Course Of Progressive Multifocal Leukoencephalopathy Research Articles

Natalizumab-associated progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS): \u201ca case report from Ireland with review of literature, clinical pitfalls and future direction\u201d

BackgroundProgressive multifocal leukoencephalopathy (PML) is one of the most serious treatment-related complications that is encountered in patients with multiple sclerosis (MS). PML is a serious complication of MS treatment which is most commonly related to natalizumab.Case presentationWe report clinical course of progressive multifocal leukoencephalopathy (PML) in a 40-year-old man who was on treatment for highly active relapsing-remitting multiple sclerosis with natalizumab (Nz). He was treated with steroids, cidofovir, and mirtazapine and went on to develop long-term disability. The case describes the evolution of PML from diagnosis up till 5 months with changes on sequential brain scans and clinical symptoms in our patient.ConclusionPatients who are on natalizumab should be aware and consented for the risk of PML. They should be periodically re-assessed for their relative PML risk. There is a growing body of evidence that suggests switching patients from natalizumab who have a higher risk of PML to other safer treatment options.

Прогресуюча мультифокальна лейкоенцефалопатія після трансплантації нирки: літературний огляд і власний клінічний випадок

This article discusses the development of progressive multifocal leukoencephalopathy after a kidney transplantation on the background of immunosuppressive therap. It’s the example of a clinical case. Based on the literature review, it is known that progressive multifocal leukoencephalopathy is a progressive demyelinating disease of the central nervous system, which is caused by reactivation of the latent JC virus; such reactivation usually occurs in immunodeficient conditions. In the clinical case, the appearance of this disease was demonstrated and its severe and potentially fatal multifocal lesion of the white matter of the brain was proved. The disease was developed on the background of immunosuppressive therapy after a history of kidney transplantation. The understanding of the clinical course of progressive multifocal leukoencephalopathy, the absence of specific neurological manifestations and course were expanded. It is noted that MRI results in addition to the clinical picture and anamnestic data help to establish the diagnosis of PML and make a differential diagnosis. Progressive multifocal leukoencephalopathy in transplant recipients receiving immunosuppressive therapy have an unfavorable prognosis.

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.

Insight into Metabolic 1H-MRS Changes in Natalizumab Induced Progressive Multifocal Leukoencephalopathy Brain Lesions.

Progressive multifocal leukoencephalopathy (PML) is a severe complication of immunosuppressive therapies, especially of natalizumab in relapsing-remitting multiple sclerosis (MS). Metabolic changes within PML lesions have not yet been described in natalizumab-associated PML in MS patients. To study metabolic profiles in natalizumab-associated PML lesions of MS patients by 1H magnetic resonance spectroscopy (1H-MRS) at different stages during the PML course. To assess changes associated with the occurrence of the immune reconstitution inflammatory syndrome (IRIS). 20 patients received 1H-MRS and imaging at 3 T either in the pre-IRIS, IRIS, early-post-PML, or late post-PML setting. Five of these patients received individual follow-up examinations, including the pre-IRIS or IRIS phase. Clinical worsening was described by changes in the Karnofsky Performance Scale (KPS) and the expanded disability status scale (EDSS) 1 year before PML and scoring at the time of 1H-MRS. In PML lesions, increased levels of the Lip/Cr ratio, driven by rising of lipid and reduction of Creatine, were found before the occurrence of IRIS (p = 0.014) with a maximum in the PML-IRIS group (p = 0.004). By contrast, marked rises of Cho/Cr in PML lesions were detected exclusively during the IRIS phase (p = 0.003). The Lip/Cr ratio decreased to above-normal levels in early-post-PML (p = 0.007, compared to normal appearing white matter (NAWM)) and to normal levels in the late-post-PML group. NAA/Cho was reduced compared to NAWM in the pre-IRIS, IRIS, and early-post-PML group. In NAA/Cr, the same effect was seen in the pre-IRIS and early-post-PML group. These cross-sectional results were confirmed by the individual follow-up examinations of four patients. NAA/Cho, Cho/Cr, and the lipid rise relative to NAWM in PML lesions were significantly correlated with the residual clinical worsening (KPS change) in post-PML patients (Spearman correlations ρ = 0.481, p = 0.018; ρ = -0.505, p = 0.014; and ρ = -0.488, p = 0.020). 1H-MRS detected clinically significant dynamic changes of metabolic patterns in PML lesions during the course of natalizumab-associated PML in MS patients. Lip/Cr and Cho/Cr may provide additional information for detecting the onset of the IRIS phase in the course of the PML disease.

Is maraviroc useful in multiple sclerosis patients with natalizumab-related progressive multifocal leukoencephalopathy?

BackgroundDespite the recent advances in the understanding of natalizumab (NTZ) related progressive multifocal leukoencephalopathy (PML) and its associated immune reconstitution inflammatory syndrome (PML-IRIS), the therapeutic options are still under investigated. In this context, the beneficial use of maraviroc is still an anecdotal observation. ObjectiveTo evaluate the impact of maraviroc in modifying the course of PML preventing IRIS or blunting IRIS manifestations. MethodsThree patients with NTZ PML included in the Italian dataset of PML were treated with maraviroc. Their longitudinal clinical and radiological course was described in detail. ResultsThe three patients were characterized by a steady clinical worsening not controlled by maraviroc. All the three patients manifested PML-IRIS, which emerged, respectively, at 62, 64 and 90days post NTZ withdrawal. This is in accordance with the data of the Italian dataset. Clinical and radiological stabilization of PML-IRIS occurred only after corticosteroids administration. ConclusionIn these three cases, maraviroc did not show any clear effect in modulating the clinical course of PML preventing IRIS. Moreover, once PML-IRIS emerged, the clinical stabilization was achieved only with the use of corticosteroids. Thus, the use of maraviroc should be regarded with extreme caution due the potential adverse events associated with its use.

Progressive multifocal leukoencephalopathy after liver transplantation can have favorable or unfavorable outcome

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC polyomavirus (JCPyV) in immunocompromised patients, including solid organ transplant recipients. We report 2 cases of PML late after liver transplantation (144 and 204months) and review the few other published cases. The clinical course of PML is characterized by a rapid progressive neurological decline coinciding with the presence of white matter lesions on magnetic resonance images. No direct antiviral therapy is available against the JCPyV. The prognosis is therefore extremely poor. Restoration of the immune response achieved by tapering or ending the immunosuppressive therapy is the basis of treatment in transplanted patients. One of our patients is alive 3years after diagnosis after total withdrawal of immunosuppressive therapy. The other presented severe rejection when tapering immunosuppression and died 26months after diagnosis.

JC Polyomavirus Abundance and Distribution in Progressive Multifocal Leukoencephalopathy (PML) Brain Tissue Implicates Myelin Sheath in Intracerebral Dissemination of Infection.

Over half of adults are seropositive for JC polyomavirus (JCV), but rare individuals develop progressive multifocal leukoencephalopathy (PML), a demyelinating JCV infection of the central nervous system. Previously, PML was primarily seen in immunosuppressed patients with AIDS or certain cancers, but it has recently emerged as a drug safety issue through its association with diverse immunomodulatory therapies. To better understand the relationship between the JCV life cycle and PML pathology, we studied autopsy brain tissue from a 70-year-old psoriasis patient on the integrin alpha-L inhibitor efalizumab following a ~2 month clinical course of PML. Sequence analysis of lesional brain tissue identified PML-associated viral mutations in regulatory (non-coding control region) DNA, capsid protein VP1, and the regulatory agnoprotein, as well as 9 novel mutations in capsid protein VP2, indicating rampant viral evolution. Nine samples, including three gross PML lesions and normal-appearing adjacent tissues, were characterized by histopathology and subject to quantitative genomic, proteomic, and molecular localization analyses. We observed a striking correlation between the spatial extent of demyelination, axonal destruction, and dispersion of JCV along white matter myelin sheath. Our observations in this case, as well as in a case of PML-like disease in an immunocompromised rhesus macaque, suggest that long-range spread of polyomavirus and axonal destruction in PML might involve extracellular association between virus and the white matter myelin sheath.

Low frequencies of central memory CD4 T cells in progressive multifocal leukoencephalopathy.

Objectives:To assess alterations in the composition of peripheral immune cells in acute progressive multifocal leukoencephalopathy (PML).Methods:Fresh blood samples from 5 patients with acute PML and 10 healthy controls were analyzed by flow cytometry for naive, central memory and effector memory CD4 and CD8 T cells, B lymphocytes, plasma cells, memory B cells, plasma blasts, and natural killer (NK) cells. The frequency of central memory CD4 T cells was determined longitudinally during the course of PML in 2 patients.Results:The frequencies of naive, central memory and effector memory CD8 T cells, B cells, plasma cells, and NK cells were not altered in patients with PML. In contrast, the frequencies of naive CD4 T cells (p = 0.04) and central memory CD4 T cells (p < 0.00001) were reduced and the frequencies of effector memory CD4 T cells were increased (p = 0.01). Longitudinal analysis showed that this pattern was preserved in a patient with fatal PML outcome and restored in one patient who recovered from PML.Conclusions:These data indicate that PML is associated with reduced frequencies of peripheral central memory helper T cells but not with alterations in the frequencies of cytotoxic T cell populations, B lymphocytes, plasma cells, or NK cells.

Favorable outcome after withdrawal of immunosuppressant therapy in progressive multifocal leukoencephalopathy after renal transplantation: Case report and literature review

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by the JC polyomavirus (JCV). Most patients with PML after renal transplantation have had poor outcomes. We describe a patient with PML after renal transplantation who had a good response to the withdrawal of immunosuppressant therapy. We performed quantitative real-time PCR testing for JCV DNA in cerebrospinal fluid (CSF), and assessed mutation of the JC virus genome detected in the CSF. At the same time, we checked cranial magnetic resonance imaging (MRI). Immunosuppressant therapy was discontinued immediately. The MRI scan that followed showed markedly decreased numbers of high intensity signals, and the results of real-time PCR for JCV DNA in CSF became negative. The patient had no other neurological deficits. Withdrawal of immunosuppressant treatment has a beneficial effect on the course of PML after renal transplantation, and quantitative PCR may facilitate the immediate withdrawal of immunosuppressant agents.

Six-year survival of progressive multifocal leukoencephalopathy associated with follicular lymphoma

Background: Progressive multifocal leukoencephalopathy (PML) occurs mainly in immunocompromised individuals as well as associated with immunomodulatory therapies including rituximab. The disease course of PML is usually progressive and fatal. The median survival of patients without HIV infection is only three months. Long-term remission is rare, but rather occurs in HIV-positive individuals.

Smoldering myeloma presenting as progressive multifocal leukoencephalopathy: a case report

IntroductionProgressive multifocal leukoencephalopathy is an opportunistic infection occurring in patients with severe cellular immunodeficiency. This case highlights the role of cellular immunodeficiency in the reactivation of John Cunningham virus in a case of an early stage plasmacytoma.Case presentationA 76-year-old Caucasian woman presented with progressive left-sided hemiparesis, accompanied by hypoesthesia, hypoalgesia and neuropsychological symptoms. Magnetic resonance imaging demonstrated new hyperattenuating lesions in the right thalamus and left-sided subcortically. A polymerase chain reaction test revealed 4500 copies of John Cunningham virus-deoxyribonucleic acid/ml in cerebrospinal fluid. Human immunodeficiency virus infection was ruled out. A bone marrow biopsy showed an early stage immunoglobulin G-kappa plasmacytoma. Cidofovir (5mg/kg) weekly for three weeks was started. A significant improvement of her neuropsychological symptoms was achieved, but motor system and sensory symptoms did not change.ConclusionsThis case shows a rapid course of progressive multifocal leukoencephalopathy with severe residual deficits. In the diagnostic workup of all patients with atypical neurologic symptoms or immunodeficiency, progressive multifocal leukoencephalopathy should be included as a differential diagnosis.

JC virus load in cerebrospinal fluid and transcriptional control region rearrangements may predict the clinical course of progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a severe disease of the central nervous system (CNS), caused by infection with the Polyomavirus JC virus (JCV). Because there are no known treatments or prognostic factors, we performed a long-term study focusing mainly on cerebrospinal fluid (CSF) samples from PML patients to describe the virological features akin to the different forms of the disease. Twenty-eight PML patients were enrolled: 10 HIV-1+ patients with classical PML (CPML), 9 HIV-1+ patients with slowly progressing or stable neurological symptoms (benign PML), 3 HIV-1+ asymptomatic patients, and 6 HIV-1-negative patients. CSF, urine, and blood samples were collected at the enrollment (baseline) and every 6 months afterwards when possible. The JCV DNA and HIV-1 RNA loads were determined, and the JCV strains were characterized. At baseline, the mean CSF JCV load was log 6.0 ± 1.2 copies/ml for CPML patients, log 4.0 ± 1.0 copies/ml for benign PML patients, log 4.2 ± 0.5 copies/ml for asymptomatic PML patients, and log 5.8 ± 1.3 copies/ml for HIV-1-negative PML patients (CPML vs. benign: P < 0.01; CPML vs. asymptomatic: P < 0.05; HIV-1 negative vs. benign: P < 0.01). Organization of the JCV transcriptional control region (TCR) showed unusual archetype structures in two long-term survival patients; the NF1 sequence was found most commonly, whereas the Sp1 binding site was the most common for both CPML patients and HIV-1 negative patients. Our results suggest that the JCV load in the CSF and the organization of the TCR should be considered as indicators of PML clinical outcome.

Indolent course of progressive multifocal leukoencephalopathy during natalizumab treatment in MS

Progressive multifocal leukoencephalopathy (PML) has developed in more than 40 patients with multiple sclerosis (MS) treated with natalizumab.1 Clifford et al.2 recently described the first 28 confirmed cases in which, in almost all, PML presented as an aggressive disease with a short interval between first symptoms and diagnosis. ### Case report. In September 2002, a 30-year-old previously healthy woman presented with walking difficulties. Neurologic examination showed a bi-pyramidal syndrome, ataxia, and sensory disturbance in all extremities. After MRI of the brain and cervical spinal cord, which showed multiple typical T2-weighted white matter lesions, diagnosis of a clinically isolated syndrome suggestive of a first episode of MS was established. In January 2003, the patient started interferon-β-1a, which she discontinued in October 2003 because of depressive symptoms. From March 2004 until December 2006, she used glatiramer acetate. Still, several clinical relapses occurred. In March 2007, the patient started natalizumab infusions. She had no clinical exacerbations since. Routine MRI of the brain 1 year later showed no active lesions. A second MRI in February 2009 was initially interpreted as showing no new lesions. In retrospect, subtle and diffuse abnormalities were visible in cortical and subcortical areas (figure). Since June 2009, she had mild progressive cognitive problems. For example, she made repetitive phone calls up to 6 times a day and was forgetting appointments. For that reason, in October 2009, a new MRI was performed, showing a new pontine lesion and progression of the diffuse abnormalities in both hemispheres (figure). Figure MRI (A) Evolution of MRI manifestations during treatment with natalizumab. Transverse T2-weighted MRI of the supratentorial and infratentorial brain. The MRI in January 2007 (A.a) was performed prior to the initiation of natalizumab therapy; …

Indolent course of progressive multifocal leukoencephalopathy during natalizumab treatment in MS

Indolent course of progressive multifocal leukoencephalopathy during natalizumab treatment in MS

Progressive multifocal leukoencephalopathy in liver transplant recipients: a case report and review of the literature

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the reactivation of the JC polyomavirus in immunocompromised patients. We report a case of PML in a liver transplant recipient and review the other published cases. The clinical course of PML is characterised by a rapid progressive neurological decline coinciding with the presence of white matter lesions on magnetic resonance images. There is no direct antiviral therapy available against the JC polyomavirus. Restoration of the immune response achieved by tapering or terminating the immunosuppressive regimen is the mainstay of treatment at present in transplanted patients. The prognosis remains, however, extremely poor regardless of treatment.

Progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a disease of the central nervous system (CNS) with destructive infection of oligodendrocytes by JC virus. PML belongs to the opportunistic infections. It is observed in patients with HIV infection, lymphoid malignancies, after organ- and stem cell transplantations and more recently in the context of modern immune-therapies with monoclonal antibodies (mAb) like natalizumab, rituximab, infliximab and efalizumab. The natural course of PML is fatal within months. More recently, the Immune Reconstitution Inflammatory Syndrome (IRIS) has been observed in patients with HIV infection treated with combination antiretroviral therapy (cART) as well as patients in whom the PML-inducing immune therapy has been terminated. In PML-IRIS the immune system contributes to the elimination of JC virus from the CNS and if PML-IRIS emerges, PML can be survived but can lead as well to catastrophic outcomes with brain herniation and death. Therefore the management of IRIS requires special knowledge in JC virus biology and patient care. JC virus infection is possibly involved in a variety of additional neurological conditions and cancer. Much will be learned within the next years that could change our view on the understanding of JC virus and human disease.

Successful Management of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy and Immune Reconstitution Syndrome in a Patient With Multiple Sclerosis

To describe a case of successful clinical management of natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution syndrome (IRIS) in a patient with multiple sclerosis. Case report. University hospital. A 41-year-old woman with relapsing-remitting multiple sclerosis developed PML after 29 natalizumab infusions. Immediate plasma exchange was combined for removal of natalizumab with application of mefloquine and mirtazapine to limit viral replication and oligodendrocyte infection. A subsequent IRIS was treated with glucocorticosteroids. After 3 months of treatment, cerebrospinal fluid tested negative for JC virus. There was a favorable outcome, and the Expanded Disability Status Scale score remained stable at 3.5 compared with before PML. In the setting of early diagnosis and consequent treatment, natalizumab-associated PML can be well managed in some cases. This situation differs from the course of PML in other conditions, eg, after the application of depleting monoclonal antibodies, in which irreversible cellular effects are associated with very high mortality.

Determinants of survival in progressive multifocal leukoencephalopathy

We sought to characterize the role of immunologic, virologic, and radiologic determinants of survival in patients with progressive multifocal leukoencephalopathy (PML). 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. 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. 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.

Presence of JC virus-specific CTL in the cerebrospinal fluid of PML patients: rationale for immune-based therapeutic strategies

There is urgent need of a treatment for progressive multifocal leukoencephalopathy (PML), caused by the polyomavirus JC (JCV). To evaluate the rationale for immunotherapy of PML, we explored whether JCV-specific cytotoxic T lymphocytes (CTL) can penetrate the central nervous system (CNS). In addition, we studied the breadth of their T-cell receptor (TCR) repertoire, and sought to establish a reliable method to expand these cells in vitro. We enrolled 18 patients in this study, including 16 with proven or possible PML (15 HIV-positive and one HIV-negative), and two HIV-positive patients with other neurological diseases. Detection of JCV-specific CTL in the blood and the cerebrospinal fluid was performed by Cr release and tetramer staining assays in 15 patients. Of 11 PML patients with analyzable cerebrospinal fluid (CSF), two had no detectable JCV-specific CTL in the blood and CSF and died 3.7 and 7.2 months later. The nine remaining patients had an inactive course of PML and detectable JCV-specific CTL in the blood. In addition, four of them (44%) also had detectable JCV-specific CTL in the CSF. Both HIV-positive patients with OND had detectable JCV-specific CTL in the blood and one in the CSF. Using tetramer technology, we obtained highly enriched JCV-specific CTL lines that were able to kill target cells presenting JCV peptides. The breadth of the TCR repertoire was CTL epitope dependent. These results indicate that JCV-specific CTL are present in the CNS of PML patients and pave the way for an immune-based therapeutic approach.

Sustained recovery of progressive multifocal leukoencephalopathy after treatment with IL-2

Currently, most patients diagnosed with progressive multifocal leukoencephalopathy (PML) are infected with HIV; highly active antiretroviral therapy (HAART) has prolonged the median survival of these patients from 3 months to 1 year.1 Despite encouraging initial case reports, other therapies, including cytosine arabinoside and alpha INF, have been disappointing for both HIV and non-HIV patients with PML.2–4 In addition to the lack of convincing evidence that these treatments alter the natural course of PML, there are concerns of toxicity in patients with low blood counts. Because a plausible biologic basis exists for a role for recombinant interleukin-2 (rIL-2) in the reconstitution of impaired antiviral immune functions, this immunotherapy was administered previously in a patient with PML with apparent success.5 Based on this report, we chose rIL-2 as initial therapy for a patient with myelodysplasia who developed PML. A 58-year-old woman with a 20-year history of myelodysplastic syndrome presented in March 2000 with dysarthria and right hand clumsiness, which developed …