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Neurological disorders associated with chronic infections are often progressive as well as challenging to diagnose and manage. Among 4.4 million persons from 2004 to 2019 receiving universal health, progressive multifocal leukoencephalopathy (PML, n = 58) and Creutzfeldt-Jakob disease (CJD, n = 93) cases were identified, revealing stable yearly incidence rates with divergent comorbidities: HIV/AIDS affected 37.8% of PML cases while cerebrovascular disease affected 26.9% of CJD cases. Most CJD cases died within 1 year (73%) although PML cases lived beyond 5 years (34.1%) despite higher initial costs of care. PML and CJD represent important neurological disorders with evolving risk variables and impact on health care.

JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML) in immunosuppressed patients. There is currently no effective specific antiviral treatment and PML management relies on immune restoration. Prognosis markers are crucially needed in this disease because of its high mortality rate. In this work, we investigated the compartmentalization of JCV strains as well as the humoral neutralizing response in various matrices to further understand the pathophysiology of PML and define markers of survival. Four patients were included, of which three died in the few months following PML onset. Cerebrospinal fluid (CSF) viral loads were the highest, with plasma samples having lower viral loads and urine samples being mostly negative. Whether at PML onset or during follow-up, neutralizing antibody (NAb) titers directed against the same autologous strain (genotype or mutant) were the highest in plasma, with CSF titers being on average 430-fold lower and urine titers 500-fold lower at the same timepoint. Plasma NAb titers against autologous genotype or mutant were lower in non-survivor patients, though no neutralization "blind spot" was observed. The surviving patient was followed up until nine months after PML onset and presented, at that time, an increase in neutralizing titers, from 38-fold against the autologous genotype to around 200-fold against PML mutants. Our results suggest that patients' humoral neutralizing response against their autologous strain may play a role in PML outcome, with survivors developing high NAb titers in both plasma and CSF.

Background and Purpose: Progressive multifocal leukoencephalopathy (PML) represents a life-threatening demyelinating disorder of the brain caused by reactivation of a rare opportunistic infection with JC Polyomavirus . The aims of this study were to describe the incidence of a susceptibility-weighted imaging hypointense rim in patients with multifocal leukoencephalopathy and to explore the histologic correlates and prognostic value of the rim with regard to the clinical outcome., Materials and Methods: This retrospective study included 18 patients with a definite diagnosis of progressive multifocal leukoencephalopathy. Ten patients were HIV-positive, 3 patients had natalizumab-associated progressive multifocal leukoencephalopathy, 1 patient had multiple myeloma, 3 patients had a history of lymphoma, and 1 was diagnosed with acute myeloid leukemia. Patients were divided into short- (up to 12 months) and long-term (>12 months) survivors. A total of 93 initial and follow-up MR imaging examinations were reviewed. On SWI, the presence and development of a hypointense rim at the periphery of the progressive multifocal leukoencephalopathy lesions were noted. A postmortem histologic examination was performed in 2 patients: A rim formed in one, and in one, there was no rim., Results: A total of 73 progressive multifocal leukoencephalopathy lesions were observed. In 13 (72.2%) patients, a well-defined thin, linear, hypointense rim at the periphery of the lesion toward the cortical side was present, while in 5 (27.8%) patients, it was completely absent. All 11 long-term survivors and 2 short-term survivors presented with a prominent SWI-hypointense rim, while 5/7 short-term survivors did not have this rim., Conclusions: The thin, uniformly linear, gyriform SWI-hypointense rim in the paralesional U-fibers in patients with definite progressive multifocal leukoencephalopathy might represent an end-point stage of the neuroinflammatory process in long-term survivors., (© 2019 by American Journal of Neuroradiology.)

Progressive multifocal leukoencephalopathy (PML) is a life-threatening opportunistic infection of immunomodulatory therapies. PML cases reported in PubMed (1995-2017) following stem-cell transplantation (HSCT) or chemoimmunotherapy (CIT) for hematologic malignancies were reviewed. We found 107 cases, 40% were HSCT recipients (32 allogeneic, 11 autologous) and 40% indolent lymphomas receiving monoclonal antibodies (mAbs). HSCT cases had longer time to PML diagnosis (10.8 vs. 4 months, p < .001), higher proportion of PML therapy response (58% vs. 25%, p = .019), lower mortality rate (56% vs. 88%, p < .001), and longer median survival (8 vs. 2 months, p < .001). Outcome differences might be caused by selection bias as HSCT patients are most likely treated aggressively; however, time-dependent immune reconstitution might also contribute to their better prognosis. Increased use of mAbs and HSCT are associated with rising PML incidence in hematological malignancies, currently constituting the second largest vulnerable population after HIV-infected patients; further research is needed for its optimal treatment.

Post-kidney transplantation progressive multifocal leukoencephalopathy (PML) is a rare disease on which there are very few published reports on record. PML is a demyelinating disease caused by a destructive infection of the oligodendrocytes by the JC polyomavirus. No effective therapeutic protocol has been established other than measures to revive the immune function by reducing or discontinuing the administration of immunosuppressive agents. Most cases are progressive and show a poor prognosis. We herein report a case in which renal function has been maintained for 2 years following the onset of PML, which was initially diagnosed 3 years after kidney transplantation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Progressive multifocal leukoencephalopathy (PML) is an emerging complication of immunosuppressive therapies, especially natalizumab in multiple sclerosis (MS). Factors associated with functional outcome of natalizumab-associated PML (natalizumab-PML) have not been sufficiently described., Methods: We retrospectively analyzed medical records of all patients with natalizumab-PML ( n = 32) treated in our hospital since 2009. Disability measured by Expanded Disability Status Scale (EDSS) at two different time points (highest available EDSS during PML and last available EDSS after PML diagnosis) served as functional outcome parameters. Clinical, laboratory, and imaging data were analyzed for association with functional outcome by applying Spearman's rho and multivariate regression analysis., Results: In all, 31/32 patients survived PML. A poor functional outcome was associated with higher age, higher initial John Cunningham virus (JCV) copy number in cerebrospinal fluid (CSF), and more extensive PML lesions on initial magnetic resonance imaging (MRI). No association between functional outcome and the duration of natalizumab therapy or a delayed PML diagnosis was observed., Conclusion: This study will be useful for neurological practice to estimate functional outcome or disease severity of natalizumab-PML in primary care settings.

Objective: To examine retrospectively the effects of plasmapheresis (PLEX) on the survival and clinical outcomes of patients with multiple sclerosis (MS) and natalizumab (NTZ)-associated progressive multifocal leukoencephalopathy (PML)., Methods: The medical literature was searched for the terms natalizumab and progressive multifocal leukoencephalopathy. A total of 193 international and 34 Italian NTZ-PML cases were included. Clinical outcome was determined by comparing the patients' clinical status at PML diagnosis with status after PML resolution. The effects on survival and clinical outcome of PLEX, sex, age, country, pre-PML Expanded Disability Status Scale score, NTZ infusion number, prior immunosuppressant exposure, PML symptoms, PML lesion location at diagnosis, CSF JC virus status and copies, additional PML treatments and steroids, and PML immune reconstitution inflammatory syndrome (IRIS) development were investigated with both univariate and multivariate analyses., Results: A total of 219 NTZ-PML cases were analyzed, and 184 (84%) underwent PLEX, which did not reduce the mortality risk or the likelihood of poor vs favorable outcomes. Country was predictive of mortality and poor outcome, while PML-IRIS development was predictive of poor outcome., Conclusions: PLEX did not improve the survival or clinical outcomes of Italian or international patients with MS and NTZ-PML, suggesting that this treatment should be performed cautiously in the future., Classification of Evidence: This study provides Class III evidence that for patients with NTZ-PML, PLEX does not improve survival. The study lacks the statistical precision to exclude an important benefit or harm of PLEX., (© 2017 American Academy of Neurology.)

Background: The monoclonal antibody natalizumab (NTZ) is a highly effective treatment for patients with multiple sclerosis (MS). However, this drug is associated with increased risk of developing Progressive Multifocal Leukoencephalopathy (PML), an opportunistic infection of central nervous system (CNS) caused by the John Cunningham polyomavirus (JCV)., Objective: To describe the 12-month clinical course of 39 patients with MS (28 women, 11 men) who developed NTZ-related PML after a mean exposure of 39 infusions., Methods: An Italian independent collaborative repository initiative collected and analyzed socio-demographic, clinical, magnetic resonance imaging (MRI) data and number of JCV-DNA copies detected on cerebrospinal fluid (CSF) samples of patients diagnosed as affected by NTZ-related PML. The evolution of disability, measured by the Expanded Disability Status Scale, was assessed at NTZ start, at PML diagnosis and after 2, 6 and 12 months from PML diagnosis. The effect of clinical and paraclinical characteristics at PML diagnosis on the final outcome was also investigated., Results: Ten patients (25.6%) were diagnosed before 24 NTZ infusions. In six cases (15.4%) the PML suspect was made on the basis of highly suggestive MRI findings in absence of any detectable change of clinical conditions (asymptomatic PML). In patients with symptomatic PML, the diagnosis was quicker for those who presented with cognitive symptoms (n = 12) rather than for those with other neurological pictures (n = 21) (p = 0.003). Three patients (7.7%) died during the 12-month observation period, resulting in a survival rate of 92.3%. Asymptomatic PML, more localized brain involvement and gadolinium-enhancement detected at MRI, as well as lower viral load were associated with a better disability outcome (p-values<0.01)., Conclusion: Our findings support that early PML diagnosis, limited CNS involvement and initial signs of immune restoration are associated with a better outcome and higher survival rate, and confirm the utility of MRI as a surveillance tool for NTZ-treated patients., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Prosperini declares received consulting fees from Biogen and Novartis; speaker honoraria from Biogen, Genzyme, Novartis and Teva; travel grants from Biogen, Genzyme, Novartis and Teva; research grants from the Italian MS Society (Associazione Italiana Sclerosi Multipla) and Genzyme. Dr. Prosperini also acts as member of steering committee AIFA (Agenzia Italiana del Farmaco) on natalizumab. Dr. De Rossi received speaker honoraria from Biogen and Teva and travel grants from Biogen, Teva and Merk Serono. Dr. Scarpazza has nothing to disclose. Dr. Moiola received honoraria for speaking or for advisory board from Sanofi-Genzyme, Biogen, Novartis and Teva. Dr. Cosottini received speaker honoraria from Biogen. Dr. Gerevini received speaker honoraria from Biogen. Dr. Capra received consulting fees from Novartis and Biogen, and lecture fees and/or travel grants from Novartis, Biogen, Genzyme and Sanofi-Aventis.

Early brain biopsy may be indicated in HIV patients with focal brain lesion. This study aimed to evaluate and compare the safety and diagnostic value of brain biopsy in HIV patients in the pre-highly active antiretroviral therapy (HAART) versus post-HAART era via meta-analysis. Appropriate studies were identified per search criteria. The local database was retrospectively reviewed to select a similar patient cohort. Patient demographics, brain biopsy technique, histopathology and patient outcomes were extracted from each study. Study-specific outcomes were combined per random-effects model. Outcomes were compared between the pre-HAART and post-HAART era. Correlations between outcomes and baseline characteristics were assessed via meta-regression analysis. The proportions of histopathological diagnosis were tabulated and compared between the pre- and post-HAART era. Survival analysis was performed for patients in the post-HAART era. A total of 26 studies (including the local database) with 1209 patients were included in this meta-analysis. The most common indications for brain biopsy were diagnosis unlikely to be toxoplasmosis (n=8, 42.1%), focal brain lesion (n=5, 26.3%) or both (n=3, 15.8%). The weighted proportions for diagnostic success were 92% (95% CI 90.0% to 93.8%), change in management 57.7% (45.9% to 69.1%) and clinical improvement 36.6% (26.3% to 47.5%). Morbidity and mortality were 5.7% (3.6% to 8.3%) and 0.9% (0.3% to 1.9%), respectively. Diagnostic success rate was significantly higher in the post-HAART than the pre-HAART era (97.5% vs 91.9%, p=0.047). The odds ratio (OR) for diagnostic success in patients with contrast-enhanced lesions was 2.54 ((1.25 to 5.15), p<0.01). The median survival for HIV patients who underwent biopsy in the post-HAART era was 225 days (90-2446). Brain biopsy in HIV patients is safe with high diagnostic yield. Early brain biopsy should be considered in patients without classic presentation of toxoplasmosis encephalitis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Natalizumab, a highly effective therapy for relapsing-remitting multiple sclerosis, is associated with a risk of progressive multifocal leukoencephalopathy (PML). The objective of this analysis was to examine factors predicting survival in a large natalizumab-associated PML global population. Patients with natalizumab-associated PML identified through postmarketing surveillance were followed up for up to 24 months using a structured questionnaire completed by treating physicians. Demographic and clinical characteristics, JC viral load, magnetic resonance imaging (MRI) results, and Expanded Disability Status Scale (EDSS) and Karnofsky Performance Scale (KPS) scores were compared in survivors and nonsurvivors. Kaplan-Meier analysis was used to model survival function. Among the 336 patients included in this analysis, 76 % survived, with mean follow-up time from PML diagnosis of 16.1 months for survivors; mean time from diagnosis to death was 4.7 months for nonsurvivors. Survivors were significantly younger at diagnosis, had significantly lower EDSS scores and higher KPS scores prior to PML diagnosis, and had significantly lower cerebrospinal fluid JC viral load at the time of diagnosis. Patients with less extensive disease on MRI at diagnosis had a higher survival rate than those with widespread disease. Survivors generally had less functional disability pre-PML, at PML diagnosis, and in subsequent months. In survivors, functional disability appeared to stabilize approximately 6 months post-PML diagnosis. In this analysis, younger age at diagnosis, less functional disability prior to PML diagnosis, lower JC viral load at diagnosis, and more localized brain involvement by MRI at the time of diagnosis appeared to predict improved survival in natalizumab-associated PML.

To evaluate the situation and perspectives of progressive multifocal leukoencephalopathy (PML) in human immunodeficiency virus (HIV)-infected patients, we investigated changes in the incidence, causes, and long-term outcome of this disease in 72 acquired immunodeficiency syndrome (AIDS) patients who were diagnosed with PML from 1996 to 2011. Patients were classified according to the date of diagnosis in the first (1996-2000, n = 35), second (2001-2006, n = 26), and recent or third highly active antiretroviral therapy (HAART) period (2007-2011, n = 11). Overall, the incidence of PML decreased from 14.8 cases/1,000 patients/year in 1996 to 2.6 in 2005 and 0.8 in 2011, and nearly two-thirds of recent cases (64 %) were observed in HIV patients not attending clinical visits. The baseline median CD4+ count was higher in recently PML-diagnosed patients (77 vs. 86 vs. 101 cells/mm(3); p < 0.01), and this fact was associated with a cerebrospinal fluid (CSF) inflammatory profile (from 11 to 31 to 55 %, p = 0.007) and with a significantly longer survival (attributable death, 54 vs. 35 vs. 36 %, respectively, p < 0.01). Thus, the overall 1-year and 3-year survival rates were 55 and 50 %, respectively, increasing to 79 % at 1 year for patients with CD4+ count above 100 cells/mm(3) at diagnosis. In a Cox regression analysis, an older age (hazard ratio, HR 0.76), a baseline CD4+ count above 100 cells/mm(3) (HR 0.33), and a CSF inflammatory profile (HR 0.12) were significantly associated with a longer survival. The clinical presentation and outcome of PML in AIDS patients continue to change dramatically. Now, a declining incidence and long-term survival is observed.

Objective: Although the prognosis of natalizumab-associated progressive multifocal leukoencephalopathy (PML) seems to be better than HIV-associated PML, little is known about the long-term functional outcome in multiple sclerosis (MS) patients and the subsequent return of MS disease activity. We evaluated retrospectively 15 patients with natalizumab-associated PML treated at our centre., Patients and Methods: Fifteen MS-PML patients (nine women, six men) were referred to us from adjacent local centres. The patients had a median natalizumab exposure of 34 months at PML diagnosis. They received standardised treatment as described in previous work. Expanded Disability Status Scale (EDSS) and Karnofsky score in the year pre-PML, at PML-diagnosis (pre-immune reconstitution inflammatory syndrome (IRIS)) and post-PML were determined in 3-6 monthly intervals., Results: The median follow-up of these 15 patients was 21.5 months. None of the 15 patients died. Three patients had a Karnofsky score of 80 or higher, nine patients between 50-70 and three patients of 40 or lower at latest examination. Eight of the 15 patients developed seizures during acute PML phase. Fifty percent of those patients were not seizure-free one year post PML, despite continuation of antiepileptic treatment. The median EDSS in the year pre-PML was 2.5, 4.5 at PML diagnosis, 6.5 post-IRIS and 5.5 at latest examination. CSF became virus-free in eight of the 15 patients after a median time of 4.5 months. In nine patients, disease reappeared after a median time of seven months from PML diagnosis., Conclusions: Although the clinical outcome of natalizumab-treated PML patients is much better than in patients with HIV-associated PML, this may be further improved by treatment at reference centres using standardised therapy regimens and transient intensive care if needed. Systematic studies of appropriate MS immunotherapies after PML are critically needed.

Objectives: The aim of the study was to investigate whether survival after progressive multifocal leukoencephalopathy (PML) diagnosis in HIV-1-infected patients was associated with central nervous system penetration-effectiveness (CPE) score and the presence or absence of protease inhibitors in the treatment regimen., Methods: In the absence of treatments demonstrated to be effective for PML in HIV-1-infected patients and in the light of the controversy surrounding the use of CPE scores to make decisions on treatment after diagnosis, we determined whether there were differences in survival at 1 year depending on the type and characteristics of treatment. A multicentre retrospective observational study including three Spanish hospitals was carried out for the period from 1 January 1994 to 31 December 2009. Patients with a PML diagnosis were included in the study if they were symptomatic and met at least two of the following three criteria: (1) compatible radiological findings; (2) a positive polymerase chain reaction for John Cunningham virus (JCV) in the cerebrospinal fluid (CSF); (3) an absence of findings suggesting another infection in the central nervous system, after general CSF cultures for virus, bacteria and mycobacteria., Results: A total of 98 patients were included in the study; 24.5% were diagnosed in the period 1994-1999, 39.8% in 2000-2004 and 35.7% in 2005-2009. The median follow-up time was 363 days (interquartile range 108-1946 days). The median CD4 count was 76 cells/uL (interquartile range 30-166 cells/uL) and 62% of patients had an HIV viral load >50 HIV-1 RNA copies/ml. Thirty-eight per cent of patients received high-penetrance treatment, and 58% received treatment that included protease inhibitors. In the analysis of survival at 1 year, a higher CPE score did not result in an improvement in survival, but the presence of protease inhibitors in the regimen was associated with a statistically significant (P = 0.03) reduction in mortality (hazard ratio 0.40; 95% confidence interval 0.18-0.91)., Conclusions: We consider that the lower mortality observed in the protease inhibitor group may be clinically relevant, and, if this is the case, a treatment based on protease inhibitors may be indicated for patients diagnosed with PML., (© 2012 British HIV Association.)

Introduction: Several presentations of neurologic complications caused by JC virus (JCV) in human immunodeficiency virus (HIV)-infected patients have been described and need to be distinguished from the "classic" form of progressive multifocal leukoencephalopathy (PMl). The objectives of this study were: 1) to describe the spectrum and frequency of presentations of JCV-associated central nervous system (CNS) diseases; 2) identify factors associated with in-hospital mortality of patients with JCV-associated CNS disease; and 3) to estimate the overall mortality of this population., Material and Methods: This was a retrospective study of HIV-infected patients admitted consecutively for JCVassociated CNS diseases in a referral teaching center in São Paulo, Brazil, from 2002 to 2007. All patients with laboratory confirmed JCV-associated CNS diseases were included using the following criteria: compatible clinical and radiological features associated with the presence of JCV DNA in the cerebrospinal fluid. JCV-associated CNS diseases were classified as follows: 1) classic PMl; 2) inflammatory PMl; and 3) JC virus granule cell neuronopathy (GCN)., Results: We included 47 cases. JCV-associated CNS diseases were classified as follows: 1) classic PMl: 42 (89%); 2) inflammatory PMl: three (6%); and 3) JC virus GCN: four (9%). Nosocomial pneumonia (p = 0.003), previous diagnosis of HIV infection (p = 0.03), and imaging showing cerebellar and/or brainstem involvement (p = 0.02) were associated with in-hospital mortality. overall mortality during hospitalization was 34%., Conclusions: Novel presentations of JCV-associated CNS diseases were observed in our setting; nosocomial pneumonia, previous diagnosis of HIV infection, and cerebellar and/or brainstem involvement were associated with in-hospital mortality; and overall mortality was high.

Background: Investigations concerning the outcome for patients suffering from neuro-AIDS treated on a neurological intensive care unit and specific predictors indicating "dead" were analyzed., Material and Methods: A total of 56 patients with a mean age of 39 ± 0.7 years, a mean CD4+ cell count of 130 ± 166 CD4+ cells/µl and viral load of 146,520 ± 198,059 copies/ml were treated on a neurological intensive care unit due to different forms of neuro-AIDS., Results: Of the patients, 34% were immigrants of whom 74% came from sub-Saharan regions. In 57% of the patients the diagnosis of HIV infection was made during therapy on the neurological intensive care unit. The median for the time between diagnosis of HIV infection and the treatment on the neurological intensive care unit was 8 days for immigrants and 10 years for residents. The most common manifestations of neuro-AIDS were cerebral toxoplasmosis, cryptococcosis and progressive multifocal leukoencephalopathy (PML). Fifty per cent of the patients (n=28) died during treatment on the neurological intensive care unit. Negative predictors for the outcome "dead" were (a) artificial ventilation, (b) antiretroviral naïve immigrant, (c) primary cerebral lymphoma and (d) missing antiretroviral therapy as a result of admission to the intensive care unit., Discussion: The rate of death during treatment of neuro-AIDS on a neurological intensive care unit is much higher than during treatment of internal medicine problems of HIV infection. Antiretroviral naïve immigrants show a much higher rate of death compared to residents in Germany. A lot of research and effort is necessary to improve the availability of the Highly Active Anti-Retroviral Therapy (HAART) worldwide in order to improve the outcome especially for immigrants with neuro-AIDS treated on a neurological intensive care unit.

Background: A post marketing surveillance study was conducted to evaluate safety and efficacy of natalizumab in Swedish multiple sclerosis (MS) patients since its introduction in August 2006 until March 2010., Methods: Patients were registered in the web-based Swedish MS-registry at 40 locations and evaluated every 6 months. Adverse events and clinical outcomes were recorded., Results: One thousand one hundred and fifty-two patients were included (71.4% female) and 149 patients stopped treatment; the main reason was planned pregnancy. Anti-natalizumab antibodies were found in 4.5% (52 patients) of which 1.6% displayed persistent antibodies. Serious adverse events were rare, but included three cases with progressive multifocal leukoencephalopathy (PML). There were seven fatal cases, probably unrelated to the natalizumab treatment. For relapsing-remitting MS patients (n=901), mean Expanded Disability Status Scale (EDSS, -10.7%), Multiple Sclerosis Severity Scale (MSSS, -20.4%), Multiple Sclerosis Impact Scale (MSIS-29, physical -9.9%, psychological -13.3%) and Symbol Digit Modalities Test (SDMT, +10.7%) all showed significant improvements during 24 months of treatment with natalizumab. The Swedish web-based MS quality registry proved to function as a platform for post-marketing MS drug surveillance, providing long-term data regarding drug effects and adverse events beyond clinical trials., Conclusions: Our results indicate that natalizumab is generally well tolerated and has sustained efficacy for patients with active MS, though the risk of PML is still an important concern.

Objective: Natalizumab, a therapy for multiple sclerosis (MS), has been associated with progressive multifocal leukoencephalopathy (PML), a rare opportunistic infection of the CNS associated with the JC virus. We assessed clinical outcomes and identified variables associated with survival in 35 patients with natalizumab-associated PML., Methods: Physicians provided Karnofsky scores and narrative descriptions of clinical status. Data were supplemented by the natalizumab global safety database., Results: At the time of analysis, 25 patients (71%) had survived. Survivors were younger (median 40 vs 54 years) and had lower pre-PML Expanded Disability Status Scale scores (median 3.5 vs 5.5) and a shorter time from symptom onset to diagnosis (mean 44 vs 63 days) compared with individuals with fatal cases. Of patients with nonfatal cases, 86% had unilobar or multilobar disease on brain MRI at diagnosis, whereas 70% of those with fatal cases had widespread disease. Gender, MS duration, natalizumab exposure, prior immunosuppressant use, and CSF JC viral load at diagnosis were comparable. Most patients were treated with rapid removal of natalizumab from the circulation. The majority of patients developed immune reconstitution inflammatory syndrome and were treated with corticosteroids. Among survivors with at least 6 months follow-up, disability levels were evenly distributed among mild, moderate, and severe, based on physician-reported Karnofsky scores., Conclusions: Natalizumab-associated PML has improved survival compared with PML in other populations. Disability in survivors ranged from mild to severe. A shorter time from symptom onset to diagnosis and localized disease on MRI at diagnosis were associated with improved survival. These data suggest that earlier diagnosis through enhanced clinical vigilance and aggressive management may improve outcomes.

Objective: We examined if the CNS Penetration-Effectiveness (CPE) score of antiretroviral drugs was associated with survival after a diagnosis of HIV-related encephalopathy, progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis, or cryptococcal meningitis., Methods: Using data from the FHDH-ANRS CO4, we compared the survival of 9,932 HIV-infected patients diagnosed with a first neurologic AIDS-defining event in the pre-combination antiretroviral therapy (cART) (1992-1995), early cART (1996-1998), or late cART (1999-2004) periods. Follow-up was subdivided (CPE < 1.5 and CPE ≥ 1.5), and relative rates (RR) of death were estimated using multivariable Poisson regression models., Results: In the pre-cART and early cART periods, regimens with CPE ≥ 1.5 were associated with lower mortality after HIV-related encephalopathy (RR 0.64; 95% confidence interval [CI] 0.47-0.86 and RR 0.45; 95% CI 0.35-0.58) and after PML (RR 0.79; 95% CI 0.55-1.12 and RR 0.45; 95% CI 0.31-0.65), compared to regimens with CPE < 1.5, while in the late cART period there was no association between the CPE score and the mortality. A higher CPE score was also associated with a lower mortality in all periods after cerebral toxoplasmosis (RR 0.68, 95% CI 0.56-0.84) or cryptococcal meningitis (RR 0.50, 95% CI 0.34-0.74). Whatever the neurologic event, these associations were not maintained after adjustment on updated plasma HIV-RNA (missing, <500, ≥500 copies/mL) with RR ranging from 0.82 (95% CI 0.36-1.91) to 1.02 (0.69-1.52)., Conclusion: At the beginning of the cART era, the CPE score was of importance for survival after severe neurologic event, while in the late cART period, the additional effect of CPE score vanished with more powerful antiretroviral regimens associated with plasma viral load control.

Background: Progressive multifocal leukoencephalopathy (PML), a rare devastating demyelinating disease caused by the polyomavirus JC (JCV), occurs in severely immunocompromised patients, most of whom have advanced-stage HIV infection. Despite combination antiretroviral therapy (cART), 50% of patients die within 6 months of PML onset. We conducted a multicenter, open-label pilot trial evaluating the survival benefit of a five-drug cART designed to accelerate HIV replication decay and JCV-specific immune recovery., Methods and Findings: All the patients received an optimized cART with three or more drugs for 12 months, plus the fusion inhibitor enfuvirtide during the first 6 months. The main endpoint was the one-year survival rate. A total of 28 patients were enrolled. At entry, median CD4+ T-cell count was 53 per microliter and 86% of patients had detectable plasma HIV RNA and CSF JCV DNA levels. Seven patients died, all before month 4. The one-year survival estimate was 0.75 (95% confidence interval, 0.61 to 0.93). At month 6, JCV DNA was undetectable in the CSF of 81% of survivors. At month 12, 81% of patients had undetectable plasma HIV RNA, and the median CD4+ T-cell increment was 105 per microliter. In univariate analysis, higher total and naive CD4+ T-cell counts and lower CSF JCV DNA level at baseline were associated with better survival. JCV-specific functional memory CD4+ T-cell responses, based on a proliferation assay, were detected in 4% of patients at baseline and 43% at M12 (P = 0.008)., Conclusions: The early use of five-drug cART after PML diagnosis appears to improve survival. This is associated with recovery of anti-JCV T-cell responses and JCV clearance from CSF. A low CD4+ T-cell count (particularly naive subset) and high JCV DNA copies in CSF at PML diagnosis appear to be risk factors for death., Trial Registration: ClinicalTrials.gov NCT00120367.

Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating disease of the brain caused by the polyomavirus JC (JCV) in immunosuppressed people. There is no cure for PML but 1-year survival has increased from 10% to 50% in HIV-infected individuals treated with highly active antiretroviral therapy. We describe herein the clinical outcome of 24 PML patients whose survival exceeded 5 years, with a mean follow-up of 94.2 months (range, 60-188 months). Of all patients, only two were females including one who had non-Hodgkin's lymphoma and was HIV negative. All 23 HIV-positive patients received highly active antiretroviral therapy, and additional experimental therapies were not associated with a better clinical outcome. Marked neurological improvement occurred in 4/24 (17%) of patients, while 11/24 (46%) had partial improvement and 9/24 (37%) remained stable. By the end of the period of observation, 8/24 (33%) of patients had no significant disability despite persistent symptoms (modified Rankin disability scale (MRDS) =1), 6/24 (25%) had slight disability and were living independently (MRDS=2), 5/24 (21%) were moderately disabled, requiring some help during activities of daily living (MRDS=3) and 5/24 (21%) had moderately severe disability, requiring constant help or institutionalisation (MRDS=4). Patients with cerebellar lesions tended to have a worse clinical outcome. MRI showed leukomalacia with ventricular enlargement secondary to destruction of the white matter at the site of previous PML lesions, and focal areas of subcortical atrophy with preservation of the cortical ribbon. Of 20 patients tested, 19(95%) had detectable CD8+ cytotoxic T-lymphocytes against JCV in their blood. In absence of a specific treatment, immunotherapies aiming at boosting the cellular immune response against JCV may improve the prognosis of PML.

Background: Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease of the brain, caused by reactivation of the polyomavirus JC (JCV). PML has classically been described in individuals with profound cellular immunosuppression such as patients with AIDS, haematological malignancies, organ transplant recipients or those treated with immunosuppressive or immunomodulatory medications for autoimmune diseases. METHODS AND CASE REPORTS: The authors describe five HIV seronegative patients with minimal or occult immunosuppression who developed PML including two patients with alcoholic cirrhosis, one with untreated dermatomyositis and two with idiopathic CD4(+) T cell lymphocytopenia. The authors performed a review of the literature to find similar cases., Results: The authors found an additional 33 cases in the literature. Of a total of 38 cases, seven (18.4%) had hepatic cirrhosis, five (13.2%) had renal failure, including one with concomitant hepatic cirrhosis, two (5.2%) were pregnant women, two (5.2%) had concomitant dementia, one (2.6%) had dermatomyositis, and 22 (57.9%) had no specific underlying diagnosis. Among these 22, five (22.7%) had low CD4(+) T cell counts (0.080-0.294x10(9)/l) and were diagnosed as having idiopathic CD4(+) lymphocytopenia, and one had a borderline CD4(+) T cell count of 0.308x10(9)/l. The outcome was fatal in 27/38 (71.1%) cases within 1.5-120 months (median 8 months) from onset of symptoms, and 3/4 cases who harboured JCV-specific T cells in their peripheral blood had inactive disease with stable neurological deficits after 6-26 months of follow-up., Discussion: These results indicate that PML can occur in patients with minimal or occult immunosuppression, and one can revisit the generally accepted notion that profound cellular immunosuppression is a prerequisite for the development of PML.

Background: Progressive multifocal leukoencephalopathy (PML) is a neurological disease most often seen among immunosuppressed patients. The incidence of PML increased with an increasing incidence of HIV/AIDS. We describe recent trends and the epidemiology of PML-associated death in the era of highly active antiretroviral therapy (HAART)., Methods: National multiple-cause-of-death data for the USA were used to identify records with PML listed as a cause of death during 1979-2005. Age-adjusted PML-associated death rates were calculated overall and by sex, race, region and HIV status., Results: The PML-associated death rates peaked in the mid-1990s and decreased from 2.76 deaths per 1 million persons in 1992-1995 to 0.66 in 2002-2005. This decrease was mainly due to a decreasing death rate among PML decedents with HIV diagnosis, males and those aged 20-49 years at death. A decline in death rate was also seen among PML decedents without HIV diagnosis, although this trend was not significant. Decedents in the latter time period were more often female, and older. The proportion of HIV-associated deaths from PML decreased between 1992-1995 (1.4%) and 2002-2005 (1.0%)., Conclusion: PML mortality has decreased significantly since 1996 when HAART became the standard of care in the USA. This decline likely reflects increased survival among HIV-positive persons who receive HAART., (Copyright © 2010 S. Karger AG, Basel.)

Background: We sought to characterize the role of immunologic, virologic, and radiologic determinants of survival in patients with progressive multifocal leukoencephalopathy (PML)., Methods: We recorded the clinical outcome of 60 patients with PML (73% HIV+) who were prospectively evaluated between 2000 and 2007 for the presence of JC virus (JCV)-specific CD8+ cytotoxic T-lymphocytes (CTL) in blood., Results: Estimated probability of survival at 1 year was 52% for HIV+/PML and 58% for HIV- patients with PML. Patients with PML with detectable CTL within 3 months of diagnosis had a 1-year estimated survival of 73% compared to 46% for those without CTL (hazard ratio [HR] for death = 0.47, 95% confidence interval [CI] 0.13-1.75, p = 0.26). Patients with CTL response had an increased likelihood of having contrast enhancement of PML lesions and immune reconstitution inflammatory syndrome (odds ratio 3.7 and 7.8). Estimated 1-year survival was 48% in HIV+ patients with PML with CD4 count <200/microL at PML diagnosis compared to 67% in those with CD4 >200/microL (HR for death 1.41, 95% CI 0.27-7.38, p = 0.68). JCV DNA was detected in the urine of 48% and in the blood of 56% of patients with PML, but viruria and viremia were not associated with survival., Conclusions: The presence of JC virus (JCV)-specific cytotoxic T-lymphocytes (CTL) was associated with a trend toward longer survival in patients with progressive multifocal leukoencephalopathy (PML), which was more pronounced than the impact of CD4 count in HIV+ patients with PML early after diagnosis. Despite the association of contrast enhancement and immune reconstitution inflammatory syndrome with JCV-specific CTL, these cannot be considered as surrogate markers for the prognostic value of the CTL. Strategies aiming at improving the cellular immune response may improve the course of PML.

Background: We investigated the incidence and outcome of progressive multifocal leukoencephalopathy (PML) in human immunodeficiency virus (HIV)-infected individuals before and after the introduction of combination antiretroviral therapy (cART) in 1996., Methods: From 1988 through 2007, 226 cases of PML were reported to the Swiss HIV Cohort Study. By chart review, we confirmed 186 cases and recorded all-cause and PML-attributable mortality. For the survival analysis, 25 patients with postmortem diagnosis and 2 without CD4+ T cell counts were excluded, leaving a total of 159 patients (89 before 1996 and 70 during 1996-2007)., Results: The incidence rate of PML decreased from 0.24 cases per 100 patient-years (PY; 95% confidence interval [CI], 0.20-0.29 cases per 100 PY) before 1996 to 0.06 cases per 100 PY (95% CI, 0.04-0.10 cases per 100 PY) from 1996 onward. Patients who received a diagnosis before 1996 had a higher frequency of prior acquired immunodeficiency syndrome-defining conditions (P = .007) but similar CD4+ T cell counts (60 vs. 71 cells/microL; P = .25), compared with patients who received a diagnosis during 1996 or thereafter. The median time to PML-attributable death was 71 days (interquartile range, 44-140 days), compared with 90 days (interquartile range, 54-313 days) for all-cause mortality. The PML-attributable 1-year mortality rate decreased from 82.3 cases per 100 PY (95% CI, 58.8-115.1 cases per 100 PY) during the pre-cART era to 37.6 cases per 100 PY (95% CI, 23.4.-60.5 cases per 100 PY) during the cART era. In multivariate models, cART was the only factor associated with lower PML-attributable mortality (hazard ratio, 0.18; 95% CI, 0.07-0.50; P < .001), whereas all-cause mortality was associated with baseline CD4+ T cell count (hazard ratio per increase of 100 cells/microL, 0.52; 95% CI, 0.32-0.85; P = .010) and cART use (hazard ratio, 0.37; 95% CI, 0.19-0.75; P = .006)., Conclusions: cART reduced the incidence and PML-attributable 1-year mortality, regardless of baseline CD4+ T cell count, whereas overall mortality was dependent on cART use and baseline CD4+ T cell count.

Background: Human immunodeficiency virus (HIV) infection predisposes to progressive multifocal leukoencephalopathy (PML). Here, we describe the incidence, presentation, and prognosis of PML in HIV-1-infected patients during the period before highly active antiretroviral therapy (HAART) (1995-1996) and during the early HAART (1997-1999) and late HAART (2000-2006) periods., Methods: Patients from a nationwide population-based cohort of adult HIV-1-infected individuals were included. We calculated incidence rates of PML and median survival times after diagnosis. We also described neurological symptoms at presentation and follow-up., Results: Among 4,649 patients, we identified 47 patients with PML. The incidence rates were 3.3, 1.8, and 1.3 cases per 1000 person-years at risk in 1995-1996, 1997-1999, and 2000-2006, respectively. The risk of PML was significantly associated with low CD4(+) cell count, and 47% of cases were diagnosed by means of brain biopsy or polymerase chain reaction analysis for JC virus. The predominant neurological symptoms at presentation were coordination disturbance, cognitive defects, and limb paresis. Thirty-five patients died; the median survival time was 0.4 years (95% confidence interval [CI], 0.0-0.7) in 1995-1996 and 1.8 years (95% CI, 0.6-3.0) in both 1997-1999 and 2000-2006. CD4(+) cell count >50 cells/microL at diagnosis of PML was significantly associated with reduced mortality., Conclusions: The incidence of PML in HIV-infected patients decreased after the introduction of HAART. Survival after PML remains poor. In the management of PML, the main focus should be on prophylactic measures to avoid immunodeficiency.

Background: The aim of this study was to analyze the incidence of new cases, survival of HIV-1-infected patients with progressive multifocal leukoencephalopathy (PML), and the characteristics of PML-associated immune reconstitution inflammatory syndrome (IRIS)., Methods: Multicenter observational cohort study of all HIV-1-infected patients newly diagnosed of PML in 7 hospitals in Barcelona (Spain) from 2002 to 2006. The annual incidence of PML was calculated. Survival was estimated using the Kaplan-Meier method. IRIS was defined as new onset or rapid worsening of PML shortly after initiation of highly active antiretroviral therapy together with a decline in HIV-1 viral load and rising of CD4 lymphocytes., Results: Sixty-one new cases of PML were diagnosed. The mean survival time was 15 months [95% confidence interval (CI), 11 to 19]. The Kaplan-Meier estimates of the probability of survival were 47.7% (95% CI, 35 to 59) at 6 months, 38.6% (95% CI, 25 to 51) at 12 months, 35.1% (95% CI, 22 to 48) at 24 months, and 25.1% (95% CI, 10 to 40) at 36 months. IRIS was diagnosed in 14 (23%) cases. Mortality was similar in patients with and without IRIS., Conclusions: PML continues to be one of the deadliest opportunistic infections in acquired immunodeficiency syndrome patients. The development of PML-associated IRIS has no influence on prognosis.

Progressive multifocal leukoencephalopathy is a demyelinating disease with a high mortality caused by the JC virus and occurs in about 5% of HIV-infected patients. Highly active anti-retroviral therapy (HAART) has a proven efficacy in prolonging the survival of patients with AIDS-associated PML, but there are differing opinions about adding cidofovir to the treatment of PML. To investigate the benefit of HAART combined with cidofovir, we retrospectively analysed the survival of 33 patients with AIDS-associated PML proven by PCR in CSF, biopsy or at autopsy. Additionally, we also analysed 37 patients with probable PML. Seventeen (51.5%) of the patients with confirmed PML were treated with HAART and 14 (42.4%) with cidofovir in any combination. Of these patients, 13 (39.4%) were treated with HAART and cidofovir in combination, four (12.1%) patients received only HAART without cidofovir and one (3%) patient received only cidofovir without HAART. Fifteen patients did not receive HAART or cidofovir. The cumulative survival was significantly longer in patients with HAART than in patients without HAART (p = 0.006), independent whether cidofovir was given or not. In comparison with single therapy with HAART, the combination of HAART and cidofovir showed no significant increase in survival (p = 0.435). Therefore, a benefit for cidofovir in addition to HAART in the treatment of PML in HIV-infected patients could not be proven.

The magnetic resonance (MR) imaging patterns of HIV-infected patients affected by progressive multifocal leukoencephalopathy (PML) in the HAART era have not been extensively documented. The aim of the present study is to describe the MR features of PML in HIV-infected patients at diagnosis, and the evolution during follow-up, evaluating the impact of HAART on imaging, and to correlate the MR pattern with the virological and immunological levels and with survival. We retrospectively reviewed MR imaging at baseline and at the last available follow-up within 6 months of diagnosis (median 4 months, range 1-6) of 31 HIV-positive patients affected by PML. A closer follow-up [median interval from diagnosis 39 days (range 20-139)] was also reported. At the onset of neurological disorder, 19 patients were naive for antiretroviral therapy, 7 patients were on HAART, and 5 patients were experienced but were not taking antiretroviral therapy. Upon PML diagnosis no significant differences at imaging were observed between naive and experienced patients and HAART-treated or non-HAART-treated patients. MR findings were not related to immunological status, either at baseline or at follow-up. A radiological improvement within 6 months was associated with a higher probability of a more favorable clinical evolution [OR 14.0 (2.2-87.2), p = 0.003]. The overall probability of survival at 6 months was 61.5%. A better survival was observed in patients with stable or improved MR imaging findings within 6 months [HR 4.55 (95%CI 1.36-15.19, p = 0.009]. Although HAART prolonged the survival of HIV-positive patients affected by PML, it did not seem to influence the PML MR pattern of presentation and the imaging evolution. Only the radiological outcome was predictive of clinical outcome.

Objectives: To analyze virological and immunological features of AIDS-related progressive multifocal leukoencepalophathy (PML) and their association to disease prognosis., Methods: In HIV-infected patients with virologically confirmed PML, JC virus (JCV) DNA load and levels of Macrophage Chemoattractant Protein (MCP)-1 were determined in cerebrospinal fluid. JCV genotypes, rearrangements and JCV DNA binding sites for cellular transcription factors were analyzed by sequencing the viral VP1 region and regulatory region (RR)., Results: 45 patients were analyzed: 60% were exposed to highly active antiretroviral therapy (HAART) after PML and 24% before the disease onset. JCV DNA load in cerebrospinal fluid was a strong predictor of patients survival. Lower levels of JCV DNA in cerebrospinal fluid were associated with the following virologic factors: viral genotype 4 (p = 0.043), more rearrangements in the RR (p = 0.046), duplication of RR block B (p = 0.028), and duplication of binding sites for cellular transcription factor NF-1 (p = 0.060). In patients with prior antiretroviral exposure there was a trend towards a higher number of binding sites for cellular transcription factors (p = 0.068). Lower JCV load was also predicted by exposure to HAART (p = 0.010), higher baseline CD4 counts (p = 0.009) and higher cerebrospinal fluid MCP-1 levels (p = 0.036). In a multiple regression model, MCP-1 levels were independently associated with JCV load., Conclusion: HAART leads to a partial immune-mediated control of JCV replication; the virus may tend to escape through the selection of rearrangements in the RR, some associated with enhanced viral replication efficiency, other resulting in multiplication of binding sites for cellular transcription factors.

Based on health insurance claims from a large U.S. health insurer, the authors identified 44 progressive multifocal leukoencephalopathy (PML) cases from 2002 through 2004 and described their characteristics, including antecedent diagnoses and treatments as well as survival. Immunosuppressive conditions such as HIV/AIDS, rather than potentially immunosuppressive treatments, were the main antecedents of PML. A lower mortality was observed among PML patients whose antecedent diagnosis was HIV/AIDS, the majority of whom received highly active antiretroviral therapy.

Introduction: Progressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) mostly occurs in different conditions of impaired cellular immunity like acquired immunodeficiency syndrome (AIDS) and rarely when humoral immunity is involved. PML remains unusual although there is a high prevalence of JCV among the population and immunosuppression is not rare because of chemotherapies., Methods: We present two groups of patients: first, we studied reports of three patients suffering from lymphoma type B who developed a PML, proved by cerebral biopsy. The second group included six HIV-infected patients who developed a PML. No biopsy was made but MRI and the physical examination suggested strong arguments for the diagnosis., Results: In the first group, PML was furthered by humoral immunosuppression (rate of immunoglobulin G under 4 g/l). Average survival was five months. In the second group, HIV-infected patients had a survival range from 2 to 58 months after the first PML symptoms and one of them is still alive., Conclusion: Humoral immunosuppression in lymphoma can contribute to the development of PML. PML prognosis is often severe but prolonged survivals were described. So it is necessary to restore a sufficient immunity level. But immunity failure may be insufficient to lead to PML. In the case of lymphomas, the role of malignant lymphocytes in multiplication and mutation of JCV might be an interesting pathophysiological hypothesis.

The aims of this study were to evaluate the clinical characteristics of HIV-negative patients affected by lymphoproliferative disorders (LPD) who developed progressive multifocal leukoencephalopathy (PML), to delineate the risk factors, and to analyze whether the new antineoplastic therapies are changing the natural history of this infectious disease. We retrospectively analyzed 46 cases with confirmed LPD-associated PML published from 1958 to 2004. Patients were stratified according to two different time periods: group A included patients diagnosed before 1989, and group B included patients diagnosed since 1990, after introduction of purine analogues. Group A patients (n = 22) had received alkylating agents and/or radiotherapy, and the majority (63.6%) had advanced Hodgkin disease. At univariate analysis, uncontrolled Hodgkin disease was the only risk factor for PML. In group B patients (n = 24), the most frequent treatments received were purine analogues (58.3%) and high-dose therapy with hematopoietic stem cell transplantation (33.3%; HDT/HSCT). B-cell chronic lymphocytic leukemia (45.8%) and aggressive non-Hodgkin lymphoma (24.9%) were the most frequent underlying LPDs. Patients treated with purine analogues were more likely to have active LPD, lower CD4 cell counts, and to be older and male than were HSCT recipients. The median interval from purine analogues or HDT/HSCT to PML was 11 months. In HDT/HSCT recipients, this interval was delayed for 10 months when peri-transplantation rituximab was used. Univariate analysis identified age >55 years, male sex, and CD4 cell counts

Progressive multifocal leukoencephalopathy (PML) is a demyelinating infection caused by the JC virus. It is an emerging disease in transplant recipients; however, it remains poorly defined. Twenty-four cases of PML reported in the literature in transplant recipients were reviewed. Of the 24 cases, nine occurred in renal, six in bone marrow, four in liver, three in heart and two in lung transplant recipients. Median time to onset was 17 months; 71% occurred within 24 months of transplantation. PML tended to occur later in the kidney recipients (P=0.04). Seventy-five percent had subacute presentation; hemiparesis (50%), apathy (46%) and confusion (38%) were the most frequently presented features. Treatment included reduction of immunosuppression and chemotherapy, mainly cidofovir. Death occurred within 2.5 months of the onset of symptoms in 17 patients (71%). PML is a unique entity that should be considered in any transplant recipient with neurological symptoms. The outcome is usually fatal, although regression has been reported.

Objective: To describe the clinical course and risk factors of death in highly active antiretroviral therapy (HAART)-treated patients with progressive multifocal leukencephalopathy (PML); to evaluate the efficacy of cidofovir in addition to HAART., Methods: Retrospective multicenter cohort study of PML in HIV-1-infected patients. Diagnosis of PML was confirmed by histology or by positive polymerase chain reaction for JC virus (JCV) in cerebrospinal fluid (CSF) or was made by typical radiologic and clinical findings., Results: Thirty-five cases of PML were identified. The diagnosis was made by histology (9 cases), detection of JCV in CSF (17 cases), and by radiologic findings (9 cases). Upon manifestation of PML, 15/35 patients had never received HAART, and 11/35 were on HAART for >6 months (median 1126 days). In 9/35 cases, clinical manifestation of PML occurred within 6 months after initiation of HAART. All patients received HAART after PML diagnosis. After a median follow-up of 553 days (range 28-2694 days), the median survival time was not reached. In 12 patients who were treated concomitantly with cidofovir, cumulative survival was significantly shorter than in patients without cidofovir (P = 0.03). Patients in whom PML was diagnosed while on HAART demonstrated a trend toward a shorter survival than HAART-naive patients (P = 0.15)., Conclusions: PML continues to occur in HIV-1-infected patients even when they are treated with HAART. Patients developing PML on HAART had a trend toward a shorter median survival compared with treatment-naive patients, and cidofovir therapy was not associated with improved survival in this cohort.

Aim: To analyse the results of a 15-year study of opportunistic diseases in AIDS patients., Material and Methods: The spectrum of opportunistic diseases were made in AIDS patients in respect to clinical, laboratory and autopsy data for the periods: 1987-1992 (n = 27, 25 deaths--92.6%), 1993-1997 (n = 95, 58 deaths--61.8%), 1998-1999 (n = 70, 28 deaths--40%), 2000-2001 (n = 126, 31 deaths--24.6%), 2002 (n = 80, 32 deaths--40%)., Results: The spectrum of opportunistic diseases in AIDS patients was determined for the above time periods and causes underlying these diseases have been determined., Conclusion: Among opportunistic diseases associated with HIV infections most prevalent were the following: tuberculosis, cytomegaloviral infections, cerebral toxoplasmosis. Leading modern trends were identified: increasing morbidity of AIDS, tuberculosis, new AIDS cases at late stages with severe opportunistic diseases (2/3 of deaths).

Human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML) remains a relevant clinical problem even in the era of highly active antiretroviral therapy (HAART). Aims of the study were to analyze clinical and treatment-related features and the survival probability of PML patients observed within the Italian Registry Investigative Neuro AIDS (IRINA) during a 29-month period of HAART. Intravenous drug use, the presence of focal signs, and the involvement of white matter at neuroradiology increased the risk of having PML. A reduced probability of PML was observed when meningeal signs were reported. Patients starting HAART at PML diagnosis and previously naïve for antiretrovirals showed significantly higher 1-year probability of survival (.58), compared to those continuing HAART (.24), or never receiving HAART (.00). Higher CD4 cell count were associated with a higher survival probability (.45). At multivariate analysis, a younger age, higher CD4, starting HAART at PML diagnosis, the absence of previous acquired immunodeficiency syndrome (AIDS)-defining events, and the absence of a severe neurologic impairment were all associated with a reduced hazard of death. The use of cidofovir showed a trend towards a reduced risk of death.

Objective: To assess the safety, tolerability and effect of cidofovir for HIV-1 associated progressive multifocal leukoencephalopathy., Design: Prospective, open-label study in nine AIDS Clinical Trials Units., Patients and Methods: Twenty-four HIV-1-infected individuals, with neuroimaging and clinical findings consistent with PML, and symptoms for 90 days or less, whose diagnosis was confirmed by the detection of JC virus DNA in the cerebrospinal fluid or brain biopsy, received cidofovir 5 mg/kg intravenously at baseline and 1 week, followed by infusions every 2 weeks with the dose adjusted for renal function. Follow-up continued to 24 weeks. The safety of cidofovir and changes in neurological examination scores between baseline and week 8 were assessed., Results: Seventeen subjects were receiving potent antiretroviral agents. Survival at 12 weeks was 54%. The CD4 cell count at entry was significantly associated with survival (P = 0.02). Five subjects discontinued treatment because of toxicity: a 50% or greater decrease in intraocular pressure in either eye in four, and proteinuria in one. Overall, magnetic resonance imaging abnormalities and neurological examination scores worsened. Only two subjects experienced a 25% or greater improvement in neurological examination scores at week 8, which were significantly better in subjects with HIV-1-RNA levels of 500 copies/ml or less at entry compared with those with HIV-1-RNA levels over 500 copies/ml (P = 0.05)., Conclusion: Cidofovir did not improve neurological examination scores at week 8. However, such scores were significantly better in subjects who entered with suppressed plasma HIV-1-RNA levels, which could be the result of control of HIV-1 infection itself or cidofovir., (Copyright 2002 Lippincott Williams & Wilkins)

JC virus (JCV) is the causative agent of progressive multifocal leukoencephalopathy (PML), a demyelinating central nervous system infection that mainly affects patients with acquired immunodeficiency syndrome. The diagnostic value of the detection of JCV DNA in cerebrospinal fluid (CSF) has been proved. A correlation between the JCV burden in CSF and the PML prognosis has been proposed. To our knowledge, the present study is the first to examine JCV burden in CSF in relation to the magnitude of neurological damage. An in-house quantitative polymerase chain reaction assay was used for measurement of the JCV burden in CSF samples from 12 patients with PML. A wide variation in JCV load (6.4 log) was found among the patient CSF samples, a finding that makes JCV load measurements worthwhile. Virus load values of >4.68 log were associated with shorter patient survival time. No correlation was found between the virus load values and the global volume of brain tissue damaged. Our data suggest that factors other than the volume of neurological lesions influence the shedding of JCV in the CSF.

Aims: Progressive multifocal leukoencephalopathy (PML) develops in up to 4-8% of all AIDS patients. Before highly active antiretroviral therapies (HAART) the median survival was only 4-6 months. In this study we analyzed epidemiological parameters in AIDS-related LMP patients in search for differences in the incidence and prognosis between before and after HAART era., Methods: Retrospective review of clinical histories of patients diagnosed of AIDS and PML at Hospital Meixoeiro in Vigo, Spain, between 01/01/94-31/05/97 (Before-HAART period) and 01/06/97-30/04/00 (After-HAART period). PML was diagnosed by clinical and neuroimaging criteria, with biopsy in 2 cases and positive JC virus hibridation in CSF in another case., Results: We identified 12 patients (global prevalence of 3.8%, without differences between periods): 11 males, 10 intravenous drugs users (IDU), mean age of 38 years (31-43). In 6, LMP was the first opportunistic infection. When PML was diagnosed, 6 patients had a HIV viral load (VL) > 250.000 copies of RNA/ml (range, 254.003-3.170.000), and overall a mean CD4 lymphocytes counts of 89 x 10(6)/ml (40-134). Three patients received cytarabine + Interferon with zidovudine (2 patients) and zidovudine + lamivudine (1 patient) and other patient HAART + cidofovir, but no improvement was observed. The median survival was 10 months in before-HAART group and 17 months in after-HAART group, with a survival > 48 months in 2 patients in the last group., Conclusions: LMP is observed in severely immunosuppressed IDU men (VL > log 5 copies RNA/ml and CD4 < 150 x 106/ml). Complementary treatments were ineffective and only in patients with HAART a prolonged survival was observed.