Survival and prognostic factors of progressive multifocal leukoencephalopathy in people living with HIV in modern ART era.

Background: The incidence of progressive multifocal leukoencephalopathy (PML) in people living with HIV (PLWH) is 2%-4%. Currently, there is no effective therapeutic strategy for the treatment of PML in PLWH, resulting in a mortality of up to 50%. This study aimed to identify risk factors of death and prognostic markers in people living with HIV with PML. Methods: A retrospective cohort study of AIDS-related PML individuals was conducted from January 1, 2015, to October 1, 2022, in Shanghai, China. PLWH who were diagnosed with PML for the first time were included. Kaplan-Meier curve and Cox regression were used to analyze the survival and its predictors. Levels of inflammatory markers and immune checkpoint inhibitors in blood and cerebrospinal fluid (CSF) were measured in the prestored samples using bead-based multiplex assay Indolamine 2,3-dioxygenase was determined using ELISA. Results: Twenty of 71 subjects had initiated antiretroviral therapy (ART) before PML onset and no patients discontinued ART during this period. In total, 34 patients (47.9%) had opportunistic infections (OIs), the median CD4+ T cell count was 73.0 (33.0-149.0) cells/µL. The estimated probability of survival at six months was 78% (95% confidential intervals [CIs]:0.63-0.85). OIs, low CD4+ T cell count were associated with lower estimated six-month survival (hazard ratio 8.01, 95% CIs: 1.80-35.00, P=0.006 and 5.01, 95% CIs:1.57-16.03, p=0.007). Indolamine 2,3-dioxygenase activity in CSF of non-survivors group were higher than survivors group (p<0.05). Conclusions: The survival rate of AIDS-related PML in the modern ART era was higher than the survival rate a decade ago. Low CD4+T cell count, OIs, were all associated with death of individuals with AIDS-related PML. The role of IDO in AIDS-related PML warrant further investigation.

Progressive multifocal leukoencephalopathy in a patient with relapsing multiple sclerosis treated with ocrelizumab: A case report.

INTRODUCTION: Progressive multifocal leukoencephalopathy is a rare but often fatal complication of some multiple sclerosis treatments. Although it has mainly been associated with natalizumab treatment, its appearance with other immunosuppressive therapies has also been reported. AIMS: The aim of this case report is to describe the development of progressive multifocal encephalopathy in a patient with relapsing-remitting multiple sclerosis treated with ocrelizumab without previous use of natalizumab. CONCLUSIONS: A summary of the presentation and disease course is provided, presented in the context of the current literature and likely pathophysiology.

Epileptic seizures associated with progressive multifocal leukoencephalopathy in HIV-infected patients in Korea.

We investigated the incidence and risk factors of seizures related to progressive multifocal leukoencephalopathy (PML) in Korean patients infected with HIV. Of the 34 patients, 14 (41.2%) developed epileptic seizures during a median follow-up of 82 months. The median time from PML diagnosis to seizure onset was 44 months, ranging from 0 to 133 months. Patients with PML who developed seizures more commonly had cognitive impairment and multiple or diffuse lesions on brain MRI. These findings highlight the increased seizure risk among HIV-infected patients with PML at any stage of the disease, particularly in cases with extensive involvement.

Sequential treatment of progressive multifocal leukoencephalopathy with intravenous immunoglobulins and pembrolizumab.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the CNS caused by the human polyomavirus 2 (JCV). PML predominantly occurs in immunocompromised patients. To date, no specific antiviral treatment exists, leaving only restoration of the immune system as possible treatment. In 2019, the monoclonal antibody pembrolizumab was reported as a potential treatment option in PML in a case series. Following case reports could not thoroughly confirm a positive outcome. Pembrolizumab targets the inhibitory programmed cell death protein 1 (PD-1) receptor on lymphocytes and is associated with beneficial expansion of pre-existing virus-specific T cells. Here we describe a patient with PML who benefited from combined treatment with intravenous immunoglobulins, maraviroc, and pembrolizumab.

Progressive multifocal leukoencephalopathy in a patient with mediastinal teratoma: a case report.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating lytic brain infection caused by the John Cunningham virus (JCV). JCV manifests primarily in patients with innate immunodeficiency or taking immunomodulatory medications. In this case study, we report a PML patient with comorbid mediastinal teratoma and mild lymphopenia. CASE PRESENTATION: A 73-year-old female presented with a 3-month history of progressive hemiplegia, hemianopsia, and cognitive impairment. She was diagnosed as PML by cerebrospinal fluid metagenomics sequencing and brain biopsy. Extensive immunological tests did not reveal an apparent immunodeficiency, but further work-up revealed that the PML was most likely the first presentation of mediastinal teratoma and the mild lymphopenia. Mirtazapine and immunoglobulin were started, the patient's condition was relatively stable and approved to be discharged from hospital. But unfortunately, she died of the lung infection 10 months after first presentation. CONCLUSIONS: This case confirms that mediastinal teratoma may induce the lymphopenia and trigger PML, delayed or incorrect diagnosis may worsen the course of the disease and result in poor prognosis.

Tofacitinib-induced Progressive Multifocal Leukoencephalopathy with Immune Reconstitution Inflammatory Syndrome.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) with subsequent immune reconstitution inflammatory syndrome (IRIS) is a rare disease associated with compromised immune systems. It has never been described in a patient taking tofacitinib. CASE PRESENTATION: A 49-year-old woman with history of systemic lupus erythematous treated with tofacitinib presented with several weeks of intermittent fevers and altered mental status. MRI revealed multifocal T2-weighted FLAIR hyperintensities in the subcortical white matter, including the subcortical U-fibers, without mass effect or contrast enhancement, compatible with PML. Tofacitinib was stopped and the patient's symptoms initially improved. However, the patient presented again less than a week after discharge with three days of left arm weakness, left facial droop, dysarthria, and one day of confusion. Repeat MRI demonstrated interval progression in T2/FLAIR hyperintensities with development of patchy gadolinium enhancement on T1-post contrasted sequences, consistent with development of IRIS in the setting of tofacitinib cessation. DISCUSSION: This is the first case describing PML-IRIS in the setting of administration and subsequent cessation of tofacitinib.

Progressive multifocal leukoencephalopathy and peripheral neuropathy in a patient with Good's syndrome.

Good's syndrome (GS) is an immunodeficiency characterized by thymoma, hypogammaglobulinemia, and impaired T-cell function. Progressive multifocal encephalopathy (PML), an infection caused by JC virus (JCV), usually occurs in patients infected with human immunodeficiency virus (HIV), or in patients on treatment with immunosuppressive or immunomodulatory drugs. There were few reports of PML due to GS, especially with the comorbidity of peripheral neuropathy. We describe a case of an uncommon presentation of PML and peripheral neuropathy in a male who presented with blurred vision, cognitive changes, limb weakness, and numbness over a 4-month period due to GS. To the best of our knowledge, this is the first report of PML and peripheral neuropathy due to GS. This case aims to highlight that it is necessary to consider the possibility of PML due to GS in patients with thymoma and intracranial lesions, and we should focus not only on opportunistic infections of the central nervous system, such as PML, but also on peripheral neuropathy.

Progressive multifocal leukoencephalopathy in a patient with occult hypogammaglobulinemia experiencing bilateral visual impairment.

INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a rare, lethal, demyelinating disease classically seen in profoundly immunosuppressed individuals. It is caused by intracerebral infection by John Cunningham polyomavirus (JCV). We report a rare case of PML in a man with presumed immunocompetence at presentation experiencing bilateral painless visual impairment. CASE DESCRIPTION: A 60-year-old man with a 3-week history of bilateral painless visual impairment attended our ophthalmology department. Unusually, he navigated around the room well and was able to read 4 of 13 Ishihara test plates in spite of a best-corrected visual acuity of counting fingers at 1 m bilaterally. Slit lamp examination, routine blood tests and optical coherence tomography (OCT) of the maculae and discs were unremarkable. Diffuse hyperintense white matter lesions on T2-weighted magnetic resonance imaging of the brain and detection of JCV within the parietal lobe tissue obtained by biopsy confirmed PML. Additional investigations identified an underlying hypogammaglobulinaemia, which may have initiated PML. He received intravenous immunoglobulin but passed away 2 months after diagnosis. CONCLUSIONS: To our knowledge this case is one of only a handful worldwide to describe PML developing in a patient with presumed immunocompetence at presentation - there was no previous history of recurrent, chronic, or atypical infections. There has only been one other report of visual symptoms presenting as the primary complaint. The case illustrates the importance of ruling out organic, central nervous system pathology in patients presenting with visual loss and normal objective visual function tests such as slit lamp examination and OCT.

Cerebellar progressive multifocal leukoencephalopathy associated with pulmonary sarcoidosis.

Progressive multifocal leukoencephalopathy can complicate the course of a patient with sarcoidosis. Here we present a rare case of a 35-year-old patient with pulmonary sarcoidosis whose course was complicated by progressive multifocal leukoencephalopathy involving the cerebellum. Neuroimaging and cerebrospinal fluid PCR played a crucial role in the diagnosis.

Acute Cerebellar Ataxia as the Presenting Symptom of Progressive Multifocal Leukoencephalopathy with HIV - A Case Report.

A 45-year-old man presented with acute onset ataxia for last 1 week. On examination he had signs of left-sided cerebellar involement. MRI brain revealed asymmetric altered signal intensities in bilateral cerebellar hemispheres suggesting demyelinating lesions. ELISA for Human Immune Deficiency virus-1 was positive. CSF JC virus DNA PCR was positive. A diagnosis of Progressive Multifocal Leukoencephalopathy (PML) was made on the basis of clinico-radiological picture and JC virus DNA PCR presence in CSF. PML is unknown and under diagnosed CNS infection seen in HIV patients mostly seen with advanced disease. We present an unusual case report where isolated cerebellar involvement occurred as the first AIDS defining event in the absence of appreciable immunodeficiency in a patient with previously undiagnosed HIV infection.

Biopsy-proven PML in an HIV-negative patient with discoid lupus: Failure to detect JC virus in CSF.

We present a case of a 58-year-old man with a history of severe discoid lupus erythematosus and acute encephalopathy and incoordination. Antinuclear antibody testing was weakly positive but all other laboratory tests for systemic lupus erythematosus were negative and serum quantitative immunoglobulins and lymphocytes were normal. MRI brain showed T2/FLAIR hyperintensities within the bilateral parietal and temporal lobes with involvement of subcortical U fibers. CSF PCR was negative for varicella-zoster virus, herpes simplex, JCV and BK virus. However, JCV antibody index was elevated (3.88; reference: < 0.2). Right parietal brain biopsy was consistent with JCV infection and diagnostic of progressive multifocal leukoencephalopathy (PML). To the best of our knowledge, this is the first reported case of PML in a patient with discoid lupus without other traditional risk factors for the disease and highlights the need for clinical vigilance in this patient population.

Grey matter abnormality in progressive multifocal leucoencephalopathy.

Progressive multifocal leucoencephalopathy (PML) is a demyelinating white matter disease that most often affects immunocompromised people infected by JC virus. The diagnostic gold standard is demonstrable viral DNA or protein from histopathological tissue. However, there are few detailed descriptions of cortical grey matter involvement on neuroimaging. Here we describe the histopathological correlate of cerebral grey matter involvement and radiological accompaniment in a patient with biopsy proven PML.

Unusual Case of Progressive Multifocal Leukoencephalopathy in a Patient With Sjögren Syndrome.

ABSTRACT: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease caused by reactivation of John Cunningham virus affecting typically subcortical and periventricular white matter of immunocompromised hosts (human immunodeficiency virus infection, hematologic malignancies). Cerebral hemispheric white matter is most commonly affected by lytic infections, leading to progressive damage to oligodendrocytes in the central nervous system. Neuroimaging usually highlights scattered foci of white matter hypodensity not attributable to contrast enhancement or mass effect. In contrast, we present an unusual case of PML predominantly affecting cervical spinal cord and brainstem in an immunocompetent host. This is a rare subset of PML case that can occur in association with connective tissue disorders (Sjögren Syndrome in this case), systemic lupus erythematosus being the most common. Progressive multifocal leukoencephalopathy should be considered in the differential diagnosis of spinal cord or brainstem lesions, particularly in the patients with connective tissue disorders.

[Unspecified encephalitis in HIV-infected patients: clinical and postmortem evaluation].

BACKGROUND: The search for an aetiology of central nervous system (CNS) lesions In HIV patients can be extremely challenging. AIM: To establish the nature and character of CNS lesion according to the data of pathological examination of deceased HIV-patients who had an antemortem clinical diagnosis of unspecified encephalitis. MATERIALS AND METHODS: We analysed clinical and laboratory data of 225 HIV-patients admitted to the ICU at the Infectious Clinical Hospital №2 (Moscow, 2018). The principal diagnosis was unspecified encephalitis characterized by cerebral oedema. Had died 183 (67.9%) patients. We conducted pathological examination in 43 (23.5%). RESULTS: CNS lesions occurred in 331 patients (58.8% of 563 ICU). The antemortem diagnosis established were as follows: 12.1% toxoplasmosis; 6.6% HIV-encephalitis; 5.1% CNS lymphoma; 3.6% cryptococcal meningoencephalitis; 3.0% cytomegaloviral diseases; 2.1% progressive multifocal leukoencephalopathy. The cause of the pathology remained unidentified in 225 patients (68% with CNS lesions). Majority of patients were ART-naive. Post-mortem verification was conducted in 29 (67.4%) deceased patients, of which HIV-encephalitis 34.5%, toxoplasmosis 10.3%, progressive multifocal leukoencephalopathy 3.4%. The nature of brain damage in the remaining 20.7% cases was not established even after post-mortem investigation. Productive lepto-meningitis 8 (27.6%), indicating a prolonged duration of the inflammatory process. In the brain 48.1% patients with subacute and productive changes, had a pre-hospital time of more than 30 days, in contrast to 11.1% of patients who had acute pathological processes in the CNS (p0.05). Autopsy didnt reveal any inflammatory changes in the brain in 14 (32.6%) patients, though cerebral oedema 93.3%, haemorrhagic syndrome 60% cases. CONCLUSION: Accurate retrospective identification of the aetiology of CNS lesions combined with assessing in vivo characterisation of the pathological process plays an essential role in subsequent formation of diagnostic approaches in pathologies of the CNS in HIV-patients.

Natalizumab in Multiple Sclerosis Treatment: From Biological Effects to Immune Monitoring.

Multiple sclerosis is a chronic demyelinating disease of the central nervous system (CNS) with an autoimmune component. Among the recent disease-modifying treatments available, Natalizumab, a monoclonal antibody directed against the alpha chain of the VLA-4 integrin (CD49d), is a potent inhibitor of cell migration toward the tissues including CNS. It potently reduces relapses and active brain lesions in the relapsing remitting form of the disease. However, it has also been associated with a severe infectious complication, the progressive multifocal leukoencephalitis (PML). Using the standard protocol with an injection every 4 weeks it has been shown by a close monitoring of the drug that trough levels soon reach a plateau with an almost saturation of the target cell receptor as well as a down modulation of this receptor. In this review, mechanisms of action involved in therapeutic efficacy as well as in PML risk will be discussed. Furthermore the interest of a biological monitoring that may be helpful to rapidly adapt treatment is presented. Indeed, development of anti-NAT antibodies, although sometimes unapparent, can be detected indirectly by normalization of CD49d expression on circulating mononuclear cells and might require to switch to another drug. On the other hand a stable modulation of CD49d expression might be useful to follow the circulating NAT levels and apply an extended interval dose scheme that could contribute to limiting the risk of PML.

Tratamiento con pembrolizumab en paciente con infección por virus de la inmunodeficiencia humana y leucoencefalopatía multifocal progresiva / Pembrolizumab treatment for progressive multifocal leukoencephalopathy in a patient with Human Immunodeficiency Virus infection

No disponible

The Role of the JC Virus in Central Nervous System Tumorigenesis.

Cancer is the second leading cause of mortality worldwide. The study of DNA tumor-inducing viruses and their oncoproteins as a causative agent in cancer initiation and tumor progression has greatly enhanced our understanding of cancer cell biology. The initiation of oncogenesis is a complex process. Specific gene mutations cause functional changes in the cell that ultimately result in the inability to regulate cell differentiation and proliferation effectively. The human neurotropic Polyomavirus JC (JCV) belongs to the family Polyomaviridae and it is the causative agent of progressive multifocal leukoencephalopathy (PML), which is a fatal neurodegenerative disease in an immunosuppressed state. Sero-epidemiological studies have indicated JCV infection is prevalent in the population (85%) and that initial infection usually occurs during childhood. The JC virus has small circular, double-stranded DNA that includes coding sequences for viral early and late proteins. Persistence of the virus in the brain and other tissues, as well as its potential to transform cells, has made it a subject of study for its role in brain tumor development. Earlier observation of malignant astrocytes and oligodendrocytes in PML, as well as glioblastoma formation in non-human primates inoculated with JCV, led to the hypothesis that JCV plays a role in central nervous system (CNS) tumorigenesis. Some studies have reported the presence of both JC viral DNA and its proteins in several primary brain tumor specimens. The discovery of new Polyomaviruses such as the Merkel cell Polyomavirus, which is associated with Merkel cell carcinomas in humans, ignited our interest in the role of the JC virus in CNS tumors. The current evidence known about JCV and its effects, which are sufficient to produce tumors in animal models, suggest it can be a causative factor in central nervous system tumorigenesis. However, there is no clear association between JCV presence in CNS and its ability to initiate CNS cancer and tumor formation in humans. In this review, we will discuss the correlation between JCV and tumorigenesis of CNS in animal models, and we will give an overview of the current evidence for the JC virus's role in brain tumor formation.

Detection of Residual Tumor With 68Ga-Pentixafor PET/CT in a Patient With Waldenström Macroglobulinemia and Concurrent John Cunningham Virus-Related Progressive Multifocal Leukoencephalopathy.

A 75-year-old man diagnosed with Waldenström macroglobulinemia (WM) complained of neurological symptoms. Baseline F-FDG PET/CT showed diffusely increased radioactivity in the bone marrow and decreased FDG uptake in the right cerebellum. After rituximab-containing immunochemotherapy, the patient had clinically partial response of WM, but the cerebellar lesion was enlarged. Repeated F-FDG PET/CT was similar to the baseline. Ga-pentixafor PET/CT detected residual tumor of WM in occipital bone and cervical lymph nodes, but there was no uptake in the cerebellar lesion. Finally, John Cunningham virus-related progressive multifocal leukoencephalopathy was confirmed.