HIV-associated Progressive Multifocal Leukoencephalopathy Research Articles

Successful treatment of HIV-associated progressive multifocal leukoencephalopathy (PML) with mirtazapine, mefloquine, and IVIG combination therapy: a case report.

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system caused by reactivation of the polyomavirus JC (JCV). Human immunodeficiency virus (HIV) infection is one of the leading causes of PML which has high morbidity and mortality due to the lack of a proven standard treatment. We found clinical and radiological improvement with the combination of high-dose methylprednisolone, mirtazapine, mefloquine, and IVIG in our patient who presented with neurological symptoms and had diagnosed concurrent acquired immunodeficiency syndrome (AIDS) and PML. To our knowledge, our case is the first HIV-associated PML which responded to this combination therapy.

Progressive multifocal leukoencephalopathy: Insights on pathogenesis and potential treatments

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease caused by the polyomavirus JC (JCV), which affects persons with an impaired immune system, such as in HIV infection, congenital immunodeficiencies or during immunosuppressive or immunomodulant therapies. Currently, there is no effective antiviral treatment for PML and its remission can only be achieved by reversing immune suppression, e.g., by starting antiretroviral treatment in patients with HIV-associated PML or by withdrawing immunosuppressive drugs in other conditions.

Progressive multifocal leukoencephalopathy: MRI findings in HIV-infected patients are closer to rituximab- than natalizumab-associated PML.

ObjectivesTo compare brain MRI findings in progressive multifocal leukoencephalopathy (PML) associated to rituximab and natalizumab treatments and HIV infection.Materials and methodsIn this retrospective, multicentric study, we analyzed brain MRI exams from 72 patients diagnosed with definite PML: 32 after natalizumab treatment, 20 after rituximab treatment, and 20 HIV patients. We compared T2- or FLAIR-weighted images, diffusion-weighted images, T2*-weighted images, and contrast enhancement features, as well as lesion distribution, especially gray matter involvement.ResultsThe three PML entities affect U-fibers associated with low signal intensities on T2*-weighted sequences. Natalizumab-associated PML showed a punctuate microcystic appearance in or in the vicinity of the main PML lesions, a potential involvement of the cortex, and contrast enhancement. HIV and rituximab-associated PML showed only mild contrast enhancement, punctuate appearance, and cortical involvement. The CD4/CD8 ratio showed a trend to be higher in the natalizumab group, possibly mirroring a more efficient immune response.ConclusionImaging features of rituximab-associated PML are different from those of natalizumab-associated PML and are closer to those observed in HIV-associated PML.Key Points • Nowadays, PML is emerging as a complication of new effective therapies based on monoclonal antibodies. • Natalizumab-associated PML shows more inflammatory signs, a perivascular distribution “the milky way,” and more cortex involvement than rituximab- and HIV-associated PML. • MRI differences are probably related to higher levels of immunosuppression in HIV patients and those under rituximab therapy.

Signs of Psychosis Leading to a Diagnosis of Progressive Multifocal Leukoencephalopathy: A Case Report

Introduction: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating process of the central nervous system that occurs in in the setting of severe immunocompromise. Patients with PML develop varying focal neurological deficits and mental status changes that have not been well-described previously. Clinical findings: We present a patient who was found by security wandering the lobby of this hospital. He was oriented only to self and unable to state a reason for presentation. Medical records were limited and included a visit to an outside hospital that documented a past medical history of HIV infection. He exhibited multiple signs of psychosis such as thought blocking and a disorganized thought process. Main diagnoses, therapeutic interventions, and outcomes: After thorough evaluation, he was diagnosed with HIV-associated PML based on a CD4 count of 68 cells/microliter, subcortical white matter signal abnormalities on brain MRI, and positive CSF PCR for JC polyomavirus. Despite initiation of antiretroviral therapy, he unfortunately clinically declined and was ultimately transitioned to hospice care. Conclusions: While survival from PML has significantly improved with the advent of antiretroviral therapy, the overall prognosis remains poor. This case report emphasizes that PML should be included in the differential diagnosis for any immunocompromised patients with mental status changes even if they do not present with overt focal neurological deficits. It also highlights the importance of continuous HIV medical care to minimize the risk of patients developing such devastating complications.

Inflammatory HIV-associated progressive multifocal leukoencephalopathy associated with high CD4 count (P4.9-009)

Inflammatory HIV-associated progressive multifocal leukoencephalopathy associated with high CD4 count (P4.9-009)

Diagnosis and Treatment of Progressive Multifocal Leukoencephalopathy Associated with Multiple Sclerosis Therapies.

Progressive multifocal leukoencephalopathy (PML) is a rare, but serious, complication encountered in patients treated with a select number of disease-modifying therapies (DMTs) utilized in treating multiple sclerosis (MS). PML results from a viral infection in the brain for which the only demonstrated effective therapy is restoring the perturbed immune system-typically achieved in the patient with MS by removing the offending therapeutic agent or, in the case of HIV-associated PML, treatment with highly active antiretroviral therapies. Other therapies for PML remain either ineffective or experimental. Significant work to understand the virus and host interaction has been undertaken, but lack of an animal model for the disorder has significantly hindered progress, especially with respect to development of treatments. Strategies to limit risk of PML with natalizumab, a drug that carries a uniquely high risk for the development of the disorder, have been developed. Identifying factors such as positive JC virus antibody status that increase PML risk, at least in theory, should decrease the incidence rate of the disease. Whether other risk factors for PML can be identified and validated or unique strategies should be employed in association with other DMTs that predispose to PML and whether this has a salutary effect on outcome remains to be demonstrated. Identifying PML early, then promptly eliminating drug in the case of natalizumab-associated PML has demonstrated better outcomes, but the complication of PML continues to carry significant morbidity and mortality. While the scientific community has yet to identify targeted therapy with proven efficacy against JCV or PML there are several candidates being studied.

Clinical analysis on HIV-associated progressive multifocal leukoencephalopathy: report of four probable cases

Objective To summarize the clinical manifestations, laboratory and MRI examinations, treatment and prognosis of 4 patients with human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML). Methods The clinical data of 4 patients with HIV-associated PML was retrospectively analyzed. Results All of the 4 cases presented with progressive neurological function deficit and limb weakness. One case was accompanied by dysphasia, and one by dizziness. These symptoms got worsened as time went on. Cranial MRI revealed demyelination, hypointense signal in T 1 WI, hyperintense signal in T 2 WI and FLAIR. DWI revealed central hypointense and peripheral hyperintense signal. Enhanced scan revealed no contrast enhancement. Two cases were treated with highly active antiretroviral therapy (HAART), and the longest survival was 20 months. Patients who did not take standard anti-HIV therapies had a poor long-term prognosis. Conclusions Patients with HIV-associated PML mainly present progressively worsened neurological function deficit. The imaging manifestations are typical. Early and timely HAART may play a role in the treatment. DOI: 10.3969/j.issn.1672-6731.2016.08.005

Neurological immune reconstitution inflammatory response: riding the tide of immune recovery.

This manuscript reviews current reports about clinical aspects of immune reconstitution inflammatory syndrome (IRIS), with a particular emphasis on IRIS in the setting of progressive multifocal leukoencephalopathy (PML) and to a lesser extent on cryptococcal meningitis and HIV. PML prognosis has been radically improved, as it has become possible to provide immune reconstitution, although some remaining morbidity and mortality results from excess inflammation. Similar pathologic responses are seen less often, but remain clinically important in cryptococcal meningitis, and HIV. Early diagnosis and active management of PML results in optimal outcomes with survival of 75% or higher in multiple recent series. These finding apply both to natalizumab and HIV-associated PML. Cryptococcal meningitis is frequently complicated by IRIS, and early treatment with antifungal therapy preceding HIV therapy provides optimal outcomes. HIV IRIS is reduced by early therapy, which is now recommended, but even on therapy, chronic dysregulated immune responses may play important roles in ongoing HIV-associated neurocognitive disease (HAND), which is common, as well as rare but more dramatic subacute encephalopathies. The clinician must actively monitor and treat both opportunistic infection and the inflammatory response that is essential to recovery but may itself augment disease and injury.

HIV-associated progressive multifocal leukoencephalopathy: longitudinal study of JC virus non-coding control region rearrangements and host immunity

John Cunningham virus (JCV), the etiological agent of progressive multifocal leukoencephalopathy (PML), contains a hyper-variable non-coding control region usually detected in urine of healthy individuals as archetype form and in the brain and cerebrospinal fluid (CSF) of PML patients as rearranged form. We report a case of HIV-related PML with clinical, immunological and virological data longitudinally collected. On admission (t0), after 8-week treatment with a rescue highly active antiretroviral therapy (HAART), the patient showed a CSF-JCV load of 16,732 gEq/ml, undetectable HIV-RNA and an increase of CD4+ cell count. Brain magnetic resonance imaging (MRI) showed PML-compatible lesions without contrast enhancement. We considered PML-immune reconstitution inflammatory syndrome as plausible because of the sudden onset of neurological symptoms after the effective HAART. An experimental JCV treatment with mefloquine and mirtazapine was added to steroid boli. Two weeks later (t1), motor function worsened and MRI showed expanded lesions with cytotoxic oedema. CSF JCV-DNA increased (26,263 gEq/ml) and JCV viremia was detected. After 4 weeks (t2), JCV was detected only in CSF (37,719 gEq/ml), and 8 weeks after admission (t3), JC viral load decreased in CSF and JCV viremia reappeared. The patient showed high level of immune activation both in peripheral blood and CSF. He died 4 weeks later. Considering disease progression, combined therapy failure and immune hyper-activation, we finally classified the case as classical PML. The archetype variant found in CSF at t0/t3 and a rearranged sequence detected at t1/t2 suggest that PML can develop from an archetype virus and that the appearance of rearranged genotypes contribute to faster disease progression.

Disease course and outcome of 15 monocentrically treated natalizumab-associated progressive multifocal leukoencephalopathy patients

ObjectiveAlthough 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...

Akinetic Mutism Caused by HIV-associated Progressive Multifocal Leukoencephalopathy was Successfully Treated with Mefloquine: A Serial Multimodal MRI Study

We report a case of a patient with highly active anti-retroviral therapy-resistant human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML). The patient showed an improvement in imaging findings and clinical symptoms after mefloquine was introduced as an additional treatment. Serial assessment of white matter lesions was conducted by proton magnetic resonance spectroscopy ((1)H-MRS) and diffusion-weighted imaging (DWI). As the clinical symptoms improved, the N-acetylaspartate/creatine ratio increased, the choline/creatine ratio decreased, and the elevated ADC value decreased. These concomitant changes suggested that (1)H-MRS and DWI were useful for the assessment of the therapeutic effect on PML.

HIV-associated PML: Changing epidemiology and clinical approach

Despite the availability of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus (HIV) infection, there has not been a dramatic decrease in the frequency of progressive multifocal leukoencephalopathy (PML) in the HIV-infected population. Usually a multifocal progressive disease of nonenhancing lesions in white matter, PML can have distinct characteristics in HIV-infected patients, including unifocal static lesions of faint contrast enhancement on imaging and involvement of gray matter. A syndrome of cerebellar degeneration has been described in association with HIV infection in patients positive for JC virus, the papovavirus responsible for PML. The standard of care for HIV-associated PML is HAART to achieve immunologic recovery and optimal HIV virologic control. The prognosis of PML has improved greatly since the advent of HAART.

Functional Energetics of CD4+-Cellular Immunity in Monoclonal Antibody-Associated Progressive Multifocal Leukoencephalopathy in Autoimmune Disorders

BackgroundProgressive multifocal leukoencephalopathy (PML) is an opportunistic central nervous system- (CNS-) infection that typically occurs in a subset of immunocompromised individuals. An increasing incidence of PML has recently been reported in patients receiving monoclonal antibody (mAb) therapy for the treatment of autoimmune diseases, particularly those treated with natalizumab, efalizumab and rituximab. Intracellular CD4+-ATP-concentration (iATP) functionally reflects cellular immunocompetence and inversely correlates with risk of infections during immunosuppressive therapy. We investigated whether iATP may assist in individualized risk stratification for opportunistic infections during mAb-treatment.Methodology/Principal FindingsiATP in PHA-stimulated, immunoselected CD4+-cells was analyzed using an FDA-approved assay. iATP of mAb-associated PML (natalizumab (n = 8), rituximab (n = 2), efalizumab (n = 1)), or other cases of opportunistic CNS-infections (HIV-associated PML (n = 2), spontaneous PML, PML in a psoriasis patient under fumaric acids, natalizumab-associated herpes simplex encephalitis (n = 1 each)) was reduced by 59% (194.5±29 ng/ml, mean±SEM) in comparison to healthy controls (HC, 479.9±19.8 ng/ml, p<0.0001). iATP in 14 of these 16 patients was at or below 3rd percentile of healthy controls, similar to HIV-patients (n = 18). In contrast, CD4+-cell numbers were reduced in only 7 of 15 patients, for whom cell counts were available. iATP correlated with mitochondrial transmembrane potential (ΔΨm) (iATP/ΔΨm−correlation:tau = 0.49, p = 0.03). Whereas mean iATP of cross-sectionally analysed natalizumab-treated patients was unaltered (448.7±12 ng/ml, n = 150), iATP was moderately decreased (316.2±26.1 ng/ml, p = 0.04) in patients (n = 7) who had been treated already during the pivotal phase III trials and had received natalizumab for more than 6 years. 2/92 (2%) patients with less than 24 months natalizumab treatment revealed very low iATP at or below the 3rd percentile of HC, whereas 10/58 (17%) of the patients treated for more than 24 months had such low iATP-concentrations.ConclusionOur results suggest that bioenergetic parameters such as iATP may assist in risk stratification under mAb-immunotherapy of autoimmune disorders.

Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases

Treatment of multiple sclerosis with natalizumab is complicated by rare occurrence of progressive multifocal leukoencephalopathy (PML). Between July, 2006, and November, 2009, there were 28 cases of confirmed PML in patients with multiple sclerosis treated with natalizumab. Assessment of these clinical cases will help to inform future therapeutic judgments and improve the outcomes for patients. The risk of PML increases with duration of exposure to natalizumab over the first 3 years of treatment. No new cases occurred during the first two years of natalizumab marketing but, by the end of November, 2009, 28 cases had been confirmed, of which eight were fatal. The median treatment duration to onset of symptoms was 25 months (range 6-80 months). The presenting symptoms most commonly included changes in cognition, personality, and motor performance, but several cases had seizures as the first clinical event. Although PML has developed in patients without any previous use of disease-modifying therapies for multiple sclerosis, previous therapy with immunosuppressants might increase risk. Clinical diagnosis by use of MRI and detection of JC virus in the CSF was established in all but one case. Management of PML has routinely used plasma exchange (PLEX) or immunoabsorption to hasten clearance of natalizumab and shorten the period in which natalizumab remains active (usually several months). Exacerbation of symptoms and enlargement of lesions on MRI have occurred within a few days to a few weeks after PLEX, indicative of immune reconstitution inflammatory syndrome (IRIS). This syndrome seems to be more common and more severe in patients with natalizumab-associated PML than it is in patients with HIV-associated PML. WHERE NEXT?: Diagnosis of natalizumab-associated PML requires optimised clinical vigilance, reliable and sensitive PCR testing of the JC virus, and broadened criteria for recognition of PML lesions by use of MRI, including contrast enhancement. Optimising the management of IRIS reactions will be needed to improve outcomes. Predictive markers for patients at risk for PML must be sought. It is crucial to monitor the risk incurred during use of natalizumab beyond 3 years.

Monocyte/macrophage trafficking in acquired immunodeficiency syndrome encephalitis: Lessons from human and nonhuman primate studies

Here the authors discuss evidence in human and animal models supporting two opposing views regarding the pathogenesis of human immunodeficiency virus (HIV) in the central nervous system (CNS): (1) HIV infection in the CNS is a compartmentalized infection, with the virus-infected macrophages entering the CNS early, infecting resident microglia and astrocytes, and achieving a state of latency with evolution toward a fulminant CNS infection late in the course of disease; or alternatively, (2) events in the periphery lead to altered monocyte/macrophage (MPhi) homeostasis, with increased CNS invasion of infected and/or uninfected MPhis. Here the authors have reevaluated evidence presented in the favor of the latter model, with a discussion of phenotypic characteristics distinguishing normal resident microglia with those accumulating in HIV encephalitis (HIVE). CD163 is normally expressed by perivascular MPhi s but not resident microglia in normal CNS of humans and rhesus macaques. In agreement with other studies, the authors demonstrate expression of CD163 by brain MPhi s in HIVE and simian immunodeficiency virus encephalitis (SIVE). CNS tissues from HIV-sero positive individuals with HIVE or HIV-associated progressive multifocal leukoencephalopathy (PML) were also examined. In HIVE, the authors further demonstrate colocalization of CD163 and CD16 (Fcgamma III recptor) gene expression, the latter marker associated with HIV infection of monocyte in vivo and permissivity of infection. Indeed, CD163(+) MPhis and microglia are often productively infected in HIVE CNS. In SIV infected rhesus macaques, CD163(+) cells accumulate perivascularly, within nodular lesions and the parenchyma in animals with encephalitis. Likewise, parenchymal microglia and perivascular MPhi s are CD163(+) in HIVE. In contrast to HIVE, CD163(+)perivascular and parenchymal MPhi s in HIV-associated PML were only associated with areas of demyelinating lesions. Interestingly, SIV-infected rhesus macaques whose viral burden was predominantly at 1 x 10(6) copies/ml or greater developed encephalitis. To further investigate the relationship between CD163(+)/CD16(+) MPhis/microglia in the CNS and altered homeostasis in the periphery, the authors performed flow-cytometric analyses of peripheral blood mononuclear cells (PBMCs) from SIV-infected rhesus macaques. The results demonstrate an increase in the percent frequency of CD163(+)/CD16(+) monocytes in animals with detectable virus that correlated significantly with increased viral burden and CD4(+) T-cell decline. These results suggest the importance of this monocyte subset in HIV/SIV CNS disease, and also in the immune pathogenesis of lentiviral infection. The authors further discuss the potential role of CD163(+)/CD16(+) monocyte/MPhi subset expansion, altered myeloid homeostasis, and potential consequences for immune polarization and suppression. The results and discussion here suggest new avenues for the development of acquired immunodeficiency syndrome (AIDS) therapeutics and vaccine design.

Identification of Polyomavirus JC Genome Sequences in Two HIV-Associated PML Cases in Bulgaria

ABSTRACTActive replication of the Polyomavirus hominis 2 (JCV) in glial cells leads to the fatal, demyelinating disease of the central nervous system, called progressive multifocal leukoencephalopathy (PML). Although more than 80% of the population is infected a significant impairment of the immune system is needed for reactivation of the latent virus. Such reactivation can be verified by a Polymerase Chain Reaction (PCR) test for detection of JCV DNA in brain tissue or cerebrospinal fluid (CSF). Here we report and discuss two cases of Bulgarian HIV-infected patients where identification of JCV supported and confirmed the diagnosis of HIV-associated PML.

Prognostic Significance of JC Virus DNA Levels in Cerebrospinal Fluid of Patients with HIV-Associated Progressive Multifocal Leukoencephalopathy

Prognostic Significance of JC Virus DNA Levels in Cerebrospinal Fluid of Patients with HIV-Associated Progressive Multifocal Leukoencephalopathy

Prognostic Significance of JC Virus DNA Levels in Cerebrospinal Fluid of Patients with HIV-Associated Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) remains a frequent and life-threatening complication of human immunodeficiency virus (HIV) infection in the era of highly active antiretroviral therapy (HAART). Although one-half of patients with this disease will survive, the outcome is unpredictable at diagnosis, and prognostic markers are needed. JC virus (JCV) DNA levels were measured in cerebrospinal fluid (CSF) samples obtained from 61 HIV-infected patients with PML, including 38 patients who were treated with HAART and 23 patients who did not receive HAART, with use of real-time polymerase chain reaction. The diagnostic reliability of the assay was evaluated by comparing CSF findings with histopathological findings in patients with PML or other HIV-related diseases of the central nervous system. The prognostic value was assessed by comparing JCV DNA levels with survival and other patient variables. The assay had a diagnostic sensitivity of 76% and specificity of 100%. In the first CSF sample obtained after onset of PML symptoms, JCV DNA values ranged from undetectable to 7.71 log copies/mL (median, 3.64 log copies/mL). JCV DNA levels >3.64 log copies/mL correlated significantly with shorter survival and lower CD4+ cell counts in patients not receiving HAART. However, neither relationship was found in patients who were treated with HAART. The analysis of sequential CSF samples obtained from 24 patients demonstrated a marked decrease in JCV DNA levels over time in HAART-treated patients showing PML stabilization, but not in untreated or HAART-treated patients with progressively fatal disease. Measurement of JCV DNA levels in CSF samples may be a useful virological marker for management of PML in patients receiving HAART.

Identification of HIV-associated progressive multifocal leukoencephalopathy: magnetic resonance imaging and spectroscopy.

Cover. Companion axial fluid-attenuated inversion recovery (FLAIR) images (top left) and magnetization transfer ratio (MTR) images (top right) of progressive multifocal leukoencephalopathy (PML). A representative proton magnetic resonance spectrum (bottom left) is also shown. Figure 1. The histological characteristics of PML include destruction of myelin (A, myelin-stained section of subcortical white matter), loss of oligodendrocytes (B, enlarged oligodendrocytes harboring intranuclear eosinophilic inclusion bodies, at arrow), and bizarre reactive astrocytes (C, transformed bizarre reactive astrocyte). Companion normal images are shown beneath each panel for comparison.

Progressive Multifocal Leukoencephalopathy in the United States, 1979–1994: Increased Mortality Associated with HIV Infection

To examine trends in progressive multifocal leukoencephalopathy (PML) mortality in the United States, we analyzed PML death rates and deaths for 1979 through 1994, using US multiple cause-of-death data. During the 16-year study period 3,894 PML deaths were reported. The age-adjusted death rate increased more than 20-fold, from less than 0.2 per million persons before 1984 to 3.3 per million persons in 1994. The increase was attributable to infection with human immunodeficiency virus (HIV) which was recorded on 2,267 (89.0%) of 2.546 death records from 1991 through 1994. PML age-adjusted death rates increased abruptly for all males beginning in 1984 and for black females in 1990. Only a small increase was observed for white females. In 1994, PML was reported in 2.1% of white males who died with HIV-associated disease compared with 1.2% of white females and 1.0% of black males and females who died of similar causes. The epidemic of PML deaths is increasing in parallel with the AIDS epidemic. The increase in HIV-associated PML deaths, first noted among males, has also become apparent among females and probably reflects the increasing importance of drug use and heterosexual transmission of HIV. The reason for the higher prevalence of PML among white males with HIV infection is unknown.