Academic literature on the topic 'Leucoencephalopathie multifocale progressive'

Progressive multifocal leucoencephalopathy has become a growing concern in natalizumab-treated multiple sclerosis patients. Here, we describe a 35-year-old patient who was treated with 34 infusions of natalizumab before complaining about visual deterioration. MRI was non-diagnostic and JC virus testing initially was negative. Electroencephalography showed severe slowing of the right hemisphere, and neuropsychological testing revealed right frontal and temporal deficits. The diagnosis of progressive multifocal leucoencephalopathy was established 2 months later by typical MRI presentation and detection of JC virus DNA in the cerebrospinal fluid. Functional neurological deficits may precede imaging features and should prompt early consideration of progressive multifocal leucoencephalopathy.

Case reportA 71 year old man presented with a three month history of gradual arm and leg weakness, followed by neck stiffness, dysphagia, dysarthria and hypophonia. Past Medical History included Burkitt's lymphoma of the jaw 14 years previously, treated with chemotherapy and radiotherapy.Examination demonstrated a restriction of upgaze and dysphonia. Tone was markedly increased, and power reduced globally at a grading of 4/5. Reflexes were brisk with an upgoing left plantar.Investigations revealed, longstanding idiopathic lymphopenia for 10 years, CT chest/abdominal/pelvis was normal, serial MRI of the brain demonstrated changes in the subcortical white matter, frontal and parietal lobes. JC virus PCR was negative, however, brain biopsy was consistent with Progressive Multifocal Leucoencephalopathy (PML).DiscussionPML is caused by reactivation of the polyomavirus JC in the CNS. Reactivation typically occurs following immunosuppression e.g. HIV, haematological malignancies and drugs. Gold standard for diagnosis is brain biopsy as JC virus PCR has a sensitivity of only 80%. Treatment is through removal of the immunosuppressive agent, and immune reconstitution.PML should be considered in all patients with a suggestive clinical and radiological presentation where there is current or historical immunosuppression, should JC virus PCR be negative a tissue biopsy should be sought.

Abstract Background Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of white matter in the central nervous system (CNS) caused by reactivation of John Cunningham (JC) virus. Drug-induced PML is increasingly reported with the widely used biological immunosuppressant drugs and molecular targeted antineoplastic agents. Monoclonal antibodies were the pioneer drugs to be associated with PML including the prototypical natalizumab. Methods Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been rarely described in this context with few case reports of ibrutinib-associated PML. Osimertinib, a third-generation EGFR TKI, was recently FDA-approved for the first-line treatment of metastatic non-small-cell lung cancer (NSCLC), and to the best of our knowledge has never been associated with PML. We describe a case report of a rapidly progressive PML likely associated with osimertinib therapy. Results A 85-year-old female with history of NSCLC, on osimertinib, was admitted with progressively worsening left hemiparesis, facial palsy, unsteady gait, recurrent falls, and episodic confusion over a period of month. Brain magnetic resonance imaging revealed foci of non-enhancing increased T2 and fluid-attenuated inversion recovery (FLAIR) signal intensity in the periventricular and bilateral cerebral subcortical white matter. MRI cervical spine was unremarkable for acute enhancing lesions. Cerebrospinal fluid (CSF) was unremarkable for infectious etiology, oligoclonal bands, and cytology. The patient was readmitted 2 weeks later with worsening neurological deficits and new lesions in the bilateral middle cerebellar peduncles, pons, midbrain, and cerebral white matter. Positive CSF JC virus PCR lead to the final diagnosis of “probable” PML. Biopsy was deferred for high clinical suspicion of PML and procedural risks outweighing benefits. Osimertinib was likely contributing to PML in the absence of other immunosuppression. Conclusion Inhibition of tyrosine kinase-dependent pathways can potentially aid in the replication of JC virus per previously reported ibrutinib-associated PML. Clinicians should be aware of PML risk in patients on osimertinib and TKI therapy, especially those with positive serum JC virus serology. Disclosures All authors: No reported disclosures.

Le polyomavirus humain JC (JCV) est un virus ubiquitaire qui infecte de façon persistante et asymptomatique la majorité de la population, entrainant occasionnellement une excrétion urinaire. Dans le contexte d'immunodépression, le JCV peut infecter les cellules gliales du système nerveux central (SNC), provoquant une maladie démyélinisante fatale, la Leucoencéphalopathie Multifocale Progressive (LEMP). Le génome du JCV est un ADN double brin circulaire de 5 kb composé de 2 régions codantes opposées -précoce et tardive- séparées par une région non codante de contrôle (NCCR). En comparaison à la séquence NCCR urinaire archétypale les séquences obtenues du SNC de patients atteints de LEMP sont constituées de réarrangements dont le rôle n'est pas entièrement connu. Pour étudier l'effet de ces réarrangements en culture cellulaire, la technologie des minicercles d'ADN a été adaptée afin de produire 4 vecteurs bidirectionnels exprimant deux gènes rapporteurs fluorescents sour le contrôle d'une NCCR archétypale (NCCR at) ou réarrangée (NCCR rr) comportant une délétion de 66 pb. Après transfection de cellules humaines gliales U-87MG et rénales HEK293, l'expression des rapporteurs à partir des NCCR at et rr a été mesurée par cytométrie en flux. Dans les cellules HEK293, l'expression des régions codantes précoce et tardive à partir de la NCCR at est similaire tandis que dans les cellules U-87MG, l'expression précoce est 2.1 fois supérieure à l'expression tardive (p <0.001). Par ailleurs, l'expression tardive à partir de la NCCR rr est similaire à l'expression précoce dans les cellules HEK293 et U-87MG. Ces résultats suggèrent que la délétion de 66 pb restaure l'expression tardive dans la lignée de glioblastome. L'utilisation d'un modèle in vitro a permis de mettre en évidence un lien particulier entre la séquence NCCR et l'expression dépendant du type cellulaire. En plus de la variabilité inter compartiment déjà décrite pour un même patient atteint de LEMP, la variabilité intra compartiment a été évaluée au moyen d'une technique de « single molecule real-time (SMRT) sequencing » à partir de 23 liquides céphalorachidiens (LCR), 1 biopsie cérébrale et 19 prélèvements urinaires de patients atteints de LEMP ainsi que 5 prélèvement urinaires de patients non atteints de LEMP. L'ensemble du génome du JCV a été amplifié en 2 fragments chevauchants aux deux extrémités, chacun constitué de la NCCR et de l'une ou l'autre des régions codantes. Les amplicons ont été séquencés par la technique SMRT PacBio. L'analyse phylogénétique montre une répartition des souches cérébrales parmi 6 génotypes différents, révélant l'absence de pathogénicité spécifique de type. Les séquences NCCR cérébrales comportent diverses délétions touchant principalement les sections b, d, et f ainsi que des insertions des sections c et e dupliquées. Chez la majorité des patients atteints de LEMP (18/23), la population virale cérébrale est composée d'au moins 2 formes de NCCR distinctes dont la structure suggère un lien d'apparition chronologique entre ces deux variants. Par ailleurs, des substitutions d'acide aminé au niveau de 7 emplacements déjà décrits dans la protéine VP1 ont été identifiées exclusivement dans les souches cérébrales. Hormis plusieurs mutations en rapport avec des polymorphismes de souches, 2 nouvelles substitutions ont été observées à partir du LCR de deux patients différents situées respectivement dans le domaine hélicase de la séquence AgLT (Tyr407Asn) et dans le domaine N-terminal du gène VP2 (Pro65Ala). Ces mutations pourraient jouer un rôle dans la pathogénicité en modifiant les capacités réplicatives virales, en créant un changement de structure de la particule virale ou en favorisant l'échappement à la réponse immune. Ce travail fournit un argument supplémentaire en faveur de l'implication des réarrangements de la NCCR dans la neuropathogénicité du JCV et apporte un éclairage nouveau sur les populations virales associées à la LEMP
JC Polyomavirus (JCV) is a ubiquitous human virus which causes asymptomatic persistent infections, and occasional urine shedding. In immune depression conditions, JCV causes a fatal disease, progressive multifocal leukoencephalopathy (PML), by infecting oligodendroglial cells of the central nervous system (CNS). The JCV double-stranded circular 5 kb genome is composed of two opposite coding regions - early and late - transcribed from opposite strands of DNA, and separated by the regulator non-coding control region (NCCR). The hallmark of NCCR prototype sequences recovered from PML brain lesions is the presence of rearrangements (rr) of unknown function, compared with urine archetype (at) NCCR sequences. To analyse the effects of such mutations on early and late expression in tissue-specific cultured cells, we produced bidirectional reporter vectors expressing two distinct fluorescent reporters under control of either rr or at JCV NCCR. We adapted the technology involving DNA circles devoid of bacterial plasmid backbone and generated four expression vector maxicircles, to investigate the effects of a single 66 bp deletion differentiating rr and at NCCR. After transfection of U-87MG (human glioblastoma cell line) and HEK293 (human kidney cell line), fluorescent reporter expressions from at and rr NCCR were analysed by cytometry analysis. In HEK293 cells, early and late expressions from at NCCR were similar, whereas in U-87 MG cells, early expression was 2.1-fold higher than late expression (p <0.001, Welch's t-test). This suggests that late expression from at NCCR is impaired in this glioblastoma cell line. Interestingly, late expression from mutated rr NCCR was similar to early expression in both HEK293 and U-87 MG cells, indicating that the 66 bp deletion restored late expression in the glioblastoma cell line. By using this in vitro model, we evidenced a relevant link between JCV NCCR sequence and cell-type dependent expression. In addition to the inter-compartment variability within patients, we further investigated the previously reported intra-compartment variability. By using a single-molecule real-time (SMRT) sequencing technology (PacBio, Pacific Biosciences) in order to obtain 3 kb amplicon sequences in a single read, we analysed precisely the JCV genomic populations in 23 cerebrospinal fluid (CSF), 1 cerebral biopsy (CB) and 19 urine samples of PML patients and 5 urine samples from non PML patients. JCV full-length genome was amplified in 2 overlapping opposite fragments, each encompassing the NCCR and either the early or the late coding sequence. Phylogenetic analysis revealed distribution of PML strains among 6 distinct genotypes, suggesting absence of specific pathogenic JCV genotype. PML JCV NCCR from cerebral samples displayed various deletions affecting mainly b, d and f sections and insertions of duplicated c and e sections. In 18/23 cerebral samples, intra compartment variability consisted in detection of at least two JCV variants and suggested a chronological emergence relationship between the two rearranged forms. In VP1, previously reported aminoacid substitutions at 7 distinct positions of sialic acid binding regions and antigenic epitopes were observed exclusively in cerebral strains. Apart single nucleotide polymorphisms evidenced over the whole viral genome, we observed, in two distinct PML CSF strains, two novel missense mutations, located in the helicase domain of LTAg sequence (Tyr407Asn) and in the N terminal domain of VP2 coding gene (Pro65Ala) respectively. These mutations could play a role in PML pathogenesis by modifying viral and/or cellular replication and transcription, by changing viral particle conformational structure and by immune response escape. This work supports the role of JCV NCCR rearrangements in PML neuropathogenesis and provides further insights in the genesis of neurotropic strains in PML lesions

The adverse psychiatric consequences of a range of monoclonal antibodies used to treat cancer are reviewed. Bevacizumab disrupts endothelial function at the blood–brain barrier and can provoke posterior reversible encephalopathy syndrome. The immune checkpoint inhibitors cause autoimmune hypophysitis and thyroiditis with associated psychopathology. Rituximab causes profound immunosuppression of B lymphocytes, and hence can reactivate childhood JC virus infection to cause progressive multifocal leucoencephalopathy. The marked neuropsychiatric toxicity of blinatumomab is described.

Neurological infections can be broadly subdivided into chronic/subacute and acute. Chronic/subacute infection usually presents with global cognitive decline, with the prototypical disease being progressive multifocal leucoencephalopathy due to infection with the JC virus in immunocompromised patients. Acute neurological infections can be defined microbiologically, by the nature of the pathogen; clinically, by the presenting signs and symptoms and initial CSF findings; or anatomically. The anatomical definitions are those occurring intracranially (‘meningitis’, where infection involves the meninges overlying the brain; ‘encephalitis’, where the brain parenchyma is involved; or ‘cerebral abscesses’) and those affecting the spinal cord (‘myelitis’). However, there is often both clinical and histological overlap between these syndromes; consequently, the terms ‘meningoencephalitis’ and ‘encephalomyelitis’ are often used. Patients with acute intracranial CNS infections provide the greatest challenge to general physicians, because urgent investigation and appropriate treatment can save lives; they therefore form the focus of this chapter.

Progressive multifocal leucoencephalopathy (PML) is an opportunistic infection of the central nervous system caused by the JC polyomavirus (JCV) It is seen almost exclusively in individuals with severe immunosuppression and has become much more widely recognized since the AIDS/HIV epidemic. Classical imaging appearances can be highly suggestive of the diagnosis but definitive evidence would include detection of JCV in CSF or a brain biopsy. Treatment is supportive and focused on immune reconstitution.