mycophenolic-acid and Leukoencephalopathy--Progressive-Multifocal

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the brain due to a polyoma virus, JC virus. Despite the ubiquity of this virus, PML is rare and almost always seen in association with an underlying immunosuppressive condition. In the last 30 years, AIDS has been the most common predisposing factor. The observation of PML attending the use of certain monoclonal antibody therapies and other pharmacological agents has raised concerns about the safety profile of these agents, but has also provided a window into the pathogenesis of PML. Certain agents, such as the monoclonal antibodies natalizumab, an α4β1 and α4β7 integrin inhibitor, and efalizumab, an antibody directed against CD11a, appear to uniquely predispose to PML. Prior to their introduction for multiple sclerosis and Crohn's disease with respect to natalizumab, and psoriasis with respect to efalizumab, PML had never been observed with these disorders. PML occurring with other agents that currently carry US FDA-mandated 'black-box' warnings, such as rituximab, an antibody directed to CD20, or mycophenolate mofetil, a drug that inhibits T- and B-cell proliferation, typically occur in the background of underlying disorders that have already been identified as risks for PML. This review will focus on the available data regarding the risk for PML with monoclonal antibodies and other drugs. A biologically plausible explanation for the increased risk of PML will be proposed, as well as potential strategies for mitigating disease risk.

Topics: Antibodies, Monoclonal; Humans; Immunosuppressive Agents; JC Virus; Leukoencephalopathy, Progressive Multifocal; Mycophenolic Acid; Risk Management

Progressive multifocal leukoencephalopathy (PML) is a rare, opportunistic and often fatal disease of the CNS which may occur under immunosuppression in transplant patients. Brain stem PML is associated with a particularly bad prognosis. Here, we present a case of a renal transplant patient treated with mycophenolate mofetil (MMF) and tacrolimus who developed brain stem PML with limb ataxia, dysarthria and dysphagia. Diagnosis was established by typical MRI features and detection of JCV-DNA in the CSF. Immune reconstitution after stopping MMF and tacrolimus led to a complete and sustained remission of symptoms with improvement of the brain stem lesion over a follow-up over 20months. In summary, early detection of PML and consequent treatment may improve neurological outcomes even in brain stem disease with a notorious bad prognosis.

Topics: Adult; Antibiotics, Antitubercular; Brain Stem; DNA; Early Diagnosis; Female; Humans; Immunosuppressive Agents; JC Virus; Kidney Failure, Chronic; Kidney Transplantation; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Mycophenolic Acid; Tacrolimus

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the central nervous system caused by JC virus. Only ten cases of PML have been reported so far in liver transplant recipients. We present a case of liver posttransplantation PML with characteristic clinical and brain MRI findings, but with an atypical late onset, developed 11 years after transplantation and after single-drug, long-term (8 years), and low-dose (750 mg twice a day) immunosuppression with mycophenolate mofetil (MMF). This is the latest onset of PML associated to liver transplant reported. The present case should help physicians to be aware of PML after transplantation, even in the long term and even under low doses of immunosuppressants, especially MMF.

Topics: Aged; Brain; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; JC Virus; Leukoencephalopathy, Progressive Multifocal; Liver; Liver Transplantation; Magnetic Resonance Imaging; Mycophenolic Acid; Opportunistic Infections

There is an increase in the number of patients with systemic lupus erythematosus (SLE) reported as developing progressive multifocal leukoencephalopathy (PML) while on intensive immunosuppressive therapy. A 39-year-old HIV-negative woman with a 10-year history of SLE presented with progressive left-side weakness while on maintenance therapy with oral prednisone and mycophenolate mofetil (MMF). On several occasions low CD4+ T-lymphocyte counts were found (68/µL). Brain magnetic resonance imaging (MRI) revealed a large lesion in the right subcortical fronto-parietal region and a smaller one in the left frontal subcortex, corresponding to the PML. In cerebrospinal fluid, polymerase chain reaction (PCR) for JC virus (JCV) was negative, but anti-JCV antibodies were highly positive. Diagnosis of probable PML was made and MMF was withdrawn. The patient's condition improved with marked reduction of left-side weakness and an increase in CD4(+) T-lymphocyte count (141/µL). Follow-up MRI showed regression of lesions and over the next 6 months the patient remained stable. In spite of the grave prognosis associated with PML, SLE patients can have an excellent outcome if immunosuppressants are discontinued as soon as the correct diagnosis is made. SLE patients with associated low CD4(+) T-lymphocyte counts should be monitored for the development of PML during immunosuppressive therapy in particular.

Topics: Adult; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Female; Humans; Immunosuppressive Agents; JC Virus; Leukoencephalopathy, Progressive Multifocal; Lupus Erythematosus, Systemic; Magnetic Resonance Imaging; Mycophenolic Acid; Virus Activation

The use of mycophenolate mofetil (MMF) is known to be associated with progressive multifocal leukoencephalopathy (PML). We report a case of PML in a patient receiving MMF, who showed improvement upon discontinuation of the drug. He was restarted on MMF, following which he went into coma. He showed prompt recovery upon stopping the drug again and made full recovery without any residual neurological deficit. This case is being reported to further highlight this neurological side-effect of MMF.

Topics: Adult; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Male; Mycophenolic Acid; Treatment Outcome

The 2008-released FDA safety report described a potential association between use of MMF and progressive multifocal leukoencephalopathy. We here report the case of an 11-yr-old kidney transplanted boy suffering from PML who showed rapid improvement parallel to withdrawal of MMF. This case contributes to the increasing knowledge on side effects of MMF treatment in children.

Topics: Child; Follow-Up Studies; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Leukoencephalopathy, Progressive Multifocal; Male; Mycophenolic Acid; Polyomavirus; Polyomavirus Infections; Risk Assessment; Transplantation Immunology; Tumor Virus Infections; Withholding Treatment

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.

Topics: Abatacept; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Autoimmune Diseases; Humans; Immunoconjugates; Immunologic Factors; Immunosuppressive Agents; Leukoencephalopathy, Progressive Multifocal; Mycophenolic Acid; Rituximab

Progressive multifocal leukoencephalopathy in a kidney transplant recipient after conversion to mycophenolic acid therapy.

Topics: Female; Graft Rejection; Humans; Immunosuppressive Agents; JC Virus; Kidney Transplantation; Leukoencephalopathy, Progressive Multifocal; Middle Aged; Mycophenolic Acid

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Antirheumatic Agents; Humans; Immunosuppressive Agents; Isoxazoles; JC Virus; Leflunomide; Leukoencephalopathy, Progressive Multifocal; Mycophenolic Acid; Natalizumab; Rituximab; Sirolimus; Tacrolimus

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the central nervous system with JC virus. Few cases have been described in lupus patients. We describe biopsy-proven PML in a lupus patient receiving mycophenolate mofetil and corticosteroids. Although the patient received no antiviral treatment, the polymerase chain reaction test for JC virus became negative in cerebrospinal fluid after immunosuppressant discontinuation and the patient survived. We discuss the restoration of immune efficiency after immunosuppressant discontinuation in this case and compare the clinical, radiological and histological features with the inflammatory PML form described in human immunodeficiency virus-infected patients.

Topics: Adrenal Cortex Hormones; Brain; Female; Humans; Immune Reconstitution Inflammatory Syndrome; Immune System; Immunocompromised Host; Immunosuppressive Agents; JC Virus; Leukoencephalopathy, Progressive Multifocal; Lupus Erythematosus, Systemic; Middle Aged; Mycophenolic Acid; Recovery of Function; Withholding Treatment

Mycophenolate mofetil (MMF) use may be associated with progressive multifocal leukoencephalopathy (PML). We conducted a retrospective cohort study of 32,757 renal transplant recipients using the United States Renal Data System kidney transplant files for the incidence, prognosis, and clinical features associated with PML occurring after kidney transplant. Subjects were transplanted from January 1, 2000 to July 31, 2004 and followed through December 31, 2004. The incidence density of PML in MMF users was 14.4 cases/100,000 person-years at risk versus 0 for non-MMF users (P=0.11) by log rank test. Factors significantly associated with PML were BK virus infection (22.2% vs. 1.1%), pretransplant transfusion (75% vs. 34%), panel reactive antibody more than 20% (56% vs. 14%), and use of antirejection medications in the first year (33% vs. 9.2%), all P less than 0.05. PML is rare in the renal transplant population. There was no significant association between PML and MMF, but MMF use in this cohort is too high to accurately assess an association.

Topics: Adult; Cohort Studies; Female; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Leukoencephalopathy, Progressive Multifocal; Male; Medicare; Middle Aged; Mycophenolic Acid; Postoperative Complications; Renal Replacement Therapy; Retrospective Studies; Survival Rate; United States

Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; JC Virus; Leukoencephalopathy, Progressive Multifocal; Mycophenolic Acid

We present the 55-year-old woman who has had kidney transplantation three times. She has been treated with immunosuppressive therapy and lamivudine for hepatitis B and C. Nine years after the last transplantation she showed neurological symptoms that presented in the form of confusion and epileptic seizures of the grand mal type. A brain MRI showed large oval zones of hyperintense MR signal in T2-weighted image and hypointense in T1-weighted image around the frontal horns of the lateral ventricles, bilaterally and in both cerebellar hemispheres. After reduction in immunosuppression and the exclusion of lamivudine from therapy, the patient was stable with normal neurological status during the course of next five years. We start from the assumption that the concomitant use of cyclosporin with mycophenolate mofetil and lamivudine, despite normal concentrations of cyclosporin, might cause the accumulation of toxic metabolites and lead to neurotoxicity that mimics PML in a chronic viral environment.

Topics: Cyclosporine; Female; Humans; Kidney Transplantation; Lamivudine; Leukoencephalopathy, Progressive Multifocal; Middle Aged; Mycophenolic Acid; Neurotoxicity Syndromes