JC Virus-Related Retinopathy.

Importance: Reactivation of the JC polyomavirus in individuals with impaired immunity is most commonly associated with progressive multifocal leukoencephalopathy. We report a case of polyomavirus-related retinopathy, representing a potentially novel manifestation of JC polyomavirus infection.

Objective: To describe a patient with common variable immunodeficiency who exhibited isolated unilateral retinopathy related to JC polyomavirus infection of the retinal ganglion cell layer.

The written symbol digit modalities test in multiple sclerosis is sensitive to cognitive and motor disability.

Background: The symbol digit modalities test is a commonly used cognitive assessment for which the written (wSDMT) version remains poorly studied in multiple sclerosis (MS).

Objective: To establish performance benchmarks, assess learning effects, and explore the utility of the wSDMT as a joint indicator of cognitive and motor disability progression in MS.

Methods: A retrospective analysis of wSDMT scores, collected over a decade in conjunction with common clinical measures, was carried out using reliable change indices and linear mixed-effects modeling.

Differential Validity in the Written, Oral, and Electronic SDMT in Multiple Sclerosis.

Background: Cognitive decline in multiple sclerosis (MS) is commonly assessed using the Symbol Digit Modalities Test (SDMT). However, the written (wSDMT), oral (oSDMT), and electronic (eSDMT) versions may display differing psychometric properties, despite often being used interchangeably.

Objective: The objective of the study is to compare the wSDMT, oSDMT, and eSDMT, including inter-test reliability, and to assess demographic and motor disability influences on test performance.

Portable ultra-low-field MRI for progressive multifocal leukoencephalopathy: Case studies, sensitivity, and potential applications.

Background And Objective: Progressive multifocal leukoencephalopathy (PML) is a severe, disabling infection caused by JC virus reactivation. PML-related disability complicates the MRI monitoring needed to assess treatment interventions in clinical trial or compassionate use settings. Portable ultra-low-field MRI (pULF-MRI) offers a convenient approach when such frequent imaging is needed.

Radiological Changes in the Spinal Cord and Brain of Patients with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP).

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive neurological disorder and shares many radiological and clinical features with other more prevalent myelopathies. Here, we quantified spinal cord and brain volumes in adults with HAM/TSP in comparison with healthy volunteers (HVs) and individuals diagnosed with relapsing-remitting or progressive multiple sclerosis (RRMS or P-MS). Clinical disability and MRI were assessed in 24 HVs, 43 HAM/TSP subjects, and 46 MS subjects.

Antigen-Specific T Cell Receptor Discovery for Treating Progressive Multifocal Leukoencephalopathy.

Background: Progressive multifocal leukoencephalopathy (PML) is a frequently fatal disease of the central nervous system caused by JC virus (JCV). Survival is dependent on early diagnosis and ability to re-establish anti-viral T cell immunity. Adoptive transfer of polyomavirus-specific T cells has shown promise; however, there are no readily available HLA-matched anti-viral T cells to facilitate rapid treatment.

Bridging the gaps between JCV infection models and human disease.

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Contribution of new and chronic cortical lesions to disability accrual in multiple sclerosis.

Cortical lesions are common in multiple sclerosis and are associated with disability and progressive disease. We asked whether cortical lesions continue to form in people with stable white matter lesions and whether the association of cortical lesions with worsening disability relates to pre-existing or new cortical lesions. Fifty adults with multiple sclerosis and no new white matter lesions in the year prior to enrolment (33 relapsing-remitting and 17 progressive) and a comparison group of nine adults who had formed at least one new white matter lesion in the year prior to enrolment (active relapsing-remitting) were evaluated annually with 7 tesla (T) brain MRI and 3T brain and spine MRI for 2 years, with clinical assessments for 3 years.

Biomarkers for progressive multifocal leukoencephalopathy: emerging data for use of JC virus DNA copy number in clinical trials.

Progressive multifocal leukoencephalopathy is a rare but devastating demyelinating disease caused by the JC virus (JCV), for which no therapeutics are approved. To make progress towards addressing this unmet medical need, innovations in clinical trial design are needed. Quantitative JCV DNA in CSF has the potential to serve as a valuable biomarker of progressive multifocal leukoencephalopathy disease and treatment response in clinical trials to expedite therapeutic development, as do neuroimaging and other fluid biomarkers such as neurofilament light chain.

Cortical lesions uniquely predict motor disability accrual and form rarely in the absence of new white matter lesions in multiple sclerosis.

Background And Objectives: Cortical lesions (CL) are common in multiple sclerosis (MS) and associate with disability and progressive disease. We asked whether CL continue to form in people with stable white matter lesions (WML) and whether the association of CL with worsening disability relates to pre-existing or new CL.

Methods: A cohort of adults with MS were evaluated annually with 7 tesla (T) brain magnetic resonance imaging (MRI) and 3T brain and spine MRI for 2 years, and clinical assessments for 3 years.

Viral Immune signatures from cerebrospinal fluid extracellular vesicles and particles in HAM and other chronic neurological diseases.

Background And Objectives: Extracellular vesicles and particles (EVPs) are released from virtually all cell types, and may package many inflammatory factors and, in the case of infection, viral components. As such, EVPs can play not only a direct role in the development and progression of disease but can also be used as biomarkers. Here, we characterized immune signatures of EVPs from the cerebrospinal fluid (CSF) of individuals with HTLV-1-associated myelopathy (HAM), other chronic neurologic diseases, and healthy volunteers (HVs) to determine potential indicators of viral involvement and mechanisms of disease.

Progressive Multifocal Leukoencephalopathy: Pathogenesis, Diagnostic Tools, and Potential Biomarkers of Response to Therapy.

JC polyomavirus (JCV) establishes an asymptomatic latent and/or persistent infection in most of the adult population. However, in immunocompromised individuals, JCV can cause a symptomatic infection of the brain, foremost progressive multifocal leukoencephalopathy (PML). In the past 2 decades, there has been increasing concern among patients and the medical community because PML was observed as an adverse event in individuals treated with modern (selective) immune suppressive treatments for various immune-mediated diseases, especially multiple sclerosis.

Characteristics of Progressive Multifocal Leukoencephalopathy Associated With Sarcoidosis Without Therapeutic Immune Suppression.

Importance: Progressive multifocal leukoencephalopathy can occur in the context of systemic sarcoidosis (S-PML) in the absence of therapeutic immune suppression and can initially be mistaken for neurosarcoidosis or other complications of sarcoidosis. Earlier recognition of S-PML could lead to more effective treatment of the disease.

Objective: To describe characteristics of patients with S-PML.

Progressive multifocal leukoencephalopathy genetic risk variants for pharmacovigilance of immunosuppressant therapies.

Background: Progressive multifocal leukoencephalopathy (PML) is a rare and often lethal brain disorder caused by the common, typically benign polyomavirus 2, also known as JC virus (JCV). In a small percentage of immunosuppressed individuals, JCV is reactivated and infects the brain, causing devastating neurological defects. A wide range of immunosuppressed groups can develop PML, such as patients with: HIV/AIDS, hematological malignancies (e.

Promise and Challenges of Checkpoint Inhibitor Therapy for Progressive Multifocal Leukoencephalopathy in HIV.

Purpose Of Review: Progressive multifocal leukoencephalopathy (PML) is a severe opportunistic infection that remains an important cause of morbidity and mortality in people living with HIV (PLWH). Immune checkpoint molecules are negative regulators of the immune response that have been targeted as a strategy to bolster anti-viral immunity in PML, with varied outcomes reported. While initiation and optimization of antiretroviral therapy remains the standard of care in HIV-related PML, the specific opportunities and risks for checkpoint blockade in these cases should be explored.

Progressive Multifocal Leukoencephalopathy Treated by Immune Checkpoint Inhibitors.

Objective: Our aim was to assess the real-world effectiveness of immune checkpoint inhibitors for treatment of patients with progressive multifocal leukoencephalopathy (PML).

Methods: We conducted a multicenter survey compiling retrospective data from 79 PML patients, including 38 published cases and 41 unpublished cases, who received immune checkpoint inhibitors as add-on to standard of care. One-year follow-up data were analyzed to determine clinical outcomes and safety profile.

Comparison of qPCR with ddPCR for the Quantification of JC Polyomavirus in CSF from Patients with Progressive Multifocal Leukoencephalopathy.

Background: Lytic infection of oligodendrocytes by the human JC polyomavirus (JCPyV) results in the demyelinating disease called progressive multifocal leukoencephalopathy (PML). The detection of viral DNA in the cerebrospinal fluid (CSF) by PCR is an important diagnostic tool and, in conjunction with defined radiological and clinical features, can provide diagnosis of definite PML, avoiding the need for brain biopsy. The main aim of this study is to compare the droplet digital PCR (ddPCR) assay with the gold standard quantitative PCR (qPCR) for the quantification of JC viral loads in clinical samples.

Lesion size and shape in central vein sign assessment for multiple sclerosis diagnosis: An in vivo and postmortem MRI study.

Background: The "central vein sign" (CVS), a linear hypointensity on T2*-weighted imaging corresponding to a central vein/venule, is associated with multiple sclerosis (MS) lesions. The effect of lesion-size exclusion criteria on MS diagnostic accuracy has not been extensively studied.

Objective: Investigate the optimal lesion-size exclusion criteria for CVS use in MS diagnosis.

Cortical lesion hotspots and association of subpial lesions with disability in multiple sclerosis.

Background: Dramatic improvements in visualization of cortical (especially subpial) multiple sclerosis (MS) lesions allow assessment of impact on clinical course.

Objective: Characterize cortical lesions by 7 tesla (T) T-/T-weighted magnetic resonance imaging (MRI); determine relationship with other MS pathology and contribution to disability.

Methods: Sixty-four adults with MS (45 relapsing-remitting/19 progressive) underwent 3 T brain/spine MRI, 7 T brain MRI, and clinical testing.

Central Vein Sign Profile of Newly Developing Lesions in Multiple Sclerosis: A 3-Year Longitudinal Study.

Background And Objectives: The central vein sign (CVS), a central linear hypointensity within lesions on T2*-weighted imaging, has been established as a sensitive and specific biomarker for the diagnosis of multiple sclerosis (MS). However, the CVS has not yet been comprehensively studied in newly developing MS lesions. We aimed to identify the CVS profiles of new white matter lesions in patients with MS followed over time and investigate demographic and clinical risk factors associated with new CVS+ or CVS- lesion development.

The neuroradiology of progressive multifocal leukoencephalopathy: a clinical trial perspective.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the CNS caused by the JC virus, which infects white and grey matter cells and leads to irreversible demyelination and neuroaxonal damage. Brain MRI, in addition to the clinical presentation and demonstration of JC virus DNA either in the CSF or by histopathology, is an important tool in the detection of PML. In clinical practice, standard MRI pulse sequences are utilized for screening, diagnosis and monitoring of PML, but validated imaging-based outcome measures for use in prospective, interventional clinical trials for PML have yet to be established.

Clinical trial of raltegravir, an integrase inhibitor, in HAM/TSP.

Objective: Human T-cell lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive myelopathy. A high proviral load (PVL) is one of the main risk factors for HAM/TSP. Recently, it was shown that raltegravir could inhibit cell-free and cell-to-cell transmission of HTLV-1 in vitro.

7T MRI Differentiates Remyelinated from Demyelinated Multiple Sclerosis Lesions.

Objective: To noninvasively assess myelin status in chronic white matter lesions of multiple sclerosis (MS), we developed and evaluated a simple classification scheme based on T1 relaxation time maps derived from 7-tesla postmortem and in vivo MRI.

Methods: Using the MP2RAGE MRI sequence, we classified 36 lesions from 4 postmortem MS brains as "long-T1," "short-T1," and "mixed-T1" by visual comparison to neocortex. Within these groups, we compared T1 times to histologically derived measures of myelin and axons.