Fatal Demyelinating Disease Research Articles

Neuroimaging Features and Outcomes of Progressive Multifocal Leukoencephalopathy (PML): A Single-Center Experience (P13-10.003)

<h3>Objective:</h3> To summarize the clinical and imaging features of progressive multifocal leukoencephalopathy (PML) and highlight the importance of a timely diagnosis. <h3>Background:</h3> PML is a rare but fatal demyelinating disease of the central nervous system caused by the reactivation of the John Cunningham (JC) virus (JCV). It has an exceedingly high mortality rate and exhibits significant cerebrospinal fluid (CSF) and neuroimaging features, which can be identified early in the disease course. <h3>Design/Methods:</h3> We conducted a single-center retrospective cohort study of patients recruited at the Department of Neurology, West Virginia University, between January 2014 and December 2021. Of the 37 enrolled patients, 12 were included based on our selection criteria. Magnetic resonance imaging (MRI) and confirmation of PML through JCV polymerase chain reaction of CSF were done in all cases. <h3>Results:</h3> Eleven out of the 12 patients (92%) had predisposing risk factors, such as hematologic malignancies (n=5) and human immunodeficiency virus (HIV) infection (n=4). Symptoms included altered mental status (n=5), seizure-like activity (n=4), unilateral weakness/paresthesia (n=3), and visual deficits (n=3). MRI revealed bihemispheric (n=7) and unilateral (n=5) lesions within the fronto-parietal (8/12) and temporo-parietal (4/12) lobes. Subcortical U-fibers were involved, and lesions were predominantly confluent (9/12) with irregular borders and without mass effect. These demonstrated hyperintensities on fluid-attenuated inversion recovery, with corresponding hypo-intensity on T1-weighted imaging and restricted diffusion. A single faint contrast-enhanced punctate lesion was reported in 3 patients; seven had no documented contrast studies. Nine (75%) received treatment, and only four cases (33.3%) survived; the mean time from diagnosis to death was 1.4 months (±0.69), and all eight patients died within three months of diagnosis. <h3>Conclusions:</h3> PML should immediately be considered in immunocompromised patients presenting with new-onset neurological symptoms and typical imaging findings. Physicians must familiarize themselves with these presentations since a rapid diagnosis and targeted intervention are critical to reducing overall mortality. <b>Disclosure:</b> Dr. Yu has nothing to disclose. Dr. Sharma has nothing to disclose. Dr. R has nothing to disclose. Dr. Sriwastava has nothing to disclose.

Hepatitis B virus-induced CD4 lymphocytopenia: A rare cause of progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a rare subacute-onset fatal demyelinating disease of the central nervous system caused by the John Cunningham (JC) virus. It usually occurs in impaired cell-mediated immunity settings such as lymphoproliferative disorders, chronic infective or granulomatous conditions on immunosuppressive medications, and human immunodeficiency virus infection. It also appears very rarely with idiopathic CD4 lymphocytopenia. We present a case of PML with visual field defect, progressive motor impairment, behavioral alteration, and dementia. Magnetic resonance imaging had features of asymmetric non-enhancing hyperintense subcortical white matter lesions in the background of chronic active hepatitis B infection. To the best of our knowledge, this is the first case report of CD4 lymphocytopenia associated PML following chronic hepatitis B infection.

Progressive multifocal leukoencephalopathy in multiple myeloma associated with daratumumab, lenalidomide, and dexamethasone

AbstractProgressive multifocal leukoencephalopathy is a rare but fatal demyelinating disease of the central nervous system with reactivation of JC virus. Herein, we describe a case of progressive multifocal leukoencephalopathy associated with a therapeutic regimen of daratumumab, lenalidomide, and dexamethasone for multiple myeloma. A 69‐year‐old man with multiple myeloma was admitted to the neurological care unit due to progressive cognitive dysfunction after seven cycles of the regimen. His CD4+ T cell count was 190 cells/μL. Diffusion‐weighted magnetic resonance imaging revealed nodular diffusion restrictions in the frontal and parietal lobes. He was diagnosed with progressive multifocal leukoencephalopathy following a positive polymerase chain reaction test for JC virus DNA in the cerebrospinal fluid. After cessation of multiple myeloma treatment, his cognition and magnetic resonance imaging findings improved within 3 months. We should recognize this potentially fatal complication in patients receiving this regimen.

Pur-Alpha Induces JCV Gene Expression and Viral Replication by Suppressing SRSF1 in Glial Cells.

ObjectivePML is a rare and fatal demyelinating disease of the CNS caused by the human polyomavirus, JC virus (JCV), which occurs in AIDS patients and those on immunosuppressive monoclonal antibody therapies (mAbs). We sought to identify mechanisms that could stimulate reactivation of JCV in a cell culture model system and targeted pathways which could affect early gene transcription and JCV T-antigen production, which are key steps of the viral life cycle for blocking reactivation of JCV. Two important regulatory partners we have previously identified for T-antigen include Pur-alpha and SRSF1 (SF2/ASF). SRSF1, an alternative splicing factor, is a potential regulator of JCV whose overexpression in glial cells strongly suppresses viral gene expression and replication. Pur-alpha has been most extensively characterized as a sequence-specific DNA- and RNA-binding protein which directs both viral gene transcription and mRNA translation, and is a potent inducer of the JCV early promoter through binding to T-antigen.Methods and ResultsPur-alpha and SRSF1 both act directly as transcriptional regulators of the JCV promoter and here we have observed that Pur-alpha is capable of ameliorating SRSF1-mediated suppression of JCV gene expression and viral replication. Interestingly, Pur-alpha exerted its effect by suppressing SRSF1 at both the protein and mRNA levels in glial cells suggesting this effect can occur independent of T-antigen. Pur-alpha and SRSF1 were both localized to oligodendrocyte inclusion bodies by immunohistochemistry in brain sections from patients with HIV-1 associated PML. Interestingly, inclusion bodies were typically positive for either Pur-alpha or SRSF1, though some cells appeared to be positive for both proteins.ConclusionsTaken together, these results indicate the presence of an antagonistic interaction between these two proteins in regulating of JCV gene expression and viral replication and suggests that they play an important role during viral reactivation leading to development of PML.

NI-53 * PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY MIMICKING HIGH GRADE GLIOMA IN AN IMMUNOCOMPETENT PATIENT: A CASE REPORT

Progressive multifocal leukoencephalopathy is an uncommon and fatal demyelinating disease of the central nervous system that is due to reactivation of the JC virus. It is most often seen in immunocompromised patients, such as those with HIV/AIDS or those on chronic immunosuppressive therapy. We present a case of biopsy-proven idiopathic PML in a presumed immunocompetent patient, with imaging characteristics suggestive of glioma. A 66-year-old white male with a history of cirrhosis presented with subacute onset of progressive deterioration of mental status, aphasia, and right hemiparesis. Laboratory and cerebrospinal fluid studies were unremarkable for any infection, autoimmune disease, and malignancy. MRI brain revealed a non-contrast enhancing lesion involving the left frontal, parietal, and temporal lobes with marked sparing of overlying cortex, characterized by increased T2/FLAIR hyperintensity, T1 hypointensity, and facilitated diffusion. MR spectroscopy of the lesion demonstrated elevated choline, with lactate peaks and decreased NAA. A high grade glioma was suspected and patient underwent a brain biopsy. Histological analysis revealed enlarged oligodendrocytes with myelin loss consistent with active demyelination. The enlarged oligodendrocytes had smudged nuclear chromatin, were positive for JC virus by in situ hydridization, and also showed strong staining for p53. A diagnosis of progressive multifocal leukoencephalopathy (PML) was made. Although rare in immunocompetent individuals, this unusual presentation suggests that PML be considered in the approach to the diagnosis and management of such lesions.

New approach for JC virus detection and its application for PML diagnosis

Progressive multifocal leukoencephalopathy (PML) is a rare but fatal demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV). The current diagnostic standard for PML is real-time PCR testing of extracted DNA for assessing the presence of JCV DNA in cerebrospinal fluid (CSF). However, because of its sensitivity, real-time PCR assay for JCV testing has a risk of false-positive results due to DNA contamination. JCV isolates recovered from the brain or CSF of PML patients contain hypervariable mutations within the non-coding control region (NCCR) of the viral genome. In our laboratory, the high-resolution melting (HRM) assay was developed to distinguish the patient-dependent NCCR patterns of JCV DNA variants in clinical specimens. The HRM-based scanning of NCCR serves as a quick and convenient technique for comparing the mutational patterns of JCV variants in clinical samples and for the confirmation of PML diagnosis when combined with routine real-time PCR testing.

Pseudovirus mimics cell entry and trafficking of the human polyomavirus JCPyV

The normally asymptomatic human polyomavirus, JCPyV, is the causative agent of a rare but fatal demyelinating disease known as progressive multifocal leukoencephalopathy (PML). Individuals at risk for developing PML include those with AIDS, with other underlying immunosuppressive diseases, and in patients treated with immunomodulatory regimens. Drugs to prevent viral reactivation in the setting of immunosuppression or immunomodulation could be used to sustain lives. Development of such drugs has been impeded by the difficulty of growing and studying the virus. We sought to develop a more efficient method for screening drugs that inhibit viral infection. Pseudovirus models have been developed which may be of use in pharmaceutical research. The use of pseudoviruses as models for viral infection is dependent on them using similar pathways for infection as virus. We screened known inhibitors of viral entry for their ability to block pseudovirus infection. Here we show that the pseudovirus based on the human polyomavirus JCPyV recapitulates virus binding, entry and trafficking. This system can be used for high-throughput screening of antiviral drugs.

Characteristics of progressive multifocal leukoencephalopathy clarified through internet-assisted laboratory surveillance in Japan

BackgroundProgressive multifocal leukoencephalopathy (PML), a rare but fatal demyelinating disease caused by JC virus (JCV), occurs mainly in immunocompromised patients. As PML develops in individuals with various underlying disorders sporadically and infrequently, a nationwide survey of PML is difficult. This study was conducted to elucidate the characteristics of PML in Japan through an internet-assisted laboratory surveillance program.MethodsA diagnostic support system for PML was established using a real-time PCR assay of JCV DNA in cerebrospinal fluid (CSF), and requests for testing were received from clinicians via specialized websites. Medical histories of patients were collected through standardized questionnaires, and a database of CSF JCV loads and clinical information was created and analyzed.ResultsFor 4 years from April 2007 to March 2011, CSF specimens from 419 patients were tested. Forty-eight individuals were found positive for JCV DNA in their CSF and were diagnosed with PML. PML primarily occurred not only in HIV-positive patients (33.3%) but also in patients with hematologic disorders after receiving stem cell transplantation, chemotherapy, and/or immunosuppressive treatment (39.6%). The frequencies of PML cases among the subjects in these two categories were 20.3% and 23.5%, respectively. Although no significant features were observed with respect to CSF JCV loads in PML patients with an HIV infection or hematologic disorder, males were predominant in both groups (100% and 89.5%, respectively). The proportion of PML cases with autoimmune disorders (6.3%) or solid-organ transplants (2.1%) was smaller than those with HIV infection or hematologic disorders, probably due to the limited availability of therapeutic monoclonal antibodies and transplantation from brain dead donors.ConclusionsThe results suggest that the internet-assisted laboratory surveillance program might be a useful strategy for collecting precise real-time information on PML on a national level. The current database provides important background information for the diagnosis and treatment of patients with risk factors for PML.

Progressive Multifocal Leukoencephalopathy in a Patient with Polymyositis: Case Report and Literature Review

To the Editor: We describe a fatal case of progressive multifocal leukoencephalopathy (PML) in a patient with polymyositis (PM) and antisynthetase syndrome treated with conventional immunosuppressive drugs. PML is a rare and fatal demyelinating disease caused by the ubiquitous John Cunningham virus (JCV)1,2. JCV infection is usually an asymptomatic event in childhood and about 60%–80% of the normal adult population are seropositive for antibodies against JCV3,4. After primary infection, the virus remains in a latent form in the bone marrow, lymphoid organs, and kidney and some studies have demonstrated that it also can establish latency in healthy brain tissue although this is a matter of debate5,6. The virus may later reactivate, undergoing genomic rearrangement in the non-coding regulatory region, and migrate to the brain, where it infects glial cells and causes a lytic infection known as PML7,8. Reactivation usually occurs during conditions of immunosuppression but there are also reports of PML development in immunocompetent individuals9. The mechanisms behind the pathway leading to viral reactivation remain insufficiently defined. The risk of PML in autoimmune diseases has recently been highlighted because of an increasing number of PML cases occurring during treatment with new biological immunosuppressive agents including natalizumab (for multiple sclerosis, MS), rituximab (RTX; for rheumatic diseases), and efalizumab (for psoriasis) and also with the newer immunosuppressant agent mycophenolate mofetil (MMF)10. In the more rare autoimmune diseases polymyositis/dermatomyositis (PM/DM) there are a few reports of PML developing in patients treated with conventional disease-modifying antirheumatic drugs9,11,12,13,14,15,16, but also in patients during off-label treatment with RTX17. The increased risk for PML associated with the new biologics has raised … Address correspondence to Dr. E. Iacobaeus; E-mail: ellen.iacobaeus{at}karolinska.se

Macrophages Counteract Demyelination in a Mouse Model of Globoid Cell Leukodystrophy

Whether microglia and macrophages are beneficial or harmful in many neurological disorders, including demyelinating diseases such as multiple sclerosis and the leukodystrophies, is currently under debate. Answering this question is of special interest in globoid cell leukodystrophy (GLD), a genetic fatal demyelinating disease, because its rapidly progressive demyelination in the nervous system is accompanied by a characteristic accumulation of numerous globoid macrophages. Therefore, we cross-bred the twitcher (twi) mouse, a bona fide model of GLD, with the macrophage-deficient osteopetrotic mutant and studied the resultant macrophage-deficient twitcher (twi+op) mouse. The twi+op mouse had few microglia and macrophages in the white matter and, interestingly, showed a more severe clinical phenotype compared to the twi mouse. The number of nonmyelinated axons in the spinal cord was significantly higher in twi+op mice than in twi mice at 45 d old. The difference appeared to be due to impaired remyelination in twi+op mice rather than accelerated demyelination. Quantitative reverse transcription PCR and immunohistochemical studies revealed that the recruitment of oligodendrocyte progenitor cells in response to demyelination was compromised in twi+op mice. Increased myelin debris in the white matter parenchyma of twi+op mice suggested that phagocytosis by macrophages may play an important role in promoting remyelination. Macrophage markers for both protective and destructive phenotypes were significantly upregulated in the spinal cord of twi mice but were close to normal in twi+op mice due to the reduced macrophage number. The overall effects of macrophages in GLD appear to be beneficial to myelin by promoting myelin repair.

Research Highlights

Research Highlights

Progressive Multifocal Leukoencephalopathy in Myelodysplastic Syndrome Involving Pure Red Cell Aplasia

Progressive multifocal leukoencephalopathy (PML) is a rare and fatal demyelinating disease of the central nervous system caused by JC polyomavirus (JCV) reactivation in an immunocompromised host. We describe a case of PML in a 76-year-old woman with myelodysplastic syndrome, who had been treated with azathioprine for a pure red cell aplasia-like condition. PML was diagnosed based on the neurologic symptoms, the magnetic resonance imaging patterns and the detection of JCV DNA in the cerebrospinal fluid. She died ten months after the diagnosis. An autopsy confirmed the diagnosis, and JCV DNA was detected in the cerebrum. Azathioprine might have triggered PML.

Longitudinal study of two cases of progressive multifocal leukoencephalopathy with a clinical benign evolution

Progressive multifocal leukoencephalopathy (PML) usually is a rapid and fatal demyelinating disease of the central nervous system (CNS), caused by JC virus (JCV). After the introduction of Highly active antiretroviral therapy (HAART), its prognosis has been modified in some cases but remains a relevant cause of morbidity in human immunodeficiency virus-seropositive (HIV+) patients. The authors report here two cases of PML, followed over time, sharing a benign course and a JCV antigen-specific T-cell response, but with different cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and clinical features. In both cases, JCV DNA detection in brain biopsies samples and specific antigenic response preceded its isolation in the CSF by several months. In one patient, during the first stage of the disease, the presence of CSF and MRI inflammatory findings, associated with the lack of JCV detection in the CSF, made the diagnosis more challenging. Given that to date a reformation of the laboratory parameters for PML diagnosis is strongly needed, this report highlights the following considerations: (a) indications for performing brain biopsy in HIV-related leukoencephalopathies of uncertain origin, and (b) the role of JCV immunologically specific T-cell response as an additional marker for PML diagnosis and indicator for good prognosis of the disease.

Semiquantitative detection of JCV‐DNA in peripheral blood leukocytes from HIV‐1‐infected patients with or without progressive multifocal leukoencephalopathy

Progressive Multifocal Leukoencephalopathy (PML) is a severe and fatal demyelinating disease that occurs especially in HIV-infected patients. It has been suggested that JC virus (JCV) migrates in peripheral blood leukocytes from the kidney to the central nervous system where it initiates demyelination. To investigate the physiopathological role of the peripheral blood virus in the development of PML, the prevalence of JCV infection and the levels of JCV DNA load were evaluated in peripheral blood leukocytes or mononuclear cells of 10 AIDS patients at the time of onset of PML symptoms, and in 150 non-PML HIV-1-infected patients using a semiquantitative PCR and ELISA-hybridization assay. In PML-AIDS patients, 60% (6/10) were positive for JCV-DNA detection in peripheral blood cells compared with 26% (13/50) and 18% (18/100) positive for non-PML HIV-infected control patients with CD4+ T lymphocyte counts below and above 200.10(6) /l, respectively (60 vs. 26%, P = 0.06; 60 vs. 18%; P = 0.007). The prevalence of JCV infection in the peripheral blood cells taken from controls appeared to be independent of the CDC stage of infection and CD4+ T lymphocyte counts. The predictive positive value of a positive JCV DNA PCR in peripheral blood cells for the diagnosis of PML in an HIV-infected patient was 16% whereas the predictive negative value was 96%. The levels of circulating JCV DNA load, ranging from 1.69 to 2.53 log of copies per 10(6) cells, did not differ between patients at time of PML symptoms onset and controls, and appeared to be independent of the clinical and the biological status in control patients. The findings do not indicate any significant JCV genomic replication activity in peripheral blood cells at the onset of PML disease, and suggest that JCV replication markers in the systemic compartment would not be valuable for predicting the development of PML in AIDS patients.