Treatment Of Progressive Multifocal Leukoencephalopathy Research Articles

Pembrolizumab for the treatment of progressive multifocal leukoencephalopathy in China.

The aim of this study is to analyze the clinical characteristics and outcomes of Chinese patients with progressive multifocal leukoencephalopathy (PML) who were treated with programmed cell death protein 1 (PD1) blockade therapies. We retrospectively analyzed patients who were admitted to our hospital between October 1, 2020, and October 1, 2022, diagnosed with PML and treated with PD1 blockade therapies. Four patients with PML who were treated with PD1 blockade therapies were identified. All patients were male, and their ages ranged from 19 to 54 years old. One patient (Case 2) exhibited mild pleocytosis, while three patients (Cases 2-4) had markedly reduced T lymphocyte cell counts prior to treatment. The time interval between symptom onset and treatment initiation ranged from six to 54 weeks. All patients received pembrolizumab treatment, with a total of two to four doses administered. Three patients who responded to pembrolizumab treatment showed clinical improvement starting around 8 weeks after the initiation of therapy. Although one patient did not show clinical improvement, they ultimately survived until the last follow-up. None of the patients in this study exhibited immune-related adverse events or immune reconstitution inflammatory syndrome. PD1 blockade appears to be a promising novel therapeutic option for PML; additional prospective studies are necessary to confirm its efficacy.

An Elusive Target: Inhibitors of JC Polyomavirus Infection and Their Development as Therapeutics for the Treatment of Progressive Multifocal Leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease caused by infection with JC Polyomavirus (JCPyV). Despite the identification of the disease and isolation of the causative pathogen over fifty years ago, no antiviral treatments or prophylactic vaccines exist. Disease onset is usually associated with immunosuppression, and current treatment guidelines are limited to restoring immune function. This review summarizes the drugs and small molecules that have been shown to inhibit JCPyV infection and spread. Paying attention to historical developments in the field, we discuss key steps of the virus lifecycle and antivirals known to inhibit each event. We review current obstacles in PML drug discovery, including the difficulties associated with compound penetrance into the central nervous system. We also summarize recent findings in our laboratory regarding the potent anti-JCPyV activity of a novel compound that antagonizes the virus-induced signaling events necessary to establish a productive infection. Understanding the current panel of antiviral compounds will help center the field for future drug discovery efforts.

Use of Pembrolizumab for Treatment of Progressive Multifocal Leukoencephalopathy in People Living with HIV.

Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating disease occurring in advanced HIV infection, caused by the reactivation of poliomavirus JC (JCV). The use of pembrolizumab for treatment is based on the inhibition of programmed cell death protein 1 (PD-1), potentially improving the anti JCV-specific response. We used pembrolizumab with combined antiretroviral treatment (cART) on a compassionate-use basis. At each administration, clinical evaluation, MRI and laboratory testing, including CD3, CD4, CD8, PD-1 markers, HIV-RNA and JCV-DNA in cerebrospinal fluid (CSF)/plasma pairs, were performed. The JCV-specific T cell response was analysed by Elispot assay. This study included five HIV patients: four male, median age 43 years (29–52), median CD4 and CD8 count 150 (15–158) and 973 (354–1250) cell/mm3, respectively; median JCV-DNA and HIV-RNA in CSF/plasma pairs 9.540/1.503 cps/mL and 2.230/619 cp/mL, respectively. Overall, patients received between two and seven doses of pembrolizumab. After treatment, we observed JCV-DNA reduction and PD-1 down-regulation both in CSF and in plasma (high in circulating CD4 and CD8 at baseline), which remained stable at low levels in all patients. Three out of five patients showed stability of clinical picture and neuroimaging, while two others died. More data are needed in order to identify predictors of response to therapy.

Sequential treatment of progressive multifocal leukoencephalopathy with intravenous immunoglobulins and pembrolizumab

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the CNS caused by the human polyomavirus 2 (JCV). PML predominantly occurs in immunocompromised patients. To date, no specific antiviral treatment exists, leaving only restoration of the immune system as possible treatment. In 2019, the monoclonal antibody pembrolizumab was reported as a potential treatment option in PML in a case series. Following case reports could not thoroughly confirm a positive outcome. Pembrolizumab targets the inhibitory programmed cell death protein 1 (PD-1) receptor on lymphocytes and is associated with beneficial expansion of pre-existing virus-specific T cells. Here we describe a patient with PML who benefited from combined treatment with intravenous immunoglobulins, maraviroc, and pembrolizumab.

Outcome of Progressive Multifocal Leukoencephalopathy Treated by Interleukin-7.

Restoring anti-JC virus (JCV) immunity is the only treatment of progressive multifocal leukoencephalopathy (PML). Interleukin-7 is a cytokine that increases number and function of T cells. We analyzed a population of PML patients who received recombinant human IL-7 (rhIL-7) to estimate survival and its determinants. After exclusion of patients with missing data or receiving other immunotherapies, findings from 64 patients with proven PML who received rhIL-7 between 2007 and 2020 were retrospectively analyzed. Logistic regression was used to analyze variables associated with one-year survival. Underlying conditions were HIV/AIDS (n=27, 42%), hematological malignancies (n=16, 25%), primary immunodeficiencies (n=13, 20%), solid organ transplantation (n=4, 6%) and chronic inflammatory diseases (n=4, 6%). One-year survival was 54.7% and did not differ by underlying condition. Survival was not associated with baseline characteristics, but with a >50% increase in blood lymphocytes (OR 4.1, 95%CI 1.2-14.9) and CD4+ T cells (OR 5.9, 95%CI 1.7-23.3), and a > 1 log copies/mL decrease in cerebrospinal fluid JCV DNA (OR 7.6, 95%CI 1.6-56.1) during the first month after rhIL-7 initiation. Side effects were mainly local and flu-like symptoms (n=8, 12.5%) and PML-immune reconstitution inflammatory syndrome (IRIS) (n=5, 8%). In this non-controlled retrospective study, survival did not differ from that expected in HIV/AIDS patients, but might have been improved in those with hematological malignancies, primary immunodeficiencies and transplant recipients. RhIL-7 might have contributed to the increase in blood lymphocytes and decrease in CSF JCV replication that were associated with better survival. ANN NEUROL 2022;91:496-505.

Immune checkpoint inhibitors in the treatment of progressive multifocal leukoencephalopathy

Immune checkpoint inhibitors in the treatment of progressive multifocal leukoencephalopathy

Advances in Treatment of Progressive Multifocal Leukoencephalopathy.

Progressive multifocal encephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV), which occurs in immunocompromised individuals. Management of PML relies on restoration of immunity within the CNS. However, when this restoration cannot be readily achieved, PML has a grim prognosis. Innovative strategies have shown promise in promoting anti‐JCV immune responses, and include T‐cell adoptive transfer or immune checkpoint inhibitor therapies. Conversely, management of immune reconstitution inflammatory syndrome, particularly in iatrogenic PML, remains a major challenge. In this paper, we review recent development in the treatment of PML. ANN NEUROL 2021;90:865–873

Pembrolizumab for treatment of progressive multifocal leukoencephalopathy in primary immunodeficiency and/or hematologic malignancy: a case series of five patients

Progressive multifocal leukoencephalopathy is a rare opportunistic infection of the brain by John Cunningham polyomavirus in immune-compromised patients. In cases where no overt option for immune reconstitution is available [e.g., in patients with primary immunodeficiency (PID)], the disease is lethal in the majority of patients. Immune checkpoint inhibition has been applied in recent years with mixed outcomes. We present four novel patients and the follow-up of a previously published patient suffering from progressive multifocal leukoencephalopathy (PML) due to PID and/or hematologic malignancy who were treated with the immune checkpoint inhibitor pembrolizumab. In two patients with PID, symptoms improved and stabilized. One patient died because of worsening PML another of intracranial hemorrhage which was unrelated to PML or its treatment with pembrolizumab. The fifth patient suffered from PID and died of a pre-existing immune dysregulation, possibly exacerbated by pembrolizumab. The long-term follow-up of the first patient provides support for therapeutic decisions during this therapy and is the longest published clinical course of a patient with checkpoint inhibition for PML. We conclude that pembrolizumab can control PML symptoms long term in a subgroup of patients with PID, in our cases for 21 and 36 months. However, therapy must be started early because symptoms are only partially reversible. In light of severe adverse events, application of pembrolizumab is only justified if the prognosis for the individual patient is very poor.

Adoptive Transfer of JC Virus-Specific T Lymphocytes for the Treatment of Progressive Multifocal Leukoencephalopathy.

ObjectiveProgressive multifocal leukoencephalopathy (PML) is still burdened by high mortality in a subset of patients, such as those affected by hematological malignancies. The aim of this study was to analyze the safety and carry out preliminary evaluation of the efficacy of polyomavirus JC (JCPyV)‐specific T cell therapy in a cohort of hematological patients with PML.MethodsBetween 2014 and 2019, 9 patients with a diagnosis of “definite PML” according to the 2013 consensus who were showing progressive clinical deterioration received JCPyV‐specific T cells. Cell lines were expanded from autologous or allogenic peripheral blood mononuclear cells by stimulation with JCPyV antigen‐derived peptides.ResultsNone of the patients experienced treatment‐related adverse events. In the evaluable patients, an increase in the frequency of circulating JCPyV‐specific lymphocytes was observed, with a decrease or clearance of JCPyV viral load in cerebrospinal fluid. In responsive patients, transient appearance of punctate areas of contrast enhancement within, or close to, PML lesions was observed, which was interpreted as a sign of immune control and which regressed spontaneously without the need for steroid treatment. Six of 9 patients achieved PML control, with 5 alive and in good clinical condition at their last follow‐up.InterpretationAmong other novel treatments, T cell therapy is emerging as a viable treatment option in patients with PML, particularly for those not amenable to restoration of specific immunity. Neurologists should be encouraged to refer PML patients to specialized centers to allow access to this treatment strategy. ANN NEUROL 2021;89:769–779

Nivolumab for treatment of progressive multifocal leukoencephalopathy in Sézary syndrome

Progressive multifocal leukoencephalopathy (PML) is a rare but severe opportunistic CNS infection caused by JC polyomavirus in immunosuppressed patients. Immune checkpoint blockade stimulates immune function and has been suggested to reinvigorate viral clearance in PML patients by expanding JCV-specific T cells1 . Among the first 13 published PML patients treated with programmed cell death 1 inhibitors (PD1I) 8 showed a mild to marked treatment response2-7 . The underlying conditions ranged from chronic lymphocytic leukemia, AIDS, Non-Hodgkin lymphoma, idiopathic lymphopenia, variable immune deficiency, Hodgkin lymphoma, B-cell lymphoma to primary and combined immunodeficiency. Here, we present a patient with Sézary syndrome (SS) who developed PML and did not benefit from treatment with nivolumab.

Successful treatment of progressive multifocal leukoencephalopathy with mirtazapine and mefloquine in refractory myeloma

Successful treatment of progressive multifocal leukoencephalopathy with mirtazapine and mefloquine in refractory myeloma

Treatment of natalizumab-associated PML with filgrastim.

ObjectiveThere is no consensus on the treatment of progressive multifocal leukoencephalopathy (PML) occurring in multiple sclerosis (MS) patients treated with natalizumab (Nz). We report novel immune activating treatment with filgrastim of Nz‐associated PML in MS patients treated at Rush University Medical Center.MethodsWe retrospectively analyzed 17 Nz‐PML patients treated at this single tertiary referral center between 2010 and 2017. We reviewed the clinical symptoms, diagnostic methods, survival, outcome and MS modifying therapy (MSMT) after Nz‐PML.Results PML occurred after an average of 49 Nz infusions. To facilitate JCV elimination by accelerating immune reconstitution inflammatory syndrome (IRIS), all patients received subcutaneous filgrastim upon PML diagnosis and discontinuation of Nz; eight received plasma exchange (PLEX). Earlier than previously published, PML‐IRIS occurred in 15 of 17 (88.2%) patients within a mean of 57.4 days (SD 21.20) after the last Nz infusion. Seven patients recovered to or near baseline. There were no PML/IRIS–related fatalities but one patient committed suicide 2.5 years later. PLEX had no impact on PML outcome. Of 17 patients, 3 (18%) had MS relapses within 1 year after PML, and 5 (29%) beyond 1 year of PML onset, which is lower than expected in highly active MS patients. Eight patients started MSMTs after Nz‐PML on an average of 26 months after Nz withdrawal.InterpretationOur findings indicate that immunoactivation with filgrastim during PML and careful management of subsequent IRIS is likely beneficial in patients with Nz‐PML, without worsening MS. The clinical course of MS may be ameliorated by PML.

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.

Successful Treatment of Progressive Multifocal Leukoencephalopathy (PML) with Recombinant Interleukin-7 (IL-7) and Maraviroc in a Patient with Idiopathic CD4 Lymphocytopenia (P1.338)

Successful Treatment of Progressive Multifocal Leukoencephalopathy (PML) with Recombinant Interleukin-7 (IL-7) and Maraviroc in a Patient with Idiopathic CD4 Lymphocytopenia (P1.338)

Interleukin-7 treatment of PML in a patient with idiopathic lymphocytopenia

Objective:To describe the compassionate use of interleukin-7 (IL-7) for treatment of progressive multifocal leukoencephalopathy (PML) in the setting of idiopathic CD8+ greater than CD4+ lymphocytopenia.Methods:A 66-year-old HIV-seronegative man presented with progressive language dysfunction. MRI showed hyperintense lesions in the left hemispheric white matter with mild contrast enhancement. A brain biopsy performed 4 months after symptom onset established the diagnosis of PML. The patient had profound lymphocytopenia with absolute lymphocyte count (ALC) at 168 cells/μL, 87 CD4+ T cells/μL, and 7 CD8+ T cells/μL. There was no evidence of hematologic malignancy or rheumatologic disease.Results:The patient received 3 intramuscular injections of IL-7 at a dose of 10 μg/kg per week with no adverse effects. ALC peaked at 595 cells/μL, CD4+ T cells at 301 cells/μL, and CD8+ T cells at 34 cells/μL 3 weeks after completion of treatment. His lesions on MRI stabilized and neurologic examination mildly improved. JCV-specific T-cell responses measured by intracellular cytokine staining were not altered after treatment with IL-7 but there was a marked increase in regulatory T cells.Conclusion:This case further supports the investigational use of IL-7 in patients who develop PML in the setting of ICL.Classification of evidence:This study provides Class IV evidence that for patients with ICL and PML, IL-7 improves PML-related-outcomes. The study is rated Class IV because it is a case report.

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.

A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes

Immune reconstitution has improved outcomes for progressive multifocal leukoencephalopathy (PML), a potentially lethal brain disease caused by JC virus (JCV). However, an antiviral treatment to control JCV is needed when immune reconstitution is delayed or not possible. On the basis of in vitro efficacy, this study evaluated the effect of mefloquine on PML and factors that may predict PML outcomes. This 38-week, open-label, randomized, parallel-group, proof-of-concept study compared patients with PML who received standard of care (SOC) with those who received SOC plus mefloquine (250 mg for 3 days, then 250 mg weekly). Patients randomized to SOC could add mefloquine treatment at week 4. The primary endpoint was change from baseline to weeks 4 and 8 in JCV DNA copy number (load) in cerebrospinal fluid (CSF). Exploratory analyses evaluated factors that might correlate with clinical outcome. The majority of enrolled patients were HIV positive. Preplanned interim data analyses suggested that the study was unlikely to successfully demonstrate a significant difference between groups; therefore, the study was terminated prematurely. There was no significant difference between groups in CSF JCV DNA loads or clinical/MRI findings. Decrease in CSF JCV DNA load from baseline to week 4 was associated with a better clinical outcome at 16 weeks, as measured by Karnofsky scores. This study found no evidence of anti-JCV activity by mefloquine. An early decrease of CSF JCV DNA load appears to be associated with a better clinical outcome.Electronic supplementary materialThe online version of this article (doi:10.1007/s13365-013-0173-y) contains supplementary material, which is available to authorized users.

Encephalitis in the Pediatric Population

1. Stephen J. Falchek, MD* 1. *Division of Pediatric Neurology, Alfred I. duPont Hospital for Children/Thomas Jefferson University, Wilmington, DE, and Philadelphia, PA. * Abbreviations: ADEM: : acute disseminated encephalomyelitis CEP: : California Encephalitis Project CNS: : central nervous system CPP: : cerebral perfusion pressure CSF: : cerebrospinal fluid HSV: : herpes simplex virus IVIG: : intravenous immune globulin MS: : multiple sclerosis PCR: : polymerase chain reaction WNV: : West Nile virus Management of encephalitis, which can be fatal, requires understanding of a broad range of causative agents, pathophysiologic mechanisms, clinical syndromes, and outcomes. After completing this article, readers should be able to: 1. Know the many causes of encephalitis, including infectious, parainfectious, and noninfectious disorders. 2. Recognize the clinical features of encephalitis. 3. Be able to conduct a diagnostic investigation of a patient with encephalitis by using clinical and laboratory criteria. 4. Know the anticipated clinical course of different types of encephalitis. 5. Be familiar with the modalities used to treat encephalitis. 6. Understand the factors that influence the outcome in a patient who has encephalitis. The broad definition of the term “encephalitis,” that is, inflammation of the brain , necessitates acknowledgment of the enormous inclusivity of the topic. The most common interpretation of the term implies a direct invasion of the brain by an infectious pathogen, most commonly, viral, fungal, or parasitic. The topic also includes examples of meningitis mediated by bacteria or other agents, which can produce extrameningeal symptoms such as lethargy or seizures, in which case, the combined term “meningoencephalitis” is used. There are also many examples of encephalitis not due to direct central nervous system (CNS) infections. Inflammatory processes due to an acute or chronic illness can result in an acute immune-mediated encephalitis, such as acute disseminated encephalomyelitis (ADEM), lupus cerebritis, and paraneoplastic syndromes. Agents or conditions that produce slowly progressive CNS symptoms, such as tertiary syphilis or “slow viruses” (the prion protein encephalopathies), also are considered examples of encephalitis. Table 1 lists only a limited number of the many pathogens and pathologic conditions that can cause either acute or subacute encephalitis. In this discussion, …

Treatment of progressive multifocal leukoencephalopathy and idiopathic CD4+ lymphocytopenia

Progressive multifocal leukoencephalopathy is a neurological disease caused by the human polyoma virus JC virus and can present in patients with known immunodeficiencies. However, when associated with idiopathic CD4+ lymphocytopenia, management of patients can be quite challenging as these are two rare diseases with limited effective treatment options. In conjunction with the case report of a patient diagnosed with both conditions presented within this issue, a discussion of available treatment strategies is detailed.

Treatment of Progressive Multifocal Leukoencephalopathy Associated with Natalizumab

We describe the clinical and therapeutic course of a 52-year-old patient with multiple sclerosis in whom progressive multifocal leukoencephalopathy (PML) developed after 12 months of therapy with natalizumab. The patient was hospitalized 2 months after the onset of neurologic and psychiatric symptoms and was treated with plasma exchange and immunoadsorption to eliminate natalizumab. After a brief improvement, he became critically ill with an apparent episode of immune reconstitution inflammatory syndrome. Steroid-pulse therapy led to stabilization of the patient's condition and clinically significant recovery. This case illustrates that prompt diagnosis and treatment may improve the outcome in patients with severe PML associated with natalizumab therapy.