Top PDF Four cases of progressive multifocal leukoencephalopathy in iatrogenic immunocompromised patients

Four cases of progressive multifocal leukoencephalopathy in iatrogenic immunocompromised patients

Four cases of progressive multifocal leukoencephalopathy in iatrogenic immunocompromised patients

4 progressive widen of WM lesions with a punctate pattern on T2w (Figure 5) and FLAIR sequences, and the appearance of necrotizing areas. Minimal mass effect and contrast enhancement were observed. Clinical and radiological findings were suggestive of PML. The CSF analysis showed hyperproteinorrachia (754 mg/L) and hyperglycorrhachia (121 mg/dL) and was weakly positive for JCV-DNA; the remaining cultural and molecular analyses and PCR amplification for viruses, fungi, and parasites were negative. The autoantibody screening was uninformative. Lymphocyte subpopulation analyses were abnormal, showing a reduction in CD4+ T-cell (20%) and CD19+/CD20+ B-cells (0%) percentage and an increase in CD8+ T-cells (58%; CD4+/CD8+ ratio 0.34); the absolute value was considerably lower due to the previous oncological therapy. The patient referred reduction in visual acuity, so visual evoked potentials and ophthalmologic examination were performed, which revealed a severe increase of latency in P100 and a bilateral visual acuity of 1/10 in the absence of ophthalmological disease. These findings confirmed the neurological aetiology of the disorder. Several electroencephalographic exams recorded a bilateral no-specific slowing-down activity. Radiological and serological findings excluded a neoplastic relapse, so diagnosis of PML was confirmed and the patient underwent treatment with Mirtazapine 30 mg daily. No further treatment was introduced considering the comorbidity. The patient showed a progressive worsening and, at discharge, she was almost blind, unable to maintain the upright position, and affected by a left hemiplegia. She died in November 2017 due PML-related sequelae.
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Progressive Multifocal Leukoencephalopathy—A Case Report in an Immunocompetent Patient

Progressive Multifocal Leukoencephalopathy—A Case Report in an Immunocompetent Patient

PML occurs more frequently in immunocompromised patients and is a major opportunistic infection associated with HIV infection, making up approximately 80% of patients with PML. Other less common causes associated with PML are haematological malignancies (13%), organ transplant recipients (5%) and auto- immune diseases treated with immunomodulators (3%) [3]. However, PML is no longer limited to the aforementioned groups, being described in patients with conditions associated with minimal immunosuppression, such as renal failure or liver cirrhosis. In addition, there are some reported cases of PML in patients without any apparent cause of immunosuppression [3]. After a review of the lit- erature, we found about twenty-four cases described in individuals with no co- morbidities and without known cause of immunosuppression, but we emphasize that in half of these cases the HIV serology was not reported.
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Angiographic Abnormalities in Progressive Multifocal Leukoencephalopathy: An Explanation Based on Neuropathologic Findings

Angiographic Abnormalities in Progressive Multifocal Leukoencephalopathy: An Explanation Based on Neuropathologic Findings

The study group included five men and one woman, ranging in age from 40 to 50 years (mean age, 44 years). Four of the patients were known to be HIV positive for periods ranging from 1 to 10 years; one patient (case 5) had a preexisting diagnosis of AIDS (as defined by the Centers for Disease Con- trol, Atlanta, GA). In the remaining two cases, the positive HIV status was established during assessment of new onset of neurologic symptoms. Risk factors for HIV infection were present in all the male patients; no obvious risk factor for HIV infection was identified in the female patient. The absolute CD4 T lymphocyte count at the time of admission to the hos- pital was available for two patients and the CD4:CD8 ratio was available in one additional case. Patient 5 had an absolute CD4 count of 72 m L (normal range, 480–1367 m L) and patient 6 had a value of 6 m L. In patient 1 there was reversal of the normal CD4:CD8 ratio (the absolute cell count was not avail- able in this patient). Presenting neurologic signs and symptoms included progressive hemiparesis in two cases, dysphasia in two, incoordination and ataxia in one, and homonymous hem- ianopsia in two; three patients also had mild cognitive impair- ment. Neurologic symptoms and signs correlated closely with the anatomic location of lesions. The time interval from the onset of neurologic symptoms to biopsy ranged from 1 to 12 weeks (mean, 5.7 weeks).
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<p>Progressive Multifocal Leukoencephalopathy: Current Insights</p>

<p>Progressive Multifocal Leukoencephalopathy: Current Insights</p>

Risk of PML is associated with several disease mod- ifying therapies (DMTs) for MS (Table 3). 56 – 60 The mode of action of DMTs plays a role in causing PML. 61 The best studied DMT associated to PML is NTZ, 61 which is a mAb that inhibits the transmembrane leukocyte receptor α -4 integrin. It prevents leukocyte adhesion to vessel walls and subsequent migration across the blood – brain barrier, resulting in immunosuppression within the CNS. The more the CNS compartment is immunocompromised, the greater the risk of PML. NTZ may also inhibit the reten- tion of lymphocytes in bone marrow and spleen, thus leading to an increase of JCPyV-infected peripheral leu- kocytes and to a possible increase of the peripheral JCPyV load. 62 As of September 3, 2019 there have been 825 con fi rmed PML cases (822 MS, 3 Crohn ’ s disease) according to latest Tysabry Safety Update information. The overall global incidence of PML in NTZ-treated patients is 4.08 per 1000 patients (95% CI 3.80 to 4.36 per 1000 patients). The duration of NTZ dosing prior to PML diagnosis ranged from 8 to 148 doses, and the mean duration of NTZ dosing at time of PML
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Improving detection of JC virus by ultrafiltration of cerebrospinal fluid before polymerase chain reaction for the diagnosis of progressive multifocal leukoencephalopathy

Improving detection of JC virus by ultrafiltration of cerebrospinal fluid before polymerase chain reaction for the diagnosis of progressive multifocal leukoencephalopathy

particles with a diameter of 35–40 nm [5], it is likely that ultrafiltration of CSF specimens could be applied to PCR assays for other neurotropic viruses with larger virions, such as those of the family Herpesviridae. Furthermore, 10-kDa pore size membrane may concentrate picornavi- ruses smaller than JCV. Using the standard procedure, JCV DNA was detected in the CSF specimens of seven of 20 patients who were suspected of having PML. The ultrafiltration of CSF was unnecessary for PCR testing in four of these cases (patients 1–4), because more than 100 copies of JCV were detected in the DNA extracts per reaction. By contrast, only 20 copies or less per reac- tion of JCV DNA were observed in the CSF specimens of another three JCV-positive individuals (patients 5–7), and the number of viral DNA copies detected by PCR was markedly increased by ultrafiltration. Moreover, the
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Magnetization transfer study of HIV encephalitis and progressive multifocal leukoencephalopathy  Groupe d'Epidémiologie Clinique du SIDA en Aquitaine

Magnetization transfer study of HIV encephalitis and progressive multifocal leukoencephalopathy Groupe d'Epidémiologie Clinique du SIDA en Aquitaine

described extensively (12–16). Usually, such lesions are detected by MR imaging and do not require histologic confirmation by cerebral bi- opsy (16). Nevertheless, there are cases of atypical presentation and, in addition, superim- posed disease processes are frequently present in infected patients. In our series, we obtained pathologic proof in only one patient with PML; however, in both groups, the clinical and imag- ing features of these diseases were typical. For the purpose of this study, we ensured the diag- nosis of PML with a polymerase chain reaction test for the JC virus either in the cerebrospinal fluid or in blood. All patients from group 2 died of PML, whereas four patients in group 1 died of
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JC Virus-Specific Immune Responses in Human Immunodeficiency Virus Type 1 Patients with Progressive Multifocal Leukoencephalopathy

JC Virus-Specific Immune Responses in Human Immunodeficiency Virus Type 1 Patients with Progressive Multifocal Leukoencephalopathy

Statistical methods. We first visualized the courses of the four immunological markers (JCV- and CMV-specific cellular immune responses and JCV-specific IgG and IgM activities) in PML cases over time. In PML nonsurvivors, only marker values before PML diagnosis were available. In PML survivors, we tested whether marker values systematically increased or decreased at PML diagnosis by using a linear mixed model with fixed effects for the mean marker levels before and after diagnosis, random effects for the patient-specific marker value levels before and after diagnosis, and measurement error. We then concentrated on the marker values at time zero (i.e., at the date of PML diagnosis or at the respective matching date for controls), defined as the closest available measurements to that time point. We compared these marker values between cases and controls using a logistic regression with Firth bias reduction and adjustment for the matching. This method has been shown to be an alternative to exact conditional regression for matched pairs, especially for continuous markers, where the latter often leads to highly discrete or even degenerate conditional distributions (18). The analysis was separately repeated for survivors and nonsurvivors and their respective controls. As sensitivity analyses, we adjusted for (log-transformed) HIV RNA, excluded patients with possible PML diagnosis, or counted only patients who died due to PML as nonsurvivors. In a second step, we compared PML survivors and nonsurvivors with respect to their time zero immunological-
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A programme for risk assessment and minimisation of progressive multifocal leukoencephalopathy developed for vedolizumab clinical trials

A programme for risk assessment and minimisation of progressive multifocal leukoencephalopathy developed for vedolizumab clinical trials

Progressive multifocal leukoencephalopathy (PML) is a rare but serious demyelinating opportunistic infection of the central nervous system caused by the JC polyomavirus. This virus is near ubiquitous, with approximately 55–60% of healthy adults harbouring a clinically latent infection. However, PML rarely develops in immunocompetent hosts [1–3]. The infection was originally recognised for its association with severe immunocompromise, such as occurs with haematologic malignancies, human immun- odeficiency virus infection/acquired immune deficiency syndrome and solid organ transplantation [4]. More recently, PML has also been reported in association with a number of immunosuppressive agents used to treat immune-mediated diseases and cancer, [2, 5–10], particu- larly monoclonal antibodies directed against cell surface integrins [11–13]. In 2005, three cases of PML were reported in clinical trials of natalizumab, among approxi- mately 3000 patients, with a mean latency of 18 months [14–16]. The findings were surprising in light of the safety profile of natalizumab up to that point, and the absence of a prior association between its mechanism of action (i.e. antibody against a4 integrin) and PML. Efalizumab, a monoclonal antibody against aLb2 integrin, was also shown to have an association with PML, which ultimately led to its withdrawal from the market [17]. Risk estimates
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Analysis of JC virus DNA purified directly from human progressive multifocal leukoencephalopathy brains.

Analysis of JC virus DNA purified directly from human progressive multifocal leukoencephalopathy brains.

Analysis of the restriction endonuclease cleavage fragments of these two DNAs and the human polyomavirus JC Mad-i DNA revealed only slight differences which mapped in a region of the gen[r]

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Progressive multifocal leukoencephalopathy in a multiple Sclerosis patient diagnosed after switching from natalizumab to fingolimod

Progressive multifocal leukoencephalopathy in a multiple Sclerosis patient diagnosed after switching from natalizumab to fingolimod

Figure 3: No signs of abnormal diffusion. Diffusion weighted MRI at 1.5 T ((a) and (c)) did reveal neither signs of central hyperdiffusibility (circles) nor signs of restricted diffusion (circles) at the edge of PML lesions (black arrows, (b) and (d)). Both of which were reported to be characteristic for PML lesions. 16]. Indeed, the JCV antibody index was markedly increased in our case and continued to rise during PML expansion. Other PML cases of elevated JCV antibody indices despite repeatedly negative PCR testing for JCV DNA in CSF have been reported [15, 16].

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Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group

Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group

JCV positivity Epidemiological analyses have uniformly shown that the preva- lence of anti-JCV antibody-positivity is signi ficantly associated with increasing MS patient age, male gender, and country of residence. 18 26 –28 In the JCV Epidemiology in MS ( JEMS) trial —which included more than 7700 patients with MS from across 10 different countries —the prevalence of anti-JCV posi- tivity across Europe ranged from 48.8% in the UK and 51.0% in Ireland, to 69.5% in Portugal. 18 Cross-sectional data showing the relationship between rising anti-JCV antibody index and duration of natalizumab therapy shows no association. 29 However, one of the co-authors of this consensus statement recently reported an increasing anti-JCV index over time in a UK cohort of natalizumab treated patients. This observation was greater than expected due to age alone and merits further evalu- ation in other populations. 30 Vennegoor et al reported 4 of 193
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Cerebral microsporidiosis manifesting as progressive multifocal leukoencephalopathy in an HIV-infected individual - a case report

Cerebral microsporidiosis manifesting as progressive multifocal leukoencephalopathy in an HIV-infected individual - a case report

Microsporidial hepatitis, sclerosing cholangitis, peri- tonitis, cardiac, sinusal, urinary, pulmonary, renal or ocular involvement have been reported [3]. Microsporidia have been detected in clinical samples from intestines, livers, muscles, corneas, kidneys, adrenals, gonads, ganglia, small arteries, biliary tracts, urine, sinuses, and brain [4,5]. Whereas the incidence of microsporidiosis has decreased in HIV-infected people since the availability of cART, this infection has been increasingly reported in non-HIV- infected individuals, such as solid organ and bone marrow transplant recipients, as well as in cancer, diabetic and eld- erly patients [6]. Furthermore, microsporidiosis has even been reported in immunocompetent persons [6,7] and in solid organ transplant recipients of latently infected donors [8]. We decided to report this case 12 years later because of this new emerging evidence and increased interest. Moreover, we now seek to alert physicians to potentially include microsporidiosis in the differential diagnosis not only in HIV-infected patients.
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Adaptive Mutations in the JC Virus Protein Capsid Are Associated with Progressive Multifocal Leukoencephalopathy (PML)

Adaptive Mutations in the JC Virus Protein Capsid Are Associated with Progressive Multifocal Leukoencephalopathy (PML)

In order to experimentally verify the role that these substitutions play in sialic acid binding by the VP1 capsid, we recombinantly produced viral like particles (VLP) from VP1 protein encoded by several different naturally occurring viruses. We generated VLPs from viral VP1 sequences encoding substitutions with one of the two strongest signals of positive selection identified by PAML, one with phenylalanine at position 269 (F269) and another one with phenylalanine at position 55 (F55). As controls we used two different VP1 genes that do not harbor any of the identified PML- associated mutations, one from a healthy individual (WT) and another one from a PML patient (Mad-1) (Table S3). Viral hemagglutination of red blood cells (RBCs) has been shown to be a reliable measure of sialic acid binding by polyomaviruses [16,29]. We tested all four VLPs in a hemagglutination assay. Strikingly, both F55 and F269 variants displayed more than 8000-fold lower HA activity than either control VLP (Table 2). Specifically, the F55 variant completely failed to agglutinate human type O RBCs even at 200 mg/ml, the highest concentration tested, and the F269 variant displayed very low HA activity as it caused hemaggluti- nation only at concentrations above 25 mg/ml. At the same time both L55 and S269 carrying variants (WT and Mad-1) caused hemagglutination of RBCs at concentrations down to 0.375 ng/ml and 6.25 ng/ml, correspondingly. We note that the F55 mutant has the single amino acid difference with its corresponding wild type variant (WT). Therefore the change in hemagglutination can be specifically attributed to this amino acid replacement. In addition to the change in position 269 the F269 mutant variant has two additional amino acid positions that are different from its corresponding control variant (Mad-1). Both of those amino acid changes are not PML specific (Table S3 and Table S2) and are unlikely to explain the difference in hemagglutination. While the
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Frequency and Phenotype of JC Virus-Specific CD8+ T Lymphocytes in the Peripheral Blood of Patients with Progressive Multifocal Leukoencephalopathy

Frequency and Phenotype of JC Virus-Specific CD8+ T Lymphocytes in the Peripheral Blood of Patients with Progressive Multifocal Leukoencephalopathy

JC virus (JCV) is a polyomavirus that infects approximately 85% of the adult population worldwide (35). In most individ- uals, the virus is quiescent in the kidney or lymphoid organs, but in the setting of severe immunosuppression, such as in patients with AIDS or hematological malignancies or in organ transplant recipients, it can reactivate and spread to the central nervous system, causing a deadly demyelinating disease of the brain named progressive multifocal leukoencephalopathy (PML). The incidence of PML is 5.1% in patients with AIDS (26) and 3.3% in patients with hematological malignancies (12). Although there is no specific treatment for this condition, the immune reconstitution induced by highly active antiretro- viral therapy (HAART) in human immunodeficiency virus (HIV)-infected patients has improved the survival from 10 to 50% in this population (17).
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JC virus DNA is present in many human brain samples from patients without progressive multifocal leukoencephalopathy.

JC virus DNA is present in many human brain samples from patients without progressive multifocal leukoencephalopathy.

In the present study, the archetype strain of JCV was identified only in normal kidney samples; JCV DNA found in non-PML-affected brain specimens and in kidney tissue from patients with [r]

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

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

The present study clarified the characteristics of PML cases in Japan based on clinical data obtained through the laboratory testing for JCV DNA in CSF specimens. Mass screening of PML patients has not been feasible in Japan due to the lack of a suitable database for PML. The current strategy deals with a relatively small number of patients but has a distinct advantage in collecting pre- cise real-time information for patients as well as speci- mens. The testing was constantly requested by the physicians via websites, despite the fact that there were at least 4 commercial laboratories providing similar assays during the study period according to our own survey. Thus, this internet-based approach is thought to be useful for sampling data for rare infectious diseases. In addition, as this diagnostic support system was con- ducted regardless of patient age, gender, underlying dis- ease or medical history, precise information could be obtained not only from PML patients but also from CSF-JCV-negative individuals with similar conditions. These data are considered to be valuable for the examin- ation of the overall background to PML in Japan.
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Insight into Metabolic 1H-MRS Changes in Natalizumab Induced Progressive Multifocal Leukoencephalopathy Brain Lesions.

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

comparing the early-post-PML situation with the late-post-PML phase, which is often characterized by a clinical stabilization. Progressive multifocal leukoencephalopathy–IRIS was defined by an inflammatory response resulting in clinical worsening of symptoms, which was associated with contrast enhancement on MRI in all patients of the IRIS group ( 23 ). The details of the PML diagnosis and disease course and the functional outcome of the study population have been reported recently ( 24 ). In brief, after the onset of neurological symptoms consistent with PML, the diagnosis was verified by JC-virus DNA detection in the cerebrospinal fluid (CSF) in 18 patients. In two patients, the CSF probes were initially JC-virus-negative, still the clinical presentation and MRI findings were indicative of PML (diagnos- tic accuracy “possible”) and no other differential diagnosis was found ( 25 ). One of these patients was tested virus positive in a follow-up puncture; in the other patient, a follow-up CSF probe was not available since the patient rejected the second puncture. CSF samples were analyzed for JC-virus DNA at the Department of Virology, University of Düsseldorf. The detection limit of the method was 10 copies/ml CSF ( 26 ). In all included participants IRIS associated with gadolinium enhancement in PML lesions was observed. After PML diagnosis, all patients received plasma exchange or immunoadsorption to remove natalizumab and sup- portive treatment with mefloquine and mirtazapine ( 9 ).
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New Approaches to Neuroimaging of Progressive Multifocal Leukoencephalopathy. Alexandra Binnie, HMS III Gillian Lieberman, M.D.

New Approaches to Neuroimaging of Progressive Multifocal Leukoencephalopathy. Alexandra Binnie, HMS III Gillian Lieberman, M.D.

• On diffusion-weighted imaging PML lesions have a core of increased diffusion (representing vasogenic edema) surrounded by a rim of decreased diffusion (representing cytotoxic edema)[r]

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JC Virus Regulatory Region Tandem Repeats in Plasma and Central Nervous System Isolates Correlate with Poor Clinical Outcome in Patients with Progressive Multifocal Leukoencephalopathy

JC Virus Regulatory Region Tandem Repeats in Plasma and Central Nervous System Isolates Correlate with Poor Clinical Outcome in Patients with Progressive Multifocal Leukoencephalopathy

The human polyomavirus JC (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy (PML). Eighty to ninety percent of the adult population is seropositive for JCV (29). After an asymptomatic primary infection during child- hood, the virus remains quiescent in the kidneys and lymphoid tissue (1, 11, 21). In the setting of immunosuppression, JCV can reactivate and cause a lytic infection of oligodendrocytes. The JCV regulatory region (JCV RR) of urine isolates is highly conserved in healthy and immunocompromised individuals and has been called the archetype (1, 20, 32). The archetype has no duplications and contains a 23-bp insert and a 66-bp insert localized at nucleotides (nt) 36 and 92 compared to the first sequenced brain isolate of JCV, MAD-1. A hypervariable form of JCV RR is found in the brain and cerebrospinal fluid (CSF) of PML patients. In the MAD-1 isolate, the RR con- tains two identical 98-bp tandem repeats.
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Is progressive multifocal leukoencephalopathy a chronic disease because of defective interfering particles or temperature-sensitive mutants of JC virus?

Is progressive multifocal leukoencephalopathy a chronic disease because of defective interfering particles or temperature-sensitive mutants of JC virus?

Virions isolated directly from diseased brain tissue had a higher buoyant density than did virus from the same PML patient passaged in culture and containing genomic deletions.. In contr[r]

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