Immune profiling of a patient with alemtuzumab-associated progressive multifocal leukoencephalopathy

2019 ◽  
Vol 25 (8) ◽  
pp. 1196-1201 ◽  
Author(s):  
Simonetta Gerevini ◽  
Ruggero Capra ◽  
Diego Bertoli ◽  
Alessandra Sottini ◽  
Luisa Imberti
Keyword(s):  
Progressive Multifocal Leukoencephalopathy ◽  
B Cell ◽  
Clinical Symptoms ◽  
Jc Virus ◽  
Treated Patient ◽  
First Case ◽  
Cell Diversity ◽  
Clonic Seizures ◽  
Magnetic Resonance Imaging Mri ◽  
Inflammatory Syndrome

A 31-year-old woman affected by multiple sclerosis (MS) experienced generalized tonic–clonic seizures 2 months after the second alemtuzumab cycle. Positive JC virus (JCV)-DNA in cerebrospinal fluid (CSF) and lesion iconography at magnetic resonance imaging (MRI) were suggestive of progressive multifocal leukoencephalopathy (PML). After 1 month, during full-blown immune reconstitution inflammatory syndrome, JCV-DNA became negative and symptoms gradually improved. New T- and B-cell output and T- and B-cell diversity were low and lymphocytes poorly responded to stimulation. This is the first case of an alemtuzumab-treated patient with clinical symptoms and radiological features compatible with PML. The lack of large T- and B-cell diversity, necessary for JCV recognition, is likely to have concurred to PML insurgence.

scholarly journals Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome in seven patients with sarcoidosis: a critical discussion of treatment and prognosis

2021 ◽  
Vol 14 ◽  
pp. 175628642110355
Author(s):  
Maike F. Dohrn ◽  
Gisa Ellrichmann ◽  
Rastislav Pjontek ◽  
Carsten Lukas ◽  
Jens Panse ◽  
...  
Keyword(s):  
Progressive Multifocal Leukoencephalopathy ◽  
Immune Reconstitution Inflammatory Syndrome ◽  
Immune Reconstitution ◽  
Opportunistic Infections ◽  
Jc Virus ◽  
Immunosuppressive Treatment ◽  
Interleukin 2 ◽  
Cerebral Magnetic Resonance Imaging ◽  
Virus Load ◽  
Inflammatory Syndrome

Progressive multifocal leukoencephalopathy (PML) is a subacute brain infection by the opportunistic John Cunningham (JC) virus. Herein, we describe seven patients with PML, lymphopenia, and sarcoidosis, in three of whom PML was the first manifestation of sarcoidosis. At onset, the clinical picture comprised rapidly progressive spastic hemi- or limb pareses as well as disturbances of vision, speech, and orientation. Cerebral magnetic resonance imaging showed T2-hyperintense, confluent, mainly supratentorial lesions. Four patients developed punctate contrast enhancement as a radiological sign of an immune reconstitution inflammatory syndrome (IRIS), three of them having a fatal course. In the cerebrospinal fluid, the initial JC virus load (8–25,787 copies/ml) did not correlate with interindividual severity; however, virus load corresponded to clinical dynamics. Brain biopsies ( n = 2), performed 2 months after symptom onset, showed spotted demyelination and microglial activation. All patients had lymphopenia in the range of 270–1150/µl. To control JC virus, three patients received a combination of mirtazapine and mefloquine, another two patients additionally took cidofovir. One patient was treated with cidofovir only, and one patient had a combined regimen with mirtazapine, mefloquine, cidofovir, intravenous interleukin 2, and JC capsid vaccination. To treat sarcoidosis, the four previously untreated patients received prednisolone. Three patients had taken immunosuppressants prior to PML onset, which were subsequently stopped as a potential accelerator of opportunistic infections. After 6–54 months of follow up, three patients reached an incomplete recovery, one patient progressed, but survived so far, and two patients died. One further patient was additionally diagnosed with lung cancer, which he died from after 24 months. We conclude that the combination of PML and sarcoidosis is a diagnostic and therapeutic challenge. PML can occur as the first sign of sarcoidosis without preceding immunosuppressive treatment. The development of IRIS might be an indicator of poor outcome.

Progressive Multifocal Leukoencephalopathy Syndrome and Immune Reconstitution Inflammatory Syndrome

2013 ◽  
Author(s):  
Aaron E. Miller ◽  
Teresa M. DeAngelis
Keyword(s):  
Monoclonal Antibody ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Immune Reconstitution Inflammatory Syndrome ◽  
Immune Reconstitution ◽  
Jc Virus ◽  
Radiographic Findings ◽  
Life Threatening ◽  
The Central Nervous System ◽  
Immunosuppressant Medications ◽  
Inflammatory Syndrome

Progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the central nervous system caused by the JC virus, typically manifests in severely immunocompromised conditions, ranging from HIV/AIDS to lymphoproliferative malignancies to the consequence of immunosuppressant medications such as natalizumab, a monoclonal antibody approved for the treatment of relapsing forms of MS. In this chapter, we discuss the typical symptomatology and radiographic findings of PML and how to distinguish it from those of MS. In addition, we review the management of PML in natalizumab-treated MS patients as well as the features of immune reconstitution inflammatory syndrome (IRIS), the potentially life-threatening consequence of natalizumab withdrawal in patients with PML.

Autoimmune/inflammatory syndrome induced by methylmethacrylate associated to seronegative antiphospholipid syndrome and diffuse large B-cell non-Hodgkin’s lymphoma

Lupus ◽  
2020 ◽  
Vol 29 (10) ◽  
pp. 1292-1296
Author(s):  
Olga Vera-Lastra ◽  
Eduardo Rojas-Milán ◽  
Ana Lilia Peralta-Amaro ◽  
Magdalena Sánchez-Uribe ◽  
Leopoldo Isaac Cruz-González ◽  
...  
Keyword(s):  
B Cell ◽  
Antiphospholipid Syndrome ◽  
Hodgkin’S Lymphoma ◽  
Granulomatous Inflammation ◽  
Hodgkin's Lymphoma ◽  
Non Hodgkin’S Lymphoma ◽  
First Case ◽  
Non Hodgkin's Lymphoma ◽  
Inflammatory Syndrome ◽  
Large B Cell

Background Autoimmune/inflammatory syndrome induced by adjuvants has been associated with different substances used for cosmetic purposes; for example, silicone, methylmethacrylate, autoimmune disorders and cancer. Discussion A 40-year-old man with a prior history of methylmethacrylate injection in the buttocks for aesthetic purposes 8 years ago, presented with deep venous thrombosis in the left leg 6 months ago, accompanied with inflammation, hardening, changes in colour, ulceration in the buttocks, arthritis, myalgias and fever. Weak and moderate lupus anticoagulant and low levels of anticardiolipin antibodies were present. Thoracoabdominal tomography showed hepatosplenomegaly and a pulmonary nodule, the biopsy of which showed chronic granulomatous inflammation. After a month, a new chest tomography showed multiple nodular pulmonary lesions. The new pulmonary biopsy showed a diffuse large B-cell non-Hodgkin’s lymphoma which was treated with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab for four cycles, with good response of the autoimmune/inflammatory syndrome, but partial response of the diffuse large B-cell non-Hodgkin’s lymphoma. Conclusion We describe the first case of seronegative antiphospholipid syndrome and lymphoma associated with methylmethacrylate in a patient with autoimmune/inflammatory syndrome.

Immune Defects of B- and T-Cell Compartments in Natalizumab-Induced Progressive Multifocal Leukoencephalopathy,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3228-3228
Author(s):  
Alessandra Sottini ◽  
Ruggero Capra ◽  
Cinzia Zanotti ◽  
Marco Chiarini ◽  
Federico Serana ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
B Cells ◽  
Progressive Multifocal Leukoencephalopathy ◽  
B Cell ◽  
B Lymphocyte ◽  
Jc Virus ◽  
Excision Circles ◽  
The Moment

Abstract Abstract 3228 Objective: Progressive multifocal leukoencephalopathy (PML) is a rare, but often fatal demyelinating brain disease caused by the JC virus, which usually occurs in immunosuppressed patients, including those with hematological malignancies or receiving monoclonal antibodies-based immunotherapies. PML is likely the result of a complex combination of several pathogenic mechanisms, such as alterations of peripheral cell-mediated immunity and mobilization of JC virus-carrying CD34+-hematopoetic stem cells and pre-B-cells. Taking advantage of the availability of samples from a multiple sclerosis (MS) patient treated with the anti-α4β1 monoclonal antibody natalizumab who developed PML, which was monitored for 35 months since before therapy initiation, we investigated the role of B and T lymphocytes in PML onset. Methods: Real-Time PCR was used to measure the release of T and B cells from the production sites by means of T-cell receptor excision circles (TRECs) and K-deleting excision circles (KRECs) analysis and to quantify transcripts for immature hematopoietic cells such as terminal deoxynucleotidyl transferase, CD34, and pre-B lymphocyte gene 1. Naïve and mature T- and B-cell subsets were identified by flow cytometry, T-cell heterogeneity was quantified by spectratyping and IgA, IgG and IgM by turbidimetric assay. Data were compared to those of untreated and natalizumab-treated MS patients and healthy donors. Results: After 34 months of natalizumab therapy, a 42 years old female developed PML, diagnosed on the basis of magnetic resonance imaging and JC virus positivity in cerebrospinal fluid. Before therapy, her thymus and bone marrow produced a significant low number of TRECs+ and KRECs+ cells. While TRECs remained low during all therapy period, KRECs and transcripts for pre-B lymphocyte gene 1, which is selectively expressed in pre-B cells, peaked after 6 months of therapy, remained high at 12 and 15 months of treatment, and then decreased at the moment of PML onset. Flow cytometry confirmed a deficient production of CD4+CD45RA+CCR7+CD31+ recent T emigrants, counterbalanced by an increased number of CD8+CCR7–CD45RA+ TEMRA cells for all observation period, but showed a modification of peripheral CD4 and CD8 cell number only at the moment of PML. While the percentage of naïve B cells increased by about 70% after 6 months of therapy, the number of B lymphocytes within each B-cell subpopulations remained low for the entire treatment period. T-cell repertoire and immunoglobulin production were altered. Interpretation: Although performed in a single patient, data all agree in demonstrating that a deficient production of new TRECs+ T lymphocytes, together with an increase of newly produced KRECs+ B cells just few months after therapy beginning may predispose to PML. These findings encourage further researches on the utility of the TRECs/KRECs assay as a potential tool for the identification of patients at risk of developing PML after monoclonal antibodies-based therapies. Disclosures: No relevant conflicts of interest to declare.

Successful pregnancy after natalizumab-associated progressive multifocal leukoencephalopathy in a patient with multiple sclerosis

2016 ◽  
Vol 23 (3) ◽  
pp. 483-486 ◽  
Author(s):  
Kalliopi Pitarokoili ◽  
Kerstin Hellwig ◽  
Carsten Lukas ◽  
Ralf Gold
Keyword(s):  
Multiple Sclerosis ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Clinical Presentation ◽  
Dimethyl Fumarate ◽  
Resonance Imaging ◽  
Successful Pregnancy ◽  
Uncomplicated Pregnancy ◽  
Pregnancy And Delivery ◽  
Magnetic Resonance Imaging Mri ◽  
Inflammatory Syndrome

We report the case of a post-progressive multifocal leukoencephalopathy (PML), multiple sclerosis (MS) patient with an uncomplicated pregnancy and delivery. A 28-year-old woman on natalizumab (total of 49 infusions) was diagnosed with PML due to typical magnetic resonance imaging (MRI) and clinical presentation. John Cunningham virus (JCV) was detected in the cerebrospinal fluid (CSF) during the immune reconstitution inflammatory syndrome (IRIS). Nine months after PML onset, JCV negativity in the CSF was observed. MS was stabilised with dimethyl fumarate (DMF), and 18 months later, a desired pregnancy was reported, resulting in the birth of a healthy boy. Our report gives new hope regarding family planning for post-PML patients.

scholarly journals Mild progressive multifocal leukoencephalopathy after switching from natalizumab to ocrelizumab

2020 ◽  
Vol 8 (1) ◽  
pp. e904
Author(s):  
Alyssa A. Toorop ◽  
Zoë Y.G. van Lierop ◽  
Eva E.M. Strijbis ◽  
Charlotte E. Teunissen ◽  
Axel Petzold ◽  
...  
Keyword(s):  
B Cells ◽  
Progressive Multifocal Leukoencephalopathy ◽  
B Cell ◽  
Case Reports ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Neurofilament Light ◽  
Longitudinal Measurements ◽  
Relapsing Remitting ◽  
Inflammatory Syndrome

ObjectiveTo describe the disease course of carryover progressive multifocal leukoencephalopathy (PML) after switching from natalizumab to ocrelizumab in 2 patients with relapsing-remitting MS.MethodsTwo case reports with 1 year of follow-up and retrospective longitudinal measurements of serum neurofilament light (NfL) levels and B-cells.ResultsPML was diagnosed 78 days (case 1) and 97 days (case 2) after discontinuation of natalizumab. Both patients developed mild immune reconstitution inflammatory syndrome (IRIS) despite B-cell depletion caused by ocrelizumab. NfL levels increased in both patients during PML-IRIS. PML-IRIS lesions stabilized after treatment with mefloquine and mirtazapine, followed by methylprednisolone, and both patients continued therapy with ocrelizumab when B-cells started to repopulate.ConclusionsThe clinical course of carryover PML was mild in both patients, suggesting that B-cell depletion possibly did not aggravate PML-IRIS in these 2 patients.

scholarly journals Progressive Multifocal Leukoencephalopathy in a Multiple Sclerosis Patient Diagnosed after Switching from Natalizumab to Fingolimod

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Tim Sinnecker ◽  
Jalal Othman ◽  
Marc Kühl ◽  
Imke Metz ◽  
Thoralf Niendorf ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Milky Way ◽  
Jc Virus ◽  
Brain Biopsy ◽  
Central Nervous System Disease ◽  
Mri Findings ◽  
Diagnostic Biomarkers ◽  
System Disease ◽  
Inflammatory Syndrome

Background. Natalizumab- (NTZ-) associated progressive multifocal leukoencephalopathy (PML) is a severe and often disabling infectious central nervous system disease that can become evident in multiple sclerosis (MS) patients after NTZ discontinuation. Recently, novel diagnostic biomarkers for the assessment of PML risk in NTZ treated MS patients such as the anti-JC virus antibody index have been reported, and the clinical relevance of milky-way lesions detectable by MRI has been discussed. Case Presentation and Conclusion. We report a MS patient in whom PML was highly suspected solely based on MRI findings after switching from NTZ to fingolimod despite repeatedly negative (ultrasensitive) polymerase chain reaction (PCR) testing for JC virus DNA in cerebrospinal fluid. The PML diagnosis was histopathologically confirmed by brain biopsy. The occurrence of an immune reconstitution inflammatory syndrome (IRIS) during fingolimod therapy, elevated measures of JCV antibody indices, and the relevance of milky-way-like lesions detectable by (7 T) MRI are discussed.

Progressive Multifocal Leukoencephalopathy Associated with Rituximab Treatment of B-Cell Lymphoproliferative Disorders: A Report of 29 Cases from the RADAR Project.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 370-370
Author(s):  
Kenneth R. Carson ◽  
Andrew M. Evens ◽  
Steven T. Rosen ◽  
Jane N. Winter ◽  
Leo I. Gordon ◽  
...  
Keyword(s):  
Progressive Multifocal Leukoencephalopathy ◽  
Hiv Infection ◽  
B Cell ◽  
Active Surveillance ◽  
Medical Literature ◽  
Jc Virus ◽  
Case Reports ◽  
B Cell Lymphoma ◽  
Lymphoproliferative Disorders ◽  
Purine Analog

Abstract Background- Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder of the brain caused by the reactivation of latent JC polyoma virus. Rituximab (Rituxan, Mabthera) is a B-cell depleting, monoclonal antibody which has been linked to reactivation of the hepatitis B virus. HIV infection, purine analog therapy, hematopoietic transplant and lymphoma have previously been associated with PML. We evaluated the characteristics of patients with B-cell lymphoproliferative disorders who developed PML after exposure to rituximab, and the quality of case reports available in the medical literature and at the FDA. Methods- Data sources included 1 observation at Northwestern Memorial Hospital, 14 reports obtained from the FDA MedWatch database, 9 case reports from the medical literature, and 21 reports from the manufacturer, Genentech, that were submitted to the FDA. Reports that did not confirm the diagnosis of PML, were associated with HIV infection, or rituximab use for a rheumatologic indication were excluded. Results- Of 47 unique case reports screened, 3 were excluded for rituximab use in rheumatologic disease, 2 for pre-existing HIV, and 13 for inadequate confirmation of the PML diagnosis. In the 29 remaining cases, survival of PML was reported in only one patient. Diagnosis was made by brain biopsy (n=6), autopsy (n=6), or MRI of brain AND positive JC virus by PCR (n=17). Five cases were seen in hematopoietic transplant recipients, 4 autologous and 1 allogeneic. Of the 24 patients who were not transplanted, 10 had purine analog exposure. Thirteen of the 14 patients that did not receive transplant or a purine analog received an alkylating agent, with 7 receiving standard R-CHOP. The median age of the 29 patients was 63.5 years (range 32–89), 15 were female and 14 male. Indications for rituximab were: large B-cell lymphoma (n=6), follicular lymphoma (n=6), CLL (n=5), Waldenstrom (n=2) and other non-Hodgkin lymphomas (n=10). Median time to diagnosis of PML from first and last rituximab doses was 10 and 5 months respectively. The median number of rituximab doses was 6. Quality comparison of source data is contained in table 1. Overall completeness ratio for literature and observed reports vs. FDA and manufacturer reports was 1.48. Conclusions: We have found 29 cases of rituximab-associated PML, of which 14 were not associated with transplantation or purine analog exposure, suggesting an association of rituximab therapy independent of these other treatment related risk factors. FDA and manufacturer reports are inferior to those available in published case reports or through active surveillance. Further examination of the relationship of rituximab to PML, using an active surveillance strategy, is warranted. Type of Information Literature and Observed Cases (n=10) %Reporting FDA and Manufacturer Cases (n=19) %Reporting Completeness Ratio Outcome 90 63 1.42 Date of Lymph 80 68 1.18 Diagnosis Date of Death 78 53 1.47 HIV Status 60 16 3.75 Specific Lymphoma Type 100 84 1.19 Dose of Rituximab 80 63 1.27 Date of 1st Dose 70 94 .74 Date of Last Dose 70 84 .83

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