Progressive multifocal leukoencephalopathy 11 years after liver transplantation: a case report
Ana Moreno‐EstébanezJavier Almeida VelascoTomás Pérez-ConchaT. González-Pinto GonzálezIñigo Gabilondo
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Natalizumab (NTZ) is a highly effective disease modifying therapy for the treatment of relapsing forms of multiple sclerosis (MS). Despite evidence to support its use as first-line therapy, risk of NTZ-associated progressive multifocal leukoencephalopathy (PML) has largely contributed to it being relegated to a second-line position. Recent preliminary data may allow for a more accurate analysis of JC virus (JCV) risk stratification of a given patient’s PML risk. Herein we propose an algorithm to help guide clinicians through this decision-making process. We recommend that NTZ be considered for first-line use in JCV antibody negative MS patients, JCV ‘low positive’ MS patients without prior exposure to immunosuppression and for a limited period (12–24 months) in JCV ‘high positive’ MS patients with an aggressive disease course . We caution against first-line use in JCV antibody ‘high positive’ patients beyond 12–24 months and any JCV antibody positive patient with a history of prior immunosuppression.
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Progressive multifocal leukoencephalopathy (PML), a destructive demyelinating infection which lytically infects oligodendrocytes, has occurred in patients treated with natalizumab. Magnetic resonance imaging (MRI) scan imaging of the brain gives clues to diagnosis but is nonspecific in distinguishing multiple sclerosis from PML. Spinal fluid detection of JC virus is specific but incompletely sensitive. Associated immunosuppression is typically of the cell-mediated type but can be poorly defined on clinical grounds.It is apparent that natalizumab is a predisposing factor for developing PML from the 3 cases of natalizumab-treated patients. There is no reliable presymptomatic way to detect PML or JC virus infection of the brain by virologic or imaging surveillance techniques. One patient with multiple sclerosis and natalizumab treatment has survived, indicating that withdrawal of antibody, possibly in combination with antiviral therapy, may permit survival. However, immune reconstitution disease is a risk after immune restoration and withdrawal of natalizumab. PML deficits would be expected to be permanent. The estimate of incidence of PML in natalizumab-treated patients is 1 per 1000. The duration of natalizumab treatment may be an independent risk factor for development of PML.PML, a usually fatal neurologic infection, should be considered as a risk factor when using natalizumab. The treatment of multiple sclerosis patients with natalizumab is a matter of informed risk, individualized for each multiple sclerosis patient.
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Progressive multifocal leukoencephalopathy (PML) is a progressive lethal demyelinating disease of the brain, caused by JC virus. Reactivation of JC virus due to reduction of cellular immunity especially in setting of AIDS, is the commonest underlying cause. PML has classically been described in individuals with profound cellular immunosuppression such as patients with AIDS, haematological malignancies, organ transplant recipients or those treated with immunosuppressive or immunomodulatory medications for autoimmune diseases. Rarely it has also been diagnosed in cases with no or minimal immunosuppression. Here, we report a 50 year-old man who presented with sudden onset multiple neurologic defi cits. Neuroimaging, histopathology, and virology studies confi rmed the diagnosis of PML. We could not however demonstrate any underlying immunodefi ciency state. Our case suggests that absence of immunodefi ciency does not exclude the possibility of PML and should be considered in immunocompetent patients with a typical clinical course and neuroimaging fi ndings.
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We observed two cases of progressive multifocal leukoencephalopathy (PML) that occurred in the same “infusion group”. The group consisted of four patients with relapsing–remitting multiple sclerosis (RRMS) who had been treated with natalizumab (NAT) in the same medical practice for more than four years at the same times and in the same room, raising concerns about viral transmission between members of the infusion group. DNA amplification and sequence comparison of the non-coding control region (NCCR) of JC virus (JCV) present in cerebrospinal fluid (CSF) samples from PML patients #1 and #2 revealed that the amplified JCV sequences differed from the JCV archetype. The NCRR of the viral DNA was unique to each patient, arguing against the possibility of viral transmission between patients. Statistical considerations predict that similar co-occurrences of PML are likely to happen in the future.
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Polyomavirus JC (JCV) has been implicated in the etiology of multiple sclerosis (MS), because it causes progressive multifocal leukoencephalopathy (PML), a multifocal demyelinating disease with many microscopical similarities to MS. During childhood, the virus establishes a latent infection in the kidneys, which can be reactivated in immunocompromised patients. During reactivation, the virus is shed in the urine. The kidney is the only known site of latent infection and reactivation. Therefore, excretion of the virus in the urine of MS patients is to be expected, if reactivated JCV is involved in the etiology of MS. We studied urine samples of 53 patients with definitive MS and of 53 controls matched for age and sex. We found no evidence of active JCV infection in MS. The hypothesis of a polyomaviral etiology of MS is not supported by the results of this study.
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Abstract Progressive multifocal leukoencephalopathy (PML), a demyelinating infectious disease caused by JC virus (JCV), occurs almost exclusively in immunocompromised patients usually with malignant diseases. We report here a Japanese female with follicular lymphoma who subsequently developed PML. In addition to JCV, human herpesvirus 6 (HHV‐6) was detected in the affected brain lesions of the patient by polymerase chain reaction and by in situ hybridization. HHV‐6, recognized as a neurotropic virus, is known to be reactivated during immunosuppression and can cause fatal complications such as encephalitis/encephalopathy. It is likely that impaired immunity associated with lymphoma and the additional immunosuppression following cytopenia‐inducing chemotherapies predisposed the patient to reactivated HHV‐6 infection. Although it remains to be clarified whether HHV‐6 plays an important role as a co‐agent with JCV in causing demyelination of the brain, our observation alerts physicians to the possible association of HHV‐6 with the pathogenesis of PML. Am. J. Hematol. 67:200–205, 2001. © 2001 Wiley‐Liss, Inc.
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Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC polyomavirus (JCPyV) in immunocompromised patients, including solid organ transplant recipients. We report 2 cases of PML late after liver transplantation (144 and 204 months) and review the few other published cases. The clinical course of PML is characterized by a rapid progressive neurological decline coinciding with the presence of white matter lesions on magnetic resonance images. No direct antiviral therapy is available against the JCPyV. The prognosis is therefore extremely poor. Restoration of the immune response achieved by tapering or ending the immunosuppressive therapy is the basis of treatment in transplanted patients. One of our patients is alive 3 years after diagnosis after total withdrawal of immunosuppressive therapy. The other presented severe rejection when tapering immunosuppression and died 26 months after diagnosis.
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The human neurotropic virus JC Polyomavirus, a member of the Polyomaviridae family, is the opportunistic infectious agent causing progressive multifocal leukoencephalopathy, typically in immunocompromised individuals. The spectrum of underlying reasons for the systemic immunosuppression that permits JCV infection in the central nervous system has evolved over the past 2 decades, and therapeutic immunosuppression arousing JCV infection in the brain has become increasingly prominent as a trigger for PML. Effective immune restoration subsequent to human immunodeficiency virus-related suppression is now recognized as a cause for unexpected deterioration of symptoms in patients with PML, secondary to a rebound inflammatory phenomenon called immune reconstitution inflammatory syndrome, resulting in significantly increased morbidity and mortality in a disease already infamous for its lethality. This review addresses current knowledge regarding JC Polyomavirus, progressive multifocal leukoencephalopathy, progressive multifocal leukoencephalopathy-related immune reconstitution inflammatory syndrome, and the immunocompromised states that incite JC Polyomavirus central nervous system infection, and discusses prospects for the future management of these conditions.
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