Natural History Study of Progressive Multifocal Leukoencephalopathy (PML)

Study Overview
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Brief Summary
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Background: - Progressive multifocal leukoencephalopathy (PML) is a severe viral infection of the brain. It is caused by JC virus. Many people have this virus in their bodies all their life, but it is usually kept in check by their immune system. If the immune system does not work right because of a disease or medication, the virus becomes active and can damage cells in the brain. Not much is known about PML or how it affects the immune system. Researchers want to study people with PML to better understand the natural history of the disease. Objectives: - To study the natural history of PML. Eligibility: - Individuals at least 2 years of age who have PML. Design: Participants will be screened with a physical exam, medical history, and imaging studies. Participants will have several visits to the National Institutes of Health Clinical Center. There will be an initial visit, monthly visits for the next 6 months, a 12-month visit, and possible visits afterward. At the initial visit, participants will give blood, urine, and spinal fluid samples. They will also have neurological tests and imaging studies of the brain. For the next five visits, participants will give blood and urine samples. They will also have neurological tests and imaging studies of the brain. The 6-month and 12-month visits will repeat the tests from the initial visit. Other optional procedures include bone marrow samples and skin biopsies. Additional blood tests and imaging studies may be performed. Treatment will not be provided as part of this study.

Detailed Description
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The objective of this study is to examine the risk factors and natural course of JCV infection and progressive multifocal leukoencephalopathy (PML). PML is a devastating, demyelinating neurological disease affecting the brain of patients with a compromised immune system. It is caused by reactivation of JC virus (JCV), a small DNA virus that infects the majority of the population without clinical significance. There are currently no treatments available for PML. We plan to study patients with suspected or confirmed PML with different underlying conditions including patients on immune-modulatory therapies for multiple sclerosis (MS), rheumatologic diseases or other autoimmune diseases, as well as patients with HIV infection or other conditions leading to a compromised immune system. Patients will be seen at defined time points during their disease course and detailed assessments will be performed to collect clinical and imaging data. Blood, cerebrospinal fluid (CSF) and urine will also be collected at these time points to evaluate the behavior and biology of the JCV and the patients immune responses to the infection. These tests will lead to a better understanding of the pathophysiology of PML and the course of this disease in different patient groups. Additionally, we will recruit a patient control cohort represented by patients with impaired immune function for any cause and considered at risk for development of PML, and a healthy volunteer cohort. The purpose of these additional cohorts is to explore and validate biomarkers for risk of development of PML and early diagnosis. Additionally, the healthy volunteer cohort may be screened and evaluated as possible donors of peripheral blood mononuclear cells (PBMC) for manufacture of virus-specific T cells. The detailed characterization described above will be used to help identify: Clinical imaging and/or laboratory features pathognomonic of JCV infection and disease course that may aid in earlier diagnosis and appropriate intervention Clinical imaging and/or laboratory features of the disease course that is predictive of clinical outcomes This information will be integrated to develop a clinically relevant, disease-specific assessment scale of PML, which is currently not available. Such a scale would be a useful tool for the clinical management of patients (i.e., for development of standards of care), as well as for clinical trial design and interpretation. The long-term objectives of this study are to improve the understanding of the disease course and underlying pathophysiology, to identify subgroups with different prognosis and/or susceptibility to interventions, and to help identify therapeutic targets and/or intervention strategies. Equally important, these efforts will allow development of a repository of cryopreserved biological samples that will be used for validation of candidate biomarkers in future studies; this data and biological bank will be made available to outside laboratories.

Official Title
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Natural History Study of Progressive Multifocal Leukoencephalopathy (PML)

Conditions
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Progressive Multifocal Leukoencephalopathy

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Suspected or confirmed PML MRI compatible with PML Able to participate in the studies and follow-up required by the protocol At least 2 years old EXCLUSION CRITERIA: Significant condition, which in the judgment of the principal investigator, would make participation in the diagnostic and research parts of evaluation impossible or risky. Medical contraindication to MRI (i.e., devices such as a cardiac pacemaker or infusion pump, other metallic implants, metallic foreign objects, body piercings that cannot be removed) Pregnancy Inability to provide informed consent, either directly or via appointed power of attorney Unwillingness to consent for collection of biological samples or their cryopreservation

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Control Patients at Risk for PML<br>Participants with impaired immune function from any cause and considered at risk for PML | |
| Healthy Volunteers<br>Healthy volunteers without impaired immune function | |
| PML Patients<br>Participants with PML | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the baseline features, of patients with PML with regards to clinical features imaging studies, immunological markers, and viral studies. | 1. Characterization of distinctive imaging features to differentiate between actively progressing PML, and PML-IRIS and inactive PML 2. Characterization of distinctive clinical features to differentiate between actively progressing PML, PML- and IRIS, and inactive PML 3. Characterization of immune and virological features to differentiate between actively progressing PML, and PML- IRIS, and inactive PML 4. Characterization of immune and virological differences across PML patient populations with different underlying disease, subjects at risk for developing PML, and healthy individuals 5. Characterization of genetic susceptibility for development of PML | one year following last enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To longitudinally follow patients with PML with thorough characterization of their clinical course, imaging correlates, immunological markers, and viral studies | 1. Temporal correlation between clinical course and imaging and/or laboratory measures 2. To identify biomarkers that can predict long-term outcome and response to treatment interventions 3. To develop a clinically relevant assessment scale for PML that identifies milestones of disease progression 4. To develop a repository of cryopreserved biological samples that will be used for validation of candidate biomarkers in future studies 5. To characterize the immune profile in blood and CSF of patients with PML 6. To determine the eligibility of PML patients for participation in other studies 7. To screen and evaluate healthy subjects as donors for manufacture of virus-specific T cells (to be administered to patients under separate, dedicated protocol) | one year following last enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Encephalitis, Immune Reconstitution Syndrome, Human Immunodeficiency Virus, Multiple Sclerosis, Natural History