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Progressive Multifocal Leukoencephalopathy/JC Virus Infection
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Epidemiology

Progressive multifocal leukoencephalopathy (PML) is an OI of the CNS, caused by the polyoma virus JC virus (JCV) and characterized by focal demyelination (1143Koralnik IJ. Progressive multifocal leukoencephalopathy revisited: has the disease outgrown its name? Ann Neurol 2006;60:162-73.). The virus has worldwide distribution and approximately 85% of adults are seropositive for JCV (1144Weber T, Trebst C, Frye S, et al. Analysis of the systemic and intrathecal humoral immune response in progressive multifocal leukoencephalopathy. J Infect Dis 1997;176:250-4.). Primary JCV infection usually occurs in childhood but is not accompanied by any identified symptoms. However, infection likely results in a chronic asymptomatic carrier state in most persons, explaining frequent virus detection in urine (30%) and tonsils (40%) of immunologically normal adults (1145Kitamura T, Aso Y, Kuniyoshi N, Hara K, Yogo Y. High incidence of urinary JC virus excretion in nonimmunosuppressed older patients. J Infect Dis 1990; 161:1128-33., 1146Sundsfjord A, Flaegstad T, Flo R, et al. BK and JC viruses in human immunodeficiency virus type 1-infected persons: prevalence, excretion, viremia, and viral regulatory regions. J Infect Dis 1994;169:485-90., 1147Monaco MC, Jensen PN, Hou J, Durham LC, Major EO. Detection of JC virus DNA in human tonsil tissue: evidence for site of initial viral infection. J Virol 1998;72:9918-23., 1148Koralnik IJ, Boden D, Mai VX, Lord CI, Letvin NL. JC virus DNA load in patients with and without progressive multifocal leukoencephalopathy. Neurology 1999;52:253-60., 1149Lednicky JA, Vilchez RA, Keitel WA, et al. Polyomavirus JCV excretion and genotype analysis in HIV-infected patients receiving highly active antiretroviral therapy. AIDS 2003;17:801-7., 1150Kato A, Kitamura T, Takasaka T, et al. Detection of the archetypal regulatory region of JC virus from the tonsil tissue of patients with tonsillitis and tonsilar hypertrophy. J Neurovirol 2004;10:244-9.). Outside of the context of HIV infection, PML is rare and usually manifests as a complication of other diseases or therapies accompanied by compromised immunity (1151Richardson EP, Jr., Webster HD. Progressive multifocal leukoencephalopathy: its pathological features. Prog Clin Biol Res 1983:105:191-203., 1152Garcia-Suarez J, de Miguel D, Krsnik I, et al. Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: impact of novel therapies. Am J Hematol 2005;80:271-8.). Interest in PML has increased outside of the HIV context as a result of three cases that developed in patients with multiple sclerosis and regional enteritis after treatment with natalizumab, a therapeutic antibody directed against alpha-4 integrins (1153Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 2005;353:362-8., 1154Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005;353:369-74., 1155Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375-81., 1156Aksamit AJ. Review of progressive multifocal leukoencephalopathy and natalizumab. Neurologist 2006;12:293-8.). More recently, two patients with SLE receiving rituximab, a therapeutic antibody directed at the B-cell antigen CD20, acquired PML (http://www.fda.gov/cder/drug/advisory/rituximab.htm). This event raises a cautionary note regarding monitoring PML risk when treating non-Hodgkin's lymphoma with rituximab in HIV-infected patients (1157Mounier N, Spina M, Gisselbrecht C. Modern management of non-Hodgkin lymphoma in HIV-infected patients. Br J Haematol 2007;136:685-98., 1158Boue F, Gabarre J, Gisselbrecht C, et al. Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkin's lymphoma. J Clin Oncol 2006;24:4123-8.). However, no reports have documented PML associated with use of rituximab in HIV infection.

Before the advent of potent combination ART, PML eventually occurred in 3%-7% of AIDS patients (1159Petito CK, Cho ES, Lemann W, Navia BA, Price RW. Neuropathology of acquired immunodeficiency syndrome (AIDS): an autopsy review. J Neuropathol Exp Neurol 1986;45:635-46., 1160Anders K, Steinsapir KD, Iverson DJ, et al. Neuropathologic findings in the acquired immunodeficiency syndrome (AIDS). Clin Neuropathol 1986;5:1-20., 1161Lang W, Miklossy J, Deruaz JP, et al. Neuropathology of the acquired immune deficiency syndrome (AIDS): a report of 135 consecutive autopsy cases from Switzerland. Acta Neuropathol 1989;77:379-90.) and was almost invariably fatal, with only rare spontaneous remission (1162Berger JR, Mucke L. Prolonged survival and partial recovery in AIDS-associated progressive multifocal leukoencephalopathy. Neurology 1988;38:1060-5.). After the widespread use of combination ART in the developed world, the incidence of PML has decreased substantially (1163d'Arminio Monforte A, Cinque P, Mocroft A, et al. Changing incidence of central nervous system diseases in the EuroSIDA cohort. Ann Neurol 2004;55:320-8.). However, morbidity and mortality associated with PML in HIV-infected patients remains high (1164Mocroft A, Collaboration AC. OIs, AIDS-defining conditions, and HIV-1 disease burden (Abstract). 14th Conference on retroviruses and opportunistic infections. Los Angeles, CA, 2007.). Unlike some of the other CNS OIs that are almost wholly prevented when CD4+ counts are maintained above 100-200 cells/µL, PML might still appear in such patients and in those on ART (1165Berger JR, Levy RM, Flomenhoft D, Dobbs M. Predictive factors for prolonged survival in acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy. Ann Neurol 1998;44:341-9., 1166Cinque P, Bossolasco S, Brambilla AM, et al. The effect of highly active antiretroviral therapy-induced immune reconstitution on development and outcome of progressive multifocal leukoencephalopathy: study of 43 cases with review of the literature. J Neurovirol 2003;9(Suppl 1):73-80.). Moreover, PML might develop in the setting of initiating ART and immune reconstitution (1166Cinque P, Bossolasco S, Brambilla AM, et al. The effect of highly active antiretroviral therapy-induced immune reconstitution on development and outcome of progressive multifocal leukoencephalopathy: study of 43 cases with review of the literature. J Neurovirol 2003;9(Suppl 1):73-80., 1167Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 2003;9(Suppl 1):25-31.).

Clinical Manifestations

PML manifests as focal neurological deficits, usually with insidious onset and steady progression. Because the demyelinating lesions might involve different brain regions, the specific deficits vary from patient to patient. Any region of the CNS might be involved, but some areas seem to be more favored, including the occipital lobes (with hemianopia), frontal and parietal lobes (hemiparesis and hemisensory deficits), and cerebellar peduncles and deep white matter (dysmetria and ataxia). Spinal cord involvement appears rare (1168Bernal F, J. T. Joseph ea. Spinal cord lesions of progressive multifocal leukoencephalopathy in an AIDS patient. J Neurovirol (In press).). Although lesions can be multiple, often one predominates clinically. Additionally, because the individual lesions expand concentrically or along white matter tracts, initial symptoms and signs often begin as "partial" deficits (e.g., weakness of one leg) that worsen and involve a larger territory (e.g., evolution to hemiparesis). The focal or multifocal nature of the pathology is responsible for the consistency of clinical presentations with distinct focal symptoms and signs rather than as a more diffuse encephalopathy or dementia, which is rare (1169Zunt JR, Tu RK, Anderson DM, Copass MC, Marra CM. Progressive multifocal leukoencephalopathy presenting as human immunodeficiency virus type 1 (HIV)-associated dementia. Neurology 1997;49:263-5.).

The time course of this evolving demyelination, with clinical progression during several weeks, often provides a clue to diagnosis, because the other major opportunistic focal brain disorders (cerebral toxoplasmosis and primary CNS lymphoma) characteristically progress more rapidly in hours or a few days, and cerebral infarcts begin even more abruptly. Headache and fever are not part of the disease, but seizures develop in nearly 20% of PML patients and are associated with PML lesions immediately adjacent to the cortex (1170Lima MA, Drislane FW, Koralnik IJ. Seizures and their outcome in progressive multifocal leukoencephalopathy. Neurology 2006;66:262-4.).

Diagnosis

The initial recognition of PML relies on a combination of clinical and neuroimaging findings. The first step is usually identifying the clinical picture of steady progression of focal neurological deficits. The MRI almost always confirms distinct white matter lesions in areas of the brain corresponding to the clinical deficits. The lesions are usually hyperintense (white) on T2-weighted and fluid attenuated inversion recovery sequences, and also characteristically hypointense (dark) on T1-weighted sequences. The latter might be subtle but helps to distinguish the PML lesion from other pathologies, including the white matter lesions of HIV encephalitis. In contrast to cerebral toxoplasmosis and primary CNS lymphoma, no mass effect or displacement of normal structures is usually evident. Although contrast enhancement is present in 10%-15% of cases, it is usually sparse, with a thin or reticulated appearance adjacent to the edge of the lesions. Exceptions to these characteristic imaging findings might be noted when the inflammatory form of PML develops in the setting of immune reconstitution after initiation of ART.

In most cases, clinical picture and imaging findings support a confident presumptive diagnosis of PML. However, confirming the presence of JCV as the cause is often an advantage. This is invaluable in atypical cases, and even in the more typical setting, helps physicians to proceed rapidly and with certainty in therapy, preventing the need to revisit diagnosis when disease progression continues. The first approach to etiological diagnosis uses PCR to identify JCV DNA in CSF obtained by lumbar puncture. This is positive in approximately 70%-90% of patients not taking ART, and a positive result can be taken as diagnostic in this clinical context (197Cinque P, Scarpellini P, Vago L, Linde A, Lazzarin A. Diagnosis of central nervous system complications in HIV-infected patients: cerebrospinal fluid analysis by the polymerase chain reaction. AIDS 1997;11:1-17., 1148Koralnik IJ, Boden D, Mai VX, Lord CI, Letvin NL. JC virus DNA load in patients with and without progressive multifocal leukoencephalopathy. Neurology 1999;52:253-60.). In patients not on ART, the number of JCV DNA copies can add additional information for prognosis, although this does not seem to hold for those on ART (1171Yiannoutsos CT, Major EO, Curfman B, et al. Relation of JC virus DNA in the cerebrospinal fluid to survival in acquired immunodeficiency syndrome patients with biopsy-proven progressive multifocal leukoencephalopathy. Ann Neurol 1999;45:816-21., 1172Bossolasco S, Calori G, Moretti F, et al. Prognostic significance of JC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy. Clin Infect Dis 2005;40:738-44.). CSF analysis may be repeated if JCV PCR is negative but suspicion remains high, and alternative diagnoses (e.g., focal VZV or primary CNS lymphoma) also are not supported by negative VZV and EBV PCR analysis. When these practices fail, brain biopsy may be undertaken unless otherwise contraindicated. PML can usually be identified by the characteristic tissue cytopathology, including oligodendrocytes with intranuclear inclusions, bizarre astrocytes, and lipid-laden macrophages, whereas JCV infection is confirmed by immunohistochemistry, in situ nucleic acid hybridization, or electron microscopy (1151Richardson EP, Jr., Webster HD. Progressive multifocal leukoencephalopathy: its pathological features. Prog Clin Biol Res 1983:105:191-203., 1173Silver SA, Arthur RR, Erozan YS,et al. Diagnosis of progressive multifocal leukoencephalopathy by stereotactic brain biopsy utilizing immunohistochemistry and the polymerase chain reaction. Acta Cytol 1995;39:35-44., 1174Jochum W, Weber T, Frye S, et al. Detection of JC virus by anti-VP1 immunohistochemistry in brains with progressive multifocal leukoencephalopathy. Acta Neuropathol 1997;94:226-31.). Because PML develops as a result of endogenous infection and high seroprevalence of JCV infection, blood serology is not useful in diagnosis.

PML developing in the setting of immune reconstitution related to ART warrants special consideration and presents some differences from classical PML. PML has been reported to occur within the first weeks to months after initiating ART in certain patients (1166Cinque P, Bossolasco S, Brambilla AM, et al. The effect of highly active antiretroviral therapy-induced immune reconstitution on development and outcome of progressive multifocal leukoencephalopathy: study of 43 cases with review of the literature. J Neurovirol 2003;9(Suppl 1):73-80., 1167Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 2003;9(Suppl 1):25-31.). Additionally, some patients exhibit atypical features that include mass effect of the PML lesions with surrounding edema and on occasion, striking contrast enhancement on MRI. This presentation has been referred to as inflammatory PML or IRIS PML. Histopathology might demonstrate perivascular mononuclear inflammatory infiltration (1175Miralles P, Berenguer J, Lacruz C, et al. Inflammatory reactions in progressive multifocal leukoencephalopathy after highly active antiretroviral therapy. AIDS 2001;15:1900-2., 1176Safdar A, Rubocki RJ, Horvath JA, Narayan KK, Waldron RL. Fatal immune restoration disease in human immunodeficiency virus type 1-infected patients with progressive multifocal leukoencephalopathy: impact of antiretroviral therapy-associated immune reconstitution. Clin Infect Dis 2002;35:1250-7., 1177Hoffmann C, Horst HA, Albrecht H, Schlote W. Progressive multifocal leucoencephalopathy with unusual inflammatory response during antiretroviral treatment. J Neurol Neurosurg Psychiatry 2003;74:1142-4., 1178Di Giambenedetto S, Vago G, Pompucci A, et al. Fatal inflammatory AIDS-associated PML with high CD4 counts on HAART: a new clinical entity? Neurology 2004;63:2452-3.). In addition, the likelihood of detecting JCV in CSF might be reduced in these patients compared with classic PML, although this needs further study (1179Antinori A, Cingolani A, Lorenzini P, et al. Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: data from the Italian Registry Investigative Neuro AIDS (IRINA). J Neurovirol 2003;9(Suppl 1):47-53., 1180Marzocchetti A, Di Giambenedetto S, Cingolani A, et al. Reduced rate of diagnostic positive detection of JC virus DNA in cerebrospinal fluid in cases of suspected progressive multifocal leukoencephalopathy in the era of potent antiretroviral therapy. J Clin Microbiol 2005;43(8):4175-7.). These cases are presumed to represent the confluence of subclinical CNS JCV infection and restoration of immune responses to JCV by ART with resultant local immune and inflammatory responses, but other undefined factors might affect PML development in this setting.

Preventing Exposure

JCV has a worldwide distribution and most persons exhibit serologic evidence of exposure by their late teens. No known way exists to prevent exposure to the virus.

Preventing Disease

JCV likely continues as a silent productive infection in the kidney in many persons, and this might increase in the presence of immunosuppression. Whether JCV is latent in the CNS or whether PML results from temporally more proximate hematogenous dissemination in those who have this disease is unknown. Protection is presumably conferred by active, effective immunosurveillance. Therefore, the only effective way to prevent disease is to prevent progressive HIV-related immunosuppression with ART (AIII).

Treatment of Disease

No established specific therapy exists for JCV infection or PML, and the main approach to treatment involves ART to reverse the immunosuppression that interferes with the normal host response to this virus. Treatment strategies depend on the patient's antiretroviral treatment status and its effect. Thus, in patients who have PML and who are not on therapy, ART should be started immediately (AII). For patients with PML who remain HIV-viremic because of antiretroviral resistance, their ART regimen should be optimized for virologic suppression (AIII). More problematic are patients who have PML despite successful virologic suppression while taking HAART. A recent report of patients who were treated intensively with four classes of ART (including enfuvirtide) suggested that this strategy might offer higher than anticipated survival (1181Gasnault J, Hendel Chavez E, et al. Acceleration of immune recovery on intensified ART improves survival in patients with AIDS-related PML: preliminary reports of the ANRS 125 Trial. 14th Conference on Retroviruses and Opportunistic Illnesses. Los Angeles, CA, 2007.). The effectiveness of an ART-intensification strategy in patients with undetectable plasma HIV requires further study (CIII). Approximately half of patients with PML in the setting of HIV infection experience a remission after initiating effective ART (1179Antinori A, Cingolani A, Lorenzini P, et al. Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: data from the Italian Registry Investigative Neuro AIDS (IRINA). J Neurovirol 2003;9(Suppl 1):47-53., 1182Clifford DB, Yiannoutsos C, Glicksman M, et al. HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy. Neurology 1999;52:623-5., 1183Dworkin MS, Wan PC, Hanson DL, Jones JL. Progressive multifocal leukoencephalopathy: improved survival of human immunodeficiency virus-infected patients in the protease inhibitor era. J Infect Dis 1999;180:621-5., 1184Gasnault J, Taoufik Y, Goujard C, et al. Prolonged survival without neurological improvement in patients with AIDS-related progressive multifocal leukoencephalopathy on potent combined antiretroviral therapy. J Neurovirol 1999;5:421-9., 1185Tassie JM, Gasnault J, Bentata M, et al. Survival improvement of AIDS-related progressive multifocal leukoencephalopathy in the era of protease inhibitors. Clinical Epidemiology Group. AIDS 1999;13:1881-7., 1186De Luca A, Giancola ML, Ammassari A, et al. Cidofovir added to HAART improves virological and clinical outcome in AIDS-associated progressive multifocal leukoencephalopathy. AIDS 2000;14:117-21., 1187Cinque P, Pierotti C, Vigano MG, et al. The good and evil of HAART in HIV-related progressive multifocal leukoencephalopathy. J Neurovirol 2001;7:358-63., 1188Marra CM, Rajicic N, Barker DE, et al. A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS. AIDS 2002;16:1791-7., 1189Berenguer JP, Miralles P, Arrizabalaga J, et al. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2003;36:1047-52.). Although their neurological deficits frequently persist, disease progression in these patients remits. Some also will experience a degree of functional improvement. In one retrospective study, including 118 consecutive patients with PML, 75 patients (63.6%) remained alive for a median of 114 weeks (2.2 years) after diagnosis of PML (1189Berenguer JP, Miralles P, Arrizabalaga J, et al. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2003;36:1047-52.). Neurological function of the survivors was categorized as cure or improvement in 33, stabilization or worsening in 40, and unknown in 2. In this study the CD4+ count at presentation was the only variable that predicted survival; the odds ratio for death among patients with CD4+ counts <100 cells/µL compared with patients who had higher CD4+ counts was 2.71. According to some case series, prognosis also depends on whether patients are not on therapy at the time of presentation (and thus whether treatment can be improved), plasma HIV RNA levels, and virologic responses to treatment (1166Cinque P, Bossolasco S, Brambilla AM, et al. The effect of highly active antiretroviral therapy-induced immune reconstitution on development and outcome of progressive multifocal leukoencephalopathy: study of 43 cases with review of the literature. J Neurovirol 2003;9(Suppl 1):73-80., 1179Antinori A, Cingolani A, Lorenzini P, et al. Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: data from the Italian Registry Investigative Neuro AIDS (IRINA). J Neurovirol 2003;9(Suppl 1):47-53., 1185Tassie JM, Gasnault J, Bentata M, et al. Survival improvement of AIDS-related progressive multifocal leukoencephalopathy in the era of protease inhibitors. Clinical Epidemiology Group. AIDS 1999;13:1881-7., 1188Marra CM, Rajicic N, Barker DE, et al. A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS. AIDS 2002;16:1791-7., 1189Berenguer JP, Miralles P, Arrizabalaga J, et al. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2003;36:1047-52., 1190Pazzi A, Galli L, et al. The relationship between outcome of progressive multifocal leukoencephalopathy and type and response to ART in previously HAART-untreated patients. 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, CA, 2007.). Contrast enhancement on imaging also might predict better outcome (1165Berger JR, Levy RM, Flomenhoft D, Dobbs M. Predictive factors for prolonged survival in acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy. Ann Neurol 1998;44:341-9.).

Several agents have been proposed or reported anecdotally as more specific treatments for PML, but none of these has proven effective after more intensive scrutiny or more extensive study. On the basis of earlier case reports and drug inhibition of JCV in cell culture, IV and intrathecal cytaribine (cytosine arabinoside) were tested in a clinical trial, but neither exhibited clinical benefit (1191Hall CD, U Dafni. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. N Engl J Med 1998;338:1345-51.). Therefore, treatment with cytarabine is not recommended (DI). Although cidofovir is not effective against JCV in cell culture (1192Hou J, Major EO. The efficacy of nucleoside analogs against JC virus multiplication in a persistently infected human fetal brain cell line. J Neurovirol 1998;4:451-6.), initial case reports and retrospective series described efficacy in HIV-infected and uninfected patients with PML (1186De Luca A, Giancola ML, Ammassari A, et al. Cidofovir added to HAART improves virological and clinical outcome in AIDS-associated progressive multifocal leukoencephalopathy. AIDS 2000;14:117-21.). However, subsequent reports, including retrospective case-control studies (1187Cinque P, Pierotti C, Vigano MG, et al. The good and evil of HAART in HIV-related progressive multifocal leukoencephalopathy. J Neurovirol 2001;7:358-63., 1189Berenguer JP, Miralles P, Arrizabalaga J, et al. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2003;36:1047-52., 1193Gasnault J, Kousignian P, Kahraman M, et al. Cidofovir in AIDS-associated progressive multifocal leukoencephalopathy: a monocenter observational study with clinical and JC virus load monitoring. J Neurovirol 2001;7:375-81.), an open-label study of cidofovir in HIV-infected PML patients (1188Marra CM, Rajicic N, Barker DE, et al. A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS. AIDS 2002;16:1791-7.) and, eventually, a meta-analysis including the patients from the four above studies (1194De Luca A, Pezzotti P. Meta-analysis of cidofovir in AIDS-related progressive multifocal leukoencephalopathy on HAART: survival and neurological outcome. 12th Conference on Retroviruses and Opportunistic Infections. Boston, MA, 2005.) demonstrated no neurological benefit. Thus, treatment with cidofovir is not recommended (DII).

Immunomodulatory approaches for treatment of PML also have been tried, but none has yet been studied in a prospective, controlled clinical trial. Although an initial retrospective analysis suggested that interferon-alpha might improve survival of HIV-infected patients with PML (1195Huang SS, Skolasky RL, Dal Pan GJ, Royal WR, McArthur JC. Survival prolongation in HIV-associated progressive multifocal leukoencephalopathy treated with alpha-interferon: an observational study. J Neurovirol 1998;4:324-32.), a subsequent retrospective analysis did not demonstrate benefit beyond that afforded by ART; therefore, interferon-alpha cannot be recommended (DIII) (1196Geschwind MD, Skolasky RI, Royal WS, McArthur JC. The relative contributions of HAART and alpha-interferon for therapy of progressive multifocal leukoencephalopathy in AIDS. J Neurovirol 2001;7:353-7.). A single report described failure of interferon-beta treatment of HIV-associated PML (1197Nath A, Venkataramana A, Reich DS, Cortese I, Major EO. Progression of progressive multifocal leukoencephalopathy despite treatment with beta-interferon. Neurology 2006;66:149-50.). Case reports describe improvement in PML-related neurological dysfunction or recovery in three non-HIV-infected patients who underwent transplantation for lymphoma and in one patient with myelodysplastic syndrome treated with interleukin-2 (1198Przepiorka D, Jaeckle KA, Birdwell RR, et al. Successful treatment of progressive multifocal leukoencephalopathy with low-dose interleukin-2. Bone Marrow Transplant 1997;20:983-7., 1199Buckanovich RJ, Liu G, Stricker C, et al. Nonmyeloablative allogeneic stem cell transplantation for refractory Hodgkin's lymphoma complicated by interleukin-2 responsive progressive multifocal leukoencephalopathy. Ann Hematol 2002;81:410-3., 1200Kunschner L, Scott TF. Sustained recovery of progressive multifocal leukoencephalopathy after treatment with IL-2. Neurology 2005;65:1510.). After a cell-culture study that indicated JCV replication could be inhibited by a topoisomerase inhibitor (1201Kerr DA, Chang CF, Gordon J, Bjornsti MA, Khalili K. Inhibition of human neurotropic virus (JCV) DNA replication in glial cells by camptothecin. Virology 1993; 196:612-8.), an analogue, topotecan, was studied in a small trial. Results suggested a salutary effect in some, although likely little different from the natural course in other AIDS patients; therefore, topotecan is not recommended (DIII) (1202Royal W, 3rd, Dupont B, McGuire D, et al. Topotecan in the treatment of acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy. J Neurovirol 2003;9:411-9.).

On the basis of a report indicating that the serotonergic 5HT2a receptor can serve as the cellular receptor for JCV in a glial cell culture system (1203Elphick GF, Querbes W, Jordan JA, et al. The human polyomavirus, JCV, uses serotonin receptors to infect cells. Science 2004;306:1380-3.), drugs that block the 5HT2a receptor, including olanzapine, zisprasidone, mirtazapine, cyproheptadine, and risperidone, have been suggested as treatment for PML (1204Altschuler EL, Kast RE. The atypical antipsychotic agents ziprasidone, risperdone and olanzapine as treatment for and prophylaxis against progressive multifocal leukoencephalopathy. Med Hypotheses 2005;65:585-6.), although the rationale for this practice has been questioned (1205Santagata S, Kinney HC. Mechanism of JCV entry into oligodendrocytes. Science 2005;309:381-2.). Although anecdotal reports of using 5HT2a receptor inhibitors are available (1143Koralnik IJ. Progressive multifocal leukoencephalopathy revisited: has the disease outgrown its name? Ann Neurol 2006;60:162-73., 1206Lima MA, Auriel E, Wthrich C, Borenstein NM, Koralnik IJ. Progressive multifocal leukoencephalopathy as a complication of hepatitis C virus treatment in an HIV-negative patient. Clin Infect Dis 2005;41:417-9., 1207Focosi D, Fazzi R, Montanaro D, Emdin M, Petrini M. Progressive multifocal leukoencephalopathy in a haploidentical stem cell transplant recipient: a clinical, neuroradiological and virological response after treatment with risperidone. Antiviral Res 2007;74:156-8., 1208Vulliemoz S, Lurati-Ruiz F, Borruat FX, et al. Favourable outcome of progressive multifocal leucoencephalopathy in two patients with dermatomyositis. J Neurol Neurosurg Psychiatry 2006;77:1079-82.), previous disappointments after case reports of "successful" treatment emphasize the need to test this strategy by formal trial. Therefore, routine use of these agents is not justified (CIII).

Because ART-induced immune reconstitution is associated with both onset and paradoxical worsening of PML, corticosteroids have also been advocated and sometimes empirically used-at varying dosages and durations-in the treatment of PML. This approach has been extended by some to include all cases of PML, including those with little or no demonstrable inflammatory component. However, no evidence supports the routine use of corticosteroids in HIV-related PML without an inflammatory response on neuroimaging (DIII). In patients with inflammatory PML, corticosteroid treatment might have a more rational basis.

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Because the main approach to PML treatment is to reverse immunosuppression, patients might experience an exuberant response that can be classified as an IRIS or immune restoration disease (IRD) (298French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS 2004;18:1615-27.). Because restoration of anti-JCV defenses is the objective of ART treatment in PML patients, the salutary therapeutic response and the immunopathology of IRIS might intersect and overlap in the same patient. The concern in these patients is to determine when the immune or inflammatory response is helpful and when harmful by virtue of local bystander cytotoxicity and edema that cause further injury and threaten brain displacement and herniation. The cellular immune response against JCV, mediated by CD8+ T-lymphocytes, is critical to the containment of PML progression and has been associated with a favorable clinical outcome (1209Du Pasquier R, Kuroda M, Zheng Y, et al. A prospective study demonstrates an association between JC virus-specific cytotoxic T lymphocytes and the early control of progressive multifocal leukoencephalopathy. Brain 2004;127:1970-8.).

However, an "excessive" response related to IRIS might be lethal as a consequence of the inflammatory reaction or, rarely, brain swelling and herniation (1210Vendrely A, Bienvenu B, Gasnault J, et al. Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy. Acta Neuropathol 2005;109:449-55.). This inflammatory PML might be the disease phenotype on initial examination in patients who have recently begun ART or might evolve after ART has been initiated in the context of PML treatment. Corticosteroids have been used to control the local inflammatory reaction and reduce associated cerebral edema in this setting. Little published information exists to support their efficacy or, more specifically, to guide dosage and duration of this treatment. Corticosteroid treatment should be as short as possible and not overused. Mild swelling, edema, or contrast enhancement might be noted in some patients who respond favorably to ART, but most often these complications require no additional treatment if the patient is clinically stable and has no sign of impending brain herniation. However, in those with progressing clinical deficits and neuoroimaging features suggesting inflammatory disease (edema, swelling, and contrast enhancement), corticosteroid treatment is justified (BIII). Although some have suggested stopping ART in the face of PML-IRIS, this is likely counterproductive and is not recommended (DIII).

Management of Treatment Failure

Because PML remission might take several weeks, no strict criteria define disease progression. However, a working definition might be continued clinical worsening and continued detection of CSF JCV at 3 months. In the case of ART treatment, the plasma HIV RNA and blood CD4+ count responses might provide ancillary predictive information. When the suppression of HIV RNA or the boost of CD4+ count fails, attention might focus on modifying ART. Augmenting ART even when plasma HIV RNA is below detection is under study. However, when HIV responds well to ART but PML continues to worsen, attempting one of the unproven and not routinely recommended therapies described above is reasonable, after all are informed of their rationale and unproven efficacy. Better treatments and their rigorous assessment are needed.

Preventing Recurrence

Patients experiencing remission of PML after ART rarely suffer a subsequent recrudescence (1187Cinque P, Pierotti C, Vigano MG, et al. The good and evil of HAART in HIV-related progressive multifocal leukoencephalopathy. J Neurovirol 2001;7:358-63.), although no formal study of this has been undertaken. The main preventive measure, based on its role in reversing the disease, is an effective ART regimen that suppresses viremia and maintains CD4+ counts (AII).

Special Considerations During Pregnancy

Diagnostic evaluation for PML should be the same in pregnant women as in nonpregnant women. Therapy during pregnancy should consist of optimizing the antiretroviral regimen.

Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents
Opportunistic infectionPreferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues
Progressive multifocal leukoencephalopathy (JC virus infections)

Initiate antiretroviral therapy in ART-nave patients (AII)

Optimize ART in patients who develop PML in phase of HIV viremia on antiretroviral therapy (AIII)

Some patients might experience a remission after initiation of ART. Although their neurological deficits frequently persist, disease progression remits.

Corticosteroids may be used in patients with progressive clinical deficits and neuroimaging features suggesting inflammatory disease (e.g., edema, swelling, and contrast enhancement) as a result of initiating ART (BIII)

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