Reports Of Progressive Multifocal Leukoencephalopathy Research Articles

Progressive multifocal leukoencephalopathy associated with thymoma with immunodeficiency: a case report and literature review

BackgroundThe development of progressive multifocal leukoencephalopathy (PML) is associated with severe cellular immunosuppression. Good’s syndrome (GS) is a rare immunodeficiency syndrome related to thymoma, with the development of humoral as well as cellular immunosuppression; however, there are few reports of PML due to GS. One report suggested that the neurological symptoms of PML related to thymoma may be improved by a reduction of immunosuppressive therapy for myasthenia gravis (MG). It is therefore necessary to identify the cause of immunodeficiency in patients with PML to enable an appropriate treatment strategy to be adopted.Case presentation:A 47-year-old Japanese woman was admitted with aphasia and gait difficulty. She had an invasive thymoma that had been treated with repeated chemotherapy, including cyclophosphamide. She had also previously been diagnosed with MG (Myasthenia Gravis Foundation of America clinical classification IIa), but her ptosis and limb weakness had completely recovered. On admission, neurological examination revealed motor aphasia and central facial weakness on the right side. Laboratory studies showed severe lymphopenia, decreased CD4+ and CD8+ T cell and CD19+ B cell counts, and reduced levels of all subclasses of immunoglobulins, suggesting GS. Serology for human immunodeficiency virus (HIV) infection was negative. Brain magnetic resonance imaging showed asymmetric multifocal white matter lesions without contrast enhancement. Cerebrospinal fluid real-time polymerase chain reaction for JC virus was positive, showing 6,283,000 copies/mL. We made a diagnosis of non-HIV-related PML complicated with GS and probable chemotherapy-induced immunodeficiency. She then received intravenous immunoglobulin therapy, mirtazapine, and mefloquine, but died of sepsis 46 days after admission.ConclusionsIt is necessary to consider the possibility of immunodeficiency due to GS in patients with PML related to thymoma. Neurologists should keep in mind the risk of PML in MG patients with thymoma, even if the MG symptoms are in remission, and should thus evaluate the immunological status of the patient accordingly.

Application of pharmacogenomics to investigate adverse drug reactions to the disease-modifying treatments for multiple sclerosis: a case–control study protocol for dimethyl fumarate-induced lymphopenia

IntroductionAdverse drug reactions (ADRs) are a global public health issue. The potential for pharmacogenomic biomarkers has been demonstrated in several therapeutical areas, including HIV infection and oncology. Dimethyl fumarate (DMF)...

An interesting presentation of progressive multifocal leukoencephalopathy in apparently immunocompetent individual

Introduction: Progressive multifocal leukoencephalopathy (PML) is a very uncommon disease in immunocompetent individual. There are only rare case reports of PML in immunocompetent hosts over the past 15 years. Almost all presented with neurological deficits that progressed over a few months to years. Frontal lobe-related behavioral change is an uncommon presentation and the rapid progression within two weeks has never been reported. Case Report: We report a 64-year-old immunocompetent male who developed progressive perseveration, less interaction, and mutism within two weeks. Neurological examination did not show apparent weakness or sensory deficit. He underwent computed tomography scan of brain, magnetic resonance imaging scans of brain and whole spine, cerebrospinal fluid analyses, and stereotactic brain biopsy. Neoplasms, demyelinating diseases, and infections were on differential list. Brain biopsy confirmed the diagnosis of PML. His clinical condition was stable after the biopsy. After discussion about prognosis, the patient decided on palliative management.

JC polyomavirus viremia and progressive multifocal leukoencephalopathy in human leukocyte antigen-sensitized kidney transplant recipients desensitized with intravenous immunoglobulin and rituximab.

Desensitization (DES) with intravenous immunoglobulin (IVIG)+rituximab is effective, safe, and increases the transplantation rate in human leukocyte antigen-sensitized patients. However, reports of progressive multifocal leukoencephalopathy (PML) caused by JC polyomavirus (JCPyV) in autoimmune patients treated with rituximab is concerning. Here, we report on the JCPyV viremia and PML status in kidney transplant patients with/without DES (non-DES). In total 1195 and 699 DNA samples from plasma in 117 DES (78% lymphocyte-depleting [LyD] induction) and 100 non-DES patients (45% LyD), respectively, were submitted for JCPyV-polymerase chain reaction. Results were compared in both groups. No patients in either DES or non-DES developed PML or presented with any neurological symptoms. The JCPyV viremia rate was similar in DES and non-DES patients (3/117 vs. 9/100, P=0.07). The JCPyV levels were low (median peak levels, 1025 copies/mL) and JCPyV viremia was observed only once during the study period in most patients. All 3 DES patients with JCPyV(+) received 1 dose rituximab and no DES patients with >1 dose rituximab showed JCPyV(+). All 3 JCPyV(+) DES patients received LyD induction, while only 2 of 9 JCPyV(+) non-DES patients did so, and the remaining 7 received non-LyD or no induction. JCPyV in leukocyte was mostly negative in DES and non-DES patients. Immunosuppression in patients with or without JCPyV(+) was similar. BK polyomavirus viremia was observed more commonly in patients with JCPyV(+) than in those without (P<0.02). Patients with IVIG+rituximab DES followed by transplantation with LyD induction and additional rituximab rarely show JCPyV viremia and appear at low risk for PML.

Quality and value implications of NCCN-compliant use of maintenance rituximab for patients with low-grade NHL.

36 Background: Rituximab maintenance for indolent, incurable non-Hodgkin lymphoma (NHL) remains controversial. NCCN supports maintenance rituximab for a span of up to two years as an alternative to watchful waiting following induction therapy. At least a dozen scientific papers have been published describing rituximab maintenance results; none has demonstrated overall survival benefit. The strongest data support comes from the PRIMA phase III trial which showed an increased PFS but no survival advantage. Increased toxicity, however, is clear and can be serious. Reports of progressive multifocal leukoencephalopathy, a rapidly fatal neurodegenerative disease, should be of especial concern to patients whose disease course can span many years. Oncology Analytics (OA) enhances cancer care quality and value by providing oncology decision-support to providers in SE USA. We hypothesized that the use of maintenance rituximab in this area of the country produces profound cost and real risk for a highly uncertain benefit to this population. Methods: We reviewed all requests for rituximab maintenance for low-grade NHL submitted by oncology practices to a major health insurer in one US region from Jul 2009-May 2014. We calculated the cumulative cost for blanket approval of such requests and the savings associated with our decision-support discussions of this questionable but NCCN-compliant practice. Results: 470 requests for maintenance rituximab for low-grade NHL were initiated within this 59-month span. The proportion of maintenance rituximab requests relative to the total chemotherapy requests decreased consistently over time, from 4.5% in the first six months of OA involvement in 2009, down to 1.5% in May 2014. The annual cost of rituximab maintenance, which depends on the dose schedule, ranges from about $30,000 to $40,000 per year. Additionally, we discovered many rituximab maintenance requests for durations exceeding two years without evidence-based support, most of which were rescinded after OA intervention. Conclusions: Ongoing OA intervention reduces risk of toxicity and enhances the quality and value of cancer care for these patients.

PML and rheumatology: The contribution of disease and drugs

Progressive multifocal leukoencephalopathy (PML), a rare, typically fatal, opportunistic infection caused by the JC virus, is becoming relevant to physicians in multiple specialties, including those who prescribe biologic agents for the treatment of autoimmune disorders. Reports of PML have led to US Food and Drug Administration alerts and warning letters regarding four immunosuppressive agents in recent years (natalizumab, rituximab, efalizumab, and mycophenolate mofetil). Consequently, informed clinical decision-making requires understanding the risk of PML associated with these therapies. An estimate of the relative frequency of PML associated with specific rheumatic conditions has been generated. Systemic lupus erythematosus appears to be associated with susceptibility to PML that cannot be fully explained by the intensity of immunosuppressive therapy. Further, the use of rituximab in patients with rheumatic disease has raised concerns. However, definitive attribution of cause is precluded by the limitations of the currently available data. All patients with rheumatic disease, regardless of the intensity of their current immunosuppressive therapy, should be considered potentially at risk of PML. With an evolving understanding of a greater clinical heterogeneity of PML, advances in diagnostic methods, and significant implications for therapy, PML should be considered in the differential diagnosis of neurologic manifestations of rheumatic diseases.

Progressive multifocal leukoencephalopathy in transplant recipients

Transplant recipients are at risk of developing progressive multifocal leukoencephalopathy (PML), a rare demyelinating disorder caused by oligodendrocyte destruction by JC virus. Reports of PML following transplantation were found using PubMed Entrez (1958-July 2010). A multicenter, retrospective cohort study also identified all cases of PML among transplant recipients diagnosed at Mayo Clinic, Johns Hopkins University, Washington University, and Amsterdam Academic Medical Center. At 1 institution, the incidence of posttransplantation PML was calculated. A total of 69 cases (44 solid organ, 25 bone marrow) of posttransplantation PML were found including 15 from the 4 medical centers and another 54 from the literature. The median time to development of first symptoms of PML following transplantation was longer in solid organ vs bone marrow recipients (27 vs 11 months, p = 0.0005, range of <1 to >240). Median survival following symptom onset was 6.4 months in solid organ vs 19.5 months in bone marrow recipients (p = 0.068). Case fatality was 84% (95% confidence interval [CI], 70.3-92.4%) and survival beyond 1 year was 55.7% (95% CI, 41.2-67.2%). The incidence of PML among heart and/or lung transplant recipients at 1 institution was 1.24 per 1,000 posttransplantation person-years (95% CI, 0.25-3.61). No clear association was found with any 1 immunosuppressant agent. No treatment provided demonstrable therapeutic benefit. The risk of PML exists throughout the posttransplantation period. Bone marrow recipients survive longer than solid organ recipients but may have a lower median time to first symptoms of PML. Posttransplantation PML has a higher case fatality and may have a higher incidence than reported in human immunodeficiency virus (HIV) patients on highly-active antiretroviral therapy (HAART) or multiple sclerosis patients treated with natalizumab.

Natalizumab for the treatment of Crohn’s disease

Natalizumab (Tysabri®, formerly known as Antegren®, Elan Pharmaceuticals [Elan; San Francisco, CA, USA] and Biogen Idec [Biogen; Cambridge, MA, USA]) is a humanized monoclonal antibody against α4 integrin, which inhibits leukocyte adhesion and migration into inflamed tissue. The drug has been shown to be more efficacious than placebo in inducing response and maintaining remission in moderate-to-severe Crohn’s disease. There have been reports of progressive multifocal leukoencephalopathy after treatment with natalizumab in Crohn’s disease and multiple sclerosis. It has been otherwise well tolerated, although it is associated with an increased risk of infections, especially influenza and influenza-like illness. The drug is not approved in Europe for the treatment of Crohn’s disease, but it is approved in the USA for the treatment of both multiple sclerosis and moderate-to-severe Crohn’s disease. Owing to the risk of progressive multifocal leukoencephalopathy, it can only be given under the TOUCH program, which is a special restricted distribution program available only to prescribers, infusion centers, pharmacies associated with infusion sites and patients who are enrolled in the program.

CD20‐depleting therapy in autoimmune diseases: from basic research to the clinic

The B lymphocyte-associated antigen CD20 is becoming an important immunotherapy target for autoimmune diseases, although its biological function has not been defined. Besides rheumatoid arthritis, growing experience with B cell-depleting therapy indicates that it may be effective in Sjögren's syndrome, dermatomyositis-polymyositis, systemic lupus erythematosus and some types of vasculitides. However, controlled clinical trials are still lacking for some of these indications. Infection has not been seen as a major limitation to this therapy, but reports of progressive multifocal leukoencephalopathy in an extremely small number of patients are of concern. Here, we review the therapeutic actions of anti-CD20 antibodies, and the recent and ongoing clinical trials with CD20-depleting therapy in autoimmune diseases.

22. Enterovirus meningitis in a patient treated with Natalizumab

Natalizumab (Tysabri) is a relatively new biological monoclonal antibody to α4β1 integrin, a molecule important in the mobilisation of lymphocytes and other non-neutrophil leukocytes from the circulation into the brain. It is available as treatment for relapsing remitting MS since autumn last year and the number of patients is steadily increasing. Despite its effectiveness, it is usually used as second line treatment due to several reports of Progressive Multifocal Leukoencephalopathy.

Up to 6 January 2009, the UK MHRA has received 19 suspected reports of progressive multifocal leukoencephalopathy (PML);

Up to 6 January 2009, the UK MHRA has received 19 suspected reports of progressive multifocal leukoencephalopathy (PML);

Natalizumab for the Treatment of Multiple Sclerosis and Crohn's Disease

To review the pharmacology, pharmacokinetics, safety, and pivotal clinical trials for natalizumab in the treatment of multiple sclerosis (MS) and inflammatory bowel disease. A PubMed/MEDLINE search was conducted (1966-June 2005), and information was obtained from Iowa Drug Information Services. Additional data sources included meeting abstracts, bibliographies from identified articles, and information from the manufacturer. Studies and review articles examining natalizumab were evaluated. All published, randomized clinical trials evaluating natalizumab in MS and IBD were included in this review. Natalizumab is the first drug in a new class of agents called selective adhesion molecule inhibitors. It has shown promising results in MS and inflammatory bowel disease and appears superior compared with current therapies in reducing relapse rates. However, 3 recent, confirmed case reports of progressive multifocal leukoencephalopathy (PML) create concern about natalizumab's use in combination with existing therapies or in undefined patient subgroups. Natalizumab was voluntarily withdrawn from the market in March 2005 while the drug's safety is further evaluated. Although long-term efficacy and safety of natalizumab have not been established, available data indicate that it is a novel drug for patients with MS or inflammatory bowel disease. Analysis of its possible association with PML will determine the risk-benefit evaluation and eventual place in therapy for natalizumab.