Progressive Multifocal Encephalopathy Research Articles

The first study of real-world efficacy and safety of Natalizumab (Tysabri®) in Iran

Objectives: Natalizumab is an injectable DMT (disease-modifying therapy) which used for RRMS (relapsing-remitting multiple sclerosis) since 2006. The drug has been available in Iran since 2014. Introduction: This study was aimed to evaluate the real-world effectiveness of Natalizumab in a referral center in Tehran, Iran. This study is the first real world analysis of efficacy and safety of Natalizumab in our country. Methods: In this retrospective study, patients with RRMS were investigated in a high-volume center in Tehran from 2019 to 2021. MS (Multiple Sclerosis) patients under treatment with Natalizumab who have received at least 3 infusions of the drug and had completed follow-up data, have been evaluated for safety and efficacy of Natalizumab. Results: 100 patients were included in the final analysis. The mean follow-up time was 20 months (6–33 months). The median EDSS (Expanded Disability Status Scale) score of patients reached to 2 from 2.5 after the treatment course (P < 0.0001). The annualized relapse rate (ARR) decreased from 0.81 (95% CI: 0.73–0.87) to 0.023 (95% CI 0.009–0.061). The median JCV (John Cunningham virus) index remained unchanged before treatment 0.85 (IQR: 0.21–2.41) compare to after the treatment 0.85 (IQR: 0.21–2.31). The number of patients with active brain and cervical MRI (Magnetic Resonance Imaging) lesions decreased significantly (P = 0.001). NEDA-3 (No evidence of disease activity) was improved from 9% to 87% after the treatment with Natalizumab. No serious adverse events except than one progressive multifocal encephalopathy (PML) case have been found. The main reasons of switching from Natalizumab to the other DMDs (Disease Modifying Drugs) were positive JC index, starting phase, noncompliance, pregnancy, MRI activity and seroconversion after starting the drug. Conclusion: Natalizumab is a safe and effective choice in RRMS patients for reducing relapse rate, disability score, active MRI lesion, and improving the NEDA (No evidence of disease activity).

Long-term survival from progressive multifocal leukoencephalopathy in living-donor liver transplant recipient with preformed donor-specific antibody

Intensive immunosuppression has enabled liver transplantation even in recipients with preformed donor-specific antibodies (DSA), an independent risk factor for graft rejection. However, these recipients may also be at high risk of progressive multifocal encephalopathy (PML) due to the comorbid immunosuppressed status. A 58-year-old woman presented with self-limited focal-to-bilateral tonic-clonic seizures 9 months after liver transplantation. She was desensitized using rituximab and plasma exchange before transplantation and was subsequently treated with steroids, tacrolimus, and everolimus after transplantation for her preformed DSA. Neurological examination revealed mild acalculia and agraphia. Cranial MRI showed asymmetric, cortex-sparing white matter lesions that increased over a week in the left frontal, left parietal, and right parieto-occipital lobes. Polymerase chain reaction (PCR) of the cerebrospinal fluid for the JC supported the diagnosis of PML. Immune reconstitution by reducing the immunosuppressant dose stopped lesion expansion, and PCR of the cerebrospinal fluid for the JC virus became negative. Graft rejection occurred 2 months after immune reconstitution, requiring readjustment of immunosuppressants. Forty-eight months after PML onset, the patient lived at home without disabling deficits. Intensive immunosuppression may predispose recipients to PML after liver transplantation with preformed DSA. Early immune reconstitution and careful monitoring of graft rejection may help improve outcomes.

Progressive multifocal leukoencephalopathy in a patient with relapsing multiple sclerosis treated with ocrelizumab.

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. 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. A summary of the presentation and disease course is provided, presented in the context of the current literature and likely pathophysiology.

Designing a Multi-Epitope Subunit Vaccine against VP1 Major Coat Protein of JC Polyomavirus.

The JC polyomavirus virus (JCPyV) affects more than 80% of the human population in their early life stage. It mainly affects immunocompromised individuals where virus replication in oligodendrocytes and astrocytes may lead to fatal progressive multifocal encephalopathy (PML). Virus protein 1 (VP1) is one of the major structural proteins of the viral capsid, responsible for keeping the virus alive in the gastrointestinal and urinary tracts. VP1 is often targeted for antiviral drug and vaccine development. Similarly, this study implied immune-informatics and molecular modeling methods to design a multi-epitope subunit vaccine targeting JCPyV. The VP1 protein epitopic sequences, which are highly conserved, were used to build the vaccine. This designed vaccine includes two adjuvants, five HTL epitopes, five CTL epitopes, and two BCL epitopes to stimulate cellular, humoral, and innate immune responses against the JCPyV. Furthermore, molecular dynamics simulation (100 ns) studies were used to examine the interaction and stability of the vaccine protein with TLR4. Trajectory analysis showed that the vaccine and TLR4 receptor form a stable complex. Overall, this study may contribute to the path of vaccine development against JCPyV.

The results of a 24-month controlled, prospective study of relapsing multiple sclerosis patients at risk for progressive multifocal encephalopathy, who switched from prolonged use of natalizumab to teriflunomide.

BackgroundNatalizumab (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.ObjectiveTo assess the safety and efficacy of rapid transition, from NTZ to teriflunomide (TFM) in RMS patients.MethodsClinically 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.ResultsMedian [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.ConclusionsThe washout-free transition of NTZ to TFM was an efficacious and safe strategy for patients at risk of developing PML.ClinicalTrials.gov Identifier: NCT01970410

Advances in Treatment of Progressive Multifocal Leukoencephalopathy.

Progressive multifocal encephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV), which occurs in immunocompromised individuals. Management of PML relies on restoration of immunity within the CNS. However, when this restoration cannot be readily achieved, PML has a grim prognosis. Innovative strategies have shown promise in promoting anti‐JCV immune responses, and include T‐cell adoptive transfer or immune checkpoint inhibitor therapies. Conversely, management of immune reconstitution inflammatory syndrome, particularly in iatrogenic PML, remains a major challenge. In this paper, we review recent development in the treatment of PML. ANN NEUROL 2021;90:865–873

Decreasing Dose and Duration of Dexamethasone Therapy for Low-Risk Childhood Acute Lymphoblastic Leukemia Aiming to Avoid Serious Viral Infections Results in Significant Increase in Isolated CNS Relapse: A Prospective Study

Background: In the era of treating childhood acute lymphoblastic leukemia (ALL) without cranial irradiation, optimization of central nervous system (CNS) active therapeutic agents is needed to prevent CNS relapse. Dexamethasone is an essential part of maintenance therapy in most current protocols for its excellent CNS penetration and anti-leukemic effect. The dose and duration of dexamethasone treatment for low-risk patients vary across trials. In our institution, we adopted the St Jude Total XV protocol with minor modifications since 2002. This treatment has resulted in 5-year OS and EFS rates of 96.4% and 94% respectively for low-risk patients. However, around 11% of patients developed serious viral infections, mainly disseminated varicella (6%), CMV retinitis (3.6%) and progressive multifocal encephalopathy (1.1%). The aim of this trial was to decrease the incidence of serious viral infections by decreasing the dose and the duration of dexamethasone treatment during maintenance therapy.Patients and Methods: This is a prospective, non-randomized trial of all consecutive low-risk ALL patients aged 1-18 years treated at the Children's Cancer Center of Lebanon that included patients diagnosed after June 2013 as well as patients diagnosed earlier who had not reached week 100 of maintenance therapy by June 2013. Low-risk patients were defined elsewhere [Muwakkit et al, Am J Hematol. 2012 Jul;87(7):678-83].For patients diagnosed after June 2013; dexamethasone dose was decreased by 25% (from 8 to 6 mg/m2/day for 5 days/week every 4 weeks) and dexamethasone pulses were stopped at week 69 instead of week 100 from start of maintenance therapy. For patients on therapy who had not reached week 69 of maintenance; dexamethasone pulses were stopped at week 69, and dexamethasone dose was decreased by 25% (from 8 to 6 mg/m2/day for 5 days/week every 4 weeks) starting June 2013. For patients who had completed 69 weeks but did not reach week 100 of maintenance by June 2013, dexamethasone pulses were stopped. The interval between dexamethasone pulses was 4 weeks for all patients, before and after the change.The number of intrathecal chemotherapy injections was not changed.For analysis, historical control patients who completed therapy before June 2013 and patients on therapy who completed more than half of their planned dexamethasone pulses (week 50) by June 2013 were assigned to group 1. Patients who were diagnosed after June 2013 and those who had received less than half of their planned dexamethasone pulses (week 50) by June 2013 were assigned to group 2.The trial was stopped in May 2017 due to the observed increased incidence of isolated CNS relapse in group 2.Results: The total number of patients was 84 in group 1 and 33 in group 2. There was no significant difference in patient characteristics between the two groups. After a median follow-up of 88 months (range: 24-177), the 4-year cumulative incidence of isolated CNS relapse increased from 0% in group 1 to 9.5% (n=3) (95% CI: 0-19.2%) in group 2 (P : 0.005). The mean cumulative dose of dexamethasone was 1129 mg/m2 (SD 49 mg/m2) for group 1 and 838 mg/m2 (SD 31 mg/m2) for group 2 (P : <0.001). The mean total duration of dexamethasone pulses from start of maintenance treatment was 97 weeks (SD 8 weeks) for group 1 and 69 weeks (SD 0 weeks) for group 2 (P <0.001). The cumulative dose of dexamethasone received by patients with isolated CNS relapse was 824, 876 and 930 mg/m2. The isolated CNS relapses occurred at weeks 74, 95 and 116 of maintenance therapy. None of the patients with isolated CNS relapse had an initial traumatic lumbar puncture. None of group 2 patients developed disseminated varicella, CMV retinitis, or progressive multifocal encephalopathy. None of the patients in both groups developed bone marrow relapse within 4 years of diagnosis. The 4-year cumulative incidence of infection-related mortality was 3.5% (95% CI: 0-7.4%) for group 1 and 0% for group 2 (P : 0.27). The 4-year OS rate was 96.4% (95% CI: 89.3-98.8%) for group 1 and 100% for group 2 (P : 0.27). The 4-year EFS rate was 96.4% (95% CI: 89.3-98.8%) for group 1 and 90.5% (95% CI: 73.2-96.8%) for group 2 (P : 0.24).Conclusions: Decreasing dose and duration of dexamethasone therapy for low-risk childhood ALL patients aiming to avoid serious viral infections led to significant increase in isolated CNS relapse. Further studies are needed to identify the optimal dose and duration of dexamethasone therapy for these patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Disease–modifying drugs for multiple sclerosis and progressive multifocal encephalopathy

Disease–modifying drugs for multiple sclerosis and progressive multifocal encephalopathy

A nationwide study on inpatient opportunistic infections in patients with chronic lymphocytic leukemia in the pre-ibrutinib era.

Opportunistic infections in chronic lymphocytic leukemia (CLL) have been described in clinical trials, single-center studies, and case reports. We performed a nationwide study to estimate the incidence and impact of inpatient opportunistic infections. The incidence rate (IR) and incidence rate ratio (IRR) for Swedish CLL patients diagnosed 1994-2013, and matched controls were calculated, as well as the case-fatality ratio (CFR). Among 8989 CLL patients, a total of 829 opportunistic infections were registered (IR 16.6 per 1000 person-years) compared with 252 opportunistic infections in 34283 matched controls (IR 0.99). The highest incidence in the CLL cohort was for Pneumocystis pneumonia (200 infections, IR 4.03); Herpes zoster (146 infections, IR 2.94), and Pseudomonas (83 infections, IR 1.66) infections. The highest risk relative to matched controls was observed for Pneumocystis pneumonia (IRR 114, 95% confidence interval 58.7-252). The 60-day CFR for CLL patients with opportunistic infections was 23% (188/821), highest for progressive multifocal encephalopathy (5/7, 71%) and aspergillosis (25/60, 42%). We have uniquely depicted the incidence of rare and serious infections in CLL patients and found a relatively high incidence of Pneumocystis pneumonia. Of the most common opportunistic infections, CLL patients with aspergillosis had the poorest prognosis.

ML-09 DIAGNOSIS AND TREATMENT OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA IN HIV POSITIVE PATIENTS

INTRODUCTIONHIV infection is known to cause a variety of central nervous system complications, such as malignant lymphoma (ML), toxoplasma encephalopathy, cryptococcal encephalopathy, progressive multifocal leukoencephalopathy (PML), brain tuberculosis and HIV encephalopathy. In our hospital, we performed brain biopsy for HIV-positive patients with central nervous system lesions suspected malignant lymphoma, or cases difficult to diagnose with blood, cerebrospinal fluid, and imaging alone. In this study, we retrospectively examined HIV-positive patients who underwent brain biopsy at our hospital, and analyzed diagnosis and treatment of patients with ML. Methods HIV-positive patients who underwent brain biopsy in our hospital from January 2010 to April 2019 were examined in this study. We analyzed background factors, preoperative examination results, pathological diagnosis, treatment and prognosis.RESULTSThere were 1,894 HIV-positive patients who were treated at our hospital during the period, of which 16 cases underwent a total of 18 brain biopsies. The final diagnosis was 7 ML (6 PCNSL, 1 brain metastasis), 3 toxoplasma encephalopathy, 1 PML, 1 brain tuberculosis, 1 immune reconstitution syndrome, 1 Penicillium marneffei infection, 1 hematoma and one case that could not be diagnosed. In patients with ML, preoperative sIL-2 receptor was higher and EBV positive cases in cerebrospinal fluid tended to be more common (p=0.051, p=0.086, respectively). Five of the six patients with PCNSL were treated at our hospital, four of which were treated with highly active antiretroviral treatment (HAART) and whole-brain irradiation and one with HAARA alone, resulting four with CR and one with SD. Four patients, except one who had sudden death of unknown cause, were still alive without recurrence (median observation period 44.5 months).CONCLUSIONAt the moment, it is difficult to diagnose ML without brain biopsy. HIV-positive status has been regarded as a poor prognosis factor in PCNSL patients, but the prognosis seems to have improved with HAART.

96. Human Papilloma Viruses Associated Diseases in a Cohort of Patients with Idiopathic CD4 Lymphopenia

BackgroundIdiopathic CD4 Lymphocytopenia (ICL) is a rare immunodeficiency characterized by an absolute CD4+ T count of < 300 cells/µL, in absence of HIV-infection or any other known cause. Patients with ICL have an increased risk of opportunistic infections. The prevalence, natural history, and spectrum of Human Papillomaviruses (HPV) associated diseases in ICL patients are unknown.MethodsICL patients were enrolled in a prospective observational study (N = 90). Demographic, clinical, and immunologic data were analyzed by nonparametric Methods. Immunophenotyping was performed by flow cytometry.ResultsThe median age of ICL patients was 48 years, 47% were women, and 92% were Caucasian. Sixty-five percent of patients had at least one opportunistic infection, with HPV being the most prevalent (34.4%), followed by cryptococcal disease (22%), shingles (15.5%), molluscum contagiosum (8.8%), Histoplasma capsulatum (4.4%), Mycobacterium avium complex (4.4%), and progressive multifocal encephalopathy (2.2%). HPV-related diseases were identified in 18 women and 13 men. ICL patients with HPV disease were younger compared with those without (median age 34 vs. 53.5 years, P < 0.0001). Nine (29%) had anogenital, 9 (29%) had a cutaneous disease (verruca plana, verrucous carcinoma, squamous cell carcinoma) while 13 (42%) had both anogenital and cutaneous disease. Patients with HPV-related disease were also more likely to have history of cryptococcal disease, shingles or molluscum (P = 0.036, P = 0.22 and 0.11, respectively). Thirteen patients had HPV-associated cancers: 7 both mucosal and skin and 3 either skin or mucosal malignancies. Patients with HPV-disease had lower CD4+ T cells (median CD4 70 vs. 114 cells/µL, P = 0.036). No differences were observed in the numbers of CD8+ T cells, B cells, NK cells, and levels of IgG between patients with and without HPV disease.ConclusionHPV-related disease represents the most common opportunistic infection in ICL patients. Patients with ICL and HPV disease are younger, have lower CD4s and high prevalence of HPV-associated malignancies. Therefore, for patients presenting early in life with severe HPV disease further immunological workup should be considered and for patients with ICL excessive screening for HPV-related malignancies should be a priority.Disclosures All Authors: No reported Disclosures.

PP182 Natalizumab Therapy For Relapsing-Remitting Multiple Sclerosis

IntroductionMultiple Sclerosis is a progressive, degenerating disease of the central nervous system (CNS), which affects more than 2.5 million people worldwide. The monoclonal antibody natalizumab (TysabriTM) has been approved by the European Medicines Agency in 2006. Yet, the treatment is associated with an increased risk of developing progressive multifocal encephalopathy (PML). The aim of the systematic review was to investigate whether natalizumab is more effective and safer than alternative pharmacological therapies or placebo over a prolonged period (≥ 36 months) with respect to annualised relapse rate (ARR), disability progression, quality of life and number of serious adverse events (SAEs).MethodsA systematic literature search was conducted considering randomized controlled trials (no restriction in length) and prospective, non-randomized controlled trials. In terms of safety, prospective single arm studies were additionally included. The risk of bias (RoB) was assessed using the Cochrane RoB tool (RCT), the ROBINS-I tool (NRCT) and the Institute of Health Economics quality appraisal checklist (IHE-20) for case series (single-arm studies). The quality of evidence was determined using the GRADE-method (Grading of Recommendations, Assessment, Development and Evaluation).ResultsFor the assessment of clinical effectiveness, three studies (one RCT and two NRCTs) met the inclusion criteria. No significant differences regarding the ARR and disability progression were detected, if natalizumab was compared to an alternative treatment with fingolimod. Yet, if compared to placebo or a group of natalizumab interrupters, a 70 percent reduction in the ARR was observed. For the assessment of safety, seven studies met the inclusion criteria. The proportion of patients suffering from SAEs ranged from 2.4 percent to 16.0 percent. In total, 35 cases of PML occurred. The results were supported by a very low quality of evidence.ConclusionsFuture research should provide more head-to-head RCTs comparing natalizumab with other disease modulating drugs along with a comprehensive documentation of adverse events.

A Pilot Study of Adoptive Cellular Immunotherapy for Progressive Multifocal Leukoencephalopathy with Ex Vivo Generated Polyomavirus-Specific T-Cells

▪Background: Progressive Multifocal Encephalopathy (PML) is a subacute infection of the central nervous system (CNS) mediated by John Cunningham (JC) polyomavirus (PyV). The disease is frequently fatal, unless adaptive immunity to JC virus is restored. The disease typically occurs in immunosuppressed patients (e.g. HIV/AIDS). In the modern era, patients with hematological malignancies treated with rituximab and/or fludarabine or following immunosuppressive therapy for transplant or autoimmunity (e.g. multiple sclerosis (MS) or Crohn's disease) are also at risk. JC-PML can also occur in patients with genetic defects of immunity. Specific treatments do not exist and immunocompromised patients with history of cancer or genetic defects of immunity have no realistic chance for rapid recovery of their ability to fight infections. In subjects with Rituximab-related PML the case-fatality ratio is >90%. Survivors can be left with severe neurological disabilities.Methods: Based on our previously established procedure for generation of multi-virus virus-specific T cells using overlapping peptide libraries (pepmixes) as immunogens, we have developed dedicated polyomavirus-specific T cells (PyVST) targeting polyomavirus BK large T (LT) and Viral Protein 1 (VP1) antigens and highly cross-reactive with the structurally-homologous JC LT and VP1 proteins (see Figure). We hypothesized that adoptive transfer of donor-derived PyVSTs could be safely used for therapy of patients with refractory JC-PML. We have developed a pilot study to test the feasibility and safety of adoptive immunotherapy strategy using PyVSTs from the partially matched healthy 1st degree relative donors (sibling, parent or offspring; NIH study 16-N-0072). Adults diagnosed with PML who have no other treatment options were eligible. Patients with MS or HIV were excluded. PyVSTs were generated from donor blood leukocytes cultured for 14 days in G-rex flasks upon stimulation with BK LT and VP1 pepmixes. Subjects underwent baseline physical examination, MRI and lumbar puncture. Upon enrollment subjects received an intravenous infusion of a fixed dose of 1x10e6 (+/-10%) PyVST cells/kg. Safety monitoring period was 28 days after each infusion. Subjects were eligible for up to two additional infusions (dose 2x10e6 PyVSTs/kg) a minimum of 28 days apart if no toxicities were observed. Serial MRI and lumbar punctures were performed to monitor response. Subjects were followed for 12 months after the last infusion.Results: Nine subjects have been enrolled and treated with at least one infusion of PyVSTs under this protocol and the trial is still accruing subjects. No immediate infusion reactions or adverse events have been observed within the safety monitoring period. No CNS immune system reconstitution syndrome (IRIS) has occurred. One subject received a single infusion and withdrew from the study following Day 14 visit due to unwillingness to travel. One subject received two doses of PyVSTs with stabilization of the disease, not requiring the 3rd infusion. This subject was withdrawn from the study just prior to the 1 year follow up visit, as he was diagnosed with the stage IV lung cancer and entered hospice. Seven subjects received 3 infusions of PyVSTs. 3 of these 7 patients died of refractory PML, all >30 days after the 3rd dose of T cells. At the time of this report one subject completed the study at one year with stable PML. The remaining subjects are in the follow-up phase of the protocol.Conclusions: We report that partially matched T cells targeting PyVs generated from healthy related donors can be safely used for adoptive immunotherapy of severely immunocompromised patients with PML. Multiple infusions of T cells are very well tolerated at the doses of up to 2x10e6 PyVST cells/kg, displaying excellent safety profile without adverse events. Furthermore, our data suggest possible efficacy of this strategy as a life-saving therapy for patients who otherwise face a dismal prognosis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

TLR3 agonism re-establishes CNS immune competence during α4-integrin deficiency.

ObjectiveNatalizumab blocks α4‐integrin‐mediated leukocyte migration into the central nervous system (CNS). It diminishes disease activity in multiple sclerosis (MS), but carries a high risk of progressive multifocal encephalopathy (PML), an opportunistic infection with JV virus that may be prompted by diminished CNS immune surveillance. The initial host response to viral infections entails the synthesis of type I interferons (IFN) upon engagement of TLR3 receptors. We hypothesized that TLR3 agonism reestablishes CNS immune competence in the setting of α4‐integrin deficiency.MethodWe generated the conditional knock out mouse strain Mx1.Cre+ α4‐integrinfl/fl, in which the α4‐integrin gene is ablated upon treatment with the TLR3 agonist poly I:C. Adoptive transfer of purified lymphocytes from poly I:C‐treated Mx1.Cre+ α4‐integrinfl/fl donors into naive recipients recapitulates immunosuppression under natalizumab. Active experimental autoimmune encephalomyelitis (EAE) in Mx1.Cre+ α4‐integrinfl/fl mice treated with poly I:C represents immune‐reconstitution.ResultsAdoptive transfer of T cells from poly I:C treated Mx1.Cre+ α4‐integrinfl/fl mice causes minimal EAE. The in vitro migratory capability of CD45+ splenocytes from these mice is reduced. In contrast, actively‐induced EAE after poly I:C treatment results in full disease susceptibility of Mx1.Cre+ α4‐integrinfl/fl mice, and the number and composition of CNS leukocytes is similar to controls. Extravasation of Evans Blue indicates a compromised blood‐brain barrier. Poly I:C treatment results in a 2‐fold increase in IFN β transcription in the spinal cord.InterpretationOur data suggest that TLR3 agonism in the setting of relative α4‐integrin deficiency can reestablish CNS immune surveillance in an experimental model. This pathway may present a feasible treatment strategy to treat and prevent PML under natalizumab therapy and should be considered for further experimental evaluation in a controlled setting.

Natalizumab-associated Progressive Multifocal Leukoencephalopathy in Patients with Multiple Sclerosis: A Mini Review.

Progressive multifocal leukoencephalopathy is a fatal demyelinating disease caused by the John Cunningham virus. It causes white matter inflammation in multiple areas of the brain. Although rare, it has been known to occur in patients with immunodeficiency states and those taking chronic immunosuppressive medications for diseases such as multiple sclerosis and psoriasis. In this article, we will discuss about the drug-induced progressive multifocal encephalopathy and its diagnosis and management in patients taking natalizumab and other disease-modifying therapies among patients with multiple sclerosis.

Neurological complication in HIV patients

Human Immunodeficiency Virus (HIV) is neurotropic and immunotropic, making themassive destruction of both systems. Although their amount has been reduced, there is still neurological presentations and complications of HIV remain common in the era of combination antiretroviral therapy (cART). Neurological opportunistic infections (OI) occur in advanced HIV diseases such as primary cerebral lymphoma, cryptococcal meningitis, cerebral toxoplasmosis, and progressive multifocal encephalopathy. Neurological problem directly related to HIV appear at any stage in the progress of HIV disease, from AIDS-associated dementia to the aseptic meningitis of primary HIV infection observed in subjects with an immune deficiency. The replication of peripheral HIV viral is able to be controlled in the era of effective antiretroviral therapy. Non-HIV-related neurological disease such as stroke increased important as the HIV population ages.

Long-term follow-up of pediatric MS patients starting treatment with injectable first-line agents: A multicentre, Italian, retrospective, observational study

Background: Few data are available on very long-term follow-up of pediatric multiple sclerosis (MS) patients treated with disease modifying treatments (DMTs). Objectives: To present a long-term follow-up of a cohort of Pediatric-MS patients starting injectable first-line agents. Methods: Data regarding treatments, annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, and serious adverse event were collected. Baseline characteristics were tested in multivariate analysis to identify predictors of disease evolution. Results: In total, 97 patients were followed for 12.5 ± 3.3 years. They started therapy at 13.9 ± 2.1 years, 88 with interferons and 9 with copaxone. During the whole follow-up, 82 patients changed therapy, switching to immunosuppressors/second-line treatment in 58% of cases. Compared to pre-treatment phase, the ARR was significantly reduced during the first treatment (from 3.2 ± 2.6 to 0.7 ± 1.5, p < 0.001), and it remained low during the whole follow-up (0.3 ± 0.2, p < 0.001). At last observation, 40% had disability worsening, but EDSS score remained <4 in 89%. One patient died at age of 23 years due to MS. One case of natalizumab-related progressive multifocal encephalopathy (PML) was recorded. Starting therapy before 12 years of age resulted in a better course of disease in multivariate analysis. Conclusion: Pediatric-MS patients benefited from interferons/copaxone, but the majority had to switch to more powerful drugs. Starting therapy before 12 years of age could lead to a more favorable outcome.

A case of atypical progressive multifocal encephalopathy mimicking acute ischemic stroke: case report and review of literature

A case of atypical progressive multifocal encephalopathy mimicking acute ischemic stroke: case report and review of literature

Progressive Multifocal Encephalopathy in a Patient with Advanced Liver Cirrhosis

Background: Progressive multifocal encephalopathy (PML) is a rare, often fatal, demyelinating disease of the central nervous system. Primary infection by JC Polyoma Virus (JCV) is asymptomatic in immunocompetent individuals, however depressed cellular immunity can lead to reactivation of the latent virus. PML is predominantly associated with marked immunosuppressed states such as cancer chemotherapy, Human Immunodeficiency Virus (HIV) infection, solid organ transplant and drugs like natalizumab. PML in occult immune deficiency states such as liver cirrhosis is extremely rare. Case Report: A 56 year-old male with a history of chronic kidney disease and advanced alcoholic cirrhosis presented with altered mental status, left-sided weakness, and a fall. He was on the wait-list for liver transplantation and had abstained from alcohol for 2 years. There was no history of HIV infection, immunosuppressant drugs or chemotherapy. His exam was notable for confusion, left-sided weakness, facial droop, and neglect. His labs were notable for a WBC of 7.3 x 1000/microL, CD4 of 180/mm and CD8 of 30/mm, creatinine of 1.28 mg/dL, and ammonia of 153 mg/dL. Magnetic resonance imaging of brain showed hyperintense T2 signal in bilateral occipital lobes, the splenium, and frontal gray-white matter junction consistent with a demyelinating process. Lumbar puncture performed was negative for bacterial infection, herpes simplex, Epstein Barr and Varicella Zoster viruses, and Cryptosporidium. Diagnosis of PML was confirmed with a positive PCR test for JCV in the serum and cerebrospinal fluid. Based on multiple co-morbidities and overall poor prognosis, no specific treatment was offered for PML. Patient died 10 weeks after initial presentation. Discussion: Liver cirrhosis as the primary risk factor for PML has only been described in four previous reports. Proposed mechanism involves depressed cellular immunity. Low CD4 T-cell counts (< 550/mm) are commonly seen in patients with liver cirrhosis. A subset of patients with liver cirrhosis was found to have CD4 counts less than 350/mm which can lead to opportunistic infections, such as PML. This has strong implications in liver transplantation (LT) where a mild or occult infection pre-LT can become life threatening due to high doses of immune suppressants after LT. Liver patients at risk for opportunistic infections can be identified and closely monitored by testing for parameters of cellular immunity such as CD4 and CD8 counts.

Anti-MAdCAM-1 therapy does not affect immune surveillance in the central nervous system

Abstract Background Blocking integrins can be associated with an increased risk of progressive multifocal encephalopathy (PML). MAdCAM-1 is an adhesion molecule that is not constitutively expressed in healthy CNS and considered mostly gut-selective. However, MAdCAM-1 is upregulated in choroid plexus epithelium during experimental autoimmune encephalomyelitis (EAE. PF-00547659 is a fully human mAb that is highly selective for MAdCAM-1. The purpose of this study was to investigate its effect on cellular elements of immune surveillance in the CNS and blood of patients with Crohn’s disease (CD). Methods All methods were tested in a control cohort of volunteers with CD (Cohort 1). Study patients (Cohort 2) had CD and prior treatment with anti-TNF and immunosuppressant therapies. Patients underwent a lumbar puncture (LP1) followed by 3 monthly injections of 225 mg PF-00547659. After the last dose, a LP2 was performed. CSF was analyzed within 24h by multi-parameter flow cytometry. Results In Cohort 1, the lymphocyte subset percentages were the same at both time points. Cohort 2 consisted of 30 patients in whom 2 LPs were performed. Their pre-treatment lymphocyte numbers were lower than those of subjects who had stopped immunosuppressants, but otherwise results were the same. CSF lymphocytes (cells per mL) shown as geometric means (CV%). LP1: 37 patients, total lymphocytes 391 (140%), CD3+/CD4+ cells 246 (152%), CD3+/CD8+ cells 100 (126%), CD4:CD8 ratio 2.46 (57%). LP2: 30 patients, total lymphocytes 513 (137%), CD3+/CD4+ cells 332 (143%), CD3+/CD8+ cells 123 (125%), CD4:CD8 ratio 2.69 (56%). Conclusion This is the first evidence that a therapeutic dose of anti-MAdCAM-1 mAb does not affect the number and composition of leukocytes in the CNS.