulatoryand immunosuppressive agentswere diagnosed with PML. 5,8 However, it wasreintroduced again as a monotherapy for MSin June 2006, and since its reintroduction 130additional cases developed PML among 83,300exposed patients through June 1, 2011.Of the three natalizumab-associated PMLcases reported in 2005, two were fatal. In one,the diagnosis of a 60-year-old man who hadreceived natalizumab for Crohn’s disease waschanged from fatal astrocytoma to PML afteranalysis of frozen serum samples revealedthat JC virus DNA was detectable in the serumthree months after the start of monotherapywith the monoclonal antibody and two monthsbefore the appearance of symptomatic PML. 42In a second case, a 46-year-old woman withrelapsing-remitting MS participating in a clinicaltrial of combined therapy with natalizumaband interferon beta-1a, in which she received37 doses of the monoclonal antibody (300 mg)every four weeks, died from PML, which wasdiagnosed by PCR assay (JCV DNA in the CSF)and confirmed at autopsy. 43 The third case,which also involved combination therapywith interferon beta-1a in a patient with MS,highlights the importance of early detection,differential diagnosis, and swift treatment response.44 Although the first PML lesion seen onMRI was indistinguishable from an MS lesion,PML was diagnosed and progressed rapidly,even though natalizumab was discontinuedand treatment with corticosteroids, cidofovir,and IV immunoglobulin was initiated. The patientbecame quadriparetic, globally aphasic,and minimally responsive; but within threemonths following natalizumab discontinuation,changes consistent with PML-IRIS weredetected and systemic cytarabine was initiated,leading to improvement in the patient’scondition in two months.The risk of PML development increaseswith duration of exposure to natalizumab.Once natalizumab was approved again for usein June 2006, no new cases of PML were reportedduring the first two years of the drug’sremarketing. The first reported case was diagnosedin July 2008 following the appearance ofsymptoms. In subsequent months, one to twocases per month were reported, for a total of31 by the end of January 2010. Of the 28 PMLcases confirmed by the end of November 2009,eight were fatal and, of the 20 who survived,many had serious morbidity and substantialand permanent disability. The median treatmentduration to onset of symptoms for all 28cases was 25 months. None of the 28 patientswere on concurrent therapy with interferonbeta and, while three patients had never receivedany disease-modifying therapy otherthan natalizumab, previous treatment withother immunosuppressants (including interferon)may have increased the risk of PML, accordingto the investigators.Treatment response in this series illustratesthe complexities of the improved prognosisin patients with natalizumab-associatedPML. In 27 cases, either plasma exchange orimmunoabsorption was used to achieve rapidclearance of natalizumab and restorationof CNS immune surveillance. In almost all ofthese cases, the subacute progression and exacerbationof earlier symptoms of PML thatare typical of IRIS occurred within days to afew weeks of plasma exchange. High-dose corticosteroidtherapy has been used to treat IRISwith some success, and in many cases in thisseries repeated courses of IV steroid were given.Death was more common among patientswho were either untreated or inadequatelytreated with corticosteroids. Prognosis wasalso related to the location of lesions and isprobably a more important prognostic factorthan is the size of the lesions. Cases in whichlesions affected such critical regions as thebrainstem had the most serious consequencesand, while higher JCV titers in the CSF are generallyassociated with larger lesions size, patientswho presented with low viral loads wereamong the fatal cases in the series. In one casein which JCV was not detected in CSF and neitherplasma exchange nor immunoabsorptionClinical Reviews of JCV and PML • July 2011 S25
Page 1 and 2: A SUPPLEMENT TO NEUROLOGY REVIEWSCl
Page 3 and 4: An Overview of JC Virusand Progress
Page 5 and 6: cation. Although PML is generally c
Page 7 and 8: JCV exposure than those who are not
Page 9 and 10: 39. Weber F, Goldmann C, Krämer M,
Page 12 and 13: diseases, which represent an autoim
Page 14: tainment of JCV in the CNS as well
Page 17 and 18: Progressive MultifocalLeukoencephal
Page 19 and 20: TABLE 2 Different forms of PMLClass
Page 21 and 22: characteristic brain changes on mag
Page 23: with HIV-associated PML, recent stu
Page 27: 22. Lebwohl M, Tyring SK, Hamilton

Mark Gudesblatt, MD

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