Progressive Multifocal Leukoencephalopathy Immune Reconstitution Inflammatory Syndrome Research Articles

The Prognosis of Progressive Multifocal Leukoencephalopathy in HIV/AIDS Patients Undergoing Highly Active Antiretroviral Treatment: A Systematic Review.

Progressive multifocal leukoencephalopathy (PML), a viral infection of the central nervous system (CNS), is most commonly associated with advanced HIV infection. Although the severe neurological conditions - PML and progressive multifocal leukoencephalopathy immune reconstitution inflammatory syndrome (PML-IRIS) - are linked to HIV, little is known about their characteristics in the era of established antiretroviral therapy (ART). The aim of this systematic review, which was performed by adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, was to determine the prognosis of PML in patients with HIV. We gathered and examined articles, including case-control and cohort studies, systematic reviews, and meta-analyses that were published between January 1, 2013, and May 2023. These articles were compiled from the following databases: Pubmed, Pubmed Central, Google Scholar, Wiley Library, and ScienceDirect. A total of 519 records were found from these databases for our systematic review after applying the proper filters. They were then further screened and put through quality appraisal tools, which ultimately led to the selection of 10 articles for the final analysis. This research offers crucial insights into the clinical consequences of PML in HIV patients receiving highly active antiretroviral therapy (HAART).

Unmasking the truth Progressive multifocal leukoencephalopathy immune reconstitution inflammatory syndrome PML IRIS in a 36 year old male with HIV

Progressive Multifocal Leukoencephalopathy – Immune Reconstitution Inflammatory Syndrome (PMLIRIS) is the subacute onset of neurological deficits that appeared or was exacerbated after initiation antiretroviral therapy (ART) for treatment of PML. It is due to severe neuroinflammation with re-establishment of immuncompetence. Approximately 25% of patients with HIV and PML develop IRIS. Clinical trials on the treatment of PML-IRIS is lacking with only limited evidence supporting the use of investigative therapies such as corticosteroids and Maraviroc. We report a case of a 36-year old Filipino male, known hypertensive and diagnosed with HIV, who presented with memory problems. He was eventually treated as a case of PML-IRIS on the 3rd week after initiation of ART. He was treated with a course of intravenous Dexamethasone, oral Mefloquine and intravenous immunoglobulin, and ART was continued. Clinical outcome in our patient shows an overall improvement of symptoms and no deterioration of neurologic deficits.

Immune reconstitution inflammatory syndrome drives emergence of HIV drug resistance from multiple anatomic compartments in a person living with HIV.

Reservoirs of HIV maintained in anatomic compartments during antiretroviral therapy prevent HIV eradication. However, mechanisms driving their persistence and interventions to control them remain elusive. Here we report the presence of an inducible HIV reservoir within antigen-specific CD4+T cells in the central nervous system of a 59-year-old male with progressive multifocal leukoencephalopathy immune reconstitution inflammatory syndrome (PML-IRIS). HIV production during PML-IRIS was suppressed by modulating inflammation with corticosteroids; selection of HIV drug resistance caused subsequent breakthrough viremia. Therefore, inflammation can influence the composition, distribution and induction of HIV reservoirs, warranting it as a key consideration for developing effective HIV remission strategies.

Unmasking the Truth: Progressive Multifocal Leukoencephalopathy–Immune Reconstitution Inflammatory Syndrome (PML-IRIS) in a 36-year Old Male with HIV, A Case Report

Progressive Multifocal Leukoencephalopathy Immune Reconstitution Inflammatory Syndrome (PMLIRIS) is the subacute onset of neurological deficits that appeared or was exacerbated after initiation antiretroviral therapy (ART) for treatment of PML. It is due to severe neuroinflammation with reestablishment of immunocompetence. Approximately 25% of patients with HIV and PML develop IRIS. Clinical trials on the treatment of PML-IRIS is lacking with only limited evidence supporting the use of investigative therapies such as corticosteroids and Maraviroc. We report a case of a 36-year old Filipino male, known hypertensive and diagnosed with HIV, who presented with memory problems. He was eventually treated as a case of PML-IRIS on the 3rd week after initiation of ART. He was treated with a course of intravenous Dexamethasone, oral Mefloquine and intravenous immunoglobulin, and ART was continued. Clinical outcome in our patient shows an overall improvement of symptoms and no deterioration of neurologic deficits.

Progressive Multifocal Leukoencephalopathy-Immune Reconstitution Inflammatory Syndrome (PML-IRIS) Presenting with Refractory Status Epilepticus in a Patient with HIV-1.

Progressive Multifocal Leukoencephalopathy-Immune Reconstitution Inflammatory Syndrome (PML-IRIS) Presenting with Refractory Status Epilepticus in a Patient with HIV-1.

BK polyomavirus associated progressive multifocal leukoencephalopathy in a person living with HIV

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the white matter central nervous system occurring in immunocompromised patients particularly those with T cell deficiency such as in HIV, haematological and solid organ malignancies and those taking immunomodulatory medications. PML is caused by JC virus however in rare cases BK virus has been isolated in the cerebral spinal fluid of patients presenting with PML.In this case we describe a 49 year old man who presented to the emergency department with a 2 week history of progressive right sided weakness and dysarthria. His background history included HIV diagnosed in 2005, he had not engaged with care in the past 2 years and had not been taking anti-retroviral therapy (ART). Other past medical history included untreated hepatitis C. His CD4 count was 90 (11%) cells/mm3 on admission and his HIV viral load VL) was 141,000 copies/ml. Magnetic resonance imaging(MRI) showed a hypointense lesion on T1, hyperintense on T2 and FLAIR without diffusion restriction and without mass effect. A lumbar puncture was performed which confirmed JC virus was positive (PCR <50 copies/ml) and also revealed BK virus was positive (PCR 46,511 copies/ml). The patient was commenced on tenofovir alafenamide fumarate/emtricitabine/darunavir/cobicistat in combination with dolutegravir 50mg twice daily. On day 40 post commencement of ART the patient was readmitted with worsening of his right arm weakness and dysarthria. A repeat MRI was performed which showed the hyperdense lesion on T2 and FLAIR appeared slightly larger with some slight enhancement with gadolinium contrast but no other features suggesting PML immune reconstitution inflammatory syndrome (IRIS). The CD4 count had increased to 141(17%) and HIV VL had decreased to 85 copies/ml. A clinical diagnosis of PML IRIS was made and the patient was commenced on prednisolone 30mg BD which lead to an initial improvement in symptoms.Interestingly in this case, both JC virus and BK virus were detected in the CSF of this patient with the level of JC virus being too low to quantify. BK virus was not detectable on peripheral serum sampling suggesting that BK virus is replicating in the CNS independent of other body sites. There have been 5 case reports in the literature of BK virus as the cause of PML.Testing for BK virus should be considered in patients presenting with signs and symptoms of PML and encephalitis particularly when no other cause is found.

Not a Disease of the Past: A Case Series of Progressive Multifocal Leukoencephalopathy in the Established Antiretroviral Era.

Progressive multifocal leukoencephalopathy (PML) and PML immune reconstitution inflammatory syndrome (PML-IRIS) can be devastating neurological processes associated with HIV, but limited knowledge of their characteristics in the established antiretroviral therapy (ART) era is available. We conducted a case series to evaluate the clinical course of PML and PML-IRIS at our urban safety-net hospital in Atlanta, GA. All HIV-positive individuals with a positive John Cunningham virus DNA polymerase chain reaction in the spinal fluid between May 1, 2013 to June 1, 2017 were identified from the electronic health records (EHRs) using the HIV Disease Registry. Demographics, symptom presentation, laboratory data, imaging results, treatment, and outcomes were abstracted from the EHR. PML and PML-IRIS were defined using the American Association of Neurology criteria. Of the 32 individuals identified, 6 (19%) were felt to have asymptomatic positive results. Of the remainder, 15 (58%) HIV-positive patients had PML and 11 (42%) PML-IRIS (2 with an unmasking presentation and 9 with a paradoxical presentation). The most common presenting symptoms were motor weakness (18, 69%), cognitive deficits (15, 58%), and dysarthria (11, 42%). Corticosteroids were used in 12 patients and maraviroc in 3 patients. Outcomes were dismal with 7 (47%) patients with PML and 9 (82%) with PML-IRIS dying or being referred to hospice, with median survival times of 266 days in the PML group and 109 days in the PML-IRIS group. Despite widespread access to ART, patients with PML continue to have poor outcomes, particularly among those who develop PML-IRIS. More research is needed to understand the risks for and prevention of PML-IRIS.

Management of Progressive Multifocal Leukoencephalopathy - Immune Reconstitution Inflammatory Syndrome (PML-IRIS) In a HIV Positive Male with Steroidal Support and Antiretroviral Therapy with Greater CNS Penetration-Effectiveness Score (CPE): A Case

Management of Progressive Multifocal Leukoencephalopathy - Immune Reconstitution Inflammatory Syndrome (PML-IRIS) In a HIV Positive Male with Steroidal Support and Antiretroviral Therapy with Greater CNS Penetration-Effectiveness Score (CPE): A Case

Magnetic resonance imaging changes following natalizumab discontinuation in multiple sclerosis patients with progressive multifocal leukoencephalopathy

Background: Detecting early progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome (PML-IRIS) is clinically relevant. Objective: Evaluating magnetic resonance imaging (MRI) changes following natalizumab (NTZ) discontinuation and preceding PML-IRIS. Methods: MRIs (including diffusion-weighted imaging (DWI), T2-weighted fluid-attenuated inversion recovery (T2-FLAIR), post-contrast T1-weighted sequences) were performed every week following PML diagnosis in 11 consecutive NTZ-PML patients. PML expansion, punctate lesions, contrast-enhancement, and mass-effect/edema were evaluated on each MRI sequence, following NTZ discontinuation. Results: PML-IRIS occurred from 26 to 89 days after NTZ discontinuation. MRI changes prior to early PML-IRIS appeared significantly more pronounced using DWI compared to T2-FLAIR imaging (p < 0.003). Two DWI features (marked PML expansion, punctate lesions) systematically preceded contrast-enhancement. Conclusion: Subtle changes may occur on DWI preceding contrast-enhancement.

No evidence of beneficial effects of plasmapheresis in natalizumab-associated PML.

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). 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. 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. 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. 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.

Natalizumab'a Bağlı Progresif Multifokal Lökoensefalopati-İmmün Rekonstitusyon İnflamatuar Sendromu Gelişen Bir Multipl Skleroz Olgusu

Aim of this study to describe the clinical and radiological features of a case of progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome (PMLIRIS) in a patient with multiple sclerosis treated with natalizumab. A 52 years old man with relapsing-remitting multiple sclerosis was switched disease-modifying therapy from glatiramer acetate to natalizumab because of two serious relapses. PML was developed after his 23rd infusion. Five cures of plasma exchange was given. On the follow up, the clinical picture of the patient was deteriorated. He was treated with 10 doses of intravenous methyprednisolone 1 g/day, followed by oral methyprednisolone treatment. He was partially improved and discharged from the hospital 4 months later with a sequel of left hemiplegia and right 4/5 hemiparesis. After 6 months, the patient died because of some systemic problems such as breath insufficiency secondary to aspiration pneumonia and gastric bleeding although there was not any suspicion of a new neurological attack. Natalizumab treated multiple sclerosis patients with any new magnetic resonance imaging (MRI) lesion, mainly subcortical white matter should suggest PML. Those patients should undergo carefull assessment, including serial clinical and MRI monitoring and cerebrospinal fluid analysis.

Progressive Multifocal Leukoencephalopathy in Multiple Sclerosis

AIDS generated a significantly increased interest in the pathogenesis, clinical manifestations, and treatment of progressive multifocal leukoencephalopathy (PML), a disease previously considered to be very rare. Scrutiny increased after a second wave of PML following the introduction of biological agents, in particular, natalizumab and efalizumab. While efalizumab, a lymphocyte function-associated antigen 1 inhibitor marketed for use in psoriasis, has been removed from the market, natalizumab, an α4β1 and α4β7 integrin inhibitor, remains widely used in the treatment of multiple sclerosis (MS). Approximately 400 cases of natalizumab-associated PML have been reported from 2005 to August 2013. Additionally, other therapies currently employed or under development for the treatment of MS may also be associated with PML, such as mycophenolate mofetil, rituximab, and alemtuzumab. Therefore, practitioners using these medications need to understand the risks associated with these agents, ways to mitigate the risk, and treatment of PML and the related condition PML immune reconstitution inflammatory syndrome. PML associated with the use of therapeutic agents, especially, natalizumab, does share similarities with HIV-related PML; however, distinct differences exist. Radiographically isolated PML is seen more commonly with natalizumab-associated PML and the disease appears to be heralded more often by cognitive and behavior disturbances. Furthermore, the mortality of natalizumab-associated PML is substantially lower. Risk mitigation strategies have been developed for the natalizumab-associated PML, which has been convincingly demonstrated to be linked to duration of therapy, JC virus seropositivity, and the prior use of immunosuppressive agents.

Impairment of JCV-specific T-cell response by corticotherapy

To investigate the impact of corticosteroids (CS) on the viral-specific T-cell response, in particular the JC virus (JCV)-specific one, in an attempt to determine the optimal timing of CS in the management of progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome (PML-IRIS). A blood draw was performed before and 7 days after the administration of IV CS to 24 patients with relapsing multiple sclerosis (MS). The phenotypic pattern of T cells was determined by CCR7 and CD45RA. To assess the impact of CS treatment on proliferative response of JCV-, influenza-, and Epstein-Barr virus (EBV)-specific T cells, a thymidine incorporation proliferation assay was performed. An intracellular cytokine staining assay was performed to determine the effect of CS treatment on the production of cytokine by virus-specific T cells. JCV T-cell assays were performed only in JCV-infected patients with MS as detected by serologies (Stratify) or detection of JCV DNA in the urine by PCR. CS led T cells, CD4+ and CD8+, toward a less differentiated phenotype. There was a significant decrease of EBV-, influenza-, and JCV-specific T-cell proliferative response upon CS treatment. There was a significant decrease in the frequency of interferon (IFN) γ- and tumor necrosis factor (TNF) α-producing JCV-specific CD8+ T cells, but not EBV- or influenza-specific CD4+ or CD8+ T cells. CS have a profound impact on the virus-specific T-cell response, especially on JCV, suggesting that when CS are considered, they should not be given before the onset of clinical or radiologic signs of IRIS. Studies addressing directly patients with MS with natalizumab-caused PML are warranted. This study provides Class III evidence that methylprednisolone treatment decreases the frequency of JCV-specific CD8+ T cells producing IFN-γ and TNFα, impairing control of JCV, suggesting this should be used to treat but not to prevent PML-IRIS. No clinical outcomes were measured.

Simultaneous Pml-Iris After Discontinuation of Natalizumab in A Patient With MS

Gheuens et al.1 presented a case of progressive multifocal leukoencephalopathy–immune reconstitution inflammatory syndrome (PML-IRIS) 2 months after natalizumab discontinuation. Their patient had an active history of ethanol abuse, which can be considered a 'functional' equivalent to immunosuppression. Interestingly, prior use of immunosuppressants has been included in the recently developed risk-stratification algorithm for PML.2 This case underscores the need for clinicians to adopt a wider concept of immunosuppression, rather than restricting it solely to the use of pharmacologic agents. We and others published 3 cases of definitive severe multiple sclerosis (MS) rebound about 2 months following natalizumab discontinuation,3-5 and further implied that younger patients are more prone to such relapses.5 However, Gheuens et al. concluded that new enhancing MRI lesions after natalizumab withdrawal may also be the manifestation of PML-IRIS.1 As experience from patients discontinuing natalizumab and switching to other therapies mounts, a high degree of clinical vigilance for both incidences (i.e., MS rebound and PML) should follow the immediate post-natalizumab period. However, until official guidelines are issued, it is unclear exactly how patients should be treated in the interval between natalizumab and the next therapeutic choice.

Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS

Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab therapy in patients with multiple sclerosis (MS), which is often accompanied by an immune reconstitution inflammatory syndrome (IRIS) after removal of the drug. We describe a patient with MS who presented with simultaneous PML-IRIS 2 months after stopping natalizumab for other reasons. The patient had widespread PML and severe IRIS. He received corticosteroids and displayed a vigorous JC virus-specific cellular immune response. Elevated myoinositol and lipid/creatine peaks measured in PML lesions by proton magnetic resonance spectroscopy ((1)H-MRS) corresponded to episodes of contrast enhancement on MRI scans and persisted after the enhancement subsided. He demonstrated steady clinical improvement, but developed marked residual atrophy in areas affected by PML and inflammation, as well as seizures. New enhancing white matter lesions, occurring after discontinuation of natalizumab, can be the manifestation of PML-IRIS rather than an MS exacerbation. Elevated myoinositol and lipid/creatine peaks appear to be more sensitive markers of inflammation in PML lesions than contrast enhancement. (1)H-MRS may become useful as a biomarker for PML-IRIS by helping clinicians determine the need for corticosteroid administration and anticipate continuing clinical recovery.

Immune Reconstitution Inflammatory Syndrome in Natalizumab-Associated PML

# {#article-title-2} Tan et al.1 postulated that early immunologic rebound in natalizumab-associated progressive multifocal leukoencephalopathy (PML) may implicate a worse outcome and survival. Unfortunately, the interval between the last natalizumab infusion and PLEX/IA was not provided. Although it did not reach significance, the time between onset of symptoms and PML diagnosis was about 75% longer in those with early PML–immune reconstitution inflammatory syndrome (IRIS), which may contribute to a worse outcome. We treated …

An Unusual Cause of Isolated Vomiting

In reference to a NeuroImage submitted by Drs. Schlaeger and Sollberger, Dr. Wang et al. clarify the anatomic location of the area postrema and explain its possible significance to radiation therapy. Other correspondents this week react to 2 articles on progressive multifocal leukoencephalopathy (PML). Dr. Phan-Ba et al. disagree with the definition of Dr. Tan et al. of early PML–immune reconstitution inflammatory syndrome (IRIS), arguing that the inflammatory MRI signs in the study's early PML-IRIS patients occurred while …