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BACKGROUND: John Cunningham virus related granule cell neuronopathy (JCV-GCN) is a rare manifestation of the reactivation of infection of the cerebellar granule cells by the JCV, mostly in immunocompromised individuals. The "hot cross bun" (HCB) sign is a cruciform hyperintensity seen in the midpons on T2-weighted and fluid attenuated inversion recovery (FLAIR) sequences on magnetic resonance imaging (MRI) of the brain. An index sub-Saharan Africa report of a case of JCV-GCN with HCB sign follows. CASE PRESENTATION: A 27-year-old HIV positive female with JCV-GCN was re-evaluated for chronic ataxia complicated by subacute progressive horizontal diplopia. Cerebrospinal fluid (CSF) had trace Mycobacterium tuberculosis (MTB) detected by GeneXpert Mycobacterium Tuberculosis/Rifampicin resistance (MTB/RIF) assay test. Brain MRI revealed diffuse severe cerebellar atrophy with a hot cross bun sign and patchy enhancement contiguous to the cerebellar dentate nuclei bilaterally. She continued Highly Active Antiretroviral Therapy (HAART) pending CSF HIV viral load counts and started standard brain TB local treatment regimen protocols with progressive improvement in limb ataxia. CONCLUSIONS: In conclusion, finding of the HCB sign may be indicative of and aid diagnosis of JCV-GCN in the right clinical context. This could be an important neuroimaging marker in this context, that may radiologically be more evident in later stages of the condition.

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INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a potentially life-threatening complication among Multiple Sclerosis (MS) patients under natalizumab treatment, with serum anti-JCV antibody titers being used for stratification risk. Given the critical role of interferon (IFN)/B-cell activating factor (BAFF) axis in humoral immune responses against viruses, we explored whether it is involved in the generation of serum anti-JCV antibodies among these patients. METHODS: 162 consecutive patients with relapsing-remitting MS under natalizumab treatment were included. Serum anti-JCV antibodies were measured at baseline, as well as 12 and 24 months after treatment initiation. Type I and II IFN-inducible genes and BAFF expression were quantitated in peripheral blood by qRT-PCR. Moreover, BAFF rs9514828, rs1041569, and rs9514827 gene variants were assessed by RFLP-PCR. RESULTS: While type I and II IFN inducible gene expression were not associated with anti-JCV serum titers, the latter were significantly correlated with BAFF gene expression. Of interest, the TTT haplotype of the studied BAFF variants was more frequently detected in male, but not female anti-JCV (+) MS patients compared to anti-JCV (-) counterparts at baseline, as well as at 12 months and 24 months of natalizumab treatment. Measures of clinical validity/utility for the BAFF TTT haplotype showed 88% specificity, 45%, positive predictive value, and sensitivity of 70% for the discrimination of anti-JCV (+) male MS patients after 24 months of treatment. CONCLUSIONS: Our study suggests an implication of the BAFF axis in the production of serum anti-JCV antibodies. Additionally, the BAFF TTT haplotype derived from the rs9514828, rs1041569, and rs9514827 variants may represent a novel risk factor for anti-JCV seropositivity and indirectly for PML development among male MS patients treated with natalizumab.

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John Cunningham virus (JCV) is most commonly acquired in childhood and is often asymptomatic throughout life. However, in the case of primary or secondary immunosuppression, it is known to cause progressive multifocal leukoencephalopathy (PML) in the central nervous system. Hereby, we describe a rare case of PML in a patient without known factors of immunosuppression or use of immunomodulation. A 53-year-old female patient was presented with progressive left-side weakness and tremors in the left hand over a period of two months. The patient was diagnosed with PML based on history, examination, cerebrospinal fluid markers, histopathology, and brain magnetic resonance imaging at presentation. Despite detailed examination, nothing was found in the patient to cause an immunosuppressed state. Therapy was started with mirtazapine with significant neurological improvement.To our knowledge, PML in immunocompetent patient with bening prognosis is a very rare condition. There is also no effective treatment. Our case is a complicated example of this condition.

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BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic offered an epidemiological opportunity to evaluate if isolation and masking affected John Cunningham (JC) virus transmission. OBJECTIVE: This study aimed to assess the proportion of natalizumab-treated patients who converted to a positive anti-JCV antibody serostatus before and during the pandemic. METHODS: Data from TYSABRI Outreach: Unified Commitment to Health (TOUCH) for 22,375 US patients treated with natalizumab with anti-JCV antibody records were assessed in epochs annually from 2017 to 2022. RESULTS: Pre-pandemic anti-JCV antibody serostatus change was observed for 7.4%-7.7%. During the first and second years of the pandemic, 7.3% and 7.2% of patients' serostatus changed, respectively. CONCLUSION: The proportion of patients with anti-JCV antibody serostatus change did not significantly differ during the first 2 years of the pandemic compared with prior years. In contrast to seasonal influenza, masking and social distancing had no discernable effect on JCV serostatus change.

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Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS). The underlying cause of MS is still unknown. Multiple risk factors have been suggested that involve a combination of genetic, environmental, and infectious factors that contribute along with a weakened immune system. There is growing evidence supporting the potential role of viral infections in the development of the disease. Viruses like human immunodeficiency virus (HIV), John Cunningham virus (JCV), Varicella-Zoster virus (VZV), human herpesvirus 6 (HHV-6), Epstein-Barr virus (EBV), and human endogenous retroviruses (HERVs) have been proposed in the pathogenesis of MS. Their pathogenetic mechanisms are not well known, but several possibilities have been discussed. The present study highlights the proposed potential molecular and genetic mechanisms underlying this viral interaction and its implications for the development of MS.

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BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease due to a lytic infection of oligodendrocytes caused by John Cunningham polyoma virus (JCV) infection. Idiopathic CD4+ T-cell lymphocytopenia (ICL) is a very rare cause of PML. METHODS: We present an individual with PML secondary to ICL treated with 3 doses of pembrolizumab, a Programmed-Death-1 Immune Checkpoint Inhibitor following with complete resolution of symptoms and conduct a review of the literature. CONCLUSION: This report illustrates the objective clinical and radiological improvement in a patient with PML due to ICL and suggests further study of immune checkpoint inhibitors as potential treatment for patients with PML.

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Progressive multifocal encephalopathy (PML) is a rare brain infection caused by the John Cunningham virus (JCV), primarily affecting immunocompromised individuals. This case report presents a unique occurrence of PML in an immunocompetent young man with a history of substance abuse. The patient exhibited progressive neurological symptoms, including weakness and sensory deficits, prompting diagnostic evaluation. Brain imaging and laboratory tests revealed evidence of PML, supported by a positive JCV antibody. Notably, HIV testing was negative. While PML is typically associated with immunosuppression, this case raises questions about potential connections between substance abuse and viral reactivation. The patient received treatment with intravenous methylprednisolone and underwent rehabilitation, emphasizing the challenging nature of PML management. This case highlights the importance of considering PML as a differential diagnosis, even in immunocompetent individuals, and underscores the need for further research into its rare presentations and associated risk factors.

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This report presents the case of a 47-year-old male patient who worked as a mathematics teacher and experienced the sudden onset of disorientation, aphasia, and acalculia during an online class. The current study reveals the first documented case of HIV and progressive multifocal leukoencephalopathy with the detection of SARS-CoV-2 and human polyomavirus 2 (previously known as John Cunningham virus) in the cerebrospinal fluid. Furthermore, serum analysis revealed elevated concentrations of interleukin (IL)-6, IL-17, and IL-8, which are potential factors known to reduce the expression of tight junctions and adhesion molecules in the extracellular matrix, thereby affecting the permeability of the blood-brain barrier. Finally, the study discusses whether SARS-CoV-2 triggers or exacerbates progressive multifocal leukoencephalopathy.

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Objectives: The primary objective was to evaluate long-term treatment persistence and safety of natalizumab in Finnish multiple sclerosis patients. The secondary objectives were to assess patient characteristics, use of natalizumab-related safety protocol, and treatment persistence in patients with different anti-John Cunningham virus antibody statuses (John Cunningham virus status). Materials & Methods: All adult multiple sclerosis patients in the Finnish multiple sclerosis register who started natalizumab between 1/2006 and 12/2018 were included in this study and followed retrospectively until treatment discontinuation or end of follow-up (12/2019). Results: In total, 850 patients were included. Median duration of natalizumab treatment was 7.8 years in John Cunningham virus negative (n = 229) and 2.1 years in John Cunningham virus positive patients (n = 115; p < 0.001). The most common cause for treatment discontinuation was John Cunningham virus positivity. After natalizumab discontinuation, patients who had a washout duration of less than 6 weeks had fewer relapses during the first 6 months (p = 0.012) and 12 months (p = 0.005) compared with patients who had a washout duration of over 6 weeks. During the median follow-up of 3.6 years, 76% of patients remained stable or improved on their Expanded Disability Status Scale. Conclusions: Treatment persistence was very high among John Cunningham virus negative patients. The study supports long-term effectiveness of natalizumab and a washout duration of less than 6 weeks after discontinuation.

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HIV-negative progressive multifocal leukoencephalopathy (PML) has a poor prognosis due to a lack of standard treatment. Herein, we report a patient with HIV-negative PML which occurred after the treatment for classical Hodgkin's lymphoma (CHL). A 71-year-old male patient was admitted to our hospital due to various neurological symptoms, including memory disturbance, dysgraphia, ataxia, and ideomotor apraxia, at 16 months after high-dose salvage chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) for primary treatment-refractory CHL. The patient's blood and serological examination results were mainly normal, including CD4-positive T lymphocyte count and serum immunoglobulin levels. T2-weighted fluid-attenuated inversion recovery MRI showed high-intensity lesions from the left occipital lobe to the corpus callosum. Moreover, the rapid intraoperative pathological assessment of biopsy specimens obtained from abnormal brain lesions suggested brain relapse of CHL. The patient's symptoms progressed rapidly; therefore, treatment with high-dose methotrexate was started, which significantly improved the patient's symptoms and MRI findings within a week. However, further examinations of the biopsy specimens with in situ hybridization and immunohistochemical examinations showed reactivation of the John Cunningham virus (JCV) in the astrocytes. Further, cells initially believed to be Hodgkin cells based on the rapid intraoperative pathological assessment were found to be destructive astrocytes, thereby confirming the diagnosis of PML. The patient was then successfully treated with combined mefloquine and mirtazapine and did not have any fatal outcomes. Based on this case, a differential diagnosis of PML from CNS involvement of CHL is important even in cases without evident biomarkers for immunodeficiency. Moreover, methotrexate was likely to be effective in improving neurological symptoms by decreasing brain parenchyma inflammation in the acute phase in this particular patient.

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Key Clinical Message: Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the brain caused by reactivation of the JC virus, which can lead to a lytic infection of oligodendrocytes. We report a patient with HIV who developed PML. Abstract: Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the brain caused by reactivation of the John Cunningham virus (JCV), which can lead to a lytic infection of oligodendrocytes. Herein, we report the case of a patient with HIV who developed PML that presented as a progressive disturbance of consciousness and movement. The patient's clinical symptoms progressively deteriorated, and positive JC viral DNA in his cerebrospinal fluid (CSF) helped us diagnose him with PML. Magnetic resonance imaging (MRI) showed multiple asymmetric subcortical and deep white-matter lesions. Although we administered immunoreconstructive therapy, the patient's condition gradually worsened. Therefore, we suggest that PML should be considered if such lesions are found in MRIs of HIV patients.

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Progressive multifocal leukoencephalopathy (PML) is a rare viral central nervous system (CNS) demyelinating disease primarily associated with a compromised immune system. PML is seen mainly in individuals with human immunodeficiency virus, lymphoproliferative disease, and multiple sclerosis. Patients on immunomodulators, chemotherapy, and solid organ or bone marrow transplants are predisposed to PML. Recognition of various PML-associated typical and atypical imaging abnormalities is critical for early diagnosis and differentiating it from other conditions, especially in high-risk populations. Early PML recognition should expedite efforts at immune-system restoration, allowing for a favorable outcome. This review aims to provide a practical overview of radiological abnormalities in PML patients and address differential considerations.

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JC polyoma virus (JCPyV), a ubiquitous polyoma virus that commonly infects people, is identified as the etiologic factor for progressive multifocal leukoencephalopathy and has been closely linked to various human cancers. Transgenic mice of CAG-loxp-Laz-loxp T antigen were established. T-antigen expression was specifically activated in gastroenterological target cells with a LacZ deletion using a cre-loxp system. Gastric poorly-differentiated carcinoma was observed in T antigen-activated mice using K19-cre (stem-like cells) and PGC-cre (chief cells), but not Atp4b-cre (parietal cells) or Capn8-cre (pit cells) mice. Spontaneous hepatocellular and colorectal cancers developed in Alb-cre (hepatocytes)/T antigen and villin-cre (intestinal cells)/T antigen transgenic mice respectively. Gastric, colorectal, and breast cancers were observed in PGC-cre/T antigen mice. Pancreatic insulinoma and ductal adenocarcinoma, gastric adenoma, and duodenal cancer were detected in Pdx1-cre/T antigen mice. Alternative splicing of T antigen mRNA occurred in all target organs of these transgenic mice. Our findings suggest that JCPyV T antigen might contribute to gastroenterological carcinogenesis with respect to cell specificity. Such spontaneous tumor models provide good tools for investigating the oncogenic roles of T antigen in cancers of the digestive system.

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The choroid plexus is situated at an anatomically and functionally important interface within the ventricles of the brain, forming the blood-cerebrospinal fluid barrier that separates the periphery from the central nervous system. In contrast to the blood-brain barrier, the choroid plexus and its epithelial barrier have received considerably less attention. As the main producer of cerebrospinal fluid, the secretory functions of the epithelial cells aid in the maintenance of CNS homeostasis and are capable of relaying inflammatory signals to the brain. The choroid plexus acts as an immunological niche where several types of peripheral immune cells can be found within the stroma including dendritic cells, macrophages, and T cells. Including the epithelia cells, these cells perform immunosurveillance, detecting pathogens and changes in the cytokine milieu. As such, their activation leads to the release of homing molecules to induce chemotaxis of circulating immune cells, driving an immune response at the choroid plexus. Research into the barrier properties have shown how inflammation can alter the structural junctions and promote increased bidirectional transmigration of cells and pathogens. The goal of this review is to highlight our foundational knowledge of the choroid plexus and discuss how recent research has shifted our understanding towards viewing the choroid plexus as a highly dynamic and important contributor to the pathogenesis of neurological infections. With the emergence of several high-profile diseases, including ZIKA and SARS-CoV-2, this review provides a pertinent update on the cellular response of the choroid plexus to these diseases. Historically, pharmacological interventions of CNS disorders have proven difficult to develop, however, a greater focus on the role of the choroid plexus in driving these disorders would provide for novel targets and routes for therapeutics.

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Colorectal cancer (CRC) is a significant contributor to cancer-related deaths caused by an unhealthy lifestyle. Multiple studies reveal that viruses are involved in colorectal tumorigenesis. The viruses such as Human Cytomegalovirus (HCMV), Human papillomaviruses (HPV16 & HPV18), and John Cunningham virus (JCV) are known to cause colorectal cancer. The molecular mechanisms of cancer genesis and maintenance shared by these viruses remain unclear. We analysed the virus-host networks and connected them with colorectal cancer proteome datasets and extracted the core shared interactions in the virus-host CRC network. Our network topology analysis identified prominent virus proteins RL6 (HCMV), VE6 (HPV16 and HPV18), and Large T antigen (JCV). Sequence analysis uncovered short linear motifs (SLiMs) in each viral target. We used these targets to identify the antiviral drugs through a structure-based virtual screening approach. This analysis highlighted that temsavir, pimodivir, famotine, and bictegravir bind to each virus protein target, respectively. We also assessed the effect of drug binding using molecular dynamic simulations, which shed light on the modulatory effect of drug molecules on SLiM regions in viral targets. Hence, our systematic screening of virus-host networks revealed viral targets, which could be crucial for cancer therapy.

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INTRODUCTION: Both chronic lymphocytic leukemia (CLL) itself and the drugs used for its treatment, pose a risk for progressive multifocal leukoencephalopathy (PML). Although the relationship between Rituximab and PML is well known, case reports that have been recently published, suggest that ibrutinib; which is used in the treatment of CLL, may increase the risk of PML. CASE REPORT: Here, we report a case of 64 year-old female patient with CLL who was previously treated with rituximab, fludarabine and bendamustin but developed PML after receiving monotherapy with ibrutinib. According to Naranjo's algorithm, the causality relationship with the drug is possible with a score of 3. The patient initially exhibited neurological symptoms. Magnetic resonance of the brain revealed a bilateral asymmetric hyperintensity in the white matter involving the parietal and occipital lobules, and there was no mass effect, edema, hemorrhagic or iscemic lesions. No enhancement of contrast media was observed. The findings were consistent with demyelination and suggestive of PML. MANAGEMENT AND OUTCOME: Mirtazapine treatment was initiated. However, neurological sympthoms continuously progressed over the following weeks and the patient, aged 64, died six weeks after diagnosis of PML. DISCUSSION: PML is a rare and often fatal demyelinating disease of the central nervous system (CNS) that is exclusively seen in immunocompromised patients and there is no specific agent to treat PML. The case discussed here, highlights that the use of ibrutinib in chronic lymphocytic leukemia (CLL) therapy may result in PML.

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Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by the polyoma John Cunningham (JC) virus. This virus is rarely pathogenic in immunocompetent individuals, being associated with profound cellular immunosuppression. We present a case of a 72-year-old woman with schizoaffective disorder who presented to the emergency department with dysarthria and right hemiataxia. The initial computer tomography was normal and the diagnosis of ischemic stroke was first assumed. However, during hospitalization there was a progressive worsening of symptoms with cerebellar ataxia, and the magnetic resonance revealed a lesion in the right middle cerebellar peduncle hypointense in T1 and hyperintense on T2/fluid attenuated inversion recovery (FLAIR) sequence, suggestive of PML. Although the first cerebrospinal fluid analysis was negative, the second one was positive for the JC virus. Furthermore, due to radiological and clinical progression, mirtazapine was started and the patient underwent a course of intravenous immunoglobulin, with no response. In parallel, causes of immunosuppression were investigated, which led to the diagnosis of idiopathic CD8+ lymphocytopenia. Due to rapid progression of symptoms and radiological worsening of lesions, pembrolizumab was administered. After the first administration of pembrolizumab there was a transitory clinical stabilization. However, shortly after the second administration of pembrolizumab, the patient developed stridor with bilateral vocal cord paralysis and subsequent symptom progression, which led to the death of the patient three months after the appearance of initial symptoms. In conclusion, we report a case of a PML in a patient with idiopathic CD8+ lymphocytopenia, enhancing the need for a high suspicion index for this entity as well as for occult and less frequent forms of immunosuppression. Although there have been various case reports of favourable outcomes with pembrolizumab for PML, more research is needed, particularly to identify patient factors that might be associated with better responses to this therapy.

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BACKGROUND: Natalizumab (NTZ) is a highly effective disease modifying treatment for relapsing multiple sclerosis (RMS), but it increases risk of progressive multifocal leukoencephalopathy (PML) in patients with serum anti- John Cunningham virus (JCV) antibodies. OBJECTIVE: To assess the safety and efficacy of rapid transition, from NTZ to teriflunomide (TFM) in RMS patients. METHODS: Clinically stable NTZ-treated, anti-JCV antibody positive RMS patients were switched to TFM 28 ± 7 days after their last dose of NTZ. The primary endpoint was proportion of relapse free patients at 24 months. RESULTS: Median [IQR] age of the 55 enrolled patients was 47 [40.7, 56.3] years, 76% were female. The median [IQR] number of prior NTZ treatments was 34 [18, 64]. annualized relapse rate (ARR) was 0.07 and 77% of the patients were relapse free at 24 months. Mean time to first GAD + lesion was 19.6 months, and to new/enlarging T2 lesion was 19.2 months. Mean time to 3 month sustained disability worsening (SDW) was 22 months and proportion free of 3-month SDW was 0.87. There were no cases of PML. CONCLUSIONS: The washout-free transition of NTZ to TFM was an efficacious and safe strategy for patients at risk of developing PML.ClinicalTrials.gov Identifier: NCT01970410.

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BACKGROUND: Progressive multifocal leukoencephalopathy (PML) caused by the JC virus is the main limitation to the use of disease modifying therapies for treatment of multiple sclerosis (MS). METHODS: To assess the PML risk in course of ocrelizumab, urine and blood samples were collected from 42 MS patients at baseline (T0), at 6 (T2) and 12 months (T4) from the beginning of therapy. After JCPyV-DNA extraction, a quantitative-PCR (Q-PCR) was performed. Moreover, assessment of JCV-serostatus was obtained and arrangements' analysis of non-coding control region (NCCR) and of viral capsid protein 1 (VP1) was carried out. RESULTS: Q-PCR revealed JCPyV-DNA in urine at all selected time points, while JCPyV-DNA was detected in plasma at T4. From T0 to T4, JC viral load in urine was detected, increased in two logarithms and, significantly higher, compared to viremia. NCCR from urine was archetypal. Plasmatic NCCR displayed deletion, duplication, and point mutations. VP1 showed the S269F substitution involving the receptor-binding region. Anti-JCV index and IgM titer were found to statistically decrease during ocrelizumab treatment. CONCLUSIONS: Ocrelizumab in JCPyV-DNA positive patients is safe and did not determine PML cases. Combined monitoring of ocrelizumab's effects on JCPyV pathogenicity and on host immunity might offer a complete insight towards predicting PML risk.

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