Progressive Multifocal Leukoencephalopathy Research Articles

Elevation of serum neurofilament light-chain levels disclose possible occult progressive multifocal leukoencephalopathy and immune reconstitution syndrome in a patient receiving ozanimod: a case report

BackgroundWe report the first case of findings suggestive of progressive multifocal leukoencephalopathy and immune restitution syndrome (PML-IRIS) in a patient with multiple sclerosis receiving ozanimod preceded by an unexpected increase in the serum neurofilament light-chain (sNfL) levels.Case reportA 57-year-old-woman treated with ozanimod for the last 8 years presented, during surveillance MRI, with findings compatible with PML-IRIS. Overt clinical symptoms were absent. sNfL levels increased 4 months earlier and peaked at presentation. Lymphocyte count reached nadir of 330/mL at 8 months earlier.ConclusionThe case illustrates the utility of sNfL levels for PML surveillance in patients receiving immunosuppressors.

Real-World Effectiveness and Safety of Carotegrast Methyl in Japanese Patients with Moderately Active Ulcerative Colitis

Introduction: Carotegrast methyl (CGM) is an oral, small-molecule α4-integrin antagonist, which became clinically available in Japan in May 2022. CGM is approved for remission induction treatment for moderately active ulcerative colitis (UC) with an inadequate response or intolerance to 5-aminosalicylates. Methods: We performed a single-center, retrospective, observational study of Japanese patients with moderately active UC to assess the real-world effectiveness and safety of CGM as remission induction treatment. Results: Of 14 patients, 71% (10/14) were women, and the median (range) age was 47 (20–68) years. Disease types were proctitis in 7% (1/14), left-sided colitis in 50% (7/14), and total colitis in 43% (6/14). With a median (range) treatment duration of 8 (2–26) weeks, the rate of endoscopic improvement (Mayo endoscopic subscore [MES] of 0 or 1) was 64% (9/14), and the rate of endoscopic remission (MES of 0) was 57% (8/14). After treatment with CGM, the median (range) MES decreased significantly from 3.0 (2–3) to 0.0 (0–3) (p = 0.008), the Mayo score decreased significantly from 7.0 (5–9) to 0.0 (0–9) (p = 0.006), and the clinical activity index decreased significantly from 6.0 (1–11) to 0.0 (0–9) (p = 0.015). Stool and diarrhea frequencies decreased significantly after initiating CGM, and the percentage of patients with bloody stool and abdominal pain tended to decrease. The cumulative relapse-free rate at week 26 among 9 patients who achieved endoscopic improvement with CGM was 77.8% (95% confidence interval, 36.5%–93.9%). No adverse drug reactions, including progressive multifocal leukoencephalopathy, were reported during the study period. Conclusion: This single-center, retrospective, observational study of 14 Japanese patients with UC showed that CGM was safe and effective as a remission induction treatment for moderately active UC with an inadequate response to 5-aminosalicylates in real-world settings.

A Case of Progressive Multifocal Leukoencephalopathy Caused by Epcoritamab

A Case of Progressive Multifocal Leukoencephalopathy Caused by Epcoritamab

Combination of low-dose, long-term immunoglobulin and mirtazapine is effective in progressive multifocal leukoencephalopathy caused by JC virus infection

BackgroundProgressive multifocal leukoencephalopathy (PML) is an often fatal disease of the central nervous system caused by opportunistic infection of John Cunningham Polyomavirus (JCV). There’s still no antiviral therapeutic strategy which was generally recognized as effective. The prognosis may differ in patients with different pathological mechanisms and treatments. We aim to report the effectiveness of combined treatment of low-dose, long-term immunoglobulin and mirtazapine in a pathologically proved PML case.Case presentationA patient presented with progressive acalculia, right-left confusion and visual neglection was recorded. She received 10-year immunosuppressive therapy for dermatomyositis. White matter lesions located in bilateral parietal lobe and callosum area symmetrically in MR scanning. JC virus analysis and brain biopsy in left parietal lobe were performed. The number of JCV copies was 2595 in CSF and 282,809 in brain specimen. Abundant foamy macrophages and the lymphatic cells were obvious in immunohistochemistry staining. Few SV-40 positive JC infected cell and more CD4 + and CD68 + cells were predominant. Immunosuppressive drugs were terminated after being diagnosed as PML for positive JCV and pathological characteristics. In addition, immunoglobulin (5 g/day) and mirtazapine (45 mg/day) were used. JC virus in CSF decreased to 0 after treatment for 4 months and was still negative in June 2023. The clinical symptoms improved, and white matter lesions recovered significantly.ConclusionsWe demonstrated that the combination treatment of IVIG and mirtazapine was effective in PML. Low-dose, long-term immunoglobulin might regulate the immune status in our case with controlled inflammatory reaction instead of destructive virus spreading. The therapy may be a prospective option for PML.

Progressive Multifocal Leukoencephalopathy (PML) in an Immunocompetent Host with Excellent Clinical Response to Pembrolizumab Therapy: A Case Report

Progressive Multifocal Leukoencephalopathy (PML) in an Immunocompetent Host with Excellent Clinical Response to Pembrolizumab Therapy: A Case Report

Shrimp Tales: A Case and Discussion on Radiographic Findings Highly Suggestive of Progressive Multifocal Leukoencephalopathy

Shrimp Tales: A Case and Discussion on Radiographic Findings Highly Suggestive of Progressive Multifocal Leukoencephalopathy

Directly Isolated Allogeneic Virus–Specific T Cells in Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a life-threatening viral infection with no approved antiviral treatment. To determine whether restoring the compromised immune system of patients with PML with directly isolated allogeneic virus-specific (DIAVIS) T cells is a promising therapeutic strategy, especially if other curative options are absent. A retrospective case series of patients with PML who were treated with DIAVIS T cells was conducted between March 2020 and February 2022. T cells were isolated from healthy donors within 24 hours and targeted against the BK polyomavirus. Patients with PML were treated monocentrically. Eligibility for treatment with DIAVIS T cells was assessed for patients with confirmed PML, and exclusion criteria included stable PML disease and previous treatment with natalizumab. Fresh DIAVIS T cells were administered with a maximum dose of 2 × 104 CD3+ cells/kg body weight. Remaining T cells were cryopreserved in divided doses and administered in additional treatments approximately 2 and 6 weeks later. Primary outcome measures were clinical response and survival of patients, compared with the outcomes of a historical reference group of PML cases receiving best supportive treatment (BST) and with recently published real-world data of patients with PML who were treated with immune checkpoint inhibition. The study cohort consisted of 28 patients (median [IQR] age, 60 [51-72] years; 20 male [71.4%]). Twenty-two patients (79%) treated with DIAVIS T cells showed response, resulting in significant clinical stabilization or improvement and a reduction in viral load. Six individuals (21%) were classified as nonresponders, deteriorated rapidly, and died, as did 2 other patients during a 12-month follow-up. Older age was the only predictor of a poor treatment response. Survival analysis revealed better 12-month survival rates (hazard ratio, 0.42; 95% CI, 0.24-0.73; P =.02) from diagnosis for patients treated with DIAVIS T cells (18 of 26 [69%]; 12-mo survival rate, 69%) compared with historical controls with BST (57 of 113 [50%]; 12-mo survival rate, including censored data, 45%). This case series of DIAVIS T-cell therapy in PML provides first class IV evidence suggesting efficacy to reduce mortality and improve functional outcome. Further prospective studies are required to confirm these results.

B-266 Therapeutic Drug Monitoring of Natalizumab and Anti-Natalizumab Antibodies

Abstract Background Natalizumab (NTZ) is a monoclonal antibody directed against the α4-integrin subunit of α4β1 and α4β7 integrins. NTZ is used to treat relapsing and remitting forms of multiple sclerosis. Although a majority of patients on standard dosing (intravenous 300 mg, every 4 weeks) reach therapeutic drug concentrations, about 10% of patients will eventually fail NTZ therapy due to the development of anti-NTZ antibodies. NTZ and anti-NTZ antibody concentrations in serum are used together to provide patient-specific pharmacokinetic and immunogenic assessment to aid in patient management. Methods Serum measurements of NTZ and anti-NTZ antibody levels are performed by lab developed electro-chemiluminescent immunoassays where assay design and principle are equivalent to biologic therapeutic drug monitoring described in our previous publication. The natalizumab drug assay is an immunoassay validated to measure free drug (pharmacodynamically active, ADA-unbound) in serum. The anti-natalizumab antibody assay utilizes a solution phase bridging method designed to measure total binding antibodies (including IgM & IgG subtypes). All anti-natalizumab antibody positive samples are confirmed for drug-specificity by an additional signal suppression step. The anti-natalizumab antibody assay is quantitative and drug-tolerant, meaning that circulating drug in patient serum does not interfere with anti-NTZ detection and quantitation. Results Here, we report concomitant measurement of NTZ and anti-NTZ antibody in 160 patient serum samples. Positive anti-NTZ levels from 24 to 235 ng/mL were found in 7.5% (12/160) patients. Anti-NTZ-free samples (148/160) had NTZ drug levels ranging from undetectable (<1.0) to 85 ug/mL. The mean and median drug level in 90 samples (results >1.0) was 10.8 and 2.7, respectively. 61/90 samples had therapeutic drug concentrations (at least 2.0 ug/mL). In the presence of anti-NTZ, 67% (8/12) had undetectable drug level and (4/12) had mean and median drug levels of 1.2 and 1.3, respectively, which is 9- or 2-fold lower than the mean and median drug levels of the anti-NTZ Ab -free group. Conclusions Low serum NTZ and high anti-NTZ are associated with loss of clinical efficacy, while elevated NTZ may increase progressive multifocal leukoencephalopathy risk. Assays to measure biologic drugs and their anti-drug antibodies in patient serum may be useful tools in dose optimization and patient management.

Neuroaxonal damage in natalizumab-treated MS patients: The role of JCV antibody titres

Background: While John Cunningham virus (JCV) is known to cause neuronal damage in progressive multifocal leukoencephalopathy (PML) among natalizumab-treated MS patients, its association with axonal loss in non-PML conditions remains unclear. Methods: In a cohort of 128 natalizumab-treated MS patients, serum neurofilament (sNfL) levels and JCV antibody titres were measured. Results: Among 128 patients (mean age = 38.4 years, 71.9% female), 51 (40%) were JCV positive. NfL levels increased by 15.3% for JCV index <0.7 (95% confidence interval [CI] = 0.963–1.381), by 18.6% for index 0.7–1.5 (95% CI = 1.009–1.394) and by 21.1% for index >1.5 (95% CI = 1.040–1.409) compared to JCV negative patients. Conclusion: These findings indicate a potential link between JCV burden and neuroaxonal degeneration in natalizumab-treated MS patients.

Identification of JC polyomavirus in upper respiratory samples from Portuguese children

BackgroundJC polyomavirus (JCPyV) is ubiquitous in the human population and the causative agent of a rare, fatal and demyelinating disease of the central nervous system named Progressive Multifocal Leukoencephalopathy (PML). The route of JCPyV transmission remains unclear, but high values of seroprevalence suggest an easy and frequent mode, such as respiratory route. ObjectivesThe present study aims to investigate the presence of JCPyV in upper respiratory samples and contribute to the elucidation of the JCPyV transmission pathway. Study designNasopharyngeal swabs from 587 Portuguese individuals, including 380 children (≤18 years) and 207 adults (>18 years), collected for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnosis between September and November 2021 were evaluated for the presence of JCPyV DNA. ResultsJCPyV DNA was detected in 3.1 % of the nasopharyngeal swabs analysed, with higher frequency of detection in samples from children (4.5 %) than from adults (0.5 %) (p = 0.005). Infection with SARS-CoV-2 does not potentiate the presence of JCPyV in upper respiratory tract, once only one adult of 28 years with confirmed SARS-CoV-2 infection showed detectable JCPyV DNA. JCPyV DNA was more frequently detected in respiratory samples from children without SARS-CoV-2 infection (6.4 %). As for this group, children under six years of age presents the highest frequency of detection (10.3 %). ConclusionsThe present study demonstrates that upper respiratory secretions of children, particularly under the age of six, may be implicated in JCPyV transmission, regardless of SARS-CoV-2 infection.

Presentation and Outcome in S1P-RM and Natalizumab-Associated Progressive Multifocal Leukoencephalopathy: A Multicenter Cohort Study.

Progressive multifocal leukoencephalopathy (PML) is a severe neurologic disease resulting from JC virus reactivation in immunocompromised patients. Certain multiple sclerosis (MS) disease-modifying therapies (DMTs) are associated with PML risk, such as natalizumab and, more rarely, sphingosine-1-phosphate receptor modulators (S1P-RMs). Although natalizumab-associated PML is well documented, information on S1P-RM-associated PML is limited. The aim of this study is to compare clinical presentations and outcomes between the 2 groups. A retrospective multicenter cohort study included patients with PML from 2009 to 2022 treated with S1P-RMs or natalizumab. Data on clinical and radiologic presentation, outcomes, immune reconstitution inflammatory syndrome (IRIS), survival, disability (using the modified Ranking scale-mRS), and MS relapses post-PML were analyzed. Of 88 patients, 84 were analyzed (20 S1P-RM, 64 natalizumab). S1P-RM-associated PML was diagnosed in older patients (median age 52 vs 44 years, p < 0.001) and after longer treatment duration (median 63.9 vs 40 months, p < 0.001). Similarly, S1P-RM patients were more prone to show symptoms at diagnosis (100 vs 80.6%, p = 0.035), had more disseminated lesions (80% vs 34.9%, p = 0.002), and had higher gadolinium enhancement (65% vs 39.1%, p = 0.042). Natalizumab patients had a higher IRIS development rate (OR: 8.3 [1.92-33.3]). Overall, the outcome (mRS) at 12 months was similar in the 2 groups (OR: 0.81 [0.32-2.0]). Yet, post-treatment MS activity was higher in S1P-RM cases (OR: 5.7 [1.4-22.2]). S1P-RM-associated PML shows reduced IRIS risk but higher post-treatment MS activity. Clinicians should tailor post-PML treatment based on pre-PML medication.

Presentation and Outcome in S1P-RM and Natalizumab-Associated Progressive Multifocal Leukoencephalopathy: A Multicenter Cohort Study.

Presentation and Outcome in S1P-RM and Natalizumab-Associated Progressive Multifocal Leukoencephalopathy: A Multicenter Cohort Study.

Safety of high efficacy therapies in older people with Multiple Sclerosis: A real-world evidence study

Introductionthe increase of older adults living with Multiple Sclerosis (MS) is associated with higher use of high efficacy therapies (HETs) in a clinical practice. The are no data regarding the safety of HET in this patient group. Objective: to analyze the safety of HETs in older people with MS (pwMS) in a real-life cohort. Methodsretrospective cohort study including pwMS under HETs (cladribine and monoclonal antibodies) treated in two specialized MS centers in Latin America. We compare: pwMS ≥ 50 years old (G1) and < 50 years old (G2). In all pwMS, presence and type of adverse events, and comorbidities were recorded. Results882 pwMS were included, 141 (15.9 %) had ≥50 years old, 47 (33.3 %) werunde HETs (G1). The most used DMT in G1 was ocrelizumab (48.9 %), mean time under HETs: 2.06 ± 0.8 years. The most frequent adverse event in G1 was urinary tract infection (UTI) (21.3 %). We did not find significant differences between G1 and G2 in infusion reactions, lymphopenia, neoplasms, respiratory infections, and liver disease. We found differences in the frequency of urinary tract infections (p = 0.004). No cases of VZV reactivation, tuberculosis or progressive multifocal leukoencephalopathy were registered. In a regression model adjusted for MS evolution, time under HET, EDSS, Charlson comorbidity index and phenotype, patients 50 ≥ under HETs did not have a higher incidence of adverse events compared to < 50 (Adjusted OR 0.72; CI95 % 0.143 -3.43, p = 0.67)} Conclusionthe short term use of HETs in pwMS older than 50 years old seems to be safe.

Progressive multifocal leukoencephalopathy in sarcoidosis successfully treated with pembrolizumab.

Progressive multifocal leukoencephalopathy (PML) is a severe, demyelinating disease of the central nervous system caused by JC virus infection. The disease can be seen in sarcoidosis patients without additional risk factors. Here, we present an individual with PML secondary to sarcoidosis treated with 8 doses of pembrolizumab, a Programmed Cell-Death-1 (PD-1) Immune Checkpoint Inhibitor who showed significant improvement. This report illustrates the objective clinical and radiological improvement in a patient with PML due to sarcoidosis, and suggests further study of immune checkpoint inhibitors as a potential treatment for sarcoidosis patients with PML.

Case report and literature review of AIDS-related progressive multifocal leukoencephalopathy diagnosed in a psychiatric department

A progresszív multifokális leukoencephalopathiát a John Cunningham-vírus reaktiválódása okozza, amely szinte kizárólag immunhiányos betegeknél fordul elő. A betegség tüneteit elsősorban a demyelinisatiós gócok lokalizációja határozza meg; a betegség a kezdeti szakaszban tünetszegény lehet, és a neurológiai tünetek csak később jelennek meg. Diagnosztikájában elsősorban a képalkotó vizsgálatok és a vírus-DNS liquorból történő kimutatása játszik fontos szerepet. Specifikus terápiája nem ismert, a cél az immunrendszer működésének helyreállítása. Kazuisztikánkban egy pszichiátriai osztályon észlelt páciens kórtörténetét ismertetjük, akinek esetében AIDS-hez köthető jobb féltekei progresszív multifokális leukoencephalopathia képe igazolódott. Korai differenciáldiagnosztikai nehézséget jelentettek a páciensnél észlelhető patológiás személyiségjegyek, illetve az élethelyzeti nehézségek és a párkapcsolati veszteség talaján kialakult krízisállapot. Esetünkkel szeretnénk felhívni a figyelmet az immunhiányos betegeknél jelentkező pszichiátriai tünetek fontosságára. Orv Hetil. 2024; 165(33): 1295–1302.

Unusual demyelinating disease in a patient with HIV infection.

Demyelinating central nervous system (CNS) disorders are a diverse group of conditions characterised by damage to the myelin sheath. These include not only primary autoimmune disorders such as multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), but secondary demyelinating conditions caused by infection and neoplasm, where immunosuppressive therapy may worsen the condition or delay definitive treatment. We describe a young man with an unusual presentation of CNS demyelinating disease associated with HIV infection and positive syphilis serology. MRI brain and spine showed a demyelinating tumefactive lesion accompanied by longitudinal extensive transverse myelitis, and we initially suspected NMOSD. However anti-aquaporin 4 antibodies were negative, going against a diagnosis of NMOSD and he then tested positive for HIV which led us to consider TB myelitis, neurosyphilis and HIV vacuolar myelopathy. He was commenced on highly active retroviral therapy and treated with steroids and immunosuppression. He did not respond to treatment as expected so a brain biopsy was required to narrow the differential. Brain biopsy initially raised the possibility of progressive multifocal leukoencephalopathy which is associated with infection with the John Cunningham (JC) virus. Ultimately JC Virus PCR on the biopsy was negative, the final report suggesting nonspecific active chronic inflammation. We detail his clinical course and the diagnostic challenges along the way.

JC virus spread is potentiated by glial replication and demyelination-linked glial proliferation.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating infection of the immunosuppressed brain, mediated by the gliotropic polyomavirus JCV. JCV replicates in human glial progenitor cells and astrocytes, which undergo viral T antigen-triggered mitosis, enabling viral replication. We asked if JCV spread might therefore be accelerated by glial proliferation. Using both in vitro analysis and a human glial chimeric mouse model of JCV infection, we found that dividing human astrocytes supported JCV propagation to a substantially greater degree than did mitotically quiescent cells. Accordingly, bulk and single cell RNA-sequence analysis revealed that JCV-infected glia differentially manifested cell cycle-linked disruption of both DNA damage response and transcriptional regulatory pathways. In vivo, JCV infection of humanized glial chimeras was greatly accentuated by cuprizone-induced demyelination and its associated mobilization of GPCs. Importantly, in vivo infection triggered the death of uninfected as well as infected glia, reflecting significant bystander death. Together, these data suggest that JCV propagation in PML may be accelerated by glial cell division. As such, the accentuated glial proliferation attending disease-associated demyelination may provide an especially favorable environment for JCV propagation, thus potentiating oligodendrocytic bystander death and further accelerating demyelination in susceptible hosts.

Progressive Multifocal Leukoencephalitis of the Immunocompromised Subject: A Case Report from Zinder National Hospital

Progressive multifocal leukoencephalitis (PML) is a rare opportunistic infection of HIV-infected individuals. It is a viral infection caused by the John Cunningham (JC) virus, which occurs during the AIDS stage. An elderly patient immunosuppressed by HIV for more than 5 years presented to the HNZ SMIT with headache, vomiting, visual disturbances, speech disorders and numbness of the limbs, all of which had been evolving in a febrile context for more than seven months. Neurological examination revealed left hemiparesis, frontal syndrome, temporal syndrome and homolateral hemianopia. Cerebral computed tomography revealed multiple lesions of leukoencephalitis. PCR revealed JC virus. The patient was put on corticosteroids, rehydration and nursing care. The course was marked by a progressive deterioration in the patient's neurological condition, culminating in death. We report the clinical, biological and CT features of this progressive multifocal leukoencephalitis.

Efficacy and Safety of Bendamustine-Rituximab as Frontline Therapy for Indolent Non-Hodgkin Lymphoma: A Real-World, Single-Center, Retrospective Study.

Background The use of bendamustine with an anti-CD20 monoclonal antibody as frontline therapy for indolent non-Hodgkin lymphoma(NHL)has become a standard of care.We aimed to evaluate the real-world efficacy and safety of bendamustine-rituximab (BR) frontline therapy for indolent NHL. Patients and methods Patients with indolent NHL treated with frontline BR therapy in Hôpital du Sacré-Coeur de Montréal, from January 2015 to August 2018 were included in this retrospective study. Results Our cohort included 42 adults with a median age of 63 years. Follicular lymphoma was the most common histology (n = 31, 74%). Most patients had advanced disease (Lugano stage III or IV, 88%). The overall response rate was 84% (complete response = 62% and partial response = 22%). Median progression-free survival (PFS) was not reached. At 30 months, PFS was 74.8% and overall survival was 90%. Grade 3-4 neutropenia occurred in 21% of patients. Infection-related adverse events were observed in 17 patients (40%). Most were grade 1 and 2 events (84%).One case of grade 5 progressive multifocal leukoencephalopathy related to John Cunningham (JC) virus reactivation was observed. The most common non-infectious-related adverse events were mild nausea and fatigue. Conclusions The efficacy and safety of BR treatment for indolent NHL were comparable in our real-life cohort compared to prior studies. This supports BR as a standard of care for indolent NHL. Future studies should assess whether the use of granulocyte-colony stimulating factors as primary prophylaxis effectively mitigates the hematological and infection-related adverse events related to BR therapy.

“One a penny, two a penny”, I saw the hot cross bun sign”

The hot cross bun sign is a radiological sign seen on MRI due to pontocerebellar demyelination and loss of neurons along with preservation of the pontine tegmentum and corticospinal tracts which is classically seen in Multiple System Atrophy (MSA). Hot cross buns have been in existence since as early as the 14th century up until the point when Schrag et al. (1998) coupled the appearance of this age-old bread with the T2 imaging characteristics of MSA. Over time the radiological sign has expanded with a differential diagnosis of spinocerebellar ataxia, progressive multifocal leukoencephalopathy, paraneoplastic cerebellar degeneration, and variant Creutzfeldt-Jakob disease.